Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]2[N:11]3[CH2:25][CH2:24][N:23]([CH3:26])[C:22](=[O:27])[C:12]3=[C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[C:8](=[O:28])[N:7]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=2)[N:6]=1)=[O:4].Cl.[NH2:39][NH:40][C:41]([NH2:43])=[O:42].C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:15]([O:14][C:13]1[C:9]2[C:8](=[O:28])[N:7]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([Cl:37])[CH:31]=3)[N:6]=[C:5]([C:3](=[O:4])[CH2:2][NH:39][NH:40][C:41]([NH2:43])=[O:42])[C:10]=2[N:11]2[CH2:25][CH2:24][N:23]([CH3:26])[C:22](=[O:27])[C:12]=12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)CBr)c32)C1=O
Reactant: NNC(N)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(C(=O)CNNC(N)=O)c32)C1=O

Procedure:
A solution of crude 4-bromoacetyl-10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (1.25 g, 2.13 mmol) in anhydrous THF, semicarbazide hydrochloride (0.35 g, 3.14 mmol), and diisopropylethylamine (0.66 mL, 3.77 mmol) was heated in a sealed tube at 100° C. for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was dissolved in DMSO and subject to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fraction provided the intermediate 2-{2-[10-(benzyloxy)-2-(3-chloro-4-fluorobenzyl)-8-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazin-4-yl]-2-oxoethyl}hydrazinecarboxamide as white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][C:9]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:10])=[O:7])([CH3:4])[CH3:3].[CH3:19][CH2:20][C:21](=O)[CH2:22][C:23](=O)[CH2:24][CH3:25].C[O-].[Na+]>CO>[CH2:20]([C:21]1[CH:22]=[C:23]([CH2:24][CH3:25])[C:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[C:9]([OH:10])[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:19]
Reactant: CCC(=O)CC(=O)CC
Reactant: CC(C)(C)OC(=O)CC(=O)CC(=O)OC(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1cc(CC)c(C(=O)OC(C)(C)C)c(O)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A mixture of di-tert-butyl 1,3-acetonedicarboxylate (10 g, 38.7 mmol), 3,5-heptanedione (6.5 g, 50.3 mmol) and sodium methoxide (2.7 g, 50.3 mmol) in methanol (100 mL) was stirred at room temperature overnight. Methanol was removed via rotary evaporation and the resulting orange sludge was partitioned between diethyl ether (100 mL) and 10% aqueous hydrochloric acid (100 mL). The separated aqueous layer was extracted with diethyl ether (50 mL×2). The combined organic portions were washed with saturated aqueous sodium chloride (20 mL), dried over sodium sulfate, filtered through a pad of silica (20 mm×40 mm) and concentrated in vacuo to yield a yellow oil (13.23 g, 97%): 1H NMR (300 MHz, CDCl3): δ 1.20 (t, 6H), 1.60 (s, 18H) 2.74 (q, 4H), 6.55 (s, 1H), 11.73 (s, 1H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnn2ccc(Cl)nc12
Yield: 97.6 %

Procedure:
Ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (22.7 g, 110 mmol) was suspended in phosphoryl trichloride (100 mL) and heated to reflux. After heating for 2 hours, the reaction mixture was cooled and concentrated to remove the excess POCl3. The residue was diluted in DCM (100 mL) and slowly added to a flask containing ice water. The mixture was separated and the aqueous layer extracted with DCM. The combined organics were dried with MgSO4, filtered and concentrated to afford ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (24.2 g, 97.6% yield) as a pale yellow solid. MS (apci) m/z=225.9 (M+H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[C:27]([F:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=2[F:30])([C:20]#[N:21])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:29][C:25]1[CH:26]=[C:27]([F:28])[C:22]([C:11]2([C:20]#[N:21])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:23]([F:30])[CH:24]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1c(F)cc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1c(F)cc(Cl)cc1F
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 108b (0.9 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (0.9 g, 91%).
Reaction SMILES: [OH-:1].[K+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]>>[O:3]=[CH:4][C@@H:5]([C@H:7]([C@@H:7]([C@@H:5]([CH2:4][OH:3])[OH:6])[OH:1])[OH:8])[OH:6]
Reactant: OCC(O)CO
Reactant: [OH-]
Agent: [K+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.17 h

Procedure:
The medium was adjusted to pH 7.0 with KOH, autoclaved at 115° C. for 10 minutes (provided that glycerol or glucose and MgSO4.7H2O were separately sterilized) and then 30 g/L of CaCO3 defined in Japanese Pharmacopoeia (subjected to hot air sterilization at 180° C. for 2 hours) was added.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:32])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:34][S:35](O)(=[O:37])=[O:36]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:32])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([S:35]([Cl:34])(=[O:37])=[O:36])=[CH:28][CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(COc1ccccc1)NCCCCCC(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=C(COc1ccc(S(=O)(=O)Cl)cc1)NCCCCCC(=O)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a cooled solution of 6-(2-phenoxy-acetylamino)-n-hexanoic acid 2-(3-nitro-benzenesulfonyl)ethyl ester (4.5 g, 9.4 mmol) in 10 mL of CH2Cl2 was added drop-wise ClSO3H (3.3 mL, 5.5 g, 5 eq., 47.0 mmol)) at 0° C. The chlorosulfonylation reaction was complete in 30 min. The thick reaction mixture was poured onto the crushed ice with vigorous stirring, resulting in a yellow gummy material mostly in the bottom of the flask. The mixture was extracted with CH2Cl2, the organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a syrupy material, which was purified by column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to give 6-[2-(4-chlorosulfonyl-phenoxy)-acetylamino]-n-hexanoic acid 2-(3-nitro-benzenesulfonyl)ethyl ester (Intermediate 19, 3.3 g, 60%) as a white foam.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[C:21]2[C:20]3[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[C:18]([O:30][CH3:31])[CH:17]=[CH:16][C:15]=3[C:14]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)=[N:13][C:12]=2[NH:11][N:10]=1.C=O.[CH:41](O)=O>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[C:21]2[C:20]3[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][N:27]([CH3:41])[CH2:26][CH2:25]4)=[C:18]([O:30][CH3:31])[CH:17]=[CH:16][C:15]=3[C:14]([C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)=[N:13][C:12]=2[NH:11][N:10]=1
Reactant: COc1ccc2c(-c3ccc(O)cc3)nc3[nH]nc(C)c3c2c1OCC1CCNCC1
Reactant: O=CO
Agent: C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(-c3ccc(O)cc3)nc3[nH]nc(C)c3c2c1OCC1CCN(C)CC1
Temperature: 110 °C
Yield: 23 %

Procedure:
To 4-{1-methyl-8-(methyloxy)-9-[(piperidin-4-ylmethyl)oxy]-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol hydrogen trifluoroacetate (47 mg, 0.11 mmol) was added 37% aqueous formaldehyde (10 μL) and formic acid (150 μL). The mixture was heated to 110° C. for 1.5 h before cooling to rt. The mixture was diluted with a 1:1 mixture of water:acetonitrile and purified by preparative HPLC. The fractions containing desired product were combined, concentrated, and lyophilized to provide 4-(1-methyl-8-(methyloxy)-9-{[(1-methylpiperidin-4-yl)methyl]oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol trifluoroacetate (14.1 mg, 0.026 mmol, 23% yield). 1H NMR (400 MHz, DMSO-d6): δ9.93 (br m, 2H), 7.87 (d, 1H), 7.48 (d, 2H), 7.44 (d, 1H), 6.96 (m, 2H), 4.00 (s, 3H), 3.45 (m, 2H), 3.00-2.96 (q, 2H), 2.83 (s, 3H), 2.74 (d, 3 h), 2.18 (m, 1H), 2.09 (br d, 2H), 1.61-1.52 (m, 2H); MS (EI) for C25H28N4O3: 433 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([CH2:15][CH2:16][CH2:17][C:18](OCC)=[O:19])[C:13]4[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=4[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:13]4[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=4[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)CCCn1c(-c2ccc3c(c2)OCO3)nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCn1c(-c2ccc3c(c2)OCO3)nc2ccccc21
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a solution of 762 mg (2.45 mmol) of ethyl 2-(1,3-benzodioxol-5-yl)-1H-benzimidazole-1-butanoate, the title compound of Example 1, in 12 mL of THF was added 2.45 mL of LAH (1M in THF) at ambient temperature, and the resulting mixture was stirred overnight. The reaction was quenched with water, extracted with ether, and the combined extracts were dried, and concentrated in vacuo. The residue was purified by silica gel chromatography to give 538 mg (83%) of 2-(1,3-benzodioxol-5-yl)-1H-benzimidazole-1-butanol as a colorless glass: 1H NMR (CDCl3) δ 1.52 (quintet, J=7.8 Hz, 2H), 1.92 (quintet, J=7.7 Hz, 2H), 3.61 (t, J=6.2 Hz, 2H), 4.29 (t, J=7.7 Hz, 2H), 6.06 (s, 2H), 6.93 (d, J=8.4 Hz, 1H), 7.15-7.25 (m, 2H), 7.25-7.37 (m, 2H), 7.38-7.45 (m, 1H), 7.78-7.88 (m, 1H); HRMS (FAB) Calc'd for M+H: 311.1396, found: 311.1447. Anal. Calc'd for [C18H18N2O3 +0.09 CH2Cl2 ]: C, 68.39; H, 5.77; N, 8.82. Found: C, 68.39; H, 5.81; N, 8.82.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([F:17])[C:11]=2[OH:18])=[O:9])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:11]1[C:12]([F:17])=[N:13][C:14]([Cl:16])=[CH:15][C:10]=1[C:8]2=[O:9]
Reactant: O=C(c1cc(Br)ccc1F)c1cc(Cl)nc(F)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1c2cc(Br)ccc2oc2c(F)nc(Cl)cc12
Temperature: 100 °C
Yield: 87.3 %

Procedure:
A solution of (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-hydroxypyridin-4-yl)methanone (730 g, 2.10 mol) in dioxane (6 L) was treated with Cs2CO3 (1024 g, 3.14 mol). The reaction mixture was heated to 100° C. for 5 hours and then cooled to RT. Water (9 L) was added and the mixture was stirred vigorously. The resulting solids were filtered, washed with water (1 L×2), hexanes (1 L×1), and EtOAc (700 mL) to provide 602 g of 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].CC1(C)C(C)(C)OB([C:22]2[CH:30]=[CH:29][C:25]3[N:26]=[CH:27][O:28][C:24]=3[CH:23]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[C:6]([C:22]2[CH:30]=[CH:29][C:25]3[N:26]=[CH:27][O:28][C:24]=3[CH:23]=2)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13]
Reactant: CC1(C)OB(c2ccc3ncoc3c2)OC1(C)C
Reactant: COC(=O)c1nc(Br)cc(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1nc(-c2ccc3ncoc3c2)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
0.024 g (0.03 mmol) of (PPh3)2PdCl2 is added to a solution of 0.3 g (1.13 mmol) of methyl 4-amino-6-bromo-3-chloropyridine-2-carboxylate in 20 ml of dioxane, and this mixture is stirred at RT for 30 min. In succession, 0.28 g (1.13 mmol) of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole, 0.47 g (3.4 mmol) of K2CO3 and 2 g (111 mmol) of H2O are then added to this mixture, which is then stirred under reflux for 6 h. The mixture is allowed to stand at RT for a further 12 h and then added to 40 ml of H2O. This mixture is extracted repeatedly with CH2Cl2, and the combined organic phase is dried over Na2SO4 and then concentrated. Purification by chromatography on silica gel using the mobile phase heptane/ethyl acetate (3/7) gives 0.1 g (29%) of product. 1H-NMR (CDCl3): δ 8.25 (s, 1H, benzoxazole), 8.15 (s, 1H, benzoxazole), 7.90, 7.80 (2d, 2H, benzoxazole), 7.20 (s, 1H, pyridine), 4.80 (bs, 2H, NH2), 4.00 (s, 3H, COOCH3).
Reaction SMILES: [F:1][C:2]1([F:34])[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:33]=[CH:32][C:22]([C:23]([NH:25]C4CCOCC4)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH2:3]1.[O:35]1[CH2:40][CH2:39][CH:38]([CH2:41]N)[CH2:37][CH2:36]1>>[F:1][C:2]1([F:34])[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:41][CH:38]4[CH2:39][CH2:40][O:35][CH2:36][CH2:37]4)=[O:24])=[CH:32][CH:33]=3)(=[O:17])=[O:18])[CH:8]=2)[CH2:3]1
Reactant: NCC1CCOCC1
Reactant: O=C(NC1CCOCC1)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Product: O=C(NCC1CCOCC1)c1ccc(S(=O)(=O)n2cc(C3CCC(F)(F)C3)c3ccccc32)cc1
Yield: 100 %

Procedure:
Using a similar procedure as for 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-yl)-benzamide using C-(Tetrahydro-pyran-4-yl)-methylamine in place of Tetrahydro-pyran-4-ylamine to give 4-[3-(3,3-Difluoro-cyclopentyl)-indole-1-sulfonyl]-N-(tetrahydro-pyran-4-ylmethyl)-benzamide (280 mg, 100% yield). Mass Spectrum (m/e): 503.98 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[CH:36][NH:37]2)=[CH:33][CH:32]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[CH:39]=[C:38]4[C:34]([CH:35]=[CH:36][NH:37]4)=[CH:33][CH:32]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: Nc1ccc2cc[nH]c2c1
Product: CCOC(=O)c1cnn2c(Nc3ccc4cc[nH]c4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 97.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.15 g, 0.36 mmol) obtained in Example 19, step 4 and 6-aminoindole (0.054 g, 0.72 mmol), the title compound (0.179 g, 98%) was obtained.
Reaction SMILES: C(OC([N:8]([C:26]1[CH:38]=[CH:37][C:29]([C:30](N2C=CN=C2)=[O:31])=[CH:28][CH:27]=1)[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][CH2:22][CH2:23][CH2:24][Br:25])=O)(C)(C)C.[OH-].[Na+].[NH2:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45]>C(Cl)(Cl)Cl>[Br:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45])=[O:31])=[CH:37][CH:38]=1
Reactant: NCC(O)CO
Reactant: CC(C)(C)OC(=O)N(CCCCCCCCCCCCCCCCBr)c1ccc(C(=O)n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(NCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-{4-[N-(t-butyloxycarbonyl)-N-(16-bromohexadecyl)amino]benzoyl}imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solid is evaporated and the residue is heated for 30 minutes at 40° C. and 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield the product as a light yellow crystalline solid.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([CH:20]([CH3:22])[CH3:21])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH:20]([C:11]1[CH:12]=[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1cc2c(c(-c3ccccc3)c1)OC(CN=[N+]=[N-])C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)c1cc2c(c(-c3ccccc3)c1)OC(CN)C2
Yield: 48 %

Procedure:
To a solution of 4-isopropylphenol (13.38 g, 98.0 mmol) with N-bromosuccinimide (17.5 g, 98 mmol) generally according to the procedure described for Example 305 afforded 13.78 g (65%) of 2-bromo-4-isopropylphenol. Treatment of 2-bromo-4-isopropylphenol (13.74 g, 41.0 mmol) with potassium carbonate (22.0 g, 160 mmol) and allyl bromide (9.23 g, 76.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-isopropylphenol. Treatment of 2-allyl-6-bromo-4-isopropylphenol (6.85 g, 27.0 mmol) with 3-chloroperoxybenzoic acid (7.72 g, 27.0 mmol, 77%) followed by potassium carbonate (9.3 g, 67.5.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.12 g, (17%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.12 g, 4.6 mmol) with p-toluenesulfonyl chloride (1.32 g, 6.9 mmol) generally according to the procedure described for Intermediate 10 gave 1.90 g (97%) of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-isopropyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.4 g, 0.94 mmol) and 2-methylphenylboronic acid (0.38 g, 2.82 mmol) generally according to the procedure described for Intermediate 35 afforded 0.19 g, (46%) of (5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.141 g, 2.17 mmol) generally according to the procedure described for Intermediate 98 afforded 0.11 g (83%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.188 g, 0.716 mmol) according to the procedure described in Example 154 afforded 0.055 g (48%) of (±)-[(5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 221-222° C. (dec).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C
Temperature: 55 °C
Reaction time: 3.5 h

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (0.67 g, 2.1 mmol) and o-toluidine (0.24 g, 2.3 mmol) in acetonitrile was heated to 55° C. and stirred for 3.5 h. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. The residue was triturated with diisopropylether. The precipitated product was filtered off and washed with diisopropyl ether giving 0.55 g (66%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[N+:31]([CH3:34])([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C@@:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)([CH2:34][N+:31]([O-:33])=[O:32])[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
Alternatively, 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (0.075 g, 0.163 mmol) and antracen-9-yl-methyl quininium bromide (0.020 g, 0.034 mmol) were dissolved in toluene (2.0 ml). Nitromethane (10 molar equivalents) and potassium carbonate (0.025 g, 0.181 mmol) were added and the resulting suspension was stirred at 50° C. for 24 h. The reaction mixture was cooled to room temperature and water was added. The resulting mixture was extracted with dichloromethane (3×) and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (0.051 g, 60%) as a white foam. Chiral HPLC analysis (Chiralpack AS-RH, Heptane/2-propanol=90:10, 1 ml/min, retention time 6.13 minutes (major enantiomer), 7.35 minutes (minor enantiomer)) indicated that the reaction proceeded with 62% enantioselectivity.