Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: CCCCBr
Reactant: OCc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cc(Cl)ccc1CO
Temperature: 100 °C
Yield: 45.9 %

Procedure:
Charged 5-chloro-2-(hydroxymethyl)phenol (965 mg, 6.09 mmol, PREPARATION 7), bromobutane (918 mmol, 6.70 mmol), K2CO3 (1.68 g, 12.19 mmol) and DMF (6 mL) to a sealed tube, and the mixture was heated to 100° C. overnight. After cooling to room temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate twice, and the organic extract was washed with water, brine and dried with anhydrous Na2SO4. Solvent removed and the residue was purified by flash column chromatograph to give 600 mg of the title compound (46%). 1H NMR (300 MHz, CDCl3): δ 0.98 (3H, t, J=7.2 Hz), 1.46-1.56 (2H, m), 1.75-1.84 (2H, m), 2.23 (1H, t, J=6.0 Hz), 4.00 (2H, t, J=6.3 Hz), 4.64 (2H, d, J=6.3 Hz), 6.85 (1H, d, J=1.8 Hz), 6.91 (1H, dd, J=1.8 Hz, 8.1 Hz), 7.19 (1H, d, J=7.8 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][CH:18]=[N:19][C:12]=3[N:11]=[C:10]2[C@H:20]([NH:22]C(=O)OC(C)(C)C)[CH3:21])=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C@@H:20]([C:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[N:19][C:12]=2[N:11]=1)[CH3:21]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1-c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)c1nc2ncccc2c(=O)n1-c1ccc(C#N)cc1
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
Compound 1 (1.05 g, 2.68 mmol) was dissolved in CH2Cl2 (40 mL) and treated with TFA (40 mL). The resulting mixture was stirred for 1.5 h then concentrated in vacuo. The concentrate was re-dissolved in CH2Cl2 (100 mL) and washed with saturated NaHCO3 (100 mL). The aqueous wash was extracted with additional CH2Cl2 (3×50 mL). The combined extracts were dried over Na2SO4, concentrated and dried under high vacuum for 17 h to give B1 (767 mg, 98%), which was suitable for use without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH:13][CH2:14][CH2:15][OH:16])[CH3:12]>CS(C)=O>[CH2:11]([N:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:14][CH2:15][OH:16])[CH3:12]
Reactant: CCNCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Product: CCN(CCO)c1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Yield: 84.7 %

Procedure:
In 30 ml of DMSO, 5.0 g (35.4 mmol) of 4-fluoronitrobenzene and 6 g (67.3 mmol) of 2-(ethylamino)ethanol were dissolved. The resultant solution was stirred under heat at 140° C. for 4 hours, followed by extraction with ethyl acetate. The solvent was distilled out under reduced pressure, followed by washing with ethyl acetate, whereby 6.3 g of yellow powder were obtained (yield: 85%).
Reaction SMILES: [Na].[CH2:2]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C>[CH2:15]([CH:3]([C:4](=[O:8])[CH2:5][CH2:6][CH3:7])[CH2:2][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)CCC(=O)OCC
Reactant: CCCCCCI
Agent: [Na]
Solvent: CCO
Product: CCCCCCC(CC(=O)OCC)C(=O)CCC
Temperature: 25 °C

Procedure:
Under an atmosphere of argon, 1.59 g (69.3 mmol) of sodium were added a little at a time to 50 ml of ethanol. The mixture was then stirred under reflux until a homogeneous solution was obtained. 11.0 g (69.3 mmol) of ethyl hexan-3-onecarboxylate were added to the hot alkoxide solution, and the mixture was stirred for 45 min. 6.51 ml (7.93 g, 52.5 mmol) of 1-iodohexane were then slowly added dropwise to the boiling mixture. The mixture was stirred under reflux for 16 h, cooled to room temperature and filtered, and the solvent was then removed under reduced pressure. The residue was taken up in dichloromethane, filtered again and concentrated. The crude product was purified chromatographically (silica gel, petroleum ether: ethyl acetate 30:1). MS (DCI, NH3): 309 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC#N>[CH2:19]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccccc1OCc1ccccc1
Yield: 94.71 %

Procedure:
To a solution of 68 (5.8 g, 34.9 mmol) in CH3CN (150 ml) was added K2CO3 (10.6 g, 76.8 mmol). The mixture was added benzyl bromide (6.57 g, 38.39 mmol) and refluxed for 8 h under N2 atmosphere. The reaction mixture was cooled to 25° and poured into H2O (500 ml), and then extracted with CH2Cl2. The organic layer was washed with H2O, dried over MgSO4 and evaporated. The crude products were purified by distillation to give 73 as colorless liquid. (8.5 g, 33.2 mmol). Yield: 94.71%; MS (EI, 70 eV): m/z 256.3 (M+); 1H-NMR (CDCl3, 200 MHz): δ 1.33=(t, J=7.2 Hz, 3H), 4.35 (q, =7.2, 7.0 Hz, 2H), 5.15 (s, 2H), 7.00 (d, =8.0 Hz, 2H), 7.32-7.45 (m, 5H), 7.49 (d, J=8.2 Hz, 1H), 7.82 (dd, J=8.2, 1.8 Hz, 1H); 13C-NMR (CDCl3, 50 MHz) δ: 166.60, 158.01, 136.77, 133.25, 131.69, 128.49, 127.80, 126.99, 121.20, 120.56, 113.75, 70.57, 60.93, 14.29; Anal. Calcd for C16H16O3: C, 74.98; H, 6.29.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH3:13])[C:11]([S:14][CH3:15])=[N:10][N:9]=1.ClC1C=C(C=CC=1)C(OO)=[O:21]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH3:13])[C:11]([S:14]([CH3:15])=[O:21])=[N:10][N:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(-c2ccccc2F)n1C
Solvent: ClCCl
Product: Cn1c(-c2ccccc2F)nnc1S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, 0° C., solution of 3-(2-fluorophenyl)-4-methyl-5-methylthio-4H-1,2,4-triazole (5.0 g, 2.2×10-2 mole) and CH2Cl2 (125 ml) was added portionwise m-chloroperoxybenzoic acid (4.83 g, 2.24×10-2 mole, 80% active MCPBA). After stirring overnight at room temperature, the reaction was diluted with CH2Cl2 until homogeneous and was then washed in turn twice with saturated aqueous NaHCO3 and once with saturated aqueous NaCl. After drying over anhydrous Na2SO4, the CH2Cl2 was evaporated leaving an oil which slowly crystallized. Crystallization from EtOAc/hexane gave a colorless solid: Mp 95°-97° C.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.Br[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[Cl-].[Na+]>C(OCC)(=O)C>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:17][S:3][C:4]2[S:5][C:6]3[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:7]=3[N:8]=2)=[CH:19][CH:20]=1)#[N:23]
Reactant: O=[N+]([O-])c1ccc2nc(S)sc2c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CSc2nc3ccc([N+](=O)[O-])cc3s2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
0.37 g (7.7 mmol) of sodium hydride (50% in mineral oil) is added batchwise to a solution of 1.5 g (7.06 mmol) of 2-mercapto-6-nitro-benzothiazole and then stirred for 30 minutes at 50° C. Then 1.45 g (7.4 mmol) of 4-bromomethylbenzonitrile is added dropwise and stirred for a further hour at 50° C. The re-action mixture is mixed with 30 ml of ethyl acetate and 70 ml of 14% sodium chloride solution, whereupon a large proportion of the title compound is obtained as a beige precipitate. The organic phase is concentrated in vacuo, the crude product precipitated is triturated with diethyl ether and the liquid phase is separated off. The solid obtained is combined with the beige precipitate.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C@H:14]([C:22](O)=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C@@H:59]([CH2:80][C:81]1[N:82]=[CH:83][NH:84][CH:85]=1)[C:60]([NH:62][C@@H:63]([CH2:73][CH:74]1[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]1)[C@@H:64]([OH:72])[CH2:65][C@@H:66]([CH:69]([CH3:71])[CH3:70])[CH:67]=[CH2:68])=[O:61].CCN(C(C)C)C(C)C>C(#N)C>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C@H:14]([C:22](=[O:23])[NH:58][C@H:59]([C:60](=[O:61])[NH:62][C@@H:63]([CH2:73][CH:74]2[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79]2)[C@@H:64]([OH:72])[CH2:65][C@@H:66]([CH:69]([CH3:70])[CH3:71])[CH:67]=[CH2:68])[CH2:80][C:81]2[N:82]=[CH:83][NH:84][CH:85]=2)[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(NCCOc1ccc(-c2ccccc2)cc1)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)NCCOc1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
A solution of 103 mg of N-[[2-(4-biphenyloxy)ethyl ]carbamoyl]-3-phenyl-L-alanine and 113 mg of BOP in acetonitrile was added to 100 mg (0.256 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide 0.052 ml of Hunig base in 5 ml of acetonitrile, and the mixture was subsequently stirred at room temperature for 12 hours. Subsequently the reaction mixture was poured onto 1N hydrochloric acid/ice, extracted with ethyl acetate, the extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by chromatography on silica gel with a 10:1 mixture of methylene chloride and methanol, to obtain 90 mg (45%) of 1-[2-(4-biphenyloxy)ethyl]-3-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]- carbamoyl]phenethyl]urea as an amorphous powder. MS: 777 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([CH3:21])=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH3:21][C:6]1[C:5]([CH2:4][CH2:3][OH:2])=[CH:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:12]=2)[N:7]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.60 g (8.40 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester, dissolved in 15 ml of dry tetrahydrofuran, was added under an argon atmosphere within 15 minutes to a stirred suspension of 0.38 g (10 mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran. The reaction was exothermic. Subsequently, the mixture was stirred at room temperature for 1 hour to complete the reduction. Then, 1 ml of ethyl acetate was added dropwise to destroy the excess of reagent, followed by water, drop after drop, under argon, with stirring and cooling. The reaction mixture was diluted with 50 ml of ethyl acetate, dried over sodium sulfate, and filtered. The filtrate was evaporated i. V. and the residue was purified by chromatography on SiO2 with a mixture of dichloromethane and tert.-butyl methyl ether (4:1) as eluent. Thereby, 1.88 g of the title compound was obtained as white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[C:23]([CH3:36])=[CH:22][N:21]=2)=[C:12]([O:37][CH3:38])[CH:11]=1>CC(N(C)C)=O>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)[C:23]([CH3:36])=[CH:22][N:21]=3)=[C:12]([O:37][CH3:38])[CH:11]=2)[CH2:4]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 64.5 %

Procedure:
(3R)—N,N-dimethylpyrrolidin-3-amine (255 mg, 2.24 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 79, 414 mg, 1.02 mmol) in DMA (4 mL) and the mixture was heated in a microwave at 140° C. for 0.5 h. The mixture was then concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). Purification by ion exchange chromatography, using an SCX column and eluting with 0.35M methanolic ammonia provided semi-purified material after concentration of appropriate fractions in vacuo. Purification by FCC, eluting with 1-8% CH3OH in CH2Cl2 gave the title compound (330 mg, 65%) as an orange dry film; 1H NMR: 1.75-1.86 (1H, m), 2.13-2.19 (1H, m), 2.21 (6H, s), 2.37 (3H, s), 2.75 (1H, s), 3.10-3.20 (2H, m), 3.21-3.27 (1H, m), 3.46 (1H, td), 3.90 (3H, s), 3.94 (3H, s), 6.56 (1H, s), 7.03 (1H, t), 7.21-7.26 (1H, m), 7.49 (1H, d), 7.94 (1H, s), 8.05 (1H, s), 8.23 (1H, s), 8.37 (1H, d), 8.39 (1H, s); m/z: ES+ MH+ 502.33.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][C@@H:6]1[C:11]([O:13]C)=O)=[O:4].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(OCCO)C>[CH2:15]([N:22]1[CH2:2][C:3](=[O:4])[N:5]2[CH2:9][C@@H:8]([OH:10])[CH2:7][C@@H:6]2[C:11]1=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)CCl
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCCO
Product: O=C1[C@H]2C[C@H](O)CN2C(=O)CN1Cc1ccccc1

Procedure:
To a solution of Example 65B (200 g, 0.90 mol, 1 equivalent) in 2-ethoxyethanol (3.2 L), benzylamine (120 mL, 1.09 mol, 1.2 equivalents) was added. To this mixture, triethylamine (152 mL, 1.08 mol, 1.28 equivalents) was added, and the mixture was refluxed for 20 hours. The reaction mixture was cooled and concentrated under reduced pressure to afford crude product. This crude material was purified by column chromatography on silica gel using a mixture of methanol-ethyl acetate gradient (0-10%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 2.11 (m, 1H), 2.46 (m, 1H), 3.50 (m, 2H), 3.73 (d, 1H, J=16), 3.76 (m, 1H), 4.00 (d, 1H, J=16), 4.45 (d, 1H, J=15), 4.50 (m, 2H), 4.72 (d, 1H, J=15), 7.30 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[NH2:12].Cl[CH2:14][C:15](=O)[CH3:16].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[CH:14]=[C:15]([CH3:16])[N:12]=[C:7]12
Reactant: CC(=O)CCl
Reactant: Nc1nccc2c(Cl)cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cn2ccc3c(Cl)cccc3c2n1
Temperature: 60 °C
Yield: 82.4 %

Procedure:
A mixture of 5-chloro-1-aminoisoquinoline (2.8 g), chloroacetone (5.4 g) and sodium bicarbonate (7.6 g) in anhydrous ethanol (35 ml) was heated at 60° C. for 16 hours and filtered by suction. The filtrate was evaporated in vacuo and the residual solid was washed with ethanol to give 7-chloro-2-methylimidazo[2,1-a]isoquinoline (2.8 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:18]N1C(=O)CCC1=O.O>O1CCCC1>[Cl:18][C:13]1[NH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1c[nH]cc1-c1cccc(C#N)c1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c[nH]c(Cl)c1-c1cccc(C#N)c1
Reaction time: 6 h
Yield: 90 %

Procedure:
To a solution of 16.5 g (72.9 mmol) of methyl 4-(3-cyano-phenyl)-1H-pyrrole-3-carboxylate in 150 ml of tetrahydrofuran are added portionwise 9.93 g (74.4 mmol) of N-chlorosuccinimide (CAS 128-09-6) and the mixture is then stirred for 6 hours at reflux. After cooling, 250 ml of water are added and the reaction product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 17.1 g of methyl 5-chloro-4-(3-cyanophenyl)-1H-pyrrole-3-carboxylate in the form of a beige-coloured powder after recrystallizing from acetonitrile, filtering off and drying.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[C:14]1([S:20]([NH:23][C:24](=[O:46])[C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:36][CH:35]=3)[CH:26]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([S:20]([NH:23][C:24](=[O:46])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[C:27]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:36][CH:35]=3)[CH:26]=2)(=[O:21])=[O:22])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
Triethylamine (0.060 g) and 0.084 g of butyryl chloride were added to a solution of 0.300 g of N-benzenesulfonyl-4-amino-3-(biphenyl-4-ylmethylamino)benzamide in 2 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was directly purified through silica-gel column chromatography to obtain 0.250 g of N-benzenesulfonyl-3-(biphenyl-4-ylmethylamino)-4-butyrylaminobenzamide. To this compound were added 5 ml of methanol and 0.50 g of 35% hydrochloric acid, and the mixture was stirred at 60° C. for 3 hours. Then, 20% potassium hydrogencarbonate was added thereto to stop the reaction, and the reaction solution was extracted with ethyl acetate and with water. The organic layer was concentrated, and the product was dissolved in a small amount of chloroform. Ether was added thereto for crystallization. The crystals precipitated were separated through filtration, and were dried to give 0.157 g of 6-benzenesulfonylcarbamoyl-1-(biphenyl-4-ylmethyl)-2-n-propylbenzimidazole potassium salt (232).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=O.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[N:8]=2)[CH:7]=1
Reactant: CN(C)c1ccc(C(=O)CBr)cc1
Reactant: Nc1cnc(Cl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1ccc(-c2cn3cc(Cl)ncc3n2)cc1
Yield: 7 %

Procedure:
In a double necked round bottomed flask equipped with condenser and under nitrogen flow were introduced 5-chloro-2-amino-pyrazine (61 mg, 0.47 mmol), 2-bromo-4′-dimethylamino-acetophenone (170 mg, 0.71 mmol) and anhydrous acetonitrile (7 mL). The reaction mixture was refluxed for 3 hrs. After it cooled down, NaHCO3 (71 mg, 0.85 mmol) was added. The reaction was refluxed for another 6 hrs. The solvent was removed and the crude product (221 mg) was purified by FCC (hex/DCM/AcOEt=2:2:1), to afford 9 mg (yield 7%) of the product as yellow solid. 1HNMR (270 MHz; CDCl3), δ 8.82 (s, 1H, Ar—H), 8.09 (s, 1H, Ar—H), 7.822 (s, 1H, Ar—H), 7.818 (d, 3JHH=8.9 Hz, 2H, Ar—H), 6.77 (d, 3JHH=8.7 Hz, 2H, Ar—H), 3.02 (s, 6H, NCH3). m/z (CI-MS): 273 ([M+1]+), 261, 239 ([M−Cl+1]+).
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][S:11][CH3:12])(OC(C)(C)C)=O.[NH2:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20].Cl>CO>[NH2:8][C@@H:9]([CH2:10][S:11][CH3:12])[C:13]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Product: CSC[C@H](N)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
tert-Butyl [(R)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-(methylthio)ethyl]carbamate was obtained as an amorphous solid, MS: 445 (M+H)+, by condensing (R)-Boc-(S-methyl)cysteine (J. Chem. Soc. C 1967, 2632) and (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol in an analogous manner to that described in Example 1g). Subsequent cleavage of the Boc protecting group using hydrochloric acid in methanol yielded (R)-2-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(methylthio)propionamide.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.O[CH2:10][C:11]1[CH:12]=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:1][CH2:10][C:11]1[CH:12]=[C:13]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(-c2cc(CO)cc(C(F)(F)F)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc(CBr)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
N-bromosuccinimide (2.24 g, 12.6 mmol) was added to a 0° C. solution of 3′-(hydroxymethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (1.66 g, 6.0 mmol) and triphenylphosphine (3.14 g, 12.0 mmol) in THF (100 mL). The reaction was warmed to ambient temperature and stirred for 18 hours. The solvent was evaporated and the residue was purified by chromatography on SiO2 with a gradient of ethyl acetate/hexanes of 5% to 40%. The product 3′-(bromomethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (1.30 g, 64%) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.65-7.80 (m, 7H), 4.56 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH2:10])=[S:9].[CH:11]1(N)[CH2:13][CH2:12]1>O>[CH:11]1([NH:10][C:8](=[S:9])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:13][CH2:12]1
Reactant: NC1CC1
Reactant: NC(=S)Cc1ccccn1
Solvent: O
Product: S=C(Cc1ccccn1)NC1CC1

Procedure:
A solution of 7.6 g. (0.05 mole) of 2-(2-pyridyl)thioacetamide in a 40% aqueous solution of cyclopropylamine is refluxed for 45 minutes. After cooling, approximately 30 ml. of water is added. The reaction mixture is extracted three times with chloroform. The extracts are combined and dried over magnesium sulfate. The solvent is removed under reduced pressure. The residue is recrystallized twice from ethyl acetate/hexane to give N-cyclopropyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH2:20][CH2:21][C:22]#[N:23]>>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:21]([CH2:20][C:13]3[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=3[Cl:11])[C:22]([NH2:23])=[N:1]2)=[CH:6][CH:7]=1
Reactant: COc1cccc(Cl)c1CCC#N
Reactant: Nc1cc(Cl)ccc1C=O
Product: COc1cccc(Cl)c1Cc1cc2ccc(Cl)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-chlorobenzaldehyde and 3-(2-chloro-6-methoxyphenyl)propionitrile.