Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1nccn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a 3-neck, 1-liter, round-bottom flask was added 2-methylimidazole (41.0 g, 0.50 mole), 4-bromoanisole (100 g, 0.53 mole) and potassium carbonate (96.0 g, 0.70 mole) in N-methyl-2-pyrrolidinone (300 ml). A small amount of cuprous chloride (2.5 g) was added. The stirred reaction mixture was heated at reflux temperature for 24 hr and then the N-methyl-2-pyrrolidinone and excess bromoanisole gently distilled. The black pot residue was partitioned between toluene and water and a black solid removed by filtration. The toluene layer was extracted with 48% hydrobromic acid (2×200 ml) and the hydrobromic acid solution was heated at reflux temperature 3 hr then stirred at room temperature overnight. The solution was then concentrated, diluted with water (500 ml) and made basic with sodium hydroxide and sodium bicarbonate solutions. The white solid which precipitated was collected and cried and a small amount recrystallized from methanol/isopropyl alcohol. The total yield was 24.88g (28.6% yield), mp 205°-208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:31])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24]C(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:31])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([OH:24])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(=O)O)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.3 %

Procedure:
tert-Butyl (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoate (0.1 g) was dissolved in DCM (2 ml), and trifluoroacetic acid (2 ml) was added. The mixture was stirred at room temperature for 1.5 h and then partitioned between water and DCM. The organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.09 g) as an colourless gum.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:26]Br>C(O)(=O)C>[Br:26][CH:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: CCc1nc2ncccc2c(=O)n1-c1ccc(F)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(Br)c1nc2ncccc2c(=O)n1-c1ccc(F)cc1
Temperature: 40 °C
Yield: 85.1 %

Procedure:
A suspension of the quinazolinone (17) (50.0 g, 0.56 mmol) and anhydrous sodium acetate (56 mg) in glacial acetic acid (1.0 mL) was heated to 40° C. and treated dropwise with a solution of bromine (90 mg, 0.56 mmol) in glacial acetic acid (5 mL). Once the starting material was fully consumed by TLC analysis, the mixture was poured onto water (5 mL), basified with saturated aqueous sodium hydrogen carbonate and extracted with tert-butylmethyl ether. The combined organic phases were dried (MgSO4), filtered, and concentrated to a solid which was purified by silica-gel column chromatography [eluent: Ethyl acetate:Hexane, 50:50, ν/ν] to give the title bromide (18) (166 mg. 85%) as an off white solid:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:40](=[O:41])[N:13]2[C:14]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])=[C:15]([S:18](C3C=CC=CC=3)(=O)=O)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:42]([C:45]1[CH:58]=[CH:57][C:48]([CH2:49][O:50][C:51]([NH:53][CH2:54][CH2:55]S)=[O:52])=[CH:47][CH:46]=1)([O-:44])=[O:43]>>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:40](=[O:41])[N:13]2[C:14]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])=[C:15]([S:18][CH2:55][CH2:54][NH:53][C:51]([O:50][CH2:49][C:48]3[CH:57]=[CH:58][C:45]([N+:42]([O-:44])=[O:43])=[CH:46][CH:47]=3)=[O:52])[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)(=O)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Yield: 86 %

Procedure:
Following a procedure similar to that described in Example 19(c), but using 4-nitrobenzyl (1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfonyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 46) and 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 86%.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C@H:14]([C@H:18]([OH:20])[CH3:19])[C:15]([OH:17])=O)=[CH:5][CH:4]=1)#[N:2].[C:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)#[N:22].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1>[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][NH:30][C:15](=[O:17])[C@H:14]([NH:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C@H:18]([OH:20])[CH3:19])=[O:28])=[CH:31][CH:32]=1)#[N:22]
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a pre-cooled (−45° C.) solution of (2R,3R)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoic acid (1.50 g, 5.55 mmol) and 4-cyanobenzohydrazide (894 mg, 5.55 mmol) in anhydrous THF (80 mL) was added 1-Hydroxybenzotriazole monohydrate (850 mg, 5.55 mmol) and N-(3-Dimethylaminopropyl)-Y-ethylcarbodimide-HCl (2.13 g, 11.1 mmol) at −45° C. followed by triethylamine (1.55 mL, 11.1 mmol). The reaction mixture warmed to room temperature and stirred for 24 h, then quenched with 5% aq. citric acid (300 mL). The solution was extracted with EtOAc (300 mL). The organic extract was washed with 5% aq. citric acid (2×150 mL), sat. aq. NaHCO3 (3×150 mL), H2O (2×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound as a light brown solid (2.12 g, 92%): 1H NMR (400 MHz, DMSO-d6, δ in ppm) 10.84 (s, 1H), 10.44 (s, 1H), 8.48 (d, J=8.8 Hz, 2H), 8.04-7.93 (m, 4H), 7.91 (d, J=8.2 Hz, 1H), 7.74 (t, J=6.8 Hz, 1H), 7.62 (t, J=7.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 5.25 (d, J=4.5 Hz, 1H), 4.32-3.97 (m, 3H), 1.32 (d, J=6.1 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:18]>C(#N)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:18])=[CH:10][CH:9]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C(=O)COc2ccc(Br)cc2)cc1
Yield: 96.1 %

Procedure:
24 g of potassium carbonate are added to a solution of 20 g (0.115 mol) of 4-bromophenol and 26.5 g (0.115 mol) of 2-bromo-4′-methoxyacetophenone in 400 of acetonitrile, and the reaction mixture is heated under reflux for five hours. The precipitate is subsequently filtered off, the filtrate is evaporated to dryness, the residue is taken up in 10 ml of water, and the aqueous solution is extracted twice with 10 ml of ethyl acetate each time. The combined organic phases are washed with 10 ml of saturated sodium chloride solution and dried over sodium sulfate. After the solvent has been stripped off, the residue is triturated with 50 ml of diethyl ether, and the resultant crystalline product is filtered off with suction in vacuo, giving 35.5 g of 2-(4-bromophenoxy)-1-(4-methoxyphenyl)ethanone as beige solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[Br:12]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:12][C:8]1[C:7]([O:10][CH3:11])=[CH:6][C:4]([NH2:5])=[C:3]([Cl:2])[CH:9]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: BrBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N)c(Cl)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.5 %

Procedure:
A stirred solution of 9.7 g (0.050 mole) of 2-chloro-5-methoxyaniline hydrochloride in 120 mL of acetic acid was cooled to 15° C. To this cold mixture was added 4.0 g (0.025 mole) of bromine. After complete addition, the mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The mixture was poured into ice water. To the resultant mixture was added a solution of 2.0 g (0.05 mole) of sodium hydroxide in 10 mL of water. This mixture was extracted with 200 mL of diethyl ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave an oil. The oil was purified by column chromatography on silica gel, eluting with methylene chloride, to yield 7.3 g of 4-bromo-2-chloro-5-methoxyaniline as a solid, mp 40°-41° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([OH:16])[CH:7]=2)[CH2:3][CH2:2]1.[C:17](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.Cl>CC(=O)CC>[CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:16][CH3:17])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(OCC2CC2)cc1O
Agent: Cl
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: COc1cc(OCC2CC2)ccc1C(=O)O
Reaction time: 12 h

Procedure:
A 3.00 g portion of methyl 4-cyclopropylmethyloxy-2-hydroxybenzoate was dissolved in 70 ml of 2-butanone, and 2.80 g of potassium carbonate and 1.9 ml of dimethyl sulfate were added, followed by 12 hours of heating under reflux. After completion of the reaction, the solvent was evaporated, the resulting residue was suspended in chloroform, and insoluble matter was removed by celite filtration. The solvent was again evaporated, and then the thus obtained residue was dissolved in 20 ml of tetrahydrofuran, mixed with 30 ml of 2N sodium hydroxide aqueous solution and subjected to 3 hours of heating under reflux. After completion of the reaction, the reaction solution was poured into 1N hydrochloric acid aqueous solution, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 2.74 g of 4-cyclopropylmethyloxy-2-methoxybenzoic acid.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:21][CH:20]=2)[C:36](=[O:38])[CH3:37])[CH:25]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(NCc2cccnc2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccc(N(Cc2cccnc2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
To a room temperature solution of 2.49 g of product from Example 83, 1.27 ml of pyridine and 30 ml of methylene chloride is added, dropwise, 0.985 g of acetyl chloride. The reaction is stirred at room temperature for 1.5 hours, poured into saturated sodium bicarbonate and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: 95% ethyl acetate/hexane) to give 2.65 g of the desired product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([CH3:16])(=[N:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Br:17][C:18]1[C:19]([O:25][CH3:26])=[N:20][C:21](Cl)=[N:22][CH:23]=1>>[CH2:14]([O:13][C:11]([N:10]=[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:21]2[N:20]=[C:19]([O:25][CH3:26])[C:18]([Br:17])=[CH:23][N:22]=2)[CH:3]=1)([CH3:16])=[O:9])=[O:12])[CH3:15]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(N)c1
Reactant: COc1nc(Cl)ncc1Br
Product: CCOC(=O)N=S(C)(=O)c1cccc(Nc2ncc(Br)c(OC)n2)c1
Yield: 43.3 %

Procedure:
Intermediate 14 was prepared in analogy to GP 2 by reaction of Intermediate 5 (1.73 g, 7.16 mmol) with commercial 5-bromo-2-chloro-4-methoxypyrimidine (2.00 g, 8.95 mmol, 1.25 eq) to give 1.33 g (43% yield) of the title compound (after crystallization from acetonitrile and column chromatography of the mother liquor residue).
Reaction SMILES: [Na].N1(CC2C=C(O)C=CC=2)CCCCC1.ClCCCC#N.[N:22]1([CH2:28][C:29]2[CH:30]=[C:31]([CH:38]=[CH:39][CH:40]=2)[O:32][CH2:33][CH2:34][CH2:35][C:36]#[N:37])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C(O)C.CCOCC.O>[N:22]1([CH2:28][C:29]2[CH:30]=[C:31]([CH:38]=[CH:39][CH:40]=2)[O:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: N#CCCCOc1cccc(CN2CCCCC2)c1
Agent: N#CCCCCl
Agent: Oc1cccc(CN2CCCCC2)c1
Agent: [Al+3]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: NCCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h

Procedure:
4.6 g (0.2 mol) of sodium are dissolved in anhydrous ethanol and 38.24 g (0.2 mol) of 3-piperidinomethylphenol [DE-A-2 917 026, Glaxo] are added thereto. After the dropwise addition of 20.71 g (0.2 mol) of 4-chlorobutyronitrile in ethanol, the batch is heated under reflux overnight with the exclusion of moisture. It is then allowed to cool, is filtered, and concentrated to dryness in vacuo. The resulting oil is taken up in ether and washed with 10% NaOH and water. Drying over Na2SO4 and concentrating yield 35.5 g (0.14 mol) of 4-(3-piperidinomethylphenoxy)butyronitrile in the form of an oil that can be used in the subsequent reaction without further purification. While cooling with ice and stirring, 59.9 mmol of 4-(3-piperidinomethylphenoxy)butyronitrile are introduced slowly into a suspension of 2.98 g (78.4 mmol) of LiAlH4 in 140 ml of anhydrous ether. After stirring for 40 min at room temperature the batch is hydrolysed, while cooling with ice, with 10 ml of water-saturated ether and 7 ml of 10% NaOH. Stirring is continued for 30 min, and then the batch is suction-filtered and the precipitate is washed several times with ether. The filtrate is washed with water, dried over Na2SO4, filtered and concentrated to dryness in vacuo to yield 4-(3-piperidinomethylphenoxy)butaneamine in the form of a low-viscosity brown oil that can be used in the subsequent reaction without further purification. The equimolar amount of 4-(3-piperidinomethylphenoxy)butaneamine is added while stirring to a suspension of N-cyanodiphenylimidocarbonate in 100 ml of diethyl ether. After stirring for approx. 15 min, the product, N-cyano-O-phenyl-N'-[4-(3-piperidinomethylphenoxy)butyl]isourea, precipitates copiously, or it crystallises when the solution is concentrated. The product is suction-filtered, washed with diethyl ether and dried.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([NH:17]C(=O)C)[CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[C:7](=[O:21])[CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[C:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([NH2:17])[CH:10]=[CH:11][C:12]=2[O:15][CH3:16])[C:7](=[O:21])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(NC(C)=O)c2c1CC(NC(C)=O)CC2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(N)c2c1CC(NC(C)=O)CC2=O
Temperature: 60 °C

Procedure:
102 mg of the compound prepared in (4) above was charged into 20 ml of 3N hydrochloric acid aqueous solution, and the mixture was heated at 60° C. for 2 hours while stirring. After cooling to 0° C., the reaction mixture was neutralized with sodium carbonate and extracted with chloroform. The extract was dried over magnesium sulfate, and subjected to silica gel column chromatograghy using an chloroform-methanol (40:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 66 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[C:22]3[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:9][C:10]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[S:11])=[CH:4][CH:3]=1.IC.[C:38](=O)([O-])[O-].[K+].[K+]>CC(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH:23]=[C:22]3[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:9][C:10]([S:11][CH3:38])=[N:12][CH2:13][CH:14]([O:15][CH3:16])[O:17][CH3:18])=[CH:6][CH:7]=1
Reactant: COC(CNC(=S)NC(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3ccccc3)c2c1)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(CN=C(NC(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3ccccc3)c2c1)SC)OC
Temperature: 25 °C
Yield: 113.2 %

Procedure:
A mixture of intermediate (6-a) (15.3 g), iodomethane (2.27 ml) and potassium carbonate (5 g) in 2-propanone (50 ml) was stirred at room temperature for one night. The mixture was evaporated, the residue was taken up in DCM and washed with K2CO3 10%. The organic layer was dried (MgSO4), filtered off and evaporated, yielding 17.8 g (100%) of (±)-methyl N-[(4-chlorophenyl)(1,2-dihydro-2-oxo-4-phenyl-6-quinolinyl)-methyl]-N'-(2,2-dimethoxy-ethyl)carbamimidothioate (interm. 6-b), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2Cl.[N:13]1(C(OC(C)(C)C)=O)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>COCCCOCCCO>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Cc1cccc2c(Cl)ccnc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: COCCCOCCCO
Product: Cc1cccc2c(N3CCNCC3)ccnc12
Temperature: 140 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
8-Methyl-4-chloroquinoline (355 mg, 2 mmol) was suspended in dipropyleneglycolmonomethylether (4 ml), a solution of tert-butyl piperazine-1-carboxylate (440 mg, 2.4 mmol) in dipropyleneglycolmonomethylether (4 ml) was added and the mixture was stirred at 140° C. overnight and the solvent was evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane and trifluoroacetic acid (1:1, 4 ml) and stirred at room temperature for 90 minutes. The mixture was evaporated to dryness under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with 5% sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (prepacked silica column, gradient ethyl acetate/methanol with the addition of 1% ammonia) to yield 364 mg of a solid (1.6 mmol, 80%). MS (APCI): m/z=227.9 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[C:31]#[N:32])=[CH:4][C:5](=[O:23])[N:6]([CH:8]([CH2:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[C:31]#[N:32])=[CH:4][C:5](=[O:23])[N:6]([CH:8]([CH2:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)C(C[C@@H]1CCCCO1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)n(C(C[C@@H]2CCCCO2)C(=O)O)cc1Cl

Procedure:
396 mg (0.83 mmol) of tert-butyl 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate (mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysed with TFA according to General Method 6A. Yield: 396 mg (quant.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([C:13]#[N:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>C(#N)C>[C:13]([CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:15])#[N:14]
Reactant: COC(=O)C(C#N)Cc1ccc(O)cc1
Reactant: Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C#N)Cc1ccc(OCc2cccc(O)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 65.44 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged 10 mL of acetonitrile. To the stirred solvent was added 2-cyano-3-(4-hydroxy-phenyl)-propanoic acid methyl ester (0.3 g, 1.57 mmol), followed by K2CO3 (0.65 g, 4.71 mmol) and 3-bromomethyl-phenol (0.294 g, 1.57 mmol). After addition, the RM was heated at 50° C. for 1 h. After 1 h, the RM was concentrated to distill off the solvent, water (20 mL) was added and the aqueous layer was extracted with ethyl acetate (15 mL×2). The organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The product was obtained as yellow liquid. (0.32 g, yield: 65.44%); MS (ESI, 120 eV): m/z=310.0 (M−H)+.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C=CC(O)=CC=1)O.CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1.[Cl:34][SiH:35]([Cl:37])[Cl:36]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.COCCOC.C(O)C>[C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:35]([Cl:37])([Cl:36])[Cl:34])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CCOC(=O)C(=C)C
Reactant: Cl[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Oc1ccc(O)cc1
Solvent: CCO
Solvent: COCCOC
Product: C=C(C)C(=O)OCCC[Si](Cl)(Cl)Cl
Temperature: 90 °C
Yield: 85 %

Procedure:
A 500 cc, 3-necked, round bottomed flask, equipped with a stirrer, thermometer, addition funnel, condenser and a nitrogen blow-by was charged with 138.6 grams of allyl methacrylate, which contained[50 ppm of hydroquinone inhibitor, 0.14 gm of Ionol™ (2,6-ditert-butyl-4-methylphenol) and 0.22 ml of a 3.8% chloroplatinic acid solution in a 1,2-dimethoxyethane/ethanol mixture. The flask contents were heated to 90° C. and dropwise addition of trichlorosilane (135.5 gm, I mol) over a 20 minute period with cooling gave an 85% yield of 3-methacryloxypropyltrichlorosilane.
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17]([O:19]C)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@@H:23]([CH2:28][OH:29])[C@@H:24]([OH:27])[CH2:25][OH:26])=[CH:11]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl.CO>[OH:29][CH2:28][C@H:23]([NH:22][CH2:21][C:12]1[C:13]2[N:14]=[CH:15][NH:16][C:17](=[O:19])[C:18]=2[NH:10][CH:11]=1)[C@@H:24]([OH:27])[CH2:25][OH:26]
Reactant: COc1ncnc2c(CN[C@@H](CO)[C@@H](O)CO)cn(COCc3ccccc3)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]cnc2c(CN[C@@H](CO)[C@@H](O)CO)c[nH]c12
Temperature: 25 °C
Yield: 45.3 %

Procedure:
To a stirred solution of the product from Example 18.2 (0.056 g, 0.14 mmol) in DCM (7 ml) at −78° C. was added boron tribromide (1.39 ml, 1.39 mmol, 1.0M in DCM). After 15 mins the reaction mixture was warmed to ambient temperature and coevaporated with methanol (3×). The residue was stirred in methanol (7N ammonia solution) for 10 mins and evaporated on to silica gel. The material was chromatographed on silica gel (chloroform-methanol-conc. ammonia, 10:9:1) giving a white solid (17 mg, 46%). 1H NMR (D2O) δ 8.03 (s, 1H), 7.59 (s, 1H), 4.41 (ABq, 2H), 3.88 (dd, J=13.2, 4.2 Hz, 1H), 3.80 (m, 1H), 3.72 (dd, J=13.2, 5.3 Hz, 1H), 3.60 (dd, J=12.5, 3.4 Hz, 2H), 3.47 (dd, J=12.5, 4.5 Hz, 1H), 3.26 (m, 1H). +ESMS found 269.1262 (M+H)+ C11H17N4O4 requires 269.1250.