Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.[Br:5][C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([CH3:23])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:24])=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:5][C:6]1[C:11]([N:12]([CH2:3][O:2][CH3:1])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([CH3:23])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:24])=[CH:8][N:7]=1
Reactant: COCCl
Reactant: Cc1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C)c1
Reaction time: 5 h

Procedure:
Methoxymethyl chloride (1.2 g, 14.3 mmol) was added dropwise to a mixture of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-methyl-benzenesulfonamide (5.0 g, 12.7 mmol) and potassium carbonate (3.2 g, 23.2 mmol) in THF (30 mL) at room temperature. After 5 h, the potassium salts were removed by vacuum filtration and the filtrate was concentrated under reduced pressure. The residual light yellow solid was chromatographed on silica gel using ethyl acetate-hexane to provide the N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-methyl-benzenesulfonamide as white crystals. MS m/z 441.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]1>CN1C(=O)CCC1>[C:31]([NH:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:26]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N[C@@H]1CCNC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CN1CCCC1=O
Product: CC(=O)N[C@@H]1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 108.5 %

Procedure:
In a 2 mL microwave vial were placed N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 80 mg, 0.24 mmol) and (R)-N-(pyrrolidin-3-yl)acetamide (62 mg, 0.48 mmol). To the sealed vial were then added NMP (2 ml), and the mixture was then heated in the microwave at 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was filtered by syringe filter and was then directly purified by preparatory HPLC (20-40% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white powder (110 mg, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ=10.84 (s, 1 H), 8.24 (d, J=6.3 Hz, 1 H), 8.01 (d, J=2.3 Hz, 1 H), 8.00-7.95 (m, 2 H), 7.65-7.59 (m, 2 H), 6.90 (s, 1 H), 6.28 (d, J=2.3 Hz, 1 H), 4.41-4.31 (m, 1H), 4.19 (br. s., 1 H), 3.96 (br. s., 2 H), 2.19 (dd, J=5.8, 12.6 Hz, 1 H), 2.01-1.91 (m, 1 H), 1.83 (s, 3 H), 1.46 (s, 6 H); ESI-MS: m/z 423.4 (M+H)+.
Reaction SMILES: [I:1]I.[C:3]1([C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)([OH:12])[C:10]#[CH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[I:1][C:11]#[C:10][C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[OH:12]
Reactant: II
Reactant: C#CC(O)(c1ccccc1)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(C#CI)(c1ccccc1)c1ccncc1
Reaction time: 3 h
Yield: 79.1 %

Procedure:
50.8 g (0.2 mol) of iodine were gradually introduced into a suspension of 42 g (0.2 mol) of 3-phenyl-3-pyridin-4-yl-1-propyn-3-ol in 500 ml of methanol at room temperature, while simultaneously adding 80 ml of concentrated sodium hydroxide solution dropwise. An almost clear solution was thereby obtained. After stirring the solution at room temperture for three hours, it was diluted with a large amount of water and the crystals which had separated out were filtered off, washed with water and dried in vacuo. After recrystallization from methanol, 53 g (79.2% of theory) of 1-iodo-3-phenyl-3-pyridin-4-yl-1-propyn-3-ol were obtained as colorless crystals of melting point 175° C. (decomposition).
Reaction SMILES: [NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CO.[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:2]([C:11]([NH:13][C@@H:14]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:15][CH2:16][S:17][CH3:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
The title compound of Example 3 (12.6 g., 26 mmoles) is dissolved in 78 ml. of methanol and 78 ml of 1 N sodium hydroxide is added dropwise with stirring to give a clear solution. After 1/2 hour, the tlc (5 percent methanol-chloroform) showed that saponification was complete.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([NH:12][OH:13])[CH2:9]2)=[CH:4][CH:3]=1.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16].CCO>C1COCC1>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:14][C:15]([N:12]([C@H:10]1[CH2:11][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9]1)[OH:13])=[O:16])[CH3:22]
Reactant: ON[C@H]1C[C@@H](c2ccc(F)cc2)C1
Reactant: CCOC(=O)CN=C=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)N(O)[C@H]1C[C@@H](c2ccc(F)cc2)C1
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a stirred solution of cis-3-(4-fluorophenyl)cyclobutylhydroxylamine (0.9 g, 5 mmol) in THF (20 ml) was added ethyl isocyanatoacetate (0.71 g, 5.5 mmol). After stirring for 10 minutes, EtOH was added. Volatiles were removed in vacuo and the resulting residue was recrystallized from ethyl acetate/n-hexane to afford 1.10 g (71% yield) of the title compound as colorless needles, m.p. 130-132° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[CH:21]([NH:24][CH3:25])([CH3:23])[CH3:22]>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:24]([CH:21]([CH3:23])[CH3:22])[CH3:25])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNC(C)C
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CC(C)N(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 27 step C from 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) and isopropyl-methyl-amine. Yellow solid. MS (ESI): 336.2 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl>CN(C)C=O>[CH3:24][N:25]([CH2:26][CH2:27][N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:8]2[C:16]([F:23])=[C:17]([F:22])[C:18]([F:21])=[C:19]([F:20])[C:7]=2[F:6])[CH2:11][CH2:12]1)[CH3:29]
Reactant: CN(C)CCCl
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 85 °C
Reaction time: 5 h
Yield: 45.9 %

Procedure:
A stirred mixture of 5 g of sodium bicarbonate, 4.44 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine, and 40 ml of dimethylformamide was treated, dropwise, with a solution of 2.15 g of 2-dimethylaminoethyl chloride in 20 ml of dimethylformamide. After stirring for five hours at 85° C., the reaction mixture was filtered, and the filtrate poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation of the volatiles afforded an oil which was eluted with 20% methanol/dichloromethane on a silica gel column via flash chromatography. The desired fractions were evaporated to afford 2.58 g of 1-[2-(N,N-dimethylamino)ethyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil. The oil was dissolved in isopropanol and the solution acidified to pH 1 with etheral hydrogen chloride to precipitate 2.05 g (29.3%) of the corresponding dihydrochloride salt, m.p. 276° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:5]=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:28][C:29]1[N:36]=[C:35](F)[C:34]([F:38])=[CH:33][C:30]=1[C:31]#[N:32]>C1COCC1>[C:31]([C:30]1[CH:33]=[C:34]([F:38])[C:35]([NH:1][C:2]2[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[N:5]=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:3]=2)=[N:36][C:29]=1[F:28])#[N:32]
Reactant: N#Cc1cc(F)c(F)nc1F
Reactant: CC(C)Oc1cc(N)n(C(=O)OC(C)(C)C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(F)c(C#N)cc2F)n(C(=O)OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of tert-butyl 5-amino-3-isopropoxy-1H-pyrazole-1-carboxylate (Method 78, 4.0 g, 16.4 mmol) in THF (45 ml) was cooled to −78° C. A 1.0M THF solution of LiHMDS (2.61 g, 15.6 mmol) was added dropwise and the reaction was stirred at −78° C. for 30 minutes. A −78° C. solution of 2,5,6-trifluoronicotinonitrile (1.3 g, 8.2 mmol) in THF (20 ml) was added dropwise via cannula to the above anion solution. Upon completion of the addition, the resulting reaction was allowed to stir for 10 minutes at −78° C., and was then quenched with water (100 ml). The reaction was allowed to warm to room temperature, extracted with DCM (3×100 ml), dried (Na2SO4), filtered, and then concentrated to give the title compound (95% conversion by LCMS) which was used without further purification. MS: Calcd.: 379. Found: [M+H]+ 380.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:21]([CH3:20])(=[O:23])=[O:22])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CO)cc(Br)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(COS(C)(=O)=O)cc(Br)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2-bromo-6-methyl-pyridin-4-yl)-methanol (0.300 g, 1.48 mmol) in dichloromethane (2.0 mL) was added DIPEA (776 μL, 4.45 mmol). The resulting mixture was cooled to 0° C. and methanesulfonyl chloride (120 μL, 1.56 mmol) was added. After 1 hour, the reaction mixture was diluted CH2Cl2 (20 mL) and washed with saturated aqueous ammonium chloride (3×10 mL), saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford methanesulfonic acid 2-bromo-6-methyl-pyridin-4-ylmethyl ester as crude product which was used in the next step without purification.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH:25]([CH2:27][CH2:28][C:29](OCC)=O)=[O:26]>>[OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:25](=[O:26])[CH2:27][CH2:28][CH:29]=[N:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)CCC=O
Reactant: CCCCCCCCCCCCCCC(O)CNCCNCCN
Product: CCCCCCCCCCCCCCC(O)CNCCN1CCN=CCCC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 339.5 g (1 mole) of N-(2-hydroxy)hexadecyldiethylenetriamine and 130.1 g (1 mole) of ethyl 3-formylpropionate. At 135° to 140° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-(2-hydroxyhexadecyl)aminoethyl-2,3,6,7-tetrahydro-1,4-diazocin-5-one.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([O:13][CH3:14])[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:11]2
Reactant: CCOC(=O)Cl
Reactant: COc1nc2ccc(Cl)cc2nc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 95 %

Procedure:
3-Amino-6-chloro-2-methoxyquinoxaline (629 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 803 mg of the titled compound (yield, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 77 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 77%). 1H NMR (300 MHz, CDCl3): δ 3.13-3.20 (m, 4H), 3.77 (s, 3H), 4.14 (s, 4H), 6.88-7.02 (m, 4H), 7.20-7.24 (m, 1H), 7.36-7.44 (m, 1H), 7.50-7.67 (m, 1H), 7.80 (s, 1H).
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([S:20][C:21]2[N:25]([CH3:26])[N:24]=[N:23][N:22]=2)[C:8]=1[CH2:27][S:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:35](N(CC)CC)C.CI>C(#N)C>[C:1]([C:5]([C:7]1[N:12]2[C:13](=[O:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:18])(=[O:19])[C:9]([CH3:35])([S:20][C:21]2[N:25]([CH3:26])[N:24]=[N:23][N:22]=2)[C:8]=1[CH2:27][S:28][C:29]1[N:33]([CH3:34])[N:32]=[N:31][N:30]=1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)C(Sc3nnnn3C)S(=O)(=O)[C@H]12
Reactant: CCN(CC)CC
Solvent: CC#N
Solvent: CI
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(CSc3nnnn3C)C(C)(Sc3nnnn3C)S(=O)(=O)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of 4-tert-butylcarbonyl-7α-methoxy-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-(1-methyl-1,2,3,4-tetrazol -5-yl)thiomethyl-3-cephem 1,1-dioxide (100 mg), prepared as described in PTC EP 90/02189 in acetonitrile (2 ml) was treated at room temperature with triethylamine (0.040 ml) and methyl iodide (0.060 ml). The reaction mixture was stirred for 30 minutes and the organic solvent completely removed in vacuo. The resulting crude residue was eventually taken up in dichloromethane and purified by flash chromatography affording the title compound as a yellowish solid (40 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCC=Cc1ccccc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCC=Cc2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a mixture of 0.62 g of 2,6-dichloro-4-(3,3,-dichloro-2-propenyloxy)phenol, 0.33 g of potassium carbonate and 20 ml of N,N-dimethylformamide was added dropwise a solution of 0.43 g of cinnamyl bromide dissolved in 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 7 hours, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.70 g of 3,5-dichloro-4-(cinnamyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (80% yield), m.p. 51.3° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:27][CH:26]=1)[CH3:24]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Product: CCc1ccc(-c2cc(NC(=O)c3cccnc3)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N45-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(4-ethylphenyl)-boronic acid (CAN 63139-21-9) as starting materials; LC-MS (UV peak area/ESI) 100%, 402.1409 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]1=[O:17].Br[C:19]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:29][CH2:30][CH:31]1[CH2:33][CH2:32]1>>[CH:31]1([CH2:30][O:29][C:20]2[CH:19]=[CH:24][C:23]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:22][C:21]=2[C:6]2[CH:5]=[CH:4][C:3](=[O:17])[N:2]([CH3:1])[CH:7]=2)[CH2:32][CH2:33]1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)ccc1=O

Procedure:
1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one was treated with 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene in a manner similar to Example 94 to give the title compound. 1H NMR (CDCl3, 400 MHz): δ 7.86 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.68-765 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 3.64 (s, 3H), 3.07 (s, 3H), 1.28-1.25 (m, 1H), 0.69-0.65 (m, 2H), 0.34-0.38 (m, 2H). LCMS (M+H)+ 334.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6])[CH3:2].[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]2[C:9]3[NH:10][C:11]4[C:16]([C:8]=3[CH2:7][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[NH:6]2)=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:22][CH:21]=1
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CN(C)c1ccc(C=O)cc1
Product: CCOC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(N(C)C)cc2)N1

Procedure:
The same method but starting from racemic tryptophan ethyl ester and 4-dimethylaminobenzaldehyde gave the title compound as white crystals m.p. 170° C.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[N+:24]([O-])=O)[CH2:4][CH3:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Yield: 98.2 %

Procedure:
A mixture of (1-ethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine (40 mg, 0.112 mmol) and 4 mg of 10% Pd/C in 10 ml of ethanol was hydrogenated at 50 psi overnight. The mixture was filtered through Celite™ and the filtrate was concentrated to dryness to give a light brown crystals which were purified through silica gel column chromatography using 1:1 chloroform:hexane as eluent to give the title compound as golden crystals (36 mg, 97%), mp 105-107° C. 1H NMR (CDCl3) δ 6.88 (s, 2H), 6.11 (s, 1H), 4.00 (brs, 1H), 3.28 (m, 1H), 3.10 (brs, 2H), 2.31 (s, 3H), 2.16 (s, 3H), 2.10 (s, 6H), 1.45-1.75 (m, 4H), 0.98 (t, 6H) ppm. The corresponding HCl salt was prepared as white solid, mp 174-178° C., 1H NMR (D2O) δ 7.09 (s, 2H), 6.63 (s, 1H), 3.65 (m, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.11 (s, 6H), 1.45-1.80 (m, 4H), 0.91 (t, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:19][CH3:20])[C:3]=1[F:21].[NH2:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]3[C:24]=2[CH:25]=[N:26][C:27]([CH3:34])=[N:28]3)=[C:4]([O:19][CH3:20])[C:3]=1[F:21]
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Reactant: COc1c(C(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(C(C)CC(O)(C=Nc2cc(F)cc3nc(C)ncc23)C(F)(F)F)ccc(Cl)c1F

Procedure:
In the same way as in Example 14, 100 mg (0.3 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 54 mg (0.3 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.1 ml of titanium tetraethoxide are reacted to give 4-(4-chloro-3-fluoro-2-methoxyphenyl)-1-[(7-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 150 mg of crude imine are cyclized in the same way as in Example 14 at −30° C. with 2.5 ml (2.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) and subsequent preparative thin-layer chromatography on amine phase (Merck) with ethyl acetate/methanol/triethylamine 25:3:1 yield 3.4 mg of product and 3 mg of the dihydroxy compound Ex. 16.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cncc(Br)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 154.5 %

Procedure:
5-Bromo-pyridin-3-carbaldehyde (15.0 g, 80.6 mmol), malonic acid (18.9 g, 181.4 mmol), and piperidine (6.6 mL, 66.9 mmol) were added to pyridine (48.9 mL). The reaction mixture was stirred at 100° C. for 1 hour, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid was dried under reduced pressure to give 28.4 g of the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].OO.C([O-])([O-])=[O:13].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([NH2:6])=[O:13]
Reactant: N#Cc1cccc(Br)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of m-bromobenzonitrile (2 g, 10 mol) in DMSO (6 mL) was added 30% H2O2 (5 g, 13 mmol) and K2CO3 at 0° C., and stirred at room temperature for 30 min. The mixture was poured into water and filtered, the solid was washed with water, dried to got the compound 0601-142 (1.8 g, 82%) as a white solid. LCMS: 200 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.41 (t, J=8.0 Hz, 1H), 7.50 (s, 1H), 7.70 (dd, J1,2=8.0, 0.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 8.03 (t, J=1.6 Hz, 1H), 8.06 (s, 1H).