Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[CH2:31][C:32]1[N:33]=[C:34]([CH3:37])[S:35][CH:36]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COc1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: COc1ccc(N(Cc2csc(C)n2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 78.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.63 g) and 4-(chloromethyl)-2-methylthiazole (0.30 g) as starting materials, 5-benzyloxy-N-(4-methoxyphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.64 g) was obtained. By the reaction and treatment in the same manner as in Example 133 using this compound (0.50 g), 5-hydroxy-N-(4-methoxyphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.31 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(Cl)C1C=CC=CC=1>O.C1(C)C=CC=CC=1.CO>[CH2:25]([O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccccc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(c1ccc(O)cc1)c1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
Combine 4,4'dihydroxybenzophenone (21.4 g, 0.10 mmol) and sodium hydroxide (4.0 g, 0.10 mmol) in water (50 mL). Heat to 80° C. Add toluene (100 mL). Add benzyl chloride (17.3 mL, 0.15 mmol) in toluene/methanol (100 mL/40 mL). Maintain heating at 70° C. to 80° C. After 3 days, cool to ambient temperature and partition the reaction mixture between ethyl acetate and water. Separate the layers and extract the aqueous layer with ethyl acetate. Combine the organic layers and extract with aqueous 1M sodium hydroxide solution and then water. Evaporate the organic layers in vacuo to give a reside. Combine the aqueous layers and allow to stand to give a solid. Collect the solid by filtration, rinse with water, and dry to give a solid. Combine the solid and the residue obtained from evaporation of the organic layers and recrystallize from toluene to give 4-benzyloxy-4'-hydroxybenzophenone: Rf =0.21 (silica gel, 30% ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[N:13]=[C:14]([Br:30])[N:15]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[C:16]=2[CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)O)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].OS(O)(=O)=O>CC(O)=O>[Br:30][C:14]1[N:15]([CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:16]2[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[C:10](=[O:11])[C:12]=2[N:13]=1
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nc(Br)n(C2CCC2)c1C(O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1c2nc(Br)n(C3CCC3)c2C(c2ccc(Cl)cc2)N1c1ccc(F)c(Cl)c1
Temperature: 110 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-cyclobutyl-1H-imidazole-4-carboxylic acid (3-chloro-4-fluoro-phenyl)-amide (step AK1; 0.470 g, 0.907 mmol) and AcOH (4.53 ml) was added H2SO4 98% (0.592 ml, 10.88 mmol). The solution was stirred for 7 h at 110° C. The reaction mixture was concentrated in vacuo. The residue was neutralized with 1M NaHCO3 and extracted with EtOAc (2×). The organic phases were washed with brine and dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 1:1), then triturated in diisopropyl ether/hexane to afford the title compound. tR: 1.29 min (LC-MS 2); ESI-MS: 496.0 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 7.79 (m, 1H), 7.49 (m, 1H), 7.38 (s, 4H), 7.35 (m, 1H), 6.89 (s, 1H), 4.73 (m, 1H), 2.45 (m, 2H), 1.86 (m, 1H), 1.63 (m, 1H), 1.42 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH3:21])[C:12]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:37](=[O:39])[CH3:38])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH3:21])[C:12]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2.49 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 15 ml of acetic anhydride and 5 ml of pyridine is stirred at 100° C. for 2 hours. The mixture is evaporated under reduced pressure to remove acetic anhydride and pyridine. Toluene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent (This operation is repeated again). 3.08 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[F:31])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH3:22])=[O:5])C.[Li+].[OH-]>O1CCOCC1>[Cl:30][C:26]1[C:25]([F:31])=[C:24]([NH:23][CH:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH3:22])[C:7]2[N:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:10][C:6]=2[C:4]([OH:5])=[O:3])[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cccc(Cl)c1F)c1ccc(Cl)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1C(Nc1cccc(Cl)c1F)c1c(C(=O)O)ccn1C(C)C
Temperature: 100 °C

Procedure:
A mixture of 2-[(3-chloro-2-fluoro-phenylamino)-(4-chloro-2-methyl-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step A3) (2.154 mmol) and 1N aqueous LiOH (8.62 mmol) in dioxane (25 mL) was heated at 100° C. for 26 h. After cooling to rt, the reaction mixture was partitioned between EtOAc and 10% w/w aqueous citric acid. The aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated to afford the title compound as a pale yellow solid which was used in the next step without further purification. tR: 5.48 min (HPLC 1); ESI-MS: tR=1.33 min, [M−H] 433/435 (LC-MS 1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]3[N:15]=2)[CH:8]=1.[Cl-].[NH4+:36]>>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:7]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([NH2:36])=[O:24])=[C:16]3[N:15]=2)[CH:8]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCN3CCOCC3)nc12
Agent: Cl
Agent: [Cl-]
Product: NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCCN3CCOCC3)nc12
Yield: 91 %

Procedure:
Prepared by the method described in Example 76, Step F, using ((R)-5-(2-(5-fluoro-2-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid hydrochloride and ammonium chloride to yield the title compound as a white solid (42.2 mg, 91% yield). MS (apci) m/z=455.1 (M+H).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:32])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[CH:27]=[CH:28][CH:29]=[C:20]([C:21]=23)[S:19]1(=[O:31])=[O:30])C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10](=[O:32])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[CH:27]=[CH:28][CH:29]=[C:20]([C:21]=23)[S:19]1(=[O:31])=[O:30]
Reactant: O=C(CCCCCCCN1c2cccc3cccc(c23)S1(=O)=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(CCCCCCCN1c2cccc3cccc(c23)S1(=O)=O)NO

Procedure:
8-(1,1-Dioxo-2H-naphtho[1,8-cd]isothiazol-2-yl)-octanoic acid benzyloxyamide (0.47 g) in methanol (30 ml) was hydrogenated for 1.5 h in the presence of palladium on barium sulfate at ambient temperature and pressure. The catalyst was removed by filtration and the solvent was evaporated. The residue was purified by column chromatography (silica gel; ethyl acetate as eluent). There was thus obtained 8-(1,1-dioxo-2H-naphtho[1,8-cd]isothiazol-2-yl)-octanoic acid hydroxyamide (61%) as a colorless oil. MS: 363 (M+H+).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:14][O:15][C:16](=[O:21])[C@H:17]([CH3:20])[CH2:18][OH:19].O>CN(C)C=O>[CH3:14][O:15][C:16](=[O:21])[C@H:17]([CH3:20])[CH2:18][O:19][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H](C)CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
Imidazole (6.44 g, 42.8 mmol) and tert-butyldimethylsilyl chloride (6.05 g, 88.8 mmol) were added to a solution of (R)-3-hydroxy-2-methylpropionic acid methyl ester (5.0 g, 42.33 mmol) in dimethylformamide (50 mL), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with hexane twice. The extract was then dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 9.3 g (95%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH:6]([C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[O:22][C:23]=2[CH3:24])=[CH:10][CH:9]=1)O)[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([O:29][CH2:30][CH3:31])[CH2:6][C:8]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]([O:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]([CH3:26])([CH3:28])[CH3:27])[O:22][C:23]=2[CH3:24])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(OCC)C(O)c1ccc(OCc2nc(C(C)(C)C)oc2C)c2ccsc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Cc1ccc(OCc2nc(C(C)(C)C)oc2C)c2ccsc12)OCC
Reaction time: 6 h
Yield: 65.8 %

Procedure:
0.200 g of the above prepared 3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-benzo[b]thiophen-7-yl]-2-ethoxy-3-hydroxy-propionic acid ethyl ester (0.433 mmol) was dissolved in 1.4 ml of trifluoroacetic acid, treated at 0° with 0.688 ml of triethylsilane (10 eq.) and then kept for 6 h at 0° under vigorous stirring. The reaction mixture was then poured onto crashed ice/AcOEt/NaHCO3, the organic layer washed with water (pH of aq. phase ˜8), dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) yielded 0.127 g of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]([NH2:25])=[S:24])=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].O.Cl>>[NH2:12][CH2:11][CH2:10][C:9]1[N:25]=[C:23]([CH2:22][O:21][CH2:20][C:11]2[NH:12][C:13]([CH3:19])=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=3[Cl:1])[C:10]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:24][CH:3]=1
Reactant: CCOC(=O)C1=C(COCC(N)=S)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: Cl
Solvent: O
Product: CCOC(=O)C1=C(COCc2nc(CCN)cs2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
This compound was prepared by the method described in Example 41 but using 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}thioacetamide as starting material. The product was characterised as a hydrochloride monohydrate, m.p. 110°-112° C. Found: C,48.44; H,4.99; N,7.15. C24H27Cl2N3O5S.HCl.H2O requires: C,48.44; H,5.04; N,7.06%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[CH3:10][N:11]=[C:12]=[O:13].O>CN(C=O)C.[Cu]Cl>[CH3:10][NH:11][C:12](=[O:13])[O:9][CH2:8][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1
Reactant: OCc1nccc(Cl)n1
Reactant: CN=C=O
Agent: Cl[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)OCc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(4-Chloropyrimidin-2-yl)methanol (Example 548, Step 1) (0.304 g, 2.10 mmol) and copper(I) chloride (0.208 g, 2.10 mmol) were taken up in DMF (10 mL) and stirred at room temperature for 5 minutes. Methyl isocyanate (0.120 g, 2.10 mmol) was added and stirring at room temperature continued for 3 hours. Water was added and the reaction mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (12-100% EtOAc-hexanes) gave the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][CH:7]=1.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15](I)=[CH:14][C:13]=1[CH3:20]>>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:14][C:13]=1[CH3:20]
Reactant: Cc1cncc(B(O)O)c1
Reactant: Cc1cc(I)cc(C)c1Br
Product: Cc1cncc(-c2cc(C)c(Br)c(C)c2)c1

Procedure:
The title compound is prepared from 5-methyl-pyridine-3-boronic acid and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=0.93 min; Mass spectrum (ESI+): m/z=276/278 (Br) [M+H]+.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(=O)([O-])O>C(O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH:12]([CH:14]([OH:18])[CH:15]([CH3:16])[CH3:17])[CH2:13]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)C(O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Sodium borohydride (237 mg, 6.26 mmol) was added to a solution of 3-(isobutyryl)azetidine-1-carboxylic acid tert-butyl ester (0.95 g, 4.18 mmol) in ethanol (7.5 mL). The resulting reaction mixture was stirred at RT for 2 h. Saturated hydrogen carbonate (25 mL) was added and the resulting mixture was stirred for further 15 min. The aqueous phase was extracted with dichloromethane (3×25 mL). The organic layer was dried over sodium sulfate and the solvents reduced in vacuo to give the crude product as yellow oil. The residue was purified by column chromatography (Si—PCC, ethyl acetate: cyclohexane: gradient 0:100 to 40:60). The solvents were reduced in vacuo to afford the title compound as colourless oil (840 mg, 88%). 1H NMR (400 MHz, CDCl3): δ 3.91-3.90 (3H, m), 3.71 (1H, dd, J=8.54, 6.04 Hz), 3.51 (1H, dd, J=7.21, 4.97 Hz), 2.70-2.63 (1H, m), 1.65-1.63 (1H, m), 1.44 (9H, s), 0.90 (6H, t, J=6.59 Hz).
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:11]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:10]2[C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:32][CH:31]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([NH:6][CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH:8]=3)[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:11]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:35][CH:34]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: O=CC1CC1
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(N)ccc2n1Cc1cccc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(NCC3CC3)ccc2n1Cc1cccc(OC)c1
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Cyclopropanecarboxaldehyde (168 mg, 2.4 mmol) was added to a stirred mixture of ethyl 5-amino-3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 160, 530 mg, 1.2 mmol) in toluene (12 mL) and molecular sieves (2 g). The reaction was stirred for 16 h and then filtered using toluene to rinse. The filtrate was concentrated in vacuo and the residue was dissolved in methanol (12 mL). Sodium borohydride (15 mg, 1.2 mmol) was added and the reaction was stirred for 2 h. The mixture was diluted with ethyl acetate (50 mL), washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 4:1 hexane/ethyl acetate afforded 480 mg (78%) of desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.45-7.48 (m, 2 H), 7.34-7.38 (m, 2 H), 7.31 (d, 1 H), 7.18 (dd, 1 H), 6.87 (dd, 1H), 6.77 (ddd, 1 H), 6.65-6.70 (m, 2 H), 6.62 (d, 1 H), 5.75 (s, 2 H), 4.68 (s, 1 H), 4.08 (q, 2 H), 3.69 (s, 3 H), 2.89 (d, 2 H), 1.37 (s, 9 H), 1.00-1.10 (m, 1 H), 0.93 (t, 3 H), 0.42-0.49 (m, 2 H), 0.16-0.25 (m, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](N(OC)C)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([Mg]Cl)[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16](=[O:17])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCCC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-benzyloxy-phenyl)-N-methoxy-N-methyl-acetamide (42.1 mmol, 12.0 g) in anhydrous THF at −10° C. was added n-butyl magnesium chloride (2.0 M solution in THF, 92.6 mmol, 46.3 mL) drop-wise. After completion of addition, the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was cooled to 0° C. and quenched with 1.0 N HCl by adding drop-wise. The reaction mixture was poured into water, extracted with ethyl acetate, and the combined extract was washed with water followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by column chromatography using 10% ethyl acetate in hexanes to provide 1-(4-benzyloxy-phenyl)-hexan-2-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:10][C:11]#[N:12])[CH2:9][CH2:8]2)[CH:2]=1.B.C1COCC1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:10][CH2:11][NH2:12])[CH2:8][CH2:9]2)[CH:2]=1
Reactant: N#CCC1(c2cccnc2)CC1
Agent: B
Solvent: C1CCOC1
Product: NCCC1(c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of 7-4 (31.3 g, 198 mmol) in 200 mL anhydrous THF was added borane-THF solution (1.5M, 660 mL, 990 mol). The reaction mixture was stirred at room temperature overnight. It was then quenched with methanol gradually until no gas was released. Then additional methanol (150 ml) was added, followed by 30 mL of 6N HCl. The mixture was stirred for 1 hr and concentrated to a viscous residue. It was then treated with 6N NaOH until pH >11 and stirred for 30 min and extracted four times with CHCl3. After solvent removal, the residue was purified using silica gel chromatography (100%EtOAc to 50% EtOAc/46% EtOH/2% NH4OH/2% H2O) to obtain the desired product 7-5 as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:40][C:41](OC2C=CC=CC=2)=[O:42])[C:27](=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH:22][C:41]([NH:40][C:26]2[CH:25]=[C:24]([Cl:23])[CH:39]=[CH:38][C:27]=2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[O:42])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: Cc1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)cc1NC(=O)OCc1ccccc1
Yield: 62 %

Procedure:
960 mg (3.00 mmol) of 3-benzyloxycarbonylamino-4-methylbenzenesulfonamide and 1.14 g (3.00 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 8 to obtain 1.14 g (yield 62% of benzyl 2-{[(3-benzyloxycarbonylamino-4-methylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 2.30 (3H, s), 5.17 (2H, s), 5.36 (2H, s), 7.20 (1H, dd), 7.33-7.48 (11H, m), 7.63 (1H, d), 7.97 (1H, d), 8.11 (1H, s), 8.25 (1H, s), 9.27 (1H, s), 10.30 (1H, s), 12.20 (1H, br).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:13]#[C:14][CH2:15]Br)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:13]#[C:14][CH2:15][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1CCNCC1
Reactant: FC(F)(F)c1cc(C#CCBr)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1cc(C#CCN2CCCCC2)cc(C(F)(F)F)c1
Reaction time: 18 h

Procedure:
A mixture of 1-(3,5-bistrifluoromethylphenyl)-3-bromoprop-1-yne (2.53 g), piperidine (5 ml) and anhydrous potassium carbonate (5 g) in dry acetone (50 ml) was heated at reflux with stirring for 18 h. Removal of the solvent under reduced pressure and distillation of the residue under reduced pressure gave 2.26 g of an oil of boiling point 95° C./0.025 mm Hg.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:13]=[O:14]
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Reaction time: 8 h
Yield: 52.6 %

Procedure:
Benzyl bromide (9 mL, 0.073 mol, 1.05 eq) was added to a stirred solution of 3,4-dihydroxybenzaldehyde (10 g, 0.07 mol, 1 eq), tetra-n-butylammonium iodide (29.4 g, 0.077 mol, 1.1 eq) and cesium carbonate (24.8 g, 0.073 mol, 1.05 eq) in N,N-dimethylformamide (200 mL). The reaction mixture was stirred overnight, and then concentrated in vacuo. The residual solution was diluted with ethyl acetate (200 mL) and washed with water (2×200 mL). The organic solution was then extracted with 0.5M aqueous sodium hydroxide (5×200 mL), and the basic extracts combined and washed with ethyl acetate (400 mL), then acidified to pH 1 with concentrated HCl and back extracted with ethyl acetate (2×300 mL). The organic extracts were combined, washed with brine (200 mL), dried over sodium sulfate and evaporated in vacuo. This gave a gummy solid, which was recrystallized from ethyl acetate and petroleum ether to give the product as a brown powder (8.4 g, 51%). 1H NMR (CDCl3) δ 9.84 (s, 1H, O═C—H), 5.84 (s, 1H, OH), 5.21 (s, 2H, CH2Ph).