Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].O>CO>[C:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
In an atmosphere of argon, 25 g (145.3 mmols) of 4-bromoaniline was dissolved in 50 ml of methanol, and the solution obtained was cooled to 0° C., and thereafter 27.4 ml (2.0-fold equivalent weight) of acetic anhydride was dropwise added thereto. Thereafter, the solution obtained was restored to room temperature, and stirred for 20 minutes. To the reaction solution obtained, 250 ml of water was added, and a white solid deposited was collected by filtration, which was then washed with water, followed by natural drying to obtain 30.8 g of N-acetyl-4-bromoaniline (yield: 99.1%; a while solid).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+:22].[K+].O>CO>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[S:7][C:8]([C:10]([O-:12])=[O:11])=[CH:9][C:5]=2[CH:4]=1.[K+:22]
Reactant: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C([O-])c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 5.00 g of methyl 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 2.93 g of potassium carbonate, 20 ml of water and 60 ml of methanol was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was recrystallized from water to obtain 3.74 g of potassium 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (hereinafter referred to as “the present compound 6”).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C.O>C(Cl)Cl>[Cl:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:9]=1)[O:11][C:12](=[O:14])[CH:13]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=c1ccc2cc(Cl)cc(Cl)c2o1
Temperature: 50 °C
Yield: 72.2 %

Procedure:
To a 2 L round bottom flask fitted with a mechanical stirrer and condenser was placed 3,5-dichlorosalicylaldehyde (200.0 g, 1.05 mol, 1 equivalent), acetic anhydride (356 g, 3.49 mol) and triethylamine (95.0 g, 0.94 mol, 0.90 equivalent). The reaction solution was heated at reflux overnight. The dark brown reaction mixture was cooled to 50° C. and water (1 L) added with stirring. After one hour the mixture was filtered and the filtrate combined with EtOH (1 L). This mixture was heated to 45° C. for one hour, cooled to room temperature, filtered and the solid (fraction A) washed with EtOH (0.5 L). The combined EtOH solutions were concentrated by rotary evaporation to produce an oil (fraction B). The solid from fraction A was dissolved in methylene chloride (1.5 L) and the resulting solution passed through a pad of silica gel (1300 mL volume). The resulting dark brown solution was concentrated to an oil that was triturated with hexanes (1.3 L) to give a solid that was isolated by filtration and washed (hexanes) to give substantially pure 6,8-dichlorocoumarin (163 g). An additional 31 g of product was obtained by treating the oil (fraction B) in a similar fashion; the oil was dissolved in methylene chloride (0.5 L) passed through a silica pad (0.5 L volume) and triturated with hexanes. The total isolated yield is 194 g or 86% of the brown solid.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[N-:9]=[N+:10]=[N-:11].[Na+]>CC(C)=O.[Cl-].[Na+].O>[N:9]([CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])=[N+:10]=[N-:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A mixture of 1-bromopinacolone (0.5 mL, 3.7 mmol) and NaN3 (0.48 g, 7.38 mmol) in 50 mL acetone was stirred overnight at room temperature. It was then poured into brine and extracted with dichloromethane. The extracts were washed with brine, were dried over Na2SO4, filtered, and were evaporated to afford the title compound as a yellow oil (524 mg, 100%). 1H NMR (DMSO-d6) δ 4.39 (s, 2H), 1.10 (s, 9H); MS (DCI+) m/z 142 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[OH-].[Na+].[CH2:21]([C:23]1([CH2:27][OH:28])[CH2:26][O:25][CH2:24]1)[CH3:22]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH2:21]([C:23]1([CH2:27][O:28][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:26][O:25][CH2:24]1)[CH3:22]
Reactant: CCC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Reaction time: 5 h

Procedure:
After adding p-toluene sulfonyl chloride (229 g (1.2 mol)), benzyltriethylammonium chloride (17.1 g (75 mmol)) and toluene (450 ml) to a glass flask of an inner volume of 2,000 ml equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, while keeping the liquid temperature below 5° C., a 35% aqueous sodium hydroxide solution (200 g (1.75 mol)) was gradually added. While keeping the liquid temperature below 10° C., 3-ethyl-3-hydroxymethyloxetane (116.2 g (1.0 mol)) was dropwise added to perform the reaction at the same temperature for 1 hour and at room temperature for 5 hours. After the completion of the reaction, toluene (150 ml) and water (250 ml) were added to a reaction solution and a liquid separation was performed. After washing a resultant organic layer with water (250 ml) twice, a magnesium sulphate was added so that the organic layer was dried. After the completion of drying, the organic layer was filtered and a resultant filtrate was concentrated under reduced pressure to give, as a colorless liquid, 3-ethyl-3-p-toluene sulfonyloxymethyloxetane having a purity of 90% (a value measured by 1H-NMR) (285 g) (an isolated yield based on 3-ethyl-3-hydroxymethyloxetane standard: 95%).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reaction time: 8 h

Procedure:
A solution of 25.03 g (109.2 mmol) N-Boc isonipecotic acid was dissolved in 200 mL THF and treated with 200 mL 1 M borane-tetrahydrofuran complex in THF, and the mixture was stirred overnight. The mixture was concentrated under vacuum, diluted with 750 mL ethyl acetate, and washed with 150 mL 1 N HCl (6×) and then saturated brine. The organic layer was dried over sodium sulfate and concentrated to give crude product as a white solid. 1H NMR (500 MHz) δ 4.15 (br d, J=13.7 Hz, 2H), 3.52 (d, J=6.2 Hz, 2H), 2.69˜2.75 (m, 2H), 1.71˜1.75 (m, 2H), 1.62˜1.70 (m, 1H), 1.47 (s, 9H), 1.12˜1.21 (m, 2H). This was used as is in the next step.
Reaction SMILES: C1(CCO)CC1.[C:7]12([CH2:17][OH:18])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.FC1C=C(F)C(F)=CC=1C(NS(C)(=O)=O)=O.[Cl:35][C:36]1[C:37](F)=[CH:38][C:39]([F:49])=[C:40]([CH:48]=1)[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:42]>>[C:7]12([CH2:17][O:18][C:37]3[C:36]([Cl:35])=[CH:48][C:40]([C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[O:42])=[C:39]([F:49])[CH:38]=3)[CH2:14][CH:13]3[CH2:12][CH:11]([CH2:10][CH:9]([CH2:15]3)[CH2:8]1)[CH2:16]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: OCCC1CC1
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 1 and making variations as required to replace 2-cyclopropylethanol with adamantan-1-ylmethanol and 2,4,5-trifluoro-N-(methylsulfonyl)benzamide with 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (WO 2012007883 A1), the title compound was obtained as a colorless solid (0.20 g, 8%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.23 (d, J=12.5 Hz, 1H), 3.72 (s, 2H), 3.35 (s, 3H), 1.99 (br s, 3H), 1.75-1.64 (m, 12H); 13C NMR (75 MHz, DMSO-d6) δ 162.3 (d, J=2.0 Hz), 159.8 (d, JC-F=255 Hz), 158.3 (d, JC-F=11 Hz), 130.6 (d, JC-F=4 Hz), 116.8 (d, JC-F=3 Hz), 113.6 (d, JC-F=14 Hz), 102.7 (d, JC-F=28 Hz), 79.1, 41.2, 38.5, 36.4, 33.4, 27.3; MS (ES+) m/z 415.6, 417.6 (M+1).
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C1CC1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1CC1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-formylcyclopropanecarboxylate in methanol (0.7 M) was added at −0° C. sodium borohydride portionwise. The resulting reaction mixture was stirred at 0° C. for 30 min and then at RT for 1.5 h. The reaction was quenched with sat. aq. NH4Cl and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, and filtered. Concentrated of the filtrate in vacuo afforded the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:27][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([F:18])([F:28])[F:29])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.1 %

Procedure:
In 20 ml of methylene chloride was dissolved 1.1 g of 4-benzyloxybenzoic acid chloride, and to the solution was slowly added a solution of 0.74 g of (R)-(+)-1,1,1-trifluoro-2-octanol ([α]D20 =+25.2°), 0 4 g of triethylamine, and a catalytic amount of dimethylaminopyridine in 10 ml of methylene chloride under ice-cooling. After warming to room temperature, the solution was stirred for 12 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride phase was successively washed with diluted hydrochloric acid, water, an aqueous 1N sodium carbonate solution, and water and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residual crude product was purified by silica gel column chromatography to obtain 1.0 g of 1,1,1-trifluoro-2-octyl 4-benzyloxybenzoate.
Reaction SMILES: [N:1]([CH2:4][C:5](=[N:9][C:10]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)[O:6][CH2:7][CH3:8])=[N+]=[N-].CO.[Cl-].[NH4+]>[Zn].O>[Cl:24][C:21]1[CH:22]=[CH:23][C:10]2[N:9]=[C:5]([O:6][CH2:7][CH3:8])[CH2:4][N:1]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]=2[CH:20]=1
Reactant: CCOC(CN=[N+]=[N-])=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: CCOC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 0.17 h

Procedure:
To a solution of 1.7 part of 2-(2-azido-1-ethoxyethylideneamino)-5-chlorobenzophenone produced in Step (2) of Example 1 in 50 parts by volume of methanol is added a solution of 1.6 part of ammonium chloride in 5 parts by volume of water. To the mixture is added 1 part of zinc powder with stirring. After 10 minutes, the resulting precipitates are removed by filtration. The filtrate is poured into 100 parts by volume of water, and extracted with ethyl acetate. Ethyl acetate layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to give 7-chloro-2-ethoxy-5-phenyl-3H-1,4-benzodiazepine as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.CO>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 40.2 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 6.49 g, 39.5 mmol) and tert-butyl-dimethyl-[(R)-2-oxiranyl-ethoxy]-silane (first eluting compound of step P.i of Preparation P; 8.0 g, 39.5 mmol) in EtOH/H2O 9-1 (240 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/MeOH followed by filtration. The filtrate containing the product was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (5.82 g, 40% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=2)[CH2:3]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([S:20][CH3:21])[N:10]=2)[CH2:3]1
Reactant: CCOC(=O)c1cnc(SC)nc1N[C@@H]1CCC[C@H](O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(N[C@@H]2CCC[C@H](O)C2)n1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a stirring solution of ethyl 4-((1R,3S)-3-hydroxycyclohexyl-amino)-2-(methylthio)pyrimidine-5-carboxylate (5 g, 16.06 mmol) in ethanol (50 ml) was added 2M sodium hydroxide (20 ml, 40.0 mmol). Stirring was continued at room temperature for 1 h. The reaction mixture was neutralized by addition of saturated citric acid. The resulting precipitate was filtered and dried to afford 4-((1R,3S)-3-hydroxycyclohexyl-amino)-2-(methylthio)pyrimidine-5-carboxylic acid (4.5 g, 15.88 mmol, 99% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.21 (br. s., 1H), 8.44-8.54 (m, 2H), 4.74 (d, J=3.90 Hz, 1H), 3.97-4.12 (m, 1H), 3.56 (d, J=3.12 Hz, 1H), 2.46 (s, 3H), 2.05-2.16 (m, 1H), 1.84 (d, J=10.15 Hz, 1H), 1.65-1.80 (m, 2H), 1.11-1.36 (m, 4H). MS (ESI) m/z 284.1 [M+1]+.
Reaction SMILES: NC1C(C(O)=O)=CN(C2N=CC3CC[C:14]4[CH:20]=[C:21]([O:24][CH3:25])C=C[C:13]=4[C:12]=3[N:11]=2)N=1.Br[C:27]1[CH:39]=[CH:38][C:30]2[NH:31]C(C(Cl)(Cl)Cl)=[N:33][C:29]=2[CH:28]=1>CC(N(C)C)=O>[NH2:33][C:29]1[CH:28]=[C:27]([C:20]2[C:21]([O:24][CH3:25])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:39]=[CH:38][C:30]=1[NH2:31]
Reactant: COc1ccc2c(c1)CCc1cnc(-n3cc(C(=O)O)c(N)n3)nc1-2
Reactant: ClC(Cl)(Cl)c1nc2cc(Br)ccc2[nH]1
Solvent: CC(=O)N(C)C
Product: COc1ncccc1-c1ccc(N)c(N)c1

Procedure:
A solution of salicylaldehyde derivative 1 (0.5 mmol) and diamine 2 (0.176 g, 0.5 mmol) in dimethylacetamide (4 mL) was stirred at 100° C. for 12 h. Solvent was evaporated and the residue was purified by preparative HPLC to give benzimidazole derivative 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: C1COCCN1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 105 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
In a 25 mL volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 2.0 g (7.4 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, and 6.45 g (74 mmol) of morpholine. The resulting mixture was stirred at 105° C. for 4 hours. After the reaction was complete, the reaction mixture was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 2.17 g (reaction yield: 92%) of 6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-one.
Reaction SMILES: [F:1][C:2]1([CH:8]([OH:11])C#N)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[BH4-].[Na+].CC(C)=O>C(O)(C)(C)C.O>[F:1][C:2]1([CH2:8][OH:11])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: N#CC(O)C1(F)CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: OCC1(F)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
2-(4-Fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile (2.06 g, 12.9 mmol) was dissolved in tert-butanol (20 mL) and water (5.0 mL). To this, sodium borohydride (537 mg, 14.2 mmol) was added and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, ice and acetone were added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated off under reduced pressure, brine was added to the residue, and extraction with chloroform was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/7) to give 4-fluorotetrahydro-2H-pyran-4-ylmethanol (1.59 g, yield: 92%).
Reaction SMILES: CI.CBr.CCl.[C:7]1([CH3:18])[CH:12]=[CH:11][C:10]([S:13]([O:16]C)(=[O:15])=[O:14])=[CH:9][CH:8]=1.CN(C)C(N(C)C)=O>CN(C=O)C.C1COCC1.CC(C)=O.C(O)(C)C>[C:7]1([CH3:18])[CH:8]=[CH:9][C:10]([S:13]([OH:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: CBr
Agent: CCl
Solvent: CN(C)C=O
Solvent: CN(C)C(=O)N(C)C
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
The methylation of the pyridine nitrogen atom in the compound of the formula XXIII, with formation of the pyridinium salt of the formula XXIV, can be carried out smoothly with numerous methylating agents, for example methyl iodide, methyl bromide, methyl chloride or methyl toluene-4-sulfonate, in a number of solvents, for example alcohols, such as isopropanol, amides, such as DMF, N,N,N′,N′-tetramethylurea, ketones, such as acetone, or ethers, such as THF, preferably at temperatures of from about 40 to about 60° C. In the reaction of the compound of the formula XXIII with methyl chloride in DMF at 45° C., for example, the compound of the formula XXIV where X=Cl is obtained in quantitative yield and a purity of about 98.4%. When the methylation is carried out on an industrial scale, it is preferred to use a less volatile methylating agent. Since an additional anion exchange, for example by ion exchange chromatography, is to be avoided if possible, a further aspect in the selection of the methylating agent is the effect of the anion X, contained in the compounds of the formulae IV, IX and I and originating from the methylating agent, on the properties of these compounds, for example on the solubility of the compound of the formula IV or a salt thereof, which is of importance in the coupling reaction of the compounds of the formulae III and IV, or on the solubilities, the precipitation properties and the physiological compatibility of the compound of the formula I. Overall, the iodides and toluene-4-sulfonates have, based on their properties, been found to be particularly favorable, preferred methylating agents thus being methyl iodide and methyl toluene-4-sulfonate (=methyl tosylate). The toluene-4-sulfonates, in particular, are distinguished, in the case of the compound of the formula IV or the toluene-4-sulfonic acid salt thereof, by the fact that they can be isolated easily, are highly soluble and have a high peptide coupling rate, and in the case of the compound of the formula I, in particular by surprisingly good precipitation properties, purity and yield. A particularly preferred methylating agent for the conversion of the compound of the formula XXIII into the compound of the formula XXIV thus is methyl toluene-4-sulfonate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH2:9]>O=[Mn]=O>[C:1]([NH2:2])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O
Reactant: N#Cc1cccnc1
Agent: O=[Mn]=O
Product: NC(=O)c1cccnc1
Temperature: 105 °C
Yield: 99 %

Procedure:
0.096 mole of 3-cyanopyridine was dissolved in 5.556 mole of water and 0.0115 mole of MnO2, prepared by above method, was added to this. The mixture was refluxed at 105° C. for 8 hrs. The reaction mixture was cooled and filtered. The filtrate was evaporated in dryness to get solid nicotinamide 0.095 mole. Yield of isonicotinamide was 98.9 mole %.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:27][C@H:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:19]([F:18])([F:28])[F:29])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC[C@@H](OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (4.3 g) in methylene chloride (50 ml) was added a solution of (R)-(+)-1,1,1-trifluoro-2-octanol (2.9 g) ([α]D22.5 =+20.1, optical purity 96.3 % ee), dimethylaminopyridine (0.6 g) and triethylamine (1.7 g) in methylene chloride (50 ml) under ice-cooling. The mixture was left to stand at the room temperature for 24 hours before being poured in ice water. The methylene chloride layer separated was washed with diluted hydrochloric acid, water, 1N aqueous sodium carbonate solution and water in this order before being dried over magnesium sulfate. After distillation was over purification by toluene/silica gel chromatography and recrystallization from ethanol gave the titled compound (3.8 g).