Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH2:12][CH2:13][S:14][CH2:15][CH2:16][OH:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH2:12][CH2:13][S:14]([CH2:15][CH2:16][OH:17])=[O:34])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCSCCO)c1cc(F)ccc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(CCO)CCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
The 2-[3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propylthio]ethanol (65 mg, 0.16 mmol) obtained in Example 250 was dissolved in dichloromethane (5 ml), followed by the addition of 3-chloroperbenzoic acid (33 mg, 0.19 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 14 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography, and the fraction obtained from the dichloromethane:methanol=30:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with diethyl ether, whereby the title, compound (50 mg, 0.12 mmol, 74%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[CH:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[OH:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:45]I>C1COCC1>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[CH:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[O:27][CH3:45])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CI
Reactant: Cc1cc(C(O)C2CCCCC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1cc(C)c(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a solution of (2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-5-methyl-4-trifluoromethyl-phenyl)-cyclohexyl-methanol (8 mg, 0.01 mmol) in THF (0.15 mL) at 0° C. was added sodium hydride (4.2 mg, 0.11 mmol). The mixture was stirred at room temperature for 30 minutes. Methyl iodide (10 μL, 0.2 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The mixture was quenched with methanol and purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound (3.6 mg, 40%). 1H NMR (400 MHz, CDCl3) δ ppm 0.92-1.20 (m, 6H) 1.41-1.51 (m, 1H) 1.61 (d, J=8.71 Hz, 2H) 1.67-1.74 (m, 1H) 1.93 (d, J=11.62 Hz, 1H) 2.46 (s, 3H) 3.04 (s, 3H) 4.04 (d, J=7.05 Hz, 1H) 4.21 (s, 3H) 4.63-4.72 (m, 3H) 4.84 (d, J=16.18 Hz, 1H) 7.27 (s, 1H) 7.30 (s, 1H) 7.63 (s, 2H) 7.77 (s, 1H). MS (ES30) Calc: 623.2, Found: 624.6 (M+1) According to the procedure described in example 23 and using the corresponding aryl bromide and aldehyde reagent, example 24 was prepared.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][N:7]([CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1.[C:41]1(=O)[CH2:45][CH2:44][CH2:43][CH2:42]1.C([BH3-])#N.[Na+]>C(O)C>[ClH:3].[ClH:1].[Cl:3][C:4]1[C:36]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:34]=[CH:33][C:5]=1[CH2:6][N:7]([CH2:19][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([NH:18][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: O=C1CCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(NC3CCCC3)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenylamine dihydrochloride (53 mg, 0.086 mmol) was diluted with absolute ethanol (3 mL). Next, both cyclopentanone (7.2 mg, 0.086 mmol) and sodium cyanoborohydride (19.2 mg, 0.3 mmol) were added to the solution. The reaction mixture was stirred at room temperature overnight and concentrated under a stream of argon. Water was added and the reaction mixture was extracted with ethyl acetate. The crude amine was purified by preparative HPLC chromatography (Varian Mega BondElut Si) to afford the title compound as the free base. Addition of 1 N HCl in Et2O gave the title compound as a white powder, 22 mg (42%). MS (ESI) 608 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:14]=1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:24]#[N:25])[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2cccc(C#N)c2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2noc([C@@H]3CCCN3)n2)c1
Yield: 73.1 %

Procedure:
(S)-3-(5-Pyrrolidin-2-yl-[1,2,4]oxadiazol-3-yl)-benzonitrile (360 mg, 73%) was prepared according to the procedure in Example 39 from (S)-2-[3-(3-cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (697 mg, 2.05 mmol) in dichloromethane (15 mL) and trifluoroacetic acid (2.4 mL) at room temperature for 2 h. 1H NMR (CDCl3), δ(ppm): 8.39 (s, 1H), 8.32 (d, 1H), 7.78 (d, 1H), 7.60 (t, 1H), 4.58 (dd, 1H), 3.22 (m, 1H), 3.13 (m, 1H), 2.34 (m, 1H), 2.14 (m, 1H), 2.00 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)=[O:12].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:11]([CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18]1)[OH:12]
Reactant: COc1cccc(C(=O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(C(O)C2CCN(CCc3ccc(F)cc3)CC2)c1OC
Reaction time: 1 h

Procedure:
To a stirred solution of (2,3-dimethoxyphenyl)[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methanone (6.0 g, 16.2 mmol) in MeOH (100 mL) at 0° C. was added NaBH4 (1240 mg, 32.8 mmol) in two portions, over a one hour period. After stirring overnight, the solution was concentrated to a solid. The solid was partitioned between water and ether. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to a solid. The solid was chromatographed on silica gel, eluting with acetone. The appropriate fractions were combined and evaporated to afford a white solid. The solid was recrystallized from cyclohexane to afford (±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol as white needles, m.p. 126°-127° C. Anal. Calcd for C22H28FNO3 : C, 70.75; H, 7.56; N, 3.75. Found: C, 70.86; H, 7.72; N, 3.93.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:9]([NH:11][C@@H:12]2[C@@H:19]3[C@@H:15]([CH2:16][NH:17][CH2:18]3)[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]([CH3:43])[C@@H:35]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([NH:11][C@@H:12]2[C@@H:19]3[C@@H:15]([CH2:16][N:17]([C:36](=[O:37])[C@@H:35]([N:34]([CH3:43])[C:32](=[O:33])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:18]3)[CH2:14][CH2:13]2)=[O:10])=[CH:25][CH:24]=1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: O=C(N[C@H]1CC[C@@H]2CNC[C@@H]21)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N1C[C@H]2CC[C@H](NC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)[C@H]2C1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2,2-Bis(4-fluorophenyl)-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide (30 mg, 0.084 mmol) and (S)-2-(tert-butoxycarbonyl(methyl)amino)-4-methylpentanoic acid (22.71 mg, 0.093 mmol) were dissolved in dichloromethane (0.5 mL) and then treated with 1-hydroxybenzotriazole hydrate (14.18 mg, 0.093 mmol). After 10 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.016 mL, 0.093 mmol) was added, and the reaction mixture was stirred at ambient temperature overnight followed by quenching with water. The material in the organic layer was purified with a 4 g silica gel cartridge eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give tert-butyl(S)-1-((3aR,4S,6aS)-4-(2,2-bis(4-fluorophenyl)acetamido)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-4-methyl-1-oxopentan-2-yl(methyl)carbamate: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.25 (s, 1H), 7.46 (td, J=8.5, 5.5, 4H), 7.08-6.96 (m, 4H), 5.08 (s, 2H), 4.29-4.18 (m, 1H), 3.80 (s, 2H), 3.69 (s, 1H), 3.43 (dd, J=11.7, 3.5, 1H), 2.93 (s, 3H), 2.63 (s, 2H), 2.10 (td, J=12.9, 6.9, 1H), 1.91-1.69 (m, 3H), 1.63 (dt, J=13.2, 6.5, 2H), 1.51 (s, 9H), 1.40-1.26 (m, 1H), 0.97 (d, J=6.5, 3H), 0.92 (d, J=6.6, 3H); MS (ESI+) m/z 584 (M+H)+.
Reaction SMILES: Cl[CH:2]([C@H:7]([OH:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:3]([O:5][CH3:6])=[O:4].ClC([C@H](O)CC)C(OC)=O.C[O-].[Na+]>CO>[O:23]1[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:2]1[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCCCCCCCCCCCCCC[C@@H](O)C(Cl)C(=O)OC
Agent: CC[C@@H](O)C(Cl)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCC[C@H]1O[C@@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To 1.3 l of methanol solution of 262 g (0.75 mol) of the methyl (3R)-2-chloro-3-hydroxyoctadecanoate (VIII) obtained in (2) above was added dropwise 150 g (0.777 mol) of a 28% methanol solution of sodium methoxide at 0 to 5° C. The mixture was stirred at room temperature for 1 hour. After confirming disappearance of the compound (VIII) by TLC, methanol was evaporated. The concentrate was cooled, adjusted to pH 8 to 9 with 1.2 l of a phosphate buffer, and extracted with 3 l of isopropyl ether. Isopropyl ether was evaporated, and the resulting crude crystals were recrystallized from heptane to give 165 g (0.529 mol; yield: 70.5%) of the title compound (V-1) (melting point: 54-55° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:5]2
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccccc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and phenylboronic acid to give (6-methoxy-1-phenyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 331 (MH+).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[Cl:14])[NH2:10].[CH:15]([S:17]([F:20])(=[O:19])=[O:18])=[CH2:16]>O>[Cl:6][C:7]1[CH:8]=[C:9]([NH:10][CH:16]=[CH:15][S:17]([F:20])(=[O:19])=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C=CS(=O)(=O)F
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(F)C=CNc1ccc(Cl)c(Cl)c1

Procedure:
A N,N-dimethylformamide solution (DMF, 100ml) of 3,4-dichloroaniline (6.48 g, 40 mmol) and ethenesulfonyl fluoride (6.7 g, 57.9 mmol) was warmed to 110° C. for three hours. The cooled dark solution was diluted to 400 ml with water and the resulting dark oily precipate was decanted from the supernatant layer. This layer was extracted with ether (4×50 ml). The combined ether extracts were added to the oily precipitate and this dark solution was washed with brine and dried over MgSO4. The organic solution was evaporated to give the crude 2-[(3,4-dichlorophenyl)amino]ethenesulfonyl fluoride as a dark liquid in quantitative yield.
Reaction SMILES: [OH-:1].[K+].[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.OO.Cl>CO>[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:1])=[O:12])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(OCCF)cc1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: O=C(O)c1ccc(OCCF)cc1
Temperature: 65 °C
Yield: 63 %

Procedure:
To a stirred solution of 50% w/v KOH (1.3 ml) and 4-(2-fluoroethoxy)benzaldehyde (0.5 g, 2.98 mmol) in MeOH (6 ml) at 65° C. was added dropwise over 20 min aqueous hydrogen peroxide (30 wt. % in water, 2.45 ml). On completion of the addition the reaction mixture was heated at 65° C. for a further 10 min. On cooling to room temperature, the reaction mixture was acidified with 1 M HCl and extracted with Et2O (3×30 ml). The combined organic extracts were washed with brine (30 ml), dried (Na2SO4) and the solvent removed under reduced pressure to give a solid which was purified by flash chromatography (1:1 Hexane/EtOAc) to give the title compound (0.278 g, 63%) as a colourless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([OH:24])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:2].[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27].Cl.CN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:21][C:22]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:2]
Reactant: CS(N)(=O)=O
Reactant: CCc1cc(CC(=O)O)ccc1OCc1ccc2ccccc2n1
Agent: CN(C)c1ccccn1
Agent: CN=C=NCCCN(C)C
Agent: Cl
Product: CCc1cc(CC(=O)NS(C)(=O)=O)ccc1OCc1ccc2ccccc2n1

Procedure:
Analogously to the procedure of Example XVI, the title compound is prepared from 1.7 g (5.3 mmol) of the compound from Example XXXV, 0.6 g (6 mmol) of methanesulphonamide, 1.2 g (6 mmol) of N-methyl-N'-dimethylaminopropylcarbodiimide hydrochloride and 0.8 g (6 mmol) of dimethylaminopyridine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[O:11][N:10]=[C:9]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:8]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClC1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH:8]=1
Reactant: COC(=O)c1ccccc1C1=NOC(c2ccccn2)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Clc1ccccc1
Product: COC(=O)c1ccccc1-c1cc(-c2ccccn2)on1
Yield: 34.8 %

Procedure:
A mixture of 11.0 g (.039 mol) of methyl 2-[5-(2-pyridyl)-2-isoxazolin-3-yl]benzoate and 9.76 g (.043 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 200 ml of chlorobenzene was held at reflux for 3 hours; the mixture was allowed to cool, was filtered, and was concentrated under vacuum to 12.0 g of residue. The residue was chromatographed on 400 g of silica gel with 20% ether in benzene to give 3.8 g (35%) of solid, mp 54-57° C. Recrystallization of a small sample gave solid with mp 58-60.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]([CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+]>C1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCO
Product: O=C(O)CCCN(C(=O)c1ccc(Cl)cc1)c1ccccc1-c1ccccc1
Yield: 72.1 %

Procedure:
15.0 g of ethyl 4-[p-chloro-N-(biphenyl-2-yl)benzamido]-butyrate is dissolved in 100 ml of benzene and, after the addition thereto of a solution of 2.8 g of potassium hydroxide in 20 ml of ethanol, is then stirred at room temperature for 5 hours. The solvent is then distilled off in vacuo, and the obtained residue is dissolved in water. The resulting aqueous solution is acidified with dilute hydrochloric acid, and the precipitate, which separates out, is taken up in methylene chloride. The residue remaining, after drying and distilling off the methylene chloride, is recrystallized from an ethanol/water mixture (2:1) to obtain 10.1 g (72.1% of theory) of 4-[p-chloro-N-(biphenyl-2-yl)benzamido]butyric acid, MP 135° to 137°.
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:30][CH2:31][CH2:32][CH3:33])[N:26]([CH2:27][CH2:28][NH2:29])[C:22]=2[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1>>[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:30][CH2:31][CH2:32][CH3:33])[N:26]([CH2:27][CH2:28][NH:29][C:1](=[O:12])[CH2:2][CH:3]([CH3:4])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[C:22]=2[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CC(C)=CCCC(C)CC(=O)O
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)CC(C)CCC=C(C)C
Yield: 67.4 %

Procedure:
Using the general method of Example 97 citronellic acid (0.3 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.5 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,7-dimethyl-6-octenamide as a white whispy solid, m.p. 163-164° C. Analysis: Calculated for C25H36N6O: %C, 68.77; %H, 8.31; %N, 19.25; Found: %C, 68.84; %H, 8.14; %N, 19.58. HRMS (EI) calcd for C25H36N6O (M+) 436.2950 found 436.2952.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OC(C)C)=O)(C(OC(C)C)=O)=[N-]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:24]2[CH:25]=[CH:26][C:21]([Br:20])=[CH:22][CH:23]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.077 g) synthesized in Example 4 and 4-bromophenol (1.75 g) were dissolved in tetrahydrofuran (50 mL), triphenylphosphine (3.20 g) and diisopropyl diazodicarboxylate (40% toluene solution, 6.54 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (3.45 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.CCCCCCC>C(Cl)Cl.O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
Maraviroc phosphate (6 gm) was dissolved in methylene chloride (50 ml) and water (40 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (3 ml) and then the layers were separated. The organic layer was dried with sodium sulfate and treated with carbon. The methylene chloride was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added n-heptane (40 ml) and stirred for 30 minutes at room temperature. The solid obtained was collected by filtration and dried to obtain 4.6 gm of maraviroc amorphous form (HPLC Purity: 99.96%).
Reaction SMILES: [Cl:1][C:2]([CH:5](Cl)[CH3:6])=[CH:3][CH3:4].[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([NH:13][C:14](=[S:16])[S-:15])=[C:11]([CH3:19])[CH:10]=1.C([NH+](CC)CC)C>>[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([NH:13][C:14](=[S:15])[S:16][CH:5]([CH3:6])[C:2]([Cl:1])=[CH:3][CH3:4])=[C:11]([CH3:19])[CH:10]=1
Reactant: CC=C(Cl)C(C)Cl
Reactant: Cc1cc(Cl)ccc1NC(=S)[S-]
Agent: CC[NH+](CC)CC
Product: CC=C(Cl)C(C)SC(=S)Nc1ccc(Cl)cc1C

Procedure:
The reactant, 2-chloro-1-methyl-2-butenyl 4-chloro2-methyldithio-carbanilate is prepared by following the procedure of Example 2 wherein 3,4-dichloro-2-pentene and triethylammonium 4-chloro-2-methyldithiocarbanilate are reacted.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=O.C[Si]([N:22]=[C:23]=[N:24][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6]/[C:5]/2=[N:24]\[C:23]#[N:22]
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC2(CCCOC2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of 6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (379 mg, 1.28 mmol) in anhydrous DCM (10 mL) was added TiCl4 (1 M solution in DCM, 2.6 mL, 2.6 mmol) dropwise within 15 minutes at room temperature. The mixture was stirred another 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (0.525 g, 0.63 mL, 2.82 mmol) dropwise. The resulting mixture was stirred for another 18 h after the addition. The reaction mixture was poured into ice-water (50 g) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylide-ne)cyanamide (350 mg, 90%), which was used for next step without further purification.