Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:44])[NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:55][C:56]1(C)[CH2:60]C(=O)[O:58][C:57]1=[O:62]>C(OCC)(=O)C>[CH3:55][C:56]([CH3:60])([CH2:2][C:1](=[O:3])[O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:44])[NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])[C:57]([OH:62])=[O:58]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((1R,3S)-3-(morpholinomethyl)cyclopentylcarbamoyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 23, 0.15 g, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.95-1.16 (m, 19H); 1.23-1.78 (m, 23H); 2.15-2.59 (m, 1H); 2.77-3.58 (m, 11H); 4.33-4.70 (m, 4H); 5.58-5.60 (s, 1H); 5.78-5.80 (s, 1H); 7.44-7.47 (s, 1H); ES Mass: [M+1] 750 (100%); HPLC: 98.08%.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OC)(=O)C(C)=C.CCCCCCCC/C=C\CCCCCCCCOCCO.C(OCCOC(=O)C=C)(=O)C=C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].S(=O)(O)[O-].[Na+]>O>[C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:1]([O:6][CH2:7][CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])(=[O:5])[CH:2]=[CH2:3]
Reactant: C=C(C)C(=O)OCCN(CC)CC
Agent: C=C(C)C(=O)OC
Agent: C=CC(=O)OCCOC(=O)C=C
Agent: CCCCCCCC/C=C\CCCCCCCCOCCO
Solvent: O
Product: C=CC(=O)OCCN(CC)CC
Reaction time: 24 h

Procedure:
50 Grams of N,N-diethylaminoethyl methacrylate, 50 g. of methyl methacrylate, 1 g. of Dupanol ME, 1 g. of Emulphor ON-870, 6 g. of ethylene diacrylate, 1 g. of potassium persulfate, and 0.5 g. of sodium bisulfite are dissolved or mixed with 1,000 g. of water. This mixture is tumbled in a water bath at 60° C. for 24 hr. to obtain a crosslinked copolymer of methyl methacrylate and N,N-diethylaminoethyl acrylate. The crosslinked polymer is separated from the aqueous dispersion by the method described in Example 4.
Reaction SMILES: [O:1]1[C:5]([CH2:6][C:7]([OH:9])=O)=[CH:4][N:3]=[CH:2]1.[CH2:10]([C@@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([CH2:35][CH3:36])=[N:28][N:29]3[CH:32]([CH3:34])[CH3:33])=[CH:25][CH:24]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C@H:17]1[CH2:18][N:19]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([CH2:35][CH3:36])=[N:28][N:29]3[CH:32]([CH3:33])[CH3:34])=[CH:25][CH:24]=2)[CH2:20][CH2:21][N:22]1[C:7](=[O:9])[CH2:6][C:5]1[O:1][CH:2]=[N:3][CH:4]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCc1nn(C(C)C)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: O=C(O)Cc1cnco1
Product: CCc1nn(C(C)C)c2cc(N3CCN(C(=O)Cc4cnco4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 34 %

Procedure:
Prepared by the method outlined for Example 189 using 2-(oxazol-5-yl)acetic acid and 6-((S)-3-benzyl-piperazin-1-yl)-1-isopropyl-3-ethyl-1H-indazole as starting materials. Product was obtained as a light brown solid (34%). LC/MS (Method B) 3.77 min, [M+1]+ 472.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:60])[NH:29][C:30]1[C:34]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH:42]([NH:55][C:56](=[O:58])[CH3:57])[C:43]([NH:45][CH2:46][CH:47]([OH:54])[CH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][CH3:51])=[O:44])=[CH:37][CH:36]=2)=[CH:33][N:32]([CH3:59])[N:31]=1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:56]([NH:55][CH:42]([C:43]([NH:45][CH2:46][C:47](=[O:54])[CH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][CH3:51])=[O:44])[CH2:41][C:38]1[CH:37]=[CH:36][C:35]([C:34]2[C:30]([NH:29][C:28](=[O:60])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:31][N:32]([CH3:59])[CH:33]=2)=[CH:40][CH:39]=1)(=[O:58])[CH3:57]
Reactant: CCC(C)(C)CC(O)CNC(=O)C(Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1)NC(C)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dess-Martin periodinane (403 mg, 0.15 mmol) was added to an ambient temperature solution of tert-butyl[4-(4-{2-(acetylamino)-3-[(2-hydroxy-4,4-dimethylhexyl)amino]-3-oxopropyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate (403 mg, 0.76 mmol) in methylene chloride (10 mL). After stirring at ambient temperature for 2 h, the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded tert-butyl [4-(4-{2-(acetylamino)-3-[(4,4-dimethyl-2-oxohexyl)amino]-3-oxopropyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate.
Reaction SMILES: [OH:1][C@H:2]([C:18]1[S:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[CH:12][CH:11]=1.CI.[C:31](=O)([O-])[O-].[K+].[K+].C[O-].[Na+]>C(#N)C.O.CO>[OH:1][C@H:2]([C:18]1[S:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH3:31])[CH3:17])=[CH:14][CH:15]=1
Reactant: CNc1ccc([C@H]2CC(=O)N(C)[C@H]2[C@H](O)c2ccc(-c3ccccc3)s2)cc1
Reactant: O=C([O-])[O-]
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CI
Product: CN(C)c1ccc([C@H]2CC(=O)N(C)[C@H]2[C@H](O)c2ccc(-c3ccccc3)s2)cc1
Reaction time: 3 h
Yield: 13.7 %

Procedure:
A mixture of (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]-1-methyl-4-[4-(methylamino)phenyl]pyrrolidin-2-one (Example 18, 70 mg, 0.18 mmol), methyl iodide (26 mg, 0.18 mmol) and potassium carbonate (49 mg, 0.36 mmol) in acetonitrile (1 mL) was stirred for 3 h. More methyl iodide (0.26 mg, 0.18 mmol) was added and the mixture was heated at the reflux temperature for 2 h. The reaction mixture was treated with sodium methoxide (20 mg, 0.36 mmol) and methanol (1 mL) and heated at the reflux temperature overnight. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (EtOAc) to give a colorless oil, which was sequentially triturated with EtOAc, Et2O and hexane to provide (±)-(4R*,5R*)-5-[(1S*)-hydroxy(5-phenyl(2-thienyl))methyl]4-[4-(dimethylamino)phenyl]-1-methylpyrrolidin-2-one (10 mg, 14%) as an off-white solid: TLC (EtOAc) Rf 0.40; HPLC ES-MS m/z (rel abundance) 407 (MH+, 100%).
Reaction SMILES: [C:1]([O:9]C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][OH:14]>C(Cl)Cl>[OH:14][CH2:13][CH2:12][NH:11][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1
Reactant: NCCO
Solvent: ClCCl
Product: O=C(NCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 11 %

Procedure:
Under an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), 2-aminoethanol (3.6 mmol), Zn4(OCOCF3)6O (0.15 mmol) and methylene chloride (2.5 mL) was stirred at room temperature for 3 days, and as a result, N-(2-hydroxyethyl)benzamide was obtained in 11% yield. The resulting compound was identified by comparison with physical property data of the known compound.
Reaction SMILES: C1(CO[CH:9]2[CH:14](OCC3C=CC=CC=3)[CH:13](OCC3C=CC=CC=3)[CH:12](COCC3C=CC=CC=3)[NH:11][CH:10]2[CH:40]([OH:45])[CH2:41][CH2:42][CH2:43]O)C=CC=CC=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[CH:40]1([OH:45])[CH:10]2[N:11]([CH2:12][CH2:13][CH2:14][CH2:9]2)[CH2:43][CH2:42][CH2:41]1
Reactant: OCCCC(O)C1NC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: OC1CCCN2CCCCC12
Reaction time: 144 h
Yield: 232.6 %

Procedure:
To a solution of Compound (XIX) (0.22 g, 0.36 mmoles) in pyridine (15 mL), cooled at -10° C., methanesulfonyl chloride (0.03 mL, 0.39 mmoles) was added. After 6 days, the mixture was evaporated under reduced pressure. The resulting oil was treated with water (5 mL) and saturated aqueous sodium bicarbonate solution (20 mL), then extracted with ether (2×30 mL). The combined organic solution was dried over magnesium sulfate and the solvent evaporated under reduced pressure. Trituration of the resulting oil with ether yielded [1S-(1α,6β,7α,8β,9α,9aβ)]-octahydro-7,8,9-tris (phenylmethoxy)-6-[(phenylmethoxy)methyl]-2H-quinolizin-1-ol (XX) as white crystals (0.13 g, 60.8%) m.p. 103°-5° C.; IR (KBr) no absorbance 1650-1770 cm-1;MS (CI13 CH4) 594 (MH+), 486 (MH+ --PhCH2OH); 1H nmr (CDCl3) δ 1.2 (m, 1H), 1.4-1.6 (m, 3H), 1.8-2.0 (m, 2H), 2.6-2.8 (t, 1H), 3.0-3.1 (d, 1H), 3.2-3.3 (m, 1H), 3.5-3.9 (m, 4H), 4.2-5.0 (m, 9H), 7.1-7.4 (m, 20H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C@@H:7]1[CH2:12][N:11]([CH3:13])[CH2:10][CH2:9][N:8]1[C:14](=[O:24])[C@H:15]([O:20]C(=O)C)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:6].C1COCC1.CO>O>[OH:20][C@H:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]([N:8]1[CH2:9][CH2:10][N:11]([CH3:13])[CH2:12][C@H:7]1[C:5]([OH:6])=[O:4])=[O:24]
Reactant: COC(=O)[C@@H]1CN(C)CCN1C(=O)[C@H](OC(C)=O)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1CCN(C(=O)[C@H](O)C(C)(C)C)[C@H](C(=O)O)C1
Yield: 59.8 %

Procedure:
A solution of LiOH (0.016 g, 0.66 mmol) in water (2 mL) was added to a stirred solution of (S)-methyl-1-{(R)-2-acetoxy-3,3-dimethylbutanoyl}-4-methylpiperazine-2-carboxylate (0.07 g, 0.22 mmol) in a 1:1 THF:MeOH mixture (3 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in water (10 mL), acidified with 1M aqueous HCl to pH 2-3 and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (0.034 g) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C@H:48]1[CH2:53][CH2:52][CH2:51][CH2:50][NH:49]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:49]4[CH2:50][CH2:51][CH2:52][CH2:53][C@@H:48]4[CH3:47])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCC[C@@H]2C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (S)-(+)-2-methylpiperidine (Aldrich) to give the title product. LC-MS (ES+) 746 [(M+H)+].
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:35][NH:34][CH2:33]2)=[N:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[OH:37][C:38]1([C:45]2[S:46][CH:47]=[CH:48][N:49]=2)[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1>>[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:33][N:34]([CH:41]3[CH2:40][CH2:39][C:38]([OH:37])([C:45]4[S:46][CH:47]=[CH:48][N:49]=4)[CH2:43][CH2:42]3)[CH2:35]2)=[N:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: O=C1CCC(O)(c2nccs2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(O)(c4nccs4)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butyl amide TFA salt and 4-hydroxy-4-thiazol-2-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:2]=1>N>[C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([CH2:9][NH2:10])=[CH:11][CH:12]=[C:13]([C:15]([F:17])([F:16])[F:18])[N:14]=2)[CH:2]=1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2C#N)c1
Agent: N
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Yield: 93.7 %

Procedure:
2-m-tolyl-6-(trifluoromethyl)nicotinonitrile (1.87 g, 7.159 mmol) was dissolved in 2 M methanolic ammonia solution (286 mL, 0.025 mmol/mL) and hydrogenated in an H-cube apparatus (10 bar, 80° C., 1 mL/min, 0.25 mol/L). After removal of the solvent under vacuum, (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (1.787 g, 94%) was obtained as a white solid. The reaction step was repeated to afford in summary 3.61 g of (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH3:10][CH2:11][O:12][C:13]([CH:15]1[CH2:21][CH2:20][C:18](=[O:19])[CH2:17][CH2:16]1)=[O:14]>Cl[Ti](OC(C)C)(OC(C)C)OC(C)C>[OH:19][C:18]1([C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)[CH2:17][CH2:16][CH:15]([C:13]([O:12][CH2:11][CH3:10])=[O:14])[CH2:21][CH2:20]1
Reactant: Fc1cccc(F)c1F
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: CC(C)O[Ti](Cl)(OC(C)C)OC(C)C
Product: CCOC(=O)C1CCC(O)(c2cc(F)c(F)c(F)c2)CC1

Procedure:
Thus, 1-triisopropyloxytitanyl, 3,4,5-trifluorobenzene--prepared by transmetalation of 3,4,5-trifluorobenzenemagnesiumbromide using chlorotriisopropyloxytitanium--is reacted chemoselectively with ethyl cyclohexanone-4-carboxylate (1) on the carbonyl group to give ethyl 4-hydroxy-4(3,4,5-trifluorophenyl)cyclohexanecarboxylate. Elimination of water, catalytic hydrogenation over Pd/C, hydrolysis and epimerization using KOH/methanol give the pure trans 4-(3,4,5-trifluorophenyl)cyclohexanecarboxylic acid-(1). The latter is converted into the mixed anhydride using pivaloyl chloride and, using N,O-dimethylhydroxylamine, into the corresponding amide. The latter is reduced in high yield using LiAlH4 to give the aldehyde IIIa'.
Reaction SMILES: N1C=CC=CC=1[C:7]1[CH:12]=[CH:11]C=CN=1.[CH:13]1([C:16]2[NH:20][N:19]=[C:18]([N:21]3[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[CH3:27])[CH:17]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:11]1([N:20]2[C:16]([CH:13]3[CH2:15][CH2:14]3)=[CH:17][C:18]([N:21]3[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[CH3:27])=[N:19]2)[CH2:12][CH2:7]1
Reactant: Cc1ccc(C)n1-c1cc(C2CC2)[nH]n1
Reactant: c1ccc(-c2ccccn2)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Product: Cc1ccc(C)n1-c1cc(C2CC2)n(C2CC2)n1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 104.2 %

Procedure:
A suspension of copper (II) acetate (0.902 g, 4.97 mmol) and 2,2′-bipyridine (0.776 g, 4.97 mmol) in DCE (20 mL) is stirred at 70° C. for 15 min, then transferred to a suspension of cyclopropyl trifluoroborate potassium salt (1.47 g, 9.94 mmol) and 5-Cyclopropyl-3-(2,5-dimethyl-pyrrol-1-yl)-1H-pyrazole (1 g, 4.97 mmol), and sodium carbonate (1.053 g, 9.94 mmol) in DCE (40 mL). The resulting dark-green mixture is stirred at 70° C. for 24 h. T The reaction mixture is partitioned between EtOAc and 1N HCl. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated. The residue (1.64 g) is purified by ISCO (EtOAc-heptane 0-30%) to provide the desired product (1.25 g) as a colorless oil. MS (ESI) m/z 242.3 (M+1).
Reaction SMILES: [NH:1]([CH2:6][CH2:7][CH2:8][OH:9])[CH2:2][CH2:3][CH2:4][OH:5].[C:10]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[CH2:11][CH2:12][CH2:13][CH2:14][C:15](ON1C(=O)CCC1=O)=[O:16]>CN(C=O)C>[OH:5][CH2:4][CH2:3][CH2:2][N:1]([CH2:6][CH2:7][CH2:8][OH:9])[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]
Reactant: O=C(CCCCC(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Reactant: OCCCNCCCO
Solvent: CN(C)C=O
Product: O=C(CCCCC(=O)N(CCCO)CCCO)OCc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 3,3′-azanediylbis(propan-1-ol) (1000 mg, 7.51 mmol, 1.0 eq) was in DMF (10 ml), was added benzyl (2,5-dioxopyrrolidin-1-yl) adipate (2503 mg, 7.51 mmol, 1.0 eq) followed by TEA (1.046 ml, 7.51 mmol, 1.0 eq). The reaction was stirred at 25 deg for 18 hr. UPLC indicated formation of desired product. DMF was removed under reduced pressure. The crude was purified by C18 Reverse phase chromatograph (eluted with 0-40% ACN/water in 16 CV). Fractions containing desired product were combined and concentrated to give the titled compound as colorless oil (1.55 g, 4.41 mmol, 58.7%). UPLC Method B: m/e=352.2171 [M+1]; Rt=3.47 min. 1H NMR (CDCl3, 500 MHz) δ 7.3-7.5 (m, 5H), 5.15 (m, 2H), 3.65 (m, 2H), 3.40 (m, 5H), 2.66 (s, 3H), 2.45 (m, 3H), 2.29 (s, 1H), 1.84 (s, 1H), 1.70 (m, 7H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31]>>[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:24]=1[S:30]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:31])=[O:32]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 81 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and conditions outlined in procedure P. M.p.=247-249° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89-7.86 (m, 1H), 7.66-7.61 (m, 1H), 7.57-7.52 (m, 1H), 7.41-7.38 (m, 1H), 3.80 (s, 3H), 3.56-3.51 (m, 2H), 3.11 (s, 2H), 2.88-2.81 (m, 2H), 2.29 (s, 3H), 2.13-2.06 (m, 2H), 1.93-1.84 (m, 2H); LCMS: 494 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=S)[C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6])[CH3:3].[C:23](OCC)(=[O:26])[NH:24][NH2:25]>>[CH3:1][N:2]([CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]2[C:23](=[O:26])[NH:24][N:25]=[C:10]2[C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6])[CH3:3]
Reactant: CN(C)CC(=O)N1c2ccccc2NC(=S)c2cccnc21
Reactant: CCOC(=O)NN
Product: CN(C)CC(=O)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
A mixture of 6,11-dihydro-11-[(dimethylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione (0.12 mole) and ethyl carbazate (1.2 mole) is heated in an oil bath preheated to 195°-205° C. using a take-off condenser (45 ml. is removed). The resulting solid is mixed with methylene chloride-water and the suspension is filtered. The filtrate is separated into layers, and the organic layer is washed with water, then brine solution and dried over anhydrous magnesium sulfate. The solvent is then evaporated and the resulting residue is repeatedly crystallized from methylene chloride to give 2,9-dihydro-9-[(dimethyl-amino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]-benzodiazepin-3-one.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[F:39])[N:20]=[C:21]4[C:26]=3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]([F:30])([F:29])[F:28])[CH:13]=2)[CH:5]=1.COC(=O)C1C=CC(COC2C=CC(C3N(CC4C=CC=CC=4)N=C4C=3C=CC=C4C(F)(F)F)=CC=2)=CC=1.[CH2:79]([NH2:86])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1.C([Mg]Br)CCC>C1COCC1.CCOCC>[CH2:79]([NH:86][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[F:39])[N:20]=[C:21]4[C:26]=3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]([F:28])([F:30])[F:29])[CH:13]=2)[CH:5]=1)[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1
Reactant: COC(=O)c1cccc(COc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccc(Cl)cc3F)c2)c1
Reactant: NCc1ccccc1
Agent: CCCC[Mg]Br
Agent: COC(=O)c1ccc(COc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NCc1ccccc1)c1cccc(COc2cccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccc(Cl)cc3F)c2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Fifty-seven milligrams (57 mg; 0.1 mmol) of 3-[3-(2-(4-chloro-2-fluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl)-phenoxymethyl]-benzoic acid methyl ester (prepared similarly to that of 4-[4-(2-benzyl-7-trifluoromethyl-2H-indazol-3-yl)-phenoxymethyl]-benzoic acid methyl ester in preparation of Example 2) were dissolved in 2 ml of dry THF followed by the addition of 110 μl of benzylamine (1 mmol). The reaction mixture was cooled to −30° C. and 450 μl of 2M solution of butylmagnesiumbromide in ether were added dropwise. Then the reaction mixture was stirred for 30 min at −30° C. and left overnight at 0° C. The reaction mixture was quenched with aq NH4Cl solution and product was extracted with EtOAc. Flash column chromatography (SiO2, dichloromethane as an eluant) afforded N-benzyl-3-({3-[2-(4-chloro-2-fluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenoxy}methyl)benzamide in 66% yleld.
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][C:2]=12.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:4]1[CH:5]=[CH:6][N:1]=[C:2]2[CH2:9][CH2:8][CH2:7][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2c1CCC2
Product: Clc1ccnc2c1CCC2
Temperature: 120 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
6,7-Dihydro-5H-cyclopenta[b]pyridine 1-oxide (2.5 g, 18 mmol) was mixed with POCl3 (20 mL). The reaction mixture was stirred at 120° C. for 3 h. The excess POCl3 was removed under reduced pressure. The residue was diluted in EtOAc (80 mL) and neutralized with aq. Na2CO3. After filtration, the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the sub-title compound (2.6 g, 93%). LCMS calc. for C8H9ClN (M+H)+: m/z=154.0. Found: 154.3.