Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[I-].[Na+].[Br:33][C:34]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:35]=1[CH:36]=[CH:37][C:38]([O:46][CH3:47])=[C:39]2[CH2:44]Cl>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:44][C:39]2[C:40]3[C:35](=[C:34]([Br:33])[CH:43]=[CH:42][CH:41]=3)[CH:36]=[CH:37][C:38]=2[O:46][CH3:47])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(Br)cccc2c1CCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
To a stirred solution of ((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (Intermediate 2) (500 mg, 1.805 mmol) in THF (10 mL) at −78° C. was added LiHMDS (1 M in THF, 2.3 mL, 2.3 mmol) dropwise over 5 min. The mixture was stirred at −78° C. for 20 min. and a mixture of sodium iodide (295.8 mg, 1.986 mmol) and 5-bromo-1-chloromethyl-2-methoxy-naphthalene (617.3 mg, 2.166 mmol) in THF (5 mL), was added dropwise over 5 min. The mixture was stirred at −78° C. for 50 min. and the cooling bath was removed. After 16 h, aqueous citric acid was added and the mixture extracted with ethyl acetate. The extract was washed with saturated sodium carbonate solution, dried and concentrated to give a material which was purified by silica gel chromatography to provide the title compound (780 mg, 82%) as a white solid. LC-MS: 528 (M+H).
Reaction SMILES: [C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:16][C:17]([N:19]([CH:25]([CH2:34][C:35]([O:37]CC)=[O:36])[CH2:26][S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:3][CH:2]=1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:1]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:16][C:17]([N:19]([CH:25]([CH2:34][C:35]([OH:37])=[O:36])[CH2:26][S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:3][CH:2]=1
Reactant: CCCCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)N(CCC(C)C)C(CSc1ccccc1)CC(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CCCCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)N(CCC(C)C)C(CSc1ccccc1)CC(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(2S)-3-(4-Biphenylyl)-N-butyl-2-[3-[(1RS)-1-(ethoxycarbonylmethyl)-2-(phenylthio)ethyl]-3-isoamylureido]propionamide (Compound No. 38-1, 402 mg) is dissolved in ethanol(2 ml), a 1 N aqueous lithium hydroxide solution (0.96 ml) is added thereto, and the mixture is stirred at room temperature for 45minutes. A 10% aqueous citric acid solution is added to the reaction mixture, and the whole is extracted with ether. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 386 mg (quantitatively) of the titled compound (Compound No. 39-1) as noncrystalline powder.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][C@H:9]([O:13][CH2:14][C:15]#[CH:16])[CH2:8][O:7]2)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:21]=[CH:22][C:23]=1I.CCN(CC)CC>[Cu]I.CN(C=O)C>[F:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:21]=[CH:22][C:23]=1[C:16]#[C:15][CH2:14][O:13][C@@H:9]1[CH2:8][O:7][C:6]2=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]2[CH2:10]1
Reactant: C#CCO[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C#CCO[C@@H]3COc4nc([N+](=O)[O-])cn4C3)c(F)c2)C(=O)O1
Yield: 37.3 %

Procedure:
To an oven dried round bottom flask was charged 2-Nitro-6(S)-prop-2-ynyloxy-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (75 mg, 0.34 mmol), N-[3-(3-Fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5(S)-ylmethyl]-acetamide (127 mg, 0.34 mmol), PhCl2(PPh3)2 (23 mg, 0.02 mmol) and CuI (3.2 mg, 0.017 mmol). The flask was flushed with nitrogen before degassed DMF (4 mL) and Et3N (0.15 mL, 1.05 mmol) were added. The resultant mixture was stirred at 80° C. for one hour before it was cooled down and partitioned into 50 mL EtOAc/50 mL water. The organic layer was washed with brine and dried over Na2SO4. Column chromatography (CH2Cl2/MeOH, v/v, 20:1 to 10:1) of the concentrated residue gave the titled compound (60 mg) as yellow solid. ESI MS m/z 474 (M+H). 1H NMR (400 MHz, MeCN-d3) 7.73 (s, 1H), 7.65 (dd, J=12.4, 2.4 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 7.39 (dd, J=8.8, 2.4 Hz, 1H), 6.84 (b, 1H), 4.20-4.99 (m, 1H), 4.76 (dt, J=12.4, 2.8 Hz, 1H), 4.67 (s, 2H), 4.53 (d, J=12.8 Hz, 1H), 4.45-4.51 (m, 1H), 4.26-4.42 (m, 2H), 4.17 (t, J=9.2 Hz, 1H), 3.85 (dd, J=9.6, 5.2 Hz, 1H), 3.56-3.68 (m, 2H), 1.98 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>O1CCOCC1>[O:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]([NH:29][C:2]3[N:7]=[C:6]([S:8][C:9]4[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=4)[CH:5]=[CH:4][N:3]=3)=[CH:30][CH:31]=2)[CH2:23][CH2:24]1
Reactant: COC(=O)c1ccc(Sc2ccnc(Cl)n2)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(Sc2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 100 °C
Yield: 49 %

Procedure:
To a stirred mixture of methyl 4-(2-chloropyrimidin-4-ylthio)benzoate (3.80 g, 14 mmol) and 4-morpholinoaniline (2.89 g, 16 mmol) in 1,4-dioxane (100 mL), was added p-toluensulfonic acid monohydrate (2.57 g, 14 mmol) in one portion. The whole was heated at 100° C. for 16 hours, cooled to room temperature, and poured into water (200 mL). The precipitate was collected by filtration, washed repeatedly with 2% aqueous citric acid, water, and ethyl acetate. It was then dried under high vacuum to afford the product (2.90 g, 51%).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([Si:37]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>C1COCC1>[CH2:30]([Si:37]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][CH2:41][CH:40]([CH:2]=[O:4])[CH2:39][CH2:38]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC[Si]1(c2ccccc2)CCC(C=O)CC1
Reaction time: 2 h

Procedure:
12 g of potassium t-butoxide was added to a mixture of 35 g of methoxymethyltriphenylphosphonium chloride and 200 ml of THF to prepare an orange ylide solution. A solution of 28 g of 4-n-heptyl-4-phenyl-4-silacyclohexanone in 50 ml of THF was added to the solution. After agitation for 2 hours at room temperature, the mixture was poured into iced water and extracted with methylene chloride. The extract was washed, dried and concentrated by a usual manner. n-Hexane was added to the resultant concentrate, followed by removal of the resultant triphenylphosphine oxide crystals by filtration. The resultant filtrate was concentrated. The concentrate was hydrolyzed with 100 ml of 20% hydrochloric acid, followed by washing, drying and concentration by a usual manner to obtain 4-n-heptyl-4-phenyl-4-silacyclohexane carbaldehyde.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]C(C)(C)C.CC[Mg+].[Br-].[O:24]=O>C1COCC1>[C:11]1([OH:24])[C:12]2[S:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=O
Reactant: c1ccc2c(c1)Sc1ccccc1S2
Agent: CC[Mg+]
Agent: [Br-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Oc1cccc2c1Sc1ccccc1S2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To a cooled (−78° C.) solution of thianthrene (10 g, 46.23 mmol) in anhydrous THF (200 ml) was added t-BuLi (1.7M in pentane, 40.81 ml, 69.34 mmol), under a nitrogen atmosphere, over a period of 10 minutes and the resulting yellow solution was then allowed to warm to room temperature and stirred vigorously for a further 16 hours. EtMgBr (3M in THF, 23 ml, 69.34 mmol) was then added in a dropwise fashion to the cooled (0° C.) reaction mixture which was then stirred for a further 45 minutes before oxygen was bubbled through the solution. After two hours the reaction was quenched by dropwise addition of 1M NaOH (100 ml) and washed with EtOAc (1×300 ml) before being acidified to pH4 with aqueous 1M HCl. The mixture was then extracted with EtOAc (3×100 mL),dried (MgSO4), filtered and concentrated in vacuo to give a mild amber slurry that was purified by flash chromatography (SiO2) (10:1, Ethyl acetate/Hexanes), to give the title compound (3.82 g, 36%) as a yellow solid. m/z (LC-MS, ESP):, RT=4.62 min, (M++1)=231
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[C:22]2[NH:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Br:16][C:17]1[C:22]2[N:23]([C:2]3[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]4[CH2:14][CH2:13]4)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=3)[CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: COc1cc(Br)c2c(c1)OCCN2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCOc3cc(OC)cc(Br)c32)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone (67.9 mg, 0.275 mmol) and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine (67 mg, 0.275 mmol) were combined in THF (1.4 mL). The mixture was cooled to 0° C. and was treated with NaHMDS (302 μL, 0.302 mmol, 1 M in THF). The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a separatory funnel containing saturated NaHCO3 and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (10% EtOAc→30% EtOAc in hexanes) to afford a brown oil. 1H NMR (300 MHz, CDCl3): δ 6.73 (d, J=1.5 Hz, 1H), 6.70 (s, 1H), 6.45 (d, J=1.3 Hz, 1H), 4.31-4.00 (m, 5H), 3.75 (s, 3H), 1.89-1.74 (m, 2H), 1.05-1.02 (m, 1H), 0.93 (t, J=7.3 Hz, 3H), 0.90-0.75 (m, 1H), 0.52-0.49 (m, 2H), 0.35-0.25 (m, 1H); HRMS (ESI) m/z 453.0459 [M+, calcd for C19H21N3O3BrCl 453.0455].
Reaction SMILES: [CH2:1]([C:3]1[C:10]([O:11]C)=[CH:9][CH:8]=[C:7]([CH2:13][CH3:14])[C:4]=1[CH:5]=[O:6])[CH3:2].B(Br)(Br)Br>>[CH2:1]([C:3]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([CH2:13][CH3:14])[C:4]=1[CH:5]=[O:6])[CH3:2]
Reactant: CCc1ccc(OC)c(CC)c1C=O
Agent: BrB(Br)Br
Product: CCc1ccc(O)c(CC)c1C=O

Procedure:
2,6-Diethyl-3-hydroxy-benzaldehyde was prepared from 2,6-diethyl-3-methoxy-benzaldehyde and boron tribromide in analogy to Example 213a): brown crystals; MS (ISP): 177.4 ([M-H]−, 100%).
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:11]2)(=[O:4])[CH3:3].[CH2:20](I)[CH2:21][CH2:22][CH3:23].C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[ClH:1].[C:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([N:16]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH2:18][CH3:19])[CH2:11]2)(=[O:4])[CH3:3]
Reactant: CCCCI
Reactant: CCCNC1CCc2c(cccc2NC(C)=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Reaction time: 8 h

Procedure:
2.83 g (0.010 mol) of 5-acetylamino-2-n-propylamino-tetraline-hydrochloride (Example 4.1.1), 2.76 g (0.015 mol) of n-butyliodide and 1.68 g (0.020 mol) of sodium hydrogen carbonate are refluxed in a mixture of 20 ml of absolute dimethylformamide and 30 ml of absolute tetrahydrofuran for 48 hours with stirring (moment of complete reaction determined by thin layer chromatography). The reaction mixture is concentrated by rotary evaporation, finally at 95° C. under a complete water-jet vacuum. The residue is shaken with 50 ml of methylene chloride and 50 ml of water and the aqueous phase separated is extracted twice more with 15 ml of methylene chloride. The combined extracts are washed with 20 ml of water, dried with sodium sulphate and concentrated by rotary evaporation, finally at 90° C. under a complete water-jet vacuum. The residue is dissolved with 10 ml of ethanol and the solution is acidified with 4.0 ml of 2.5 N ethanolic hydrochloric acid (0.0I mol HCl). After the addition of diethylether until turbidity is just starting, the title compound crystallises. After standing overnight it is suction filtered at 5° C., washed with a mixture of ethanol and ether and dried at 80° C. until a constant weight is obtained. Yield 2.56 g (75.5% of theory), melting point 217° C. After recrystallisation from methanol/ether the melting point does not change.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH3:8])[CH:6]([CH3:9])[CH2:5][CH:4]([OH:10])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>ClCCl.C(OCC)C>[CH3:1][CH:2]1[CH:7]([CH3:8])[CH:6]([CH3:9])[CH2:5][C:4](=[O:10])[CH2:3]1
Reactant: CC1CC(O)CC(C)C1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: CC1CC(=O)CC(C)C1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
3,4,5-trimethylcyclohexanol obtained in step 1 was dissolved in dichloromethane. Dess-Martin reagent (3.1 g, 7.34 mmol) was added in one portion. Trifluoroacetic acid anhydride (0.56 mL, 7.34 mmol) was added, and the solution was stirred at RT for 18 h. Sodium hydroxide (1 N, 30 mL) and diethyl ether (100 mL) were added. The reaction mixture was stirred at RT for one hour. The organic layer was washed with NaOH (1N, 30 ml), brine 930 ml), dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by SiO2 chromatography (Hexane/EtOAc 5:1) to give 3,4,5-trimethylcyclohexanone (758 mg, 73.6% from 3,4,5-trimethylphenol).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][S:10](O)(=[O:12])=[O:11].C(Cl)(=O)C([Cl:19])=O>C1COCC1.CN(C=O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][S:10]([Cl:19])(=[O:12])=[O:11]
Reactant: O=S(=O)(O)Cc1ccccc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)Cc1ccccc1C(F)(F)F
Yield: 87.5 %

Procedure:
To a suspension of (2-trifluoromethylphenyl)methanesulfonic acid (20.3 g, 84 mmol) in THF (1.9 L) and DMF (5.0 mL) at −20° C. was added oxalyl chloride (44.7 mL, 0.5 mol) slowly dropwise over 1 hr. The bath temperature was maintained below 0° C. for 4 h, at which point the reaction was evaporated to a volume of ˜250 mL and diluted with 500 mL of ethyl acetate. This solution was washed with brine in a separatory funnel and dried over magnesium sulfate. The solution was then evaporated to a brown oil. This oil was taken up in 500 mL of pet ether (30-50°) and heated with a heat gun until the oil went into solution. The solution was then placed into a dry-ice acetone bath to cool resulting in formation of a white crystalline material. This material was collected via filtration and dried to afford 19 g (85%) of (2-trifluoromethylphenyl)methanesulfonyl chloride as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([S:16][C:17]#N)[N:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].SC[C@H]([C@@H](CS)O)O.ClC1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH3:37])=[O:35])[CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([S:16][C:17]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH3:37])=[O:35])[CH:29]=3)[N:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: N#CSc1csc(Nc2ccc([N+](=O)[O-])cn2)n1
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Sc2csc(Nc3ccc([N+](=O)[O-])cn3)n2)ccn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Methanol (115 mL) was added to N-(5-nitropyridin-2-yl)-4-thiocyanatothiazol-2-amine (3.24 g, 11.6 mmol) and dithiothreitol (3.6 g, 23.3 mmol) at 23° C. Methyl 4-chloropicolinate (2.18 g, 12.8 mmol) was then added followed by potassium phosphate (3.27 g, 15.4 mmol) and DMF (115 mL). The reaction was stirred overnight, then poured into ice/water (1.5 L). The resulting precipitate was filtered on paper and dried under vacuum to give the title material (4.05 g, 90%). LC/MS (M+H)+: 390, (M−H)−: 388. HPLC ret. time (Condition E): 1.683 min.
Reaction SMILES: [CH2:1]([C@@:8]([OH:28])([CH2:25][CH2:26][OH:27])[C:9]([N:11]1[C@H:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[CH2:22][C@H:14]2[O:13][C:12]1([CH3:24])[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CCOCC>[CH2:1]([C@:8]([OH:28])([C:9]([N:11]1[C@H:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[CH2:22][C@H:14]2[O:13][C:12]1([CH3:23])[CH3:24])=[O:10])[CH2:25][CH:26]=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@@H]2Cc3ccccc3[C@@H]2N1C(=O)[C@](O)(CCO)Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)O[C@@H]2Cc3ccccc3[C@@H]2N1C(=O)[C@](O)(CC=O)Cc1ccccc1
Yield: 73.1 %

Procedure:
A solution of (R)-2-benzyl-1-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3 aH-indeno[1,2-d]oxazol-3-yl)-2,4-dihydroxybutan-1-one (47) (0.12 g, 0.31 mmol) in dry CH2Cl2 (5 mL) was added over 1 min to a stirred solution of Dess-Martin periodinate (0.146 g, 0.35 mmol) in dry CH2Cl2 (10 mL). After 30 min the homogeneous mixture was diluted with ether and poured into cold saturated NaHCO3 (10 mL) containing Na2S2O3 (2.2 g). The organic layer was washed with aqueous saturated NaHCO3, brine and dried (MgSO4). The solvents were evaporated below 20° C. to give the title compound (0.086 g, 72%). The residue was immediately used for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].C(OC(=O)[NH:38][CH2:39][CH2:40][NH2:41])(C)(C)C>>[NH2:38][CH2:39][CH2:40][NH:41][C:18]([C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:23]([Cl:25])=[CH:24][C:2]=2[Cl:1])[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)=[O:20]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NCCN
Product: NCCNC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1

Procedure:
The title compound was prepared according to the method described for Example 49 using 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111) and tert-butyl(2-aminoethyl)carbamate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[I:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(I)cc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 10 h
Yield: 60 %

Procedure:
To a mixture of 2.6 g of 2-amino-3-methylbenzoic acid and 100 ml of N,N-dimethylformamide was added 2.3 g of N-iodosuccinimide at room temperature, and the mixture was stirred at room temperature for 10 hours. After water was poured to the reaction mixture, a deposited precipitate was collected by filtration to obtain 1.7 g of 2-amino-5-iodo-3-methylbenzoic acid of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].ClC1C=C2C(C(CC(O)=O)=[C:30]([C:34]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:35])N2)=CC=1>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:30]=1[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=1)=[O:35]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)nc1
Product: COC(=O)Cc1c(C(=O)c2ccc(C)cn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-5-methylpyridine (Preparation is described in step 1 of Example 32).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH2:15][CH:16]=[O:17])[C:4]([NH:6][C:7]1[S:8][C:9]([O:12][CH3:13])=[N:10][N:11]=1)=[O:5])[CH3:2].Cl>O>[CH3:13][O:12][C:9]1[S:8][C:7]([N:6]2[CH:16]([OH:17])[CH2:15][CH2:14][N:3]([CH2:1][CH3:2])[C:4]2=[O:5])=[N:11][N:10]=1
Reactant: CCN(CCC=O)C(=O)Nc1nnc(OC)s1
Agent: Cl
Solvent: O
Product: CCN1CCC(O)N(c2nnc(OC)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-ethyl-3-(5-methoxy-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (100 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: Cl[C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10](N[C@@H]3CC4C(=CC=CC=4)[C@H]3NC=O)=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:25].[OH-:26].[Li+]>CO>[C:10]([C:6]1[NH:5][C:4]2[C:3]([Cl:25])=[CH:2][S:9][C:8]=2[CH:7]=1)([OH:11])=[O:26]
Reactant: [OH-]
Reactant: O=CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: [Li+]
Solvent: CO
Product: O=C(O)c1cc2scc(Cl)c2[nH]1
Yield: 99.9 %

Procedure:
3-Chloro-5-methoxycarbonyl-4H-thieno[3,2-b]pyrrole (Method 1; 0.61 g, 2.83 mmol) was taken up in MeOH (10 ml) and was heated under reflux. Aqueous lithium hydroxide (2.0 M, 3.0 ml, 6.0 mmol) was added portionwise over 45 minutes. The mixture was heated under reflux for 30 minutes before being cooled and concentrated. Water (20 ml) was added and the solution was neutralised using aqueous hydrochloric acid (2.0 M, 3.0 ml). The solution was extracted using EtOAc, and the combined organic layers were concentrated to afford the title compound as a yellow solid (0.57 g, 100%). NMR: 12.4 (1H, br), 7.4 (1H, s), 7.0 (1H, s); m/z 200.3.