Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:21])=[N:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: OC(c1ccccc1)c1ccc(Br)cn1
Temperature: -70 °C

Procedure:
2,5 dibromopyridine (15.0 g, 63.3 mmol) was added to toluene (450 ml) and it was cooled at −70° C. BuLi (1.6 M in hexanes)(41 ml, 66.5 mmol, 1.05 eg) was added dropwise over 1 hour, then reaction mixture was stirred at −70° C. for another hour. Benzaldehyde (7.4 g, 69.6 mmol, 1.1 eg) dissolved in toluene (5 mL) was added slowly. The mixture was stirred at −70° C. for 30 min., then warmed to 0° C. Quenched with Sat NH4Cl (200 mL) and phases partitioned. Aqueous phase was extracted with EtOAc (100 mL) and combined organic washed with brine, dried, evaporated. Residue was chromatographed with 15% EtOAc/hexane to yield the title compound.
Reaction SMILES: [F:1][CH2:2][C:3]([O:6][C:7](=[O:53])[O:8][CH2:9][O:10][C:11]1[N:12]([C:47]2[N:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[N:13]=[C:14]([C@H:16]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([NH2:46])=[N:38]C(OCC(C)=C)=O)=[CH:33][CH:32]=2)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]=2[F:29])[N:15]=1)([CH3:5])[CH3:4].[C:54]([OH:57])(=[O:56])[CH3:55]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[C:54]([OH:57])(=[O:56])[CH3:55].[F:1][CH2:2][C:3]([O:6][C:7](=[O:53])[O:8][CH2:9][O:10][C:11]1[N:12]([C:47]2[N:48]=[CH:49][CH:50]=[CH:51][N:52]=2)[N:13]=[C:14]([C@H:16]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37](=[NH:38])[NH2:46])=[CH:33][CH:32]=2)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]=2[F:29])[N:15]=1)([CH3:5])[CH3:4]
Reactant: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nc(OCOC(=O)OC(C)(C)CF)n(-c3ncccn3)n2)c2cc(OC)cc(OCCO)c2F)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(=N)N)cc2)c2nc(OCOC(=O)OC(C)(C)CF)n(-c3ncccn3)n2)c1
Temperature: 45 °C
Reaction time: 15 h

Procedure:
Under nitrogen atmosphere, to a mixture of carbonic acid 5-{(R)-(4-{amino-[2-methylallyloxycarbonylimino]methyl}phenylamino)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}-2-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yloxymethyl ester 2-fluoro-1,1-dimethylethyl ester (Example 56b, 63.5 mg), acetic acid (49 μL) and N,N-dimethylformamide (0.70 ml), tetrakis(triphenylphosphine) palladium (0) (4.9 mg) was added, and the resulting mixture was stirred at 45° C. for 15 hours. After cooling the mixture to room temperature, the reaction solution containing the captioned compound was divided into 3 equal lots, and used for the following reactions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1C(OC)=O.Br>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)cc1F
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](c3ccc(F)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
(2R,4S)-methyl 2-(2,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (187 mg, 0.55 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 4.36 mL, 24.87 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(2,4-difluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (93 mg, 60%). 1H NMR (600 MHz, dmso) δ 1.36 (q, 1H), 1.46 (dq, 1H), 1.83-1.89 (m, 1H), 1.90-1.95 (m, 1H), 2.72 (dt, 1H), 2.89 (tt, 1H), 3.06-3.12 (m, 1H), 3.89 (dd, 1H), 5.73 (s, 1H), 7.03 (dt, 1H), 7.11-7.17 (m, 1H), 7.52-7.59 (m, 1H). HRMS Calculated for [C14H14F2N2O2+H]+: 281.1101. Found: 281.1106
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[F:14].[N+:15]([CH:18]([CH3:20])[CH3:19])([O-:17])=[O:16].C1CCN2C(=NCCC2)CC1.Cl>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][C:18]([CH3:20])([N+:15]([O-:17])=[O:16])[CH3:19])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[F:14]
Reactant: C=C(C(=O)OC)c1ccc(Cl)c(F)c1
Reactant: CC(C)[N+](=O)[O-]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(CC(C)(C)[N+](=O)[O-])c1ccc(Cl)c(F)c1
Yield: 106.7 %

Procedure:
Methyl 2-(4-chloro-3-fluorophenyl)acrylate (1.00 g, 4.66 mmol) and 2-nitropropane (502 uL, 5.59 mmol) were dissolved in MeCN (16 mL) and treated with DBU (835 uL, 5.59 mmol) at room temperature. The mixture was allowed to stir over the weekend to completion. The mixture was poured into 1M HCl solution and extracted with ethyl acetate (2×). The combined organic portions were washed with water (1×), then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to yield methyl 2-(4-chloro-3-fluorophenyl)-4-methyl-4-nitropentanoate (1.51 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[C:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1)[CH3:5]>CCOC(C)=O.CN(C=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:44])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]1[C:19]([C:20]([F:22])([F:23])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[N:15]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.7 %

Procedure:
A solution of tert-butyl 4-(4-((4-((2-(1-methoxy-1-oxopropan-2-yl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I52) (0.108 g, 0.177 mmol) in EtOAc (5 mL) and DMF (10 mL) was added to a suspension of 10% Pd/C (80 mg) in EtOAc (5 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered and the solvent removed in vacuo to yield a brown residue. The residue was redissolved in DMF (15 mL) and added to a suspension of 10% Pd/C (55 mg) in DMF (5 mL). The reaction was stirred at room temperature for 24 hours under an atmosphere of hydrogen. The reaction was filtered through a pad of celite washing with EtOAc (100 mL). Removal of the solvent under reduced pressure yielded a brown viscous oil which was purified by column chromatography on silica gel (0-15% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I53) (84.3 mg, 77%) as a pale yellow viscous oil; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.59-7.54 (m, 2H), 7.38 (s, 1H), 7.33-7.30 (m, 1H), 7.25-7.17 (m, 5H), 4.25 (s, 2H), 4.11 (q, J=7.1 Hz, 1H), 3.64 (s, 3H), 3.23-3.02 (m, 4H), 2.81 (t, J=12.0 Hz, 2H), 2.64 (tt, J=12.0, 3.4 Hz, 1H), 1.83 (d, J=12.9 Hz, 2H), 1.67-1.59 (m, 2H), 1.50-1.48 (d, J=7.0 Hz, 3H; s, 9H). LCMS Method C: rt 7.15 min; m/z 635 [M+Na]+, 613 [M+H]+, 557 [M-tButyl+2H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH2:42][CH2:43][CH2:44][CH3:45])[C:3]([NH:5][CH2:6][C@@H:7]1[O:11]C(C)(C)[N:9](C(OC(C)(C)C)=O)[C@H:8]1[CH2:21][C@H:22]([CH:26]([OH:41])[C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][N:33]2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:29][CH:28]=1)[CH:23]([CH3:25])[CH3:24])=[O:4].[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[NH2:9][C@@H:8]([CH2:21][C@H:22]([CH:26]([OH:41])[C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][N:33]2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:29][CH:28]=1)[CH:23]([CH3:25])[CH3:24])[C@@H:7]([OH:11])[CH2:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([CH3:46])[CH2:42][CH2:43][CH2:44][CH3:45].[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]
Reactant: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C(C)C)C(O)c1ccc2cnn(CCCOC)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC(C)(C)C(=O)NC[C@H](O)[C@@H](N)C[C@@H](C(C)C)C(O)c1ccc2cnn(CCCOC)c2c1
Reaction time: 1 h

Procedure:
To a stirred solution of (4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-(hydroxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (45 mg, 0.07 mmol) in CH2Cl2 (8 mL) at 0° C. was added TFA (2 mL). The mixture was stirred for ˜1 h and concentrated. The residue was purified by preparative HPLC to give N-((2S,3S,5S)-3-amino-2-hydroxy-5-(hydroxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptyl)-2,2-dimethylhexanamide as its TFA salt (15 mg, 42%). 1H NMR (400 MHz, CD3OD): δ 8.00 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.55 (m, 1H), 7.17 (m, 1H), 4.50 (m, 2H), 3.84-3.68 (m, 2H), 3.45 (m, 1H), 3.27 (s, 3H), 3.25-3.18 (m, 3H), 2.13 (m, 2H), 1.89-1.72 (m, 2H), 1.55 (m, 3H), 1.32-1.11 (m, 9H), 0.99-0.80 (m, 12H); MS: 489 (M++1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)=[C:8]([C@H:17]([OH:31])[C@@H:18]2[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)[CH:7]=[CH:6][CH:5]=1.BrC[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>C1COCC1>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][O:31][C@@H:17]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([F:3])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)[C@@H:18]1[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:19]1)[CH3:39]
Reactant: CCOC(=O)CCBr
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
To a slurry of 60% NaH in oil (0.75 g, 18.7 mmol) in THF (30 mL) was added a solution of (R)-tert-butyl 2-((S)-(6-fluoro-3′-methylbiphenyl-2-yl)(hydroxy)methyl)morpholine-4-carboxylate (2.5 g, 6.23 mmol) in THF (20 mL) dropwise at and then the reaction mixture was stirred for about 1 h at rt. A solution of ethyl 3-bromopropionate (1.55 g, 9.35 mmol) in THF (20 mL) was added dropwise while the temperature was maintained at −15 to −5° C. The mixture was allowed to warm slowly to rt and stirred for ˜2 h until the reaction was complete by tlc analysis. The reaction was cooled in an ice bath, quenched with satd aq NH4Cl (120 mL) and extracted with EtOAc. The combined organic extracts were washed with brine, dried over NaSO4, concentrated and purified by flash chromatography to afford (R)-tert-butyl 2-((S)-(2-ethoxy-2-oxoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (570 mg, 19%). MS (E/Z): 488 (M+H+)
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl.O>[Br:23][C:6]1[C:5]([OH:11])=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=[C:2]([Br:1])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc(Br)c(C(=O)O)cc1O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(Br)c(C(=O)O)c(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
step 3—To a solution of 120 (1.0 eq, 2.27 mmol, 621 mg) in DCM (10 mL) at RT was added in three portions NBS (2.0 eq, 4.55, 809 mg). The mixture was stirred RT for 30 min. The reaction was diluted with water, the organic layer was separated, dried (MgSO4) and concentrated to afford 767 mg of 2,6-dibromo-4-tert-butyl-3-hydroxybenzoic acid (122) as a light brownish solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][CH3:37])(=[O:35])[CH2:33]O.[NH:38]1[C:42]([CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)=[N:41][N:40]=[N:39]1>ClCCl>[CH3:37][O:36][C:32](=[O:35])[CH2:33][N:41]1[C:42]([CH:43]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]2)=[N:38][N:39]=[N:40]1
Reactant: COC(=O)CO
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cn1nnnc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triphenylphosphine (1.28 g, 4.89 mmol), DEAD (804 μL, 4.89 mmol), and methyl glycolate (378 μL, 4.89 mmol) were added to a solution of tert-butyl 4-(1H-tetraazol-5-yl)piperidine-1-carboxylate (619.7 mg, 2.447 mmol) in dichloromethane (20 mL). The reaction mixture was stirred for 16 h at rt and then concentrated under reduced pressure. Purification by MPLC (silica gel, 10-50% EtOAc/hexanes) afforded tert-butyl 4-[1-(2-methoxy-2-oxoethyl)-1H-tetraazol-5-yl]piperidine-1-carboxylate. ESI-MS calculated for C14H23N5O4: 325.36, found 348 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.C=O.[C:20]([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:1][C:2]1[C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:20])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(OC2CCCNC2)ccc2[nH]ncc12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(OC2CCCN(C)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
Acetic acid (0.060 ml) was added to a methanolic solution (1.0 ml) of the 4-methyl-5-(piperidin-3-yloxy)-1H-indazole (46 mg, 0.20 mmol) obtained in Example 422, followed by adding thereto paraformaldehyde (30 mg, 1.0 mmol), and the resulting mixture was stirred at room temperature for 2 hours. Then, a solution of sodium cyanoborohydride (63 mg, 1.0 mmol) in methanol (1.0 ml) was added thereto and the resulting mixture was stirred at room temperature for 18 hours. After a 1N-aqueous sodium hydroxide solution (0.8 ml) was added to the reaction solution, the solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate/triethylamine=5/15/1) to obtain 4-methyl-5-[(1-methylpiperidin-3-yl)oxy]-1H-indazole (34 mg, 70%).
Reaction SMILES: CCCCCC.[H-].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([N:26]=[C:27]=[S:28])[C:22]([CH3:29])=[N:21]1>C1COCC1>[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([NH:26][C:27]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=3)[CH:13]=[CH:14]2)=[S:28])[C:22]([CH3:29])=[N:21]1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: Cc1nn(C)c(C)c1N=C=S
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nn(C)c(C)c1NC(=S)n1ccc2cc(Cl)ccc21
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A stirred slurry of hexane washed potassium hydride (0.423 g, 10.6 mmol) in 50 mL of dry THF was treated portionwise with 5-chloroindole (1.6 g, 10.6 mmol). The mixture was stirred until a clear solution was obtained. A solution of (1,3,5-trimethyl-pyrazol-4-yl)-isothiocyanate (1.8 g, 10.6 mmol) of step A in 5 mL THF was slowly added and stirring was continued for 1 hour. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residual solid foam was triturated with Et2O-hexane overnight to provide 2.0 g of the title compound as a tan solid, m.p. 165-166° C. (59% of theory).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:13])[N:4]=1.[C:14]1([CH:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH2:8][CH:9]([OH:13])[CH2:10][N:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[CH:20]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27]2)[N:4]=1
Reactant: CSc1ccc2c(O)cccc2n1
Reactant: O=C(C(c1ccccc1)c1ccccc1)N1CCNCC1
Product: CSc1ccc2c(OCC(O)CN3CCN(C(=O)C(c4ccccc4)c4ccccc4)CC3)cccc2n1

Procedure:
An epoxy compound was prepared from 2-methylthio-5-hydroxyquinoline in accordance with the same procedure as in Example 1-(a), and reaction and treatment were then carried out using this epoxy compound and N-(α,α-diphenylacetyl)piperazine to obtain the desired compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:23]=[N:22][C:21]([NH:24][NH:25]C(=O)CC2CCCCC2)=[CH:20][C:19]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:23]=[N:22][C:21]([N:24]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH2:25])=[CH:20][C:19]=1[C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1
Reactant: O=C(CC1CCCCC1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Reactant: O=C(O)Cc1ccccc1
Product: NN(C(=O)Cc1ccccc1)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Yield: 47 %

Procedure:
The title compound (42 mg, 47%) as a white foam was prepared from 2-phenylacetic acid (41 mg, 0.3 mmol) and 1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (66 mg, 0.2 mmol) according to the procedures described for N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-cyclohexylacetohydrazide (Example 7A). HPLC/MS (method A): retention time=3.30 min, (M+H)+=449.2.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:2][C:1]([C:11]1[C:6]([Cl:5])=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=1)=[O:3]
Reactant: Fc1ccc(Cl)cc1F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(F)c(F)cc1Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
23.6 g (0.3 mol) of acetyl chloride was added to a mixture comprising 29.7 g (0.2 mol) of 1-chloro-3,4-difluorobenzene and 40.0 g (0.3 mol) of aluminum chloride at a temperature of from 20° to 40° C. Then, the mixture was stirred at 120° C. for two hours. While still being hot, the mixture was poured on 250 g of ice, and the separated oil was extracted with ethylene chloride. The extract was neutralized and washed with water, and the solvent was distilled off under reduced pressure to obtain 31.2 g (yield: 82%) of 2-chloro-4,5-difluoroacetophenone. This compound was analyzed, and the analytical values were as follows. Boiling point: 65°-67° C./4-5 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:31])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[CH:26]=[C:25]([C:27]([NH2:29])=O)[CH:24]=[C:23]([CH3:30])[C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[NH2:29][CH2:27][C:25]1[CH:24]=[C:23]([CH3:30])[C:21]2[N:22]=[C:18]([C:12]3[C:13](=[O:17])[NH:14][CH:15]=[CH:16][C:11]=3[NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:31])[NH:19][C:20]=2[CH:26]=1
Reactant: Cc1cc(C(N)=O)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Solvent: C1CCOC1
Product: Cc1cc(CN)cc2[nH]c(-c3c(NCC(O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 59 %

Procedure:
To a solution of (±)-2-{4-[2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-7-methyl-3H-benzimidazole-5-carboxylic acid amide (20 mg, 0.046 mmol) in THF (1 mL) was added borane-tetrahydrofuran complex (1 M solution) (0.45 mL, 0.45 mmol). The reaction mixture was stirred at room temperature for 10 h and quenched with acetic acid (2 drops). After removal of most solvent, the residue was extracted with EtOAc, washed with brine, dried over Na2SO4. After concentration, the crude product was purified by prep. HPLC to yield the title compound (11.5 mg, 60%). 1H NMR (400 MHz, CD3OD) δ 7.53 (1H, s), 7.50 (1H, s), 7.39 (1H, d, J=7.5 Hz), 7.24–7.32 (3H, m), 7.13 (1H, s), 6.26 (1H, d, J=7.5 Hz), 4.99 (1H, dd, J=4.8, 6.8 Hz), 4.19 (2H, s), 3.72 (1H, dd, J=4.8, 13.6 Hz), 3.64 (1H, dd, J=6.8, 13.6 Hz), 2.62 (3H, s). LCMS (M+H)+ m/z 424 (t=2.10 min.).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[H][H]>CO>[CH2:1]1[CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C@H:9]([OH:10])[CH2:11]1
Reactant: O=C1CCCc2ccccc21
Reactant: [H][H]
Solvent: CO
Product: O[C@@H]1CCCc2ccccc21
Temperature: 60 °C
Reaction time: 20 h

Procedure:
In a 50-ml autoclave, 3.3 mg (0.005 mmol, S/C=1000) of RuCl((R,R)—O-HT-Tsdpen) was placed, and the autoclave was purged with nitrogen. Subsequently, 0.73 g (5.0 mmol) of α-tetralone and 4.4 ml of methanol were added thereto, then hydrogen gas was charged to 3.0 MPa. Subsequently, the mixture was stirred for 20 hours at 60° C. The reaction liquid was subjected to a GC analysis, and as a result, (R)-1-tetralol was obtained at a conversion rate of 52.0% with an optical purity of 99.3% ee.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[CH3:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:14])=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: Cc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Part A. A 2-L, three-necked, round-bottomed flask equipped with an addition funnel, reflux condenser, and a nitrogen sweep to an HCl gas scrubber was charged with 2-methylbenzoic acid (503 g, 3.69 mol). The apparatus was cooled in an ice bath, and thionyl chloride (750 mL, 10.3 mol) was added over a period of 15 minutes. After complete addition, the ice bath was removed and the reaction mixture was warmed to about 45° in order to completely dissolve the 2-methylbenzoic acid. The reaction mixture was then allowed to gradually cool with stirring to room temperature overnight. The excess thionyl chloride and the HCl and SO2 reaction side-products were removed by vacuum distillation to afford 2-methylbenzoyl chloride as an oil, which was used without further purification. This material was transferred immediately into an addition funnel and added with mechanical stirring in 30-50 mL portions over a period of one hour to a commercial 40% dimethylamine solution (1500 mL, 13.35 mmol) which was maintained below 25° by periodic cooling with a dry ice-acetone bath. After complete addition the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with ether, and the combined organic extracts were washed with water, dried, and concentrated. The resulting oil was distilled under vacuum to afford N,N,2-trimethylbenzamide (409 g, 2.49 mol, 68% yield) as an oil: bp 88° (0.4 torr); IR(neat) 1650 cm-1 ; 1H NMR(CDCl3) δ 7.07-7.30 (m,4H), 3.11(s,3H), 2.81(s,3H), 2.27(s,3H). Anal. Calcd for C10H13NO: C,73.59; H,8.03; N,8.58. Found: C,73.66; H,8.18; N,8.42.