Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=[C:17]([C:26]([O:28]C)=[O:27])[CH:16]=2)=[CH:10][N:9]=1)=[O:7])(C)(C)C.[OH-].[Na+]>CO.C1COCC1>[C:26]([C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)([OH:28])=[O:27]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)nc2)c2c(c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2c(Oc3ccc(C(=O)O)nc3)cc(C(=O)O)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 124.8 %

Procedure:
To a solution of 5-(6-methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester (163a) (110 mg, 0.275 mmol) in 2 mL MeOH and 1 mL THF was added 1N aqueous NaOH (0.55 mL, 0.55 mmol). The mixture was stirred at room temperature overnight, heated at 60° C. for 6 hr, then concentrated, acidified to pH ˜3 with 1N aqueous HCl, extracted with 3×EtOAc, dried over Na2SO4, and concentrated to give 113 mg white solid. LCMS for C17H15NO6 m/z 330.00 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.[BH4-].[Na+].[OH-].[Na+]>CO>[Cl:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:17][CH:14]1[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1cccc(CNC2CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
The mixture of 2-chloro-3-trifluoromethylbenzaldehyde (37.4 g, 179.5 mmol) and cyclopropylamine (25.2 mL, 359.1 mmol) in MeOH (500 mL) was stirred at rt overnight. Subsequently, NaBH4 (9.2 g, 233.4 mmol) was added at 0° C. and the mixture was allowed to warm to rt overnight. 1M NaOH was added (100 mL) and the solvent was evaporated under reduced pressure. Brine (100 mL) was added and extracted with EtOAc (3×100 mL). 2N HCl (100 mL) was added and extracted with Et2O (3×100 mL). The org. phase was washed with 2N HCl (100 mL). To the combined water phase 2N NaOH was added (to pH=14) and the mixture was extracted with EtOAc (3×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The corresponding product was isolated as a colourless liquid (33.7 g, 75%). LC-MS: tR=0.66 min; ES+: 250.17.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@:29]([OH:44])([C@H:36]([S:38][CH:39]([CH2:42]O)[CH2:40][OH:41])[CH3:37])[CH2:30][N:31]1[CH:35]=[N:34][CH:33]=[N:32]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:4]1[CH:20]=[CH:19][C:7]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[O:41][CH2:40][C@H:39]([S:38][C@H:36]([CH3:37])[C@:29]([C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[F:21])([OH:44])[CH2:30][N:31]4[CH:35]=[N:34][CH:33]=[N:32]4)[CH2:42][O:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(=O)c1ccc(NC(=O)c2ccc(C=O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(=O)c1ccc(NC(=O)c2ccc([C@H]3OC[C@H](S[C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)CO3)cc2)cc1

Procedure:
In the same manner as that described in Example 3(3), a reaction was carried out using 4′-acetyl-4-formylbenzanilide (200 mg, 0.75 mmol), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (256 mg, 0.71 mmol) and p-toluenesulfonic acid monohydrate (243 mg, 1.3 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 3(3) to give the trans isomer of the title compound (280 mg, yield 65%) as a white solid which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([C:30]([O:32]C)=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:18]([CH2:34][CH2:35][CH3:36])[CH:17]=2)[C:13](=[O:37])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:38])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([C:30]([OH:32])=[O:31])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:18]([CH2:34][CH2:35][CH3:36])[CH:17]=2)[C:13](=[O:37])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:38])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)c(CCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(OC(C(=O)O)c2ccccc2)c(CCC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 10 %

Procedure:
To a solution the product of Example 3, Step A (11 mg; 0.22 mmol) in MeOH (2 mL) was added NaOH (1.5 eq, 2.0N) and a few drops of water. After stirring for 20 hours at room temperature, the reaction mixture was concentrated in vacuo, dissolved in water/THF, treated with HCl (5 eq) for 30 minutes at room temperature, concentrated in vacuo, and chromatographed on a Sephadex LH-20 column eluting with MeOH to afford 11 mg (99%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23][SH:24])[CH3:20]>O>[CH2:19]([O:21][C:22]([C:23]1[S:24][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH:4]=1)=[O:25])[CH3:20]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-chloro-5-nitro-benzaldehyde (31.01 g, 167.1 mmol) in 330 mL of anhydrous DMP at 0° C. was added K2CO3 (27.80 g, 201.1 mmol), followed by slow addition of mercapto-acetic acid ethyl ester (18.5 mL, 168.7 mmol). After stirring at 0° C. for 20 min, the resulting mixture was allowed to warm to rt and stir at rt overnight. The reaction mixture was then poured into 1.5 L of water. The solid formed was filtered and washed with 600 mL of water. After drying, 5-nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester was obtained as pale solid. MS (EI): cal'd 252.0 (MH+), exp 252.1 (I).
Reaction SMILES: [C:1](C1N(CC[C@H](NS(C2C=CC=CC=2)(=O)=O)C)CCS1)([OH:3])=[O:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]([C:47]2[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=2[Cl:54])[C@H:34]([CH3:46])[CH2:35][CH2:36][N:37]2[CH2:41][CH:40](CC(O)=O)[S:39][CH2:38]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1.[OH-].[K+].[K+].[Br-]>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]([C:47]2[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=2[Cl:54])[C@H:34]([CH3:46])[CH2:35][CH2:36][N:37]2[CH2:41][CH:40]([C:1]([OH:3])=[O:2])[S:39][CH2:38]2)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: C[C@H](CCN1CCSC1C(=O)O)NS(=O)(=O)c1ccccc1
Reactant: C[C@H](CCN1CSC(CC(=O)O)C1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Product: C[C@H](CCN1CSC(C(=O)O)C1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
4-chloro-N-(2,5-dichlorophenyl)-N-(3-(5-carboxy-3-thiazolidinyl)-1(R)-methylpropyl)benzenesulfonamide was prepared analogous to 4-chloro-N-2,5-dichlorophenyl)-N-(3-(2-carboxy-3-thiazolidinyl)-1(R)-methylpropyl)benzenesulfonamide by reacting 4-chloro-N-(2,5-dichlorophenyl)-N-(3-(5-carboxymethyl-3-thiazolidinyl)-1(R)-methylpropyl)benzenesulfonamide with 50% aqueous KOH. Yield=70%; White foam: IR (KBr) 1467, 1350, 1167, 1094, 753, 622 cm−1; MS (ESI+), 525 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][C:5]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[O:21])[CH2:15][CH2:14]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=O)[NH2:2].C(N(CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[C:1]([CH2:4][C:5]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[O:21])[CH2:15][CH2:14]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)#[N:2]
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(N)=O)CCCCC3)CC2)nc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC#N)CCCCC3)CC2)nc1
Reaction time: 24 h
Yield: 89.9 %

Procedure:
To a solution of N-[1-[2-[1-(carbamoylmethyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide (154 mg) dissolved in dichloromethane (3 mL) was added triethylamine (0.10 mL). Methanesulfonyl chloride (0.038 mL) was added to the solution under ice cooling. After allowing the temperature to rise to room temperature, the solution was stirred for 24 hours. Triethylamine (0.14 mL) and methanesulfonyl chloride (0.063 mL) were further added to the solution under ice cooling. The solution was stirred at room temperature for 24 hours. Water was added to he solution and it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography (silica gel, chloroform:methanol=20:1) to give the title compound (133 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Nc1ccccn1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1Nc1ccccn1
Reaction time: 1.67 h
Yield: 84.6 %

Procedure:
A mixture of 2-nitro-N-(2-pyridyl)-4-trifluoromethylaniline (1.00 g, 3.5 mmol), 5% palladium on carbon (0.23 g) and methanol (50 ml) was stirred under a hydrogen atmosphere for 100 min. The mixture was filtered through a pad of celite and the filtrate was concentrated to dryness to give 0.75 g (85%) of the titled compound as yellow brown solids.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[CH:12][C:13]([OH:18])=[C:14]([CH:17]=1)[CH:15]=[O:16]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:12]1[C:13]([OH:18])=[C:14]([CH:17]=[C:10]([F:9])[CH:11]=1)[CH:15]=[O:16]
Reactant: O=Cc1cc(F)ccc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(F)cc(Br)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.2 %

Procedure:
N-bromosuccinimide (1.51 g, 8.52 mmol) was added to a magnetically stirred solution of 5-fluoro-2-hydroxybenzaldehyde (1 g, 7.1 mmol) in DMF (10 mL) and the mixture was stirred at room temperature for 5 hour. The mixture was diluted with ethyl acetate and the organic layer was washed with 5% citric acid, brine, dried over anhydrous sodium sulfate and concentrated by evaporation. Product was purified from the residue by chromatography over silica gel employing 50% ethyl acetate/hexanes to give 3-bromo-5-fluoro-2-hydroxybenzaldehyde (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[NH2:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>CC(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[NH:9][C:25](=[O:26])[CH2:24][Cl:23])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CCl)NC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 21.9 parts of 4-fluoro-α-(4-fluorophenyl)benzenemethanamine in 160 parts of 2-propanone were added 11.66 parts of sodium carbonate. Then there were added dropwise 12.43 parts of 2-chloroacetyl chloride at a temperature below 30° C. (cooling in an ice-bath was necessary). Upon completion, stirring was continued first for one hour at room temperature and further for 2 hours at reflux. After cooling to room temperature, the sodium carbonate was filtered off and washed with 2-propanone. The filtrate was evaporated and the residue was crystallized from 2,2'-oxybispropane, yielding 20.6 parts of N-[bis(4-fluorophenyl)-methyl]-2-chloroacetamide; mp. 127.6° C. (intermediate 4).
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)(C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:20][C:15]1[CH:14]=[C:13](/[CH:12]=[CH:11]/[CH2:10][CH2:9][OH:8])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(C)(C)[Si](C)(C)OCC/C=C/c1ccc(Cl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To solution of Intermediate 2A (2.2 g, 5.2 mmol) in THF (50 mL) cooled to 0° C. was added TBAF (6.3 mL, 6.3 mmol) via dropwise addition. The reaction mixture was stirred at 0° C. for 1 h, then diluted with ethyl acetate (200 mL). The organic layer was washed with water (2×100 mL), dried over Na2SO4 and dried in vacuo. The product was purified by silica gel chromatography (80 g silica gel; linear gradient 0-25% ethyl acetate for 30 min) to obtain 917 mg (97% yield) of Intermediate 2B. HPLC/MS (Method D) RT=1.00 min, [M−H2O+1]+ 199.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:23])[NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)=[CH:8][C:9]=1[CH3:10])=[O:4].O[Li].O>C1COCC1.O>[NH:18]1[C:19]2[C:15](=[C:14]([CH2:13][NH:12][C:11]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([CH3:10])[CH:8]=3)=[O:23])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCc2cccc3[nH]ccc23)sc1C(=O)O
Yield: 114.5 %

Procedure:
A solution of 5-[(1H-indol-4-ylmethyl)-carbamoyl]-3-methyl-thiophene-2-carboxylic acid methyl ester (115 mg, 0.35 mmol) in THF/water (6 ml/3 ml) was treated with LiOH.H2O (157 mg, 3.5 mmol) at rt for 24 h. The reaction mixture was quenched with 1N HCl and extracted with EtOAc. The layers were separated. The organic layer was successively washed with water and brine, then dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (126 mg, 100% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:14][CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Bromo-1-(bromomethyl)-2-nitrobenzene (Heterocycles 1994, 39, 767) (8.3 g, 28 mmol) was dissolved in methanol (75 ml) at 0° C. 30% Sodium methoxide in methanol solution (10.7 ml, 56 mmol) was added dropwise and the solution stirred at room temperature for 4 hours. The mixture was concentrated to a small volume and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and then washed with saturated aqueous sodium bicarbonate solution, water (×3), brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (hexane to ethyl acetate) to afford the title compound (D16). MS (ES+) m/e 246/248 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:35])[C:23]=1[O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH2:5][CH:6]([CH2:19][OH:20])[CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:35])[C:23]=1[O:24][Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:32]([CH3:33])[CH3:34])[CH2:5][CH:6]([CH:19]=[O:20])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(CCC(CO)Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC(C=O)Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2.9 g (5.72 μmmol) of methyl 4-[3-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)-4-hydroxybutyl]benzoate in 50 ml of dichloromethane is mixed with 1.48 g (6.87 mmol) of pyridinium chlorochromate (PCC) and stirred at room temperature for 12 h. After conversion is complete, about 10 g of silica gel are added, and the solvent is removed to dryness in vacuo. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1). 1.96 g (68% of theory) of a colorless solid are obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][P:27](=[O:30])([CH3:29])[CH3:28]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:26][P:27](=[O:30])([CH3:29])[CH3:28])[C:13](=[O:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CP(C)(=O)CCl
Reactant: O=c1[nH]c(=O)n(-c2ccccc2)c2ncn(Cc3ccccc3)c12
Product: CP(C)(=O)Cn1c(=O)c2c(ncn2Cc2ccccc2)n(-c2ccccc2)c1=O

Procedure:
The title substance was prepared from 6.5 g (0.02 mol) of 7-benzyl-3-phenylxanthine and 3.1 g (0.0245 mol) of chloromethyldimethylphosphine oxide analogously to Example 67.
Reaction SMILES: Br.[C:2]1([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11](=[S:19])[C@H:10]([NH:20][C:21](=O)[O:22]CC3C=CC=CC=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(Cl)=O.[CH:44]1([CH2:50][CH2:51]C(O)=O)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>CN(C=O)C.C1COCC1.ClCCl.C(O)(=O)C>[CH:44]1([CH2:50][CH2:51][C:21]([NH:20][CH:10]2[N:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[S:19])=[O:22])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: O=C(O)CCC1CCCCC1
Reactant: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2NC1=S)OCc1ccccc1
Agent: Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(CCC1CCCCC1)NC1N=C(c2ccccc2)c2ccccc2NC1=S
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen bromide was bubbled at room temperature through a solution of (+)-phenylmethyl N-[(3R)-2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl]carbamate (0.9 g, 2.1 mmol), acetic acid (5 mL) and dichloromethane (5 mL). After 2 h., the solvent was evaporated under reduced pressure, ether was added and the solid was collected and dried in vacuo. A sample (0.58 g, 1.8 mmol) was suspended in THF (10 mL), triethylamine (0.24 mL, 0.18 g, 1.8 mmol) was added and the mixture was stirred at room temperature for 3 h. In a separate flask, oxalyl chloride (0.20 mL, 0.29 g, 2.3 mmol) was added to a solution of cyclohexanepropionic acid (0.33 mL, 0.30 g, 1.9 mmol) and DMF (1 drop) in THF (10 mL) and the mixture was stirred at room temperature for 3 h. The two mixtures were combined, triethylamine (0.32 mL, 0.23 g, 2.3 mmol) was added and the mixture was stirred at room temperature for 2.5 h. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with water, saturated aqueous sodium hydrogen carbonate, water (2×) and brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (99.5:0.5) and the residue was recrystallized from EtOAc/Hexane to give 3-cyclohexyl-N-(2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)propanamide as a solid. m.p. 113°-119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(#N)C>[CH:24]1([CH2:23][N:13]2[CH:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[CH:11][C:12]2=[O:15])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCC1CCCCC1
Reactant: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc(=O)n(CC3CCCCC3)c2)cc1
Yield: 31.4 %

Procedure:
According to Scheme 5 Step 2: To a solution of 5-(4-methoxyphenyl)pyridin-2(1H)-one (1 eq, 0.35 mmol, 70 mg, Example 7 Step 1) in acetonitrile (2 mL) were added K2CO3 (10 eq, 3.50 mmol, 0.48 g) and (bromomethyl)cyclohexane (10 eq, 3.50 mmol, 0.49 mL). The reaction was microwaved for 10 minutes at 180° C. The reaction was allowed to cool. The reaction was then filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 15 g SiO2) using CH2Cl2/AcOEt (80/20, Rf=0.3). The product was further purified by reverse phase C18 column using water/acetonitrile 60/40 to afford 1-(cyclohexylmethyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (0.11 mmol, 32 mg, 31%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:27])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](Cl)[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]>NCCCO>[F:1][C:2]([F:27])([O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:13][CH2:9][CH2:8][CH2:7][OH:6])[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Agent: NCCCO
Product: OCCCNc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1

Procedure:
2 g (5.0 mmol)of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine are stirred for 44 h at 100° in 30 ml of 3-amino-1-propanol. After concentration by evaporation and chromatography (methylene chloride:methanol:conc. ammonia solution=95:5:1), N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-[2-(3-hydroxy-propyl-amino)-4-pyridyl]-2-pyrimidineamine is obtained; m.p. 141°-145°, MS(FAB): 438 (M+ +H), Rf =0.28 (methylene chloride:methanol:conc. ammonia solution=95:5:1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:6]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc(CO)c(Cl)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl 2-chloro-4-hydroxybenzoate (4.43 g) and 2,6-lutidine (6.64 mL) in DCM (50 mL) cooled with an ice bath was added triisopropylsilyl trifluoromethanesulfonate (7.66 mL). After being stirred at 0° C. for 1 h, saturated aqueous NaHCO3 was added thereto. The mixture was diluted with Et2O and layers were separated. The aqueous layer was extracted with Et2O. The combined organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane). The product was dissolved in diethyl ether (175 mL). To the solution cooled with an ice bath was added lithium aluminum hydride (1.08 g). After being stirred at 0° C. for 30 min, sodium sulfate decahydrate was added thereto. The mixture was filtered through a pad of celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (6.87 g).