Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([N:5]1[CH:10]=[C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH2:8][C:7]([CH:17]=[O:18])=[CH:6]1)=O.C(N(CC)CC)C>CO>[CH3:16][N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]1[CH2:8][C:7]([CH:17]=[O:18])=[CH:6][NH:5][CH:10]=1
Reactant: COC(=O)N1C=C(C=O)CC([C@@H]2CCCN2C)=C1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCC[C@H]1C1=CNC=C(C=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104 %

Procedure:
To a solution of (S)-3-formyl-5-(1-methyl-pyrrolidin-2-yl)-4H-pyridine-1-carboxylic acid methyl ester III (0.0124 g, 0.05 mmol) in 2 mL of anhydrous MeOH was slowly added triethylamine (0.02 mL, 0.15 mmol), and the reaction mixture was stirred at RT for 1 day. Evaporation of the solvent afforded a quantitative yield (0.010 g) of (S)-5-(1-methyl-pyrrolidin-2-yl)-1,4-dihydro-pyridine-3-carbaldehyde IV as a yellow oil. The product was used without further purification. IR (thin film, neat, NaCl): 3416–3244, 2957, 1595, 1509, 1377, 1228 cm−1. 1H NMR (CDCl3, 300 MHz) δ 9.14 (s, 1 H), 6.85 (d, 1 H, J=6 Hz), 6.48 (s, 1 H), 6.00–5.99 (m, 1 H), 3.05–3.00 (m, 3 H), 2.45 (m, 1 H), 2.19–2.11 (m, 4 H), 1.83–1.67 (m, 4 H); 13C NMR (CDCl3, 75 MHz) δ 189.59, 146.95, 119.91, 119.01, 112.67, 70.03, 57.03, 40.69, 28.96, 22.80, 20.37. HRMS Calcd for C11H16N2O: 193.1341 [M+H]+. Found: 193.1334 [M+H]+. [α]28D−80.7 (c=0.55, CH2Cl2).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][C@H:22]1[CH2:26][CH2:25][N:24]([C:27]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH2:23]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A mixture of di-tert-butyl [{(3S)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]pyrrolidin-1-yl}methylylidene]biscarbamate 279 (0.34 g, 0.56 mmol) and Pd/C (0.15 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 280 (0.28 g, 97%) as white solid.
Reaction SMILES: [Br:1][C:2]1(F)[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.Cl.[F:10][CH:11]([F:15])[CH2:12][NH:13][CH3:14].CCN(C(C)C)C(C)C>>[Br:1][C:2]1[N:3]=[C:4]([N:13]([CH2:12][CH:11]([F:15])[F:10])[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: FC1(Br)C=CC=CN1
Reactant: CNCC(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(F)F)c1cccc(Br)n1

Procedure:
88.0 mg (0.50 mmol) 2-bromo-2-fluoropyridine, 78.9 mg (0.60 mmol) (2,2-difluoro-ethyl)-methyl-amine hydrochloride and 0.17 mL (1.00 mmol) DIPEA are stirred at 90° C. over night. The reaction is quenched by the addition of water and extracted with DCM. The combined org. layers are dried over MgSO4, filtered and the solvent is removend in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOCCOCCBr
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCOCCOc1ccc(C(=O)OC)cc1F
Yield: 89.1 %

Procedure:
Into a 500-ml, round-bottom flask equipped with a magnetic stirrer, heating mantle and condenser were placed 5.7 g (33.5 mmol) methyl 3-fluoro-4-hydroxybenzoate, 8.5 g (43.2 mmol) 1-bromo-2-(2-ethoxyethoxy)-ethane, 23.2 g of powdered anhydrous potassium carbonate and 350 ml acetonitrile. After stirring the reaction mixture under reflux for four hours, TLC analysis showed that none of the phenolic starting material remained. Three hundred ml of the acetonitrile was then distilled off and 300 ml dichloromethane was added. The reaction mixture was filtered through Celite and the solids were washed thoroughly with dichloromethane. Evaporation of the filtrate yielded product in the form of a yellow oil. Purification by flash chromatography on silica gel with 4% diethyl ether in dichloromethane, followed by low temperature recrystallization from pentane, yielded 8.55 g of white crystals, 89%, m.p. 33-36.5° C. The structure was confirmed by infrared, nuclear magnetic resonance and mass spectral analyses. ##STR22##
Reaction SMILES: [C:1]1([C:7]#[C:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:10]([Si](C)(C)C)=[N+:11]=[N-:12].Cl>C(OCC)C>[CH3:9][C:8]1[N:10]=[N:11][NH:12][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#Cc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Product: Cc1nn[nH]c1-c1ccccc1
Temperature: 155 °C

Procedure:
##STR7## 1-Phenyl-1-propyne (2.52 g) and azidotrimethylsilane (2.48 g, Me3SiN3) were sealed into a heavy-walled glass reactor at -70° C. and 0.5 mm Hg. The mixture was heated 11 days at 155° C., cooled, dissolved in diethyl ether (Et2O), and stirred briefly with 5 percent HCl. After washing with a small amount of NaHCO3 solution, the Et2O solution was evaported to give 3.06 g (89%) cream white solid, mp 173.5-174.0 whose NMR spectrum and elemental analysis confirm its structure.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:13][C:7]2[N:8]=[CH:9][NH:10][C:11](=[O:12])[C:6]=2[CH:5]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CN(C=O)C>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:8]1[C:7]2[S:13][C:4]([CH3:3])=[CH:5][C:6]=2[C:11](=[O:12])[NH:10][CH2:9]1
Reactant: BrCCCCBr
Reactant: Cc1cc2c(=O)[nH]cnc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(s1)N(CCCCBr)CNC2=O
Reaction time: 96 h

Procedure:
To a stirring mixture of NaH (1.7 g, 0.072 mol) in 150 ml anhydrous DMF at room temperature was added 4.0 g (0.024 mol) of 6-methyl thieno[2,3-d]pyrimidin-4(3H)-one (IV-3) and, after the cessation of gas evolution, 20.7 g (0.96 mol) of 1,4-dibromobutane was added. Reaction was complete after 4 days. The solution was concentrated in vacuo, the residue partitioned between CH2Cl2 and water, and the organic phase isolated, dried (MgSO4), and filtered. The filtrate was concentrated and excess dibromobutane removed by Kugelrohr distillation. The solid product residue weighed 4.12 g (57%). The NMR was consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[N:7]=[C:6]2[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[CH3:41])[CH2:30][CH2:29]1)=O.O1CCCC1.B.O>O1CCCC1>[Cl:40][C:36]1[C:35]([CH3:41])=[C:34]([N:31]2[CH2:32][CH2:33][N:28]([CH2:26][CH2:25][C:6]3[C:5]4[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=4)[N:7]=3)[CH2:29][CH2:30]2)[CH:39]=[CH:38][CH:37]=1
Reactant: COc1ccc(Cn2nc(CC(=O)N3CCN(c4cccc(Cl)c4C)CC3)c3cc(OC)c(OC)cc32)cc1OC
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(CCN3CCN(c4cccc(Cl)c4C)CC3)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
1-((5,6-Dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazol-3-yl)acetyl)-4-(3-chloro-2-methylphenyl)piperazine (60.5 g) was suspended in tetrahydrofuran (1000 ml). Then 1.0 mol-borane tetrahydrofuran complex tetrahydrofuran solution (500 ml) was added thereto and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and water (30 ml) was added to thereby decompose the excessive reagent. After evaporation of the tetrahydrofuran under reduced pressure, conc. hydrochloric acid (300 ml) was added and the mixture was stirred at 50° C. for 1 hour. The aqueous layer was returned to room temperature and made alkaline with potassium carbonate. Then it was extracted with chloroform (3000 ml) and the organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue thus obtained was purified by using a silica gel column (chloroform/ethanol=40/1). Thus a colorless solid (50.0 g) was obtained. This product was recrystallized from ethanol to give 46.3 g of colorless prism crystals (m.p.: 148°-150° C.)
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14]O)=[C:9]([CH3:16])[CH:8]=[CH:7][CH:6]=1>O1CCCC1.ClCCl>[Cl:4][C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][NH:3][CH2:1][CH3:2])=[C:9]([CH3:16])[CH:8]=[CH:7][CH:6]=1
Reactant: CCN
Reactant: Cc1cccc(Cl)c1NCCCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNCCCNc1c(C)cccc1Cl
Yield: 54.3 %

Procedure:
A mixture of a 2.0 M solution of ethylamine in tetrahydrofuran (139.5 mL) and the hydrobromide salt of Example 12, Step A (9.5 g) was stirred at ambient temperature under nitrogen for 48 hours. The tetrahydrofuran was removed in vacuo and the residue was partitioned between dichloromethane and 1N sodium hydroxide. The extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 95:5 to 80:20 dichloromethane-methanol containing 0.2% ammonium hydroxide) gave the title compound (3.4 g, 54.3%) as a yellow oil, which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>ClCCl>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:17]=1[C:18]([NH:20][C:21]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1)=[O:22])=[O:19]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cn1
Solvent: ClCCl
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(-c2ccc(Cl)cc2)cn1
Reaction time: 3 h
Yield: 62.4 %

Procedure:
5-(4-Chlorophenyl)-2-pyridylamine (0.6 gram), 2,6-dichlorobenzoyl isocyanate (0.8 gram), in a small amount of dichloromethane were reacted at room temperature. A slight exothermic reaction was followed by an almost immediate precipitate. After 3 hours at room temperature, the reaction mixture was cooled in an ice bath and then filtered to give 770 mg of colorless crystals. The identity of the product was confirmed by NMR analysis, m.p. 230°-233° C.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH3:22][NH:23][C:24]([NH2:26])=[S:25]>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:26]=[C:24]([NH:23][CH3:22])[S:25][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CNC(N)=S
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Product: CNc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.355 g, 0.959 mmol) in ethanol (10 mL) in a 25 mL round bottom flask was added N-methylthiourea (0.086 g, 0.959 mmol). The solution was heated to reflux for 14 hours and cooled to room temperature. The resulting suspension was concentrated in vacuo, suspended in ethyl acetate (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), dried over sodium sulfate and filtered. Isooctane was added to the filtrate until the solution became cloudy yielding a pale yellow fluffy solid which was collected by vacuum filtration. This solid was dissolved in methylene chloride and washed with sodium carbonate solution (10% solution), dried over sodium sulfate, and concentrated yielding a solid. This solid was recrystallized from methylene chloride-isooctane yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-methylaminothiazole (0.135 g, 39%) as a pale yellow powder: mp 243°-244° C.; 1HNMR 400 mHz 7.90 (q, J=4.76 Hz, 1 H), 7.81 (d, J=8.50 Hz, 2 H), 7.49-7.43 (m, 2 H), 7.41 (t, J=8.70 Hz, 2 H), 7.19 (t, J=8.95 Hz, 2 H), 3.22 (s, 3 H), 2.90 (d, J=4.80 Hz, 3 H); MS (FAB) m/z 363 (M+H). HRMS Δ=-0.2 mmu.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH3:17][OH:18]>>[OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[NH:5])[O:18][CH3:17]
Reactant: CO
Reactant: N#Cc1cccc(Cc2c[nH]cn2)c1O
Agent: Cl
Product: COC(=N)c1cccc(Cc2c[nH]cn2)c1O
Reaction time: 20 h

Procedure:
A suspension of 14.1 g (0.071 mole) of 2-hydroxy-3-(1H-imidazol-4-ylmethyl)-benzonitrile (prepared in example 1.1 above) in 420 ml of methanol is cooled to -40° C. and saturated with gaseous hydrochloric acid. The suspension is allowed to return to 10° C. and is saturated once again with gaseous hydrochloric acid. The reaction mixture is kept at that temperature for 20 hours. The solution is concentrated to 200 ml, 300 ml of ice-cold water and 300 ml of ethyl acetate are added to the concentrated solution and the solution is then neutralized using an aqueous sodium bicarbonate solution. The solution is filtered, and the aqueous phase is separated from the organic phase, then the aqueous phase is extracted twice with 300 ml of ethyl acetate and the organic phases are combined. The organic phase is washed with a saturated aqueous sodium chloride solution, is then dried over magnesium sulfate, filtered and evaporated under reduced pressure. 15.4 g of methyl 2-hydroxy-3-(1H-imidazol- 4-ylmethyl)-benzenecarboximidate are obtained as a beige solid product which is taken up in 210 ml of absolute ethanol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([O:13]C(C)C)=[O:12])=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl>[OH-].[Na+]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:18]=[CH:17][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)OC(=O)c1ccc(N2CCOCC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(N2CCOCC2)nc1
Temperature: 55 °C

Procedure:
A solution of isopropyl 6-chloronicotinate (6.0 g, 0.03 mol) and morpholine (13 mL, 0.15 mol) in isopropyl alcohol (60 mL) was heated at reflux for 72 hours. The solution was allowed to cool to ambient temperature overnight. The resulting precipitate was isolated by filtration, washed with isopropyl alcohol and dried to provide isopropyl 6-morpholinonicotinate. The filtrate was diluted with water. The resulting precipitate was isolated by filtration, washed with water and dried to provide isopropyl 6-morpholinonicotinate. The combined yield was 8.3 g. The isopropyl 6-morpholinonicotinate was combined with 1 N sodium hydroxide (40 mL) and the resulting suspension was stirred at 50-60° C. until all of the solid had dissolved. The solution was stirred at ambient temperature overnight during which time a precipitate formed. This material was isolated by filtration and identified as starting material. The filtrate was neutralized with concentrated hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water and dried to provide 3.3 g of crude product. This material was recrystallized from methanol/dichloromethane to provide 6-morpholinonicotinic acid as a solid, m.p. 259-261° C. Analysis: Calculated for C10H12N2O3: %C, 57.19; %H, 5.81; %N, 13.48; Found: %C, 57.50; %H, 5.71; %N, 13.53.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[CH3:14][C:15]([CH3:17])=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH:15]([CH3:17])[CH3:14])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-amino-1-N-Boc pyrrolidine (1.0 eq, 2.68 mmol) in methanol (15 mL) was added acetone (1.07 eq), sodium cyano borohydride (2.0 eq) and few drops of acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (30%). 1H-NMR (CDCl3) δ: 1.05 (6H, d), 1.45 (9H, s), 1.60 (1H, m), 2.80–3.00 (2H, m), 3.20–3.70 (4H, m). ESI-MS m/z: 229 (M+1), UV retention time: 0.77 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Si:21]([O:28][CH2:29][CH2:30][CH2:31][NH2:32])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[Si:21]([O:28][CH2:29][CH2:30][CH2:31][NH:32][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:16])([C:24]([CH3:26])([CH3:27])[CH3:25])([CH3:23])[CH3:22]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(C)(C)[Si](C)(C)OCCCN
Product: CC(C)(C)[Si](C)(C)OCCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (1.5 g, 4.3 mmol) and 3-(tert-butyl(dimethyl)silyl)oxypropan-1-amine (0.98 g, 5.12 mmol). The title compound was obtained as a yellow solid (1.1 g, 49% yield).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:46][CH2:47][CH3:48])[C:42]([CH3:45])=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:46][CH2:47][CH3:48])[C:42]([CH3:45])=[CH:43][N:44]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ncc(C)n4CCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ncc(C)n4CCC)cc2)CCN3CC(C)C)cc1
Yield: 73.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[5-methyl-1-propylimidazol-2-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (450 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (244 mg) in dichloromethane (15 ml) at −78° C. The reaction vessel was removed from a dry ice-acetone bath, and an aqueous solution of sodium thiosulfate was added to the reaction vessel with strongly stirring. The mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[5-methyl-1-propylimidazol-2-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (340 mg) (Compound 365) as yellow amorphous.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[O:12][CH3:13]>CO.O>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=1[CH2:3][CH:2]=[O:1])[C:8]#[N:9]
Reactant: COc1cc(C#N)ccc1CC(O)CO
Solvent: CO
Solvent: O
Product: COc1cc(C#N)ccc1CC=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,3-dihydroxypropyl)-3-methoxybenzonitrile (500 mg, 2.6 mmol) in 10 mL of methanol and 3 mL of water was cooled to 0° C. by ice bath, then NaIO4 (830 mg, 3.9 mmol) was added and the mixture was stirred at 0° C. for two hours. The reaction was monitored according to TLC. The mixture was filtered and concentrated. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and then purified by flash column chromatography to give 3-methoxy-4-(2-oxoethyl)benzonitrile. MS m/z 176 (M+1)+.
Reaction SMILES: S(=O)(=O)(O)O.[BrH:6].[CH3:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:11]=[C:10]([CH3:22])[C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=1>O>[Br:6][CH2:29][C:25]1[CH:24]=[C:23]([C:9]2[C:8]([CH3:7])=[CH:13][C:12]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:11][C:10]=2[CH3:22])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CO)c1
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(CBr)c1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
Concentrated sulfuric acid (1.4 g) was added dropwise to 48% hydrobromic acid (15 ml) at room temperature and [2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]-[1,1′-biphenyl]-3-yl]methanol (25 g) synthesized in accordance with the method described in [WO 2008/001931 pamphlet] was divided into five portions and added to the mixture. The reaction mixture was stirred at 60° C. for 2.5 hours and 48% hydrobromic acid (3.3 ml) was added to the mixture. The mixture was further stirred for 1 hour at the same temperature. After the reaction mixture was allowed to cool, water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The obtained organic phase was washed with water, then washed with brine, and dried over anhydrous sodium sulfate. From the organic phase, the solvent was removed by evaporation under reduced pressure to give the title compound (27 g) as a pale yellow solid.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH2:31][CH2:32][CH3:33]>CN(C=O)C>[CH2:30]([N:6]1[C:5]([C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:17]#[N:18])=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]1=[O:11])[CH2:31][CH2:32][CH3:33]
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 55 °C
Reaction time: 24 h
Yield: 50.4 %

Procedure:
To a stirred mixture of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (Compound 1) (2.97 g, 10 mmol) and powdered anhydrous potassium carbonate (1.66 g, 12 mmol) in DMF (20 mL), was added iodobutane (1.37 mL, 12 mmol). The mixture was then stirred in an oil bath (50-60° C.) for 24 hr. and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 1.78 g (50%) of 3-(3-butyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (47) as a white foam. 1H-NMR (200 MHz, CDCl3) δ 0.80 (3H, d, J=3.2 Hz), 0.83 (3H, d, J=3.2 Hz), 1.12 (3H, d, J=7.0 Hz), 1.23 (3H, d), J=7.0 Hz), 1.90 (1H, m), 2.25 (1H, m), 2.53 (3H, s), 2.93 (1H, dd, J=14.2 Hz, J=7.4 Hz), 3.75 (1H, dd, J=14.2 Hz, J=7.4 Hz), 7.80 (1H, s), 7.92 (1H, s), 8.03 (1H, s), 9.03 (1H, s); m/z (EI) 353 (M+).