Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:37][N:38]1[CH2:43][CH2:42]N[CH2:40][CH2:39]1>C1COCC1>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([N:18]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)N3CCN(C)CC3)cc21
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with 1-methyl-piperazine (1 equivalent). After an additional 18 hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-3 as an oil in 95% yield.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H].ClCCl>C(OCC)(=O)C.[Pd]>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(C#Cc3ccccc3)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(CCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, to a solution of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(phenylethynyl)pyrazin-2-amine (7p) (400 mg, 996 μmol) in ethyl acetate (20 mL) was added Palladium/charcoal activated (10% Pd) (80.0 mg) at room temperature. The atmosphere in the reaction flask was replaced with hydrogen gas and the mixture was stirred at room temperature for 3 hours. After replacing the atmosphere of the reaction system again with argon, to the mixture was added dichloromethane (15 mL) and stirred at room temperature for an hour. The catalyst was removed by filtration. After concentration under reduced pressure, the residue was purified by column chromatography (silica gel 40 g, n-hexane/ethyl acetate=2/1) to give Compound 7r (403 mg, 994 μmol, 99.8%) as a brown oily substance. Rf=0.48 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 0.18 (s, 6H), 0.93 (s, 9H), 2.92 (t, 3H, J=8.0 Hz), 3.05 (t, 3H, J=8.0 Hz), 6.25 (s, 2H), 6.81-6.90 (AA′BB′, 2H), 7.10-7.18 (m, 1H), 7.18-7.35 (m, 4H), 7.75-7.85 (AA′BB′, 2H), 8.27 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.5 (2C), 18.0, 25.6 (3C), 31.7, 34.0, 120.0 (2C), 125.7, 126.1 (2C), 128.2 (2C), 128.5 (2C), 130.9, 135.6, 138.5, 140.1, 141.9, 152.3, 154.6; IR (KBr, cm−1) 507, 635, 677, 698, 750, 781, 841, 914, 1009, 1103, 1146, 1167, 1213, 1254, 1389, 1420, 1454, 1512, 1605, 2857, 2928, 2955, 3061, 3318.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2=[N:3][C:4]([CH3:11])=[CH:5][CH:6]=[C:7]2[N:8]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CC(=O)Nc1ccccc1
Product: Cc1ccc2nc(C)n(-c3ccccc3)c2n1
Yield: 62.7 %

Procedure:
Method A applied to 2-chloro-6-methyl-3-nitropyridine (86 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) afforded the title compound as brown viscous oil (70 mg, 63%). 1H NMR (DMSO) δ 2.42 (s, 3H), 3.31 (s, 3H), 7.11 (d, J=8.0Hz, 1H), 7.51-7.63 (m, 5H), 7.89 (d, J=8.0Hz, 1H); 13C NMR δ 14.6, 23.8, 118.0, 126.1, 127.7, 128.7, 129.4, 132.1, 134.8, 148.3, 150.9, 151.1. HRMS: cal. for C14H14N3 [M+H+]: 224.1188; found: 224.1184.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][O:7][C@@H:6]([C@H:9]2[O:13][N:12]=[C:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=4)=[O:22])[CH:15]=3)[CH2:10]2)[CH2:5][O:4]1.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([NH:1][CH2:2][C@@H:3]1[CH2:8][O:7][C@@H:6]([C@H:9]2[O:13][N:12]=[C:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([C:21]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([O:32][CH3:33])[CH:26]=4)=[O:22])[CH:15]=3)[CH2:10]2)[CH2:5][O:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](CN)CO4)C3)nc(C)n2)ccc1F
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NO[C@H]([C@H]4CO[C@H](CNC(C)=O)CO4)C3)nc(C)n2)ccc1F
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a stirred solution of 6-((S)-5-((2R,5R)-5-(aminomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.08 g, 0.174 mmol, Preparation #J.1) in DCM (5 mL) at 0° C., was added TEA (0.073 mL, 0.522 mmol, Spectrochem) followed by acetyl chloride (0.015 mL, 0.209 mmol, Spectrochem). The reaction mixture was stirred for 30 min, was diluted with DCM (30 mL) and washed with water (2×20 mL). The organic layer dried over sodium sulphate and concentrated under reduced pressure. The resulting crude material was purified by preparative TLC eluting with 60% EtOAc in hexane to afford 6-((S)-5-((2R,5R)-5-(acetamidomethyl)-1,4-dioxan-2-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 0.065 g (74%); 1H NMR (400 MHz, DMSO): δ 9.50 (t, J=5.6 Hz, 1H), 8.13 (s, 1H), 7.93 (t, J=5.6 Hz, 1H), 7.17-7.11 (m, 2H), 6.89-6.81 (m, 1H), 4.81-4.75 (m, 1H), 4.48 (d, J=6.4 Hz, 2H), 3.88-3.86 (m, 1H), 3.81 (s, 3H), 3.78-3.63 (m, 2H), 3.46-3.36 (m, 4H), 3.32-3.22 (m, 2H), 3.08-3.00 (m, 2H) 2.75 (s, 3H), 1.79 (s, 3H); LC/MS (Table 1, Method e) Rt=2.69 min; MS: m/z 502 (m+H)+.
Reaction SMILES: [CH:1](=O)[CH3:2].[N+:4]([C:7]1[N:8]=[C:9]2[N:14]([CH:15]=1)[CH2:13][CH2:12][C@H:11]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=1)[O:10]2)([O-:6])=[O:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:30]([CH:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][C@@H:11]3[O:10][C:9]4=[N:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:15][N:14]4[CH2:13][CH2:12]3)=[CH:23][CH:22]=2)[CH2:25][CH2:26]1)[C:31]1[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1)[CH3:2]
Reactant: CC=O
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(Nc4ccc(C(F)(F)F)cc4)CC3)cc1)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(c1ccc(C(F)(F)F)cc1)C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetaldehyde (2.2 ml) was added to an acetic acid solution (11 ml) of N-{1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-(4-trifluoromethylphenyl)amine (2.2 g). Subsequently, sodium triacetoxyborohydride (2.52 g) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, and neutralized with a 5 N sodium hydroxide aqueous solution and a saturated sodium hydrogen carbonate aqueous solution. The resulting precipitate was collected by filtration and dried. The solid thus obtained was purified by silica gel column chromatography (methylene chloride:ethyl acetate=50:50) and recrystallized from acetone-ethyl acetate to afford the title compound as a yellow powder (1.96 g).
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([CH2:36]C(OCC)=O)[C:22](=[O:35])[CH2:23][N:24]2C(=O)C3=CC=CC=C3[C:25]2=[O:34])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.CN>ClCCl.CO>[Cl:1][C:2]1[C:20]([N:21]2[CH2:36][C:25](=[O:34])[NH:24][CH2:23][C:22]2=[O:35])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CCOC(=O)CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: CN
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N4CC(=O)NCC4=O)c3Cl)c2n1
Reaction time: 24 h
Yield: 50 %

Procedure:
To the solution of 8-[2,6-dichloro-3-[N-ethoxycarbonylmethyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methylquinoline (527 mg) in dichloromethane (5.3 ml) was added 30% solution of methylamine in methanol (2 ml) at ambient temperature. After stirring for 24 hours, the reaction mixture was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel 50 ml) eluting with dichloromethane/methanol (20/1, V/V) and by crystallizing from isopropyl ether to give 8-[2,6-dichloro-3-(2,5-dioxopiperazin-1-yl)benzyloxy]-2-methylquinoline (187 mg) as colorless crystals.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[C:12]([C:19]([O:21]C)=[O:20])[N:11]=2)=[O:9])=[CH:6][C:5]=1[O:25][CH3:26].O1CCOCC1.S([O-])(O)(=O)=O.[K+]>CO>[NH2:3][C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[C:12]([C:19]([OH:21])=[O:20])[N:11]=2)=[O:9])=[CH:6][C:5]=1[O:25][CH3:26]
Reactant: COC(=O)c1nc(C(=O)c2ccc(N)c(OC)c2)n2ccccc12
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(C(=O)c2nc(C(=O)O)c3ccccn23)ccc1N

Procedure:
1.67 ml (1.67 mmol) of a 1N aqueous sodium hydroxide solution are added to 0.272 g (0.84 mmol) of methyl 3-(4-amino-3-methoxybenzoyl)imidazo[1,5-a]pyridine-1-carboxylate obtained in example 150 in 12 ml of a mixture (1/1) of dioxane and methanol. After heating at reflux for 2 hours, the reaction medium is concentrated under reduced pressure. The residue is taken up in water and then acidified with 0.239 g (1.7 mmol) of potassium hydrogensulfate. The precipitate formed is filtered off, washed with water and ethyl ether, and dried. 0.22 g of an orange solid is collected, which solid is salified in the sodium salt.2.55H2O form. Melting point: 226° C.; 1H NMR (d6-DMSO): 3.86 (3H, s), 6.71 (1H, d), 7.06-7.11 (1H, m), 7.24-7.30 (1H, m), 7.89 (1H, s), 8.34 (1H, d), 8.59 (1H, d), 9.63 (1H, d)
Reaction SMILES: CS(O)(=O)=O.[CH:6]([O:19][C:20]([C:22]1[N:23]2[CH:26]([S:27][CH2:28][C:29]=1[C:30]1[S:34][C:33]([NH:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=1)[CH:25]([NH:42]C(OC(C)(C)C)=O)[C:24]2=[O:50])=[O:21])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[NH2:42][CH:25]1[C:24](=[O:50])[N:23]2[CH:26]1[S:27][CH2:28][C:29]([C:30]1[S:34][C:33]([NH:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=1)=[C:22]2[C:20]([O:19][CH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4cccnc4)s3)CSC12
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4cccnc4)s3)CSC12
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
Methanesulphonic acid (37.7 cc) is added in the course of 5 minutes to a solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-[2-(pyridin-3-yl-amino)thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (37.22 g) in acetonitrile (372 cc). The mixture is stirred for 5 minutes and the reaction solution is then added to a mixture of a saturated solution of sodium bicarbonate (870 cc), distilled water (1,740 cc) and methylene chloride (580 cc). The mixture is stirred for 10 minutes and the precipitate is filtered off and washed with distilled water (4×100 cc). The product is dried to give 7-amino-2-benzhydryloxycarbonyl-3-[2-(pyridin-3-yl-amino)thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene (27.66 g) in the form of a pale yellow crystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=2)=[CH:7][CH:6]=1)[CH3:2]>CC(O)=O.CO.[Zn]>[CH2:1]([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2nc(Cl)ncc2[N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(Oc2nc(Cl)ncc2N)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of Compound 16a (2.12 g; 6.55 mmol) in AcOH (15 mL) and CH3OH (20 mL) was added Zn (2.57 g; 39.31 mmol) in portions at room temperature. The reaction mixture was stirred at room temperature for 6 h. The solid was collected by filtration and washed with CH3OH. The filtrate was concentrated. The residue was quenched with aqueous NaOH (<1N) and adjusted to pH ˜7, and extracted with EtOAc (2×20 mL). The organic layer was dried over MgSO4 and concentrated. The crude product was purified by normal phase chromatography (SiO2) to give Compound 16b. 1H NMR (300 MHz, CDCl3): δ 8.15 (d, 2H), 7.95 (s, 1H), 7.25 (d, 2H), 4.45 (q, 2H), 1.4 (t, 3H); MS: m/z 294.1 (M+H)+.
Reaction SMILES: Cl.Cl.[OH:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[N:10]1[CH2:15][CH2:14][C:13]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:12][CH2:11]1.C(OC(N1CCC(N2CCC3(C4C(=CC=CC=4)CCC3)CC2)C(O)C1)=O)(C)(C)C.C(OC(N1CCC(O)C(N2CCC3(C4C(=CC=CC=4)CCC3)CC2)C1)=O)(C)(C)C.[I:83][C:84]1[CH:85]=[C:86]([CH:89]=[CH:90][CH:91]=1)[CH2:87]Br>CCO.C(N(CC)CC)C>[I:83][C:84]1[CH:85]=[C:86]([CH:89]=[CH:90][CH:91]=1)[CH2:87][N:7]1[CH2:8][CH2:9][CH:4]([OH:3])[CH:5]([N:10]2[CH2:15][CH2:14][C:13]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[CH2:12][CH2:11]2)[CH2:6]1
Reactant: BrCc1cccc(I)c1
Reactant: OC1CCNCC1N1CCC2(CCCc3ccccc32)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCc4ccccc43)CC2)C(O)C1
Agent: CC(C)(C)OC(=O)N1CCC(O)C(N2CCC3(CCCc4ccccc43)CC2)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1CCN(Cc2cccc(I)c2)CC1N1CCC2(CCCc3ccccc32)CC1

Procedure:
A mixture of 21c and 22c derived from a mixture of 19c and 20c as described above (676 mg, 1.81 mmol), 3-iodobenzylbromide (2.17 mmol, 645 mg), and triethylamine (10 mL) in absolute EtOH (20 mL) was refluxed for 18 h. Volatiles were removed under reduced pressure and the red residue was treated with water. After extraction in dichloromethane (3×30 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a dark red semi-solid residue. Chromatographic purification (silica gel, 50% ethyl acetate-hexanes) afforded 276 mg (30%) of the crude product as a yellow oil. The two regioisomers were separated by HPLC (Silica gel, Hexane/Isopropanol/Triethylamine: 98/2/0.02) and 13d was obtained as a white crystalline solid (166 mg, 18%). Only a trace of the other isomer was recovered. The hydrochloride of 13d was prepared in satd methanolic saturated HCl and subsequently recrystallized from 50% i-PrOH-hexanes to provide a white powder; mp 245° C. 1H NMR (CDCl3)δ1.59-2.06 (m, 8, 2 N-CH2 --CH2), 2.41-2.48 (m, 2, Ar-CH2 --CH 2), 2.52-2.62 (m, 2, CH2CHOH), 2.75-2.78 (m, 4, Ar-CH2 --CH2 --CH2), 2.83-2.92 (m, 2, CH2 --CH2 --CHOH), 3.01-3.06 (d, 2, N-CH2 --CHN, J=10.0 Hz), 3.38-3.56(m, 3, Ar-CH2 --N+CH-N), 3.85 (s, 1, CH--OH), 7.02-7.31 (m, 5, arom.), 7.44-7.48(d, 1, arom., J=7.8 Hz), 7.58-7.62 (d, 1, arom., J=7.9 Hz), 7.68 (s, 1, arom.).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:41]=[CH:40][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22](OS(C(F)(F)F)(=O)=O)=[N:21]2)=[CH:17][CH:16]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:42][C:43]1[CH:48]=[CH:47][C:46]([C:22]2[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]4[N:4]=[C:5]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)[O:6][C:2]=4[CH3:1])=[CH:41][CH:40]=3)[N:21]=2)=[CH:45][CH:44]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccc(F)cc1
Yield: 45.3 %

Procedure:
Tetrakis(triphenolphosphine)palladium (130 mg) was added to a mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-trifluoromethanesulfonyloxy-1H-pyrazol-4-yl]propionate (1.31 g), 4-fluorophenylboronic acid (0.31 g), 2N aqueous sodium carbonate solution (2.9 ml), ethanol (3 ml), and toluene (50 ml). This mixture was refluxed under an argon atmosphere for 13 hours. Ethyl acetate was added to this reaction mixture, and the mixture was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-(4-fluorophenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (540 mg, yield 45%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 93–94° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:37]=[CH:36][C:35]5[O:34][CH2:33][O:32][C:31]=5[CH:30]=4)[CH2:24][CH2:23]3)=[O:21])=[CH:14][CH:13]=2)[CH:3]=1.C(O)C>[C].[Pd].O1CCOCC1>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:37]=[CH:36][C:35]5[O:34][CH2:33][O:32][C:31]=5[CH:30]=4)[CH2:26][CH2:27]3)=[O:21])=[CH:16][CH:17]=2)=[N:5][CH:6]=1
Reactant: Cc1cc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)ncc1N
Reaction time: 8 h

Procedure:
3-(4-hydroxyphenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one (0.38 g, 1.0 mmol) was dissolved in DMF (6 mL). To the resulting solution was added 60% sodium hydride (0.05 g, 1.2 mmol) and 2-chloro-4-methyl-5-nitropyridine (0.196 g, 1.1 mmol), and the resulting reaction solution was stirred overnight at room temperature. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield the intermediate product 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one. The 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one was dissolved in a mixed solvent consisting of ethanol (4 mL) and dioxane (1 mL). To this solution was added 10% palladium-carbon (0.034 g), and the resulting solution was subjected to catalytic reduction for 8 hours at atmospheric pressure and room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:methanol=20:1), to thereby yield 0.22 g of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30](O)=[O:31])[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][S:64]([CH2:67][CH2:68][CH2:69][O:70][C:71]1[CH:76]=[CH:75][C:74]([NH2:77])=[C:73]([O:78][CH3:79])[CH:72]=1)(=[O:66])=[O:65]>>[CH3:63][S:64]([CH2:67][CH2:68][CH2:69][O:70][C:71]1[CH:76]=[CH:75][C:74]([NH:77][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C@:17]3([C:12]4[C:11](=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:73]([O:78][CH3:79])[CH:72]=1)(=[O:65])=[O:66]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(OCCCS(C)(=O)=O)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OCCCS(C)(=O)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Yield: 52.6 %

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.2 g, 0.35 mmol), was reacted with diisopropylethylamine (0.22 g, 1.7 mmol), diphenylphosphinic chloride (0.16 g, 0.7 mmol), then reacted with 4-(3-methanesulfonyl-propoxy)-2-methoxy-phenylamine prepared in Example 180 (0.13 g, 0.5 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(3-methanesulfonyl-propoxy)-2-methoxy-phenyl]amide as a yellow solid (Yield 0.13 g, 51%).
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)[CH2:3]CC.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([C:31]1[CH:36]=[C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:49][CH2:48][C:47]5[CH:50]=[C:51]([O:54][CH3:55])[CH:52]=[CH:53][C:46]=5[NH:45][C:44]4=[O:56])[CH2:39][CH:38]3C#C)[C:34]([Si](C)(C)C)=[CH:33][N:32]=1)=[O:30])[CH2:24][CH2:23]2.Cl>C1COCC1>[C:2]([C:34]1[C:35]([N:37]2[CH2:38][CH2:39][CH:40]([N:43]3[CH2:49][CH2:48][C:47]4[CH:50]=[C:51]([O:54][CH3:55])[CH:52]=[CH:53][C:46]=4[NH:45][C:44]3=[O:56])[CH2:41][CH2:42]2)=[CH:36][C:31]([C:29]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([F:19])=[CH:28][CH:27]=3)[CH2:23][CH2:24]2)=[O:30])=[N:32][CH:33]=1)#[CH:3]
Reactant: C#CC1CC(N2CCc3cc(OC)ccc3NC2=O)CCN1c1cc(C(=O)N2CCc3cc(F)ccc32)ncc1[Si](C)(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc(C(=O)N2CCc3cc(F)ccc32)cc1N1CCC(N2CCc3cc(OC)ccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
86 μL (86 μmol) of a 1N tetrabutylammonium fluoride solution in THF were added to 35 mg (57 mol) 3-[2′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-5′-trimethylsilanyl-ethynyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]-diazepin-2-one in 1.5 mL THF and the mixture was stirred for 3 h at RT. Then the reaction mixture was combined with a 0.1 molar aqueous hydrochloric acid solution and the precipitate formed was suction filtered.