Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8]O)=[C:6]([CH2:10][CH3:11])[N:5]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:4]=1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[OH:33][CH2:34][CH:35]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][NH:36]1>C(Cl)Cl.C(#N)C.CN(C)C=O.O>[CH2:1]([C:3]1[C:7]([CH2:8][N:36]2[CH:35]([CH2:34][OH:33])[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[C:6]([CH2:10][CH3:11])[N:5]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:4]=1)[CH3:2]
Reactant: OCC1Cc2ccccc2CN1
Reactant: CCc1nn(-c2c(C)cc(C)cc2C)c(CC)c1CO
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCc1nn(-c2c(C)cc(C)cc2C)c(CC)c1CN1Cc2ccccc2CC1CO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
To a solution of 272 mg (1.0 mmol) of 3,5-diethyl-1-(2,4,6-trimethylphenyl)pyrazole-4-methanol in 5 mL of methylene chloride cooled to 0° C. under dry nitrogen in a 25 mL 3-neck flask, was added to 0.2 mL (2.5 mmol) of triethylamine and 0.092 mL (2.0 mmol) of methanesulfonyl chloride. This mixture was stirred for 15 minutes at 0° C. and then 0.648 g (4.0 mmol) of (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline in 1 mL of 50:50 dimethylformamide acetonitrile was added. The reaction mixture was heated at reflux overnight whereupon no starting material was seen by TLC. The cooled reaction mixture was diluted with water and the product was extracted with ethyl acetate. After drying (brine wash, magnesium sulfate) and evaporation, the crude product was chromatographed on silica gel, eluting with 10:1 and 5:1 hexane/ethyl acetate to give 184 mg (44%) of the desired product. 1H-NMR (CDCl3):0.80 (3H, t, J=7), 1.18 (3H, t, J=7), 1.92 (6H, s), 2.21 (2H, q, J=7), 2.28 (3H, s), 2.55 (2H, q, J=7), 2.97 (2H, d of d, J=7), 3.25 (1H, m), 3.50-3.66 (5H, m), 3.80 (2H, d, J=12), 6.82-7.16 (6H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C[O:26]CC(Cl)=O.C(N(CC)CC)C>O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:18])=[O:26])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(N)c3)c2c1

Procedure:
The title compound was prepared using 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.150 g, 0.47 mmol) in tetrahydrofuran (5 mL), 2-methoxy acetyl chloride (0.086 mL, 0.94 mmol) and triethyl amine (0.327 mL, 2.35 mmol). The crude product was isolated after partition of the reaction mixture between ethyl acetate and water. The yield was not calculated: ES-MS (m/z) 391 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4](Cl)[N:3]=1.C(NC(C)C)(C)C.[C:31]1([CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:39][CH2:38][CH:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
N-[(1S,2R,3S,4R)-4-(2,6-Dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (160 mg, 0.44 mmol) is dissolved in THF (5 ml) under an atmosphere of argon. Diisopropylamine (69 mg, 0.53 mmol) is added followed by 2,2-diphenylethylamine (96 mg, 0.49 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water −0.1% TFA). 1H nmr (MeOD, 400 MHz); 8.00 (s, 1H), 7.40-7.15 (m, 10H), 4.75 (m, 1H), 4.60 (m, 1H), 4.50 (m, 1H), 4.20 (m, 3H), 3.95 (m, 1H), 2.85 (m, 1H), 2.40 (q, 2H), 2.10 (m, 1H), 1.20 (t, 3H), MS (ES+) m/e 521 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[N:3][CH:2]=1.[CH3:10]O>>[CH3:10][O:8][C:7]([C:5]1[CH:6]=[N:1][CH:2]=[N:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1cncnc1
Reactant: CO
Product: COC(=O)c1cncnc1
Temperature: 25 °C
Yield: 77 %

Procedure:
Crude pyrimidine-5-carboxylic acid (2.4 g, 19.38 mmol) was suspended in 100 ml methanol in a round bottom flask fitted with a reflux condenser, drying tube, and a dropping funnel, and 2.8 ml thionyl chloride was added dropwise with stirring. The suspension was stirred and refluxed overnight; then cooled to room temperature and the solvents evaporated in vacuo. Ice cold water (50 ml) was added, basified to pH 8 (sat. NaHCO3), and extracted with chloroform (3×50 ml). The organics were dried (MgSO4), filtered and evaporated in vacuo to yield 2.07 g crude yellow crystals (77%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.[H-].[Na+]>CN(C)C=O>[CH3:29][N:21]([C:19]1[CH:20]=[C:15]([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:18]=1[N+:30]([O-:32])=[O:31])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1[N+](=O)[O-]
Yield: 57.7 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-phenylphenol (4.0 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6.5 g), sodium hydride (55 wt. %, 1.13 g) and anhydrous N,N-dimethylformamide (35 ml) and the reaction mixture was purified to give the title compound (5.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[C:4]([Cl:13])[C:3]=1[N:14]1[N:18]=[C:17]([CH3:19])[CH:16]=[N+:15]1[O-].F[B-](F)(F)F.C[O+](C)C.C[S-].[Na+]>O1CCCC1>[Cl:13][C:4]1[CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:14]1[N:18]=[C:17]([CH3:19])[CH:16]=[N:15]1
Reactant: CCOC(=O)c1cc(Cl)c(-n2nc(C)c[n+]2[O-])c(Cl)c1
Agent: C[O+](C)C
Agent: C[S-]
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Cl)c(-n2ncc(C)n2)c(Cl)c1

Procedure:
2-(2,6-dichloro-4-ethoxycarbonylphenyl)-4-methyl-2H-1,2,3-triazole 1-oxide (2 g) was treated with trimethyloxonium tetrafluoroborate in a similar manner to Example 2. The product was dissolved in tetrahydrofuran and and treated as in Example 3 with sodium methanethiolate (0.4 g) to give 2-(2,6-dichloro-4-ethoxycarbonylphenyl)-4-methyl-2H-1,2,3-triazole, m.p. 136°-137.5°. (Compound 35)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([CH2:20][OH:21])[CH2:8]2)=[CH:4][CH:3]=1.[O-][O-].[Mg+2]>ClCCl>[Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([CH:20]=[O:21])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: OCC1=NN(c2ccc(F)cc2F)C(c2ccc(Br)s2)C1
Agent: [Mg+2]
Agent: [O-][O-]
Solvent: ClCCl
Product: O=CC1=NN(c2ccc(F)cc2F)C(c2ccc(Br)s2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.1 %

Procedure:
[5-(5-Bromo-thiophen-2-yl)-1-(2,4-difluoro-phenyl)-4,5-dihydro-1H-pyrazol-3-yl]-methanol (12.9 g, 34.5 mmol) prepared in Step 4 and magnesium dioxide (MnO2) (30.0 g, 344.6 mmol) were added to dichloromethane (115.0 mL). The reaction mixture was stirred at room temperature for 3 days and then filtered to obtain a yellow filtrate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane) to give 9.1 g of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=2[F:26])=[O:18])=[C:13]([Cl:27])[CH:12]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:27][C:13]1[CH:12]=[C:11]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:9])[CH:16]=[CH:15][C:14]=1[C:17]([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=1[F:26])=[O:18]
Reactant: O=C(c1cc(O)ccc1F)c1ccc(Br)cc1Cl
Reactant: Cc1cc(Cl)ccc1N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(O)ccc2F)c(Cl)c1
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
4-Chloro-2-methyl-phenylamine (73 μL, 0.60 mmol) was dissolved in 5 mL dry 1,4-dioxane in a reaction vial under an argon atmosphere. Compound 511 (200 mg, 0.60 mmol) was added and dissolved in the solvent. Rac-BINAP (18 mg, 0.028 mmol), Pd2(dba)3 (17 mg, 0.018 mmol) and Cs2CO3 (277 mg, 0.84 mmol) were added. The reaction vial was flushed with argon, closed and then stirred at 130° C. for 10 min. in a microwave oven. The reaction mixture was filtered through Celite and then purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) (v:v=1:9 to 1:4) as the eluent to afford the title compound as yellow solid. 13C NMR (CDCl3)
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)(=[O:23])[CH2:19][C:20](O)=[O:21].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:18](=[O:23])[CH2:19][C:20](=[O:21])[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)Nc1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CC(=O)N(c2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 50 °C
Yield: 70.7 %

Procedure:
In a 300-ml glass flask equipped with a thermometer, a reflux condenser and a stirrer, 5.0 g of N-benzyl-N′-phenylurea synthesized in Exemplary Synthesis 1, 2.5 g of malonic acid, 20 ml of toluene, and 5.6 g of acetic anhydride were put, the content was heated under stirring so as to adjust the inner temperature to 80° C., and kept under stirring at 80° C. for 3 hours. The content was then cooled to 50° C., washed with 15 ml of water, and the aqueous phase was discarded. The organic layer was kept under stirring at room temperature, and 5 ml of isopropanol was dropped therein. The content was further stirred at 10° C. or below for 0.5 hours, filtered under suction to collect a deposited crystal, the crystal was washed with cold isopropanol, and dried, to thereby obtain 4.6 g of 1-benzyl-3-phenylbarbituric acid as an intermediate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[N:25][NH2:26])[C:15]2[C:20](Cl)=[CH:19][N:18]=[C:17]3[NH:22][CH:23]=[CH:24][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+]>CN1C(=O)CCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]3=[C:16]4[CH:24]=[CH:23][NH:22][C:17]4=[N:18][CH:19]=[C:20]3[NH:26][N:25]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN1CCCC1=O
Product: c1ccc(CN2CCC(c3n[nH]c4cnc5[nH]ccc5c34)CC2)cc1
Yield: 40.8 %

Procedure:
A mixture of 4-((1-benzylpiperidin-4-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (0.85 g, 2.44 mmol), sodium tert-butoxide (0.565 g, 5.87 mmol), palladium acetate (0.0055 g, 0.024 mmol) and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butyl phosphine (0.0136 g, 0.0244 mmol) was heated in NMP (10 mL) at about 160° C. in a CEM Discover microwave for about 30 min. The NMP was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (50 mL) and EtOAc (50 mL). The organic phase was separated, washed with brine (55 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was suspended in MeCN (10 mL) and the precipitate was collected by filtration and dried in vacuo to yield 1-(1-benzylpiperidin-4-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine as a tan solid (0.33 g, 40%): LC/MS (Table 2, Method n) Rt=1.42 min; MS m/z: 332 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[CH:6]=1)[CH2:3][NH2:4].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=O)[CH3:22])=[CH:16][CH:15]=1>>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[CH:6]=2)[CH3:22])=[CH:16][CH:15]=1
Reactant: CC(=O)Cc1ccc(C)cc1
Reactant: CCc1cccc(C(O)CN)c1
Product: CCc1cccc(C(O)CNC(C)Cc2ccc(C)cc2)c1

Procedure:
The title compound was prepared as described in Example 3 using 2-hydroxy-2-(3-ethylphenyl)ethanamine and (4-methylphenyl)propanone. The residual oil was chromatographed on Kieselgel 60. Elution with 2% methanolchloroform gave the title compound, isolated as the hydrochloride salt, as a 54:46 mixture of diastereoisomers m.p. 97-104. τ(d6DMSO) 8.85 (3H, d, J=6 Hz), 8.8 (3H, d, J=6 Hz), 7.7 (3H, s), 7.4 (2H, q, =6 Hz), 6.3-7.2 (5H, m), 4.9 (1H, m), 3.8 (1H, broad, disappears with D2O), 2.8 (4H, s), 2.6-2.8 (4H, m), 1.1+0.2 (2H, broad, both disappear with D2O).
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[N:11][O:12][C:8]=3[C:7]([OH:18])=[C:6]([C:19](OCC)=[O:20])[N:5]=2)[CH2:3][CH2:2]1.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>C(=O)(O)[O-].[Na+]>[CH:1]1([C:4]2[C:9]3[C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[N:11][O:12][C:8]=3[C:7]([OH:18])=[C:6]([C:19]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:20])[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1nc(C2CC2)c2c(-c3cccs3)noc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(C2CC2)c2c(-c3cccs3)noc2c1O
Temperature: 25 °C
Yield: 70.5 %

Procedure:
Ethyl 4-cyclopropyl-7-hydroxy-3-(thiophen-2-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (47 mg, 0.142 mmol) and glycine (428 mg, 5.70 mmol) were added to sodium methoxide solution (8.5 mL, 4.27 mmol, 0.5 M in MeOH) and the mixture was refluxed for 48 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was redissolved in 10 mL of water and acidified to pH 3 by addition of concentrated hydrochloric acid. The resulting precipitate was isolated by filtration to give 51 mg of crude solid. The solid was dissolved in saturated sodium bicarbonate (20 mL), and washed with EtOAc. The aqueous layer was acidified to pH 3 with 4M HCl and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated to give 36 mg of the title compound. MS: (−) m/z 358.30 (M−1).
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([N:8]([C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7]>O.CO.C1COCC1>[Cl:3][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([N:8]([C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][C:10]([F:12])([F:11])[F:13])=[O:7]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N(CC(F)(F)F)C(=O)c1ccccc1Cl)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)[C@H](N(CC(F)(F)F)C(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
A solution of LiOH (153 mg, 3.64 mmol, 1.5 eq.) in water (8 ml) was added to a cooled (0° C.) solution of (R)-methyl 3-(2-chloro-N-(2,2,2-trifluoroethyl)benzamido)-2,3-dihydro-1H-indene-5-carboxylate (B-41) (1.0 g, 2.43 mmol, 1.0 eq.) in MeOH:THF (1:1, 16 ml) and the reaction mixture was then stirred at RT for 5 h. After completion of the reaction (monitored by TLC), the mixture was evaporated to dryness and diluted with water (15 ml). The aqueous layer was acidified to pH ˜3 using 1N HCl and then extracted with ethyl acetate (2×30 ml). The organic layer was washed with brine (20 ml), dried over anhydrous Na2SO4 and evaporated to afford the desired product as a white solid. Yield: 88% (850 mg, 2.14 mmol).
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[C:11]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([CH2:13][CH:14]=[CH2:15])[CH:7]([CH2:8][CH2:9][CH:10]2[OH:22])[CH2:6]1)#[N:4].[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28]Br.C1OCCOCCOCCOCCOCCOC1>C1COCC1>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH2:28][O:22][C@@H:10]2[CH2:9][CH2:8][C@@H:7]3[N:12]([CH2:13][CH:14]=[CH2:15])[C@@:11]2([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:5]([C:3]#[N:4])[CH2:6]3)[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: C=CCN1C2CCC(O)C1(c1ccccc1)C(C#N)C2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)[C@@H](C#N)C2
Reaction time: 20 h
Yield: 76.4 %

Procedure:
Sodium hydride (60% in oil, 28 mg, 0.7 mmol) was added to a stirred mixture of 1R*,2R*,5S*,7S*)-7-cyano-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octan-2-ol (Description 25; 50 mg, 0.18 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (0.6 ml, 3.27 mmol) and 18-crown-6 (38 mg, 0.14 mmol) in THF (4 ml) at room temperature. The reaction mixture was stirred for 20 hours, quenched with brine and extracted into dichloromethane. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (68 mg, 74%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1>C(O)C.[Pd]>[CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1
Reactant: CN(C)C(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)c1cccc(N)c1
Yield: 86.3 %

Procedure:
N,N-Dimethyl-3-nitrobenzamide (D23) (0.94 g, 4.8 mmol) was hydrogenated in ethanol (100 ml) over 10% Palladium-Charcoal (0.25 g) for 1 hour. The catalyst was removed by filtration through Kieselguhr, and the filtrate concentrated in vacuo to afford the title compound as a light brown solid (0.68 g, 87%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (10 ml) was suspended 60% sodium hydride (60 mg). The compound 1 (200 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, ethyl chloroformate (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-ethoxycarbonyl-quinoline (compound 7, 220 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][CH2:17][C:18]([O:20]CC)=[O:19])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][N:26]([CH3:37])[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:12]3[CH:38]=[CH:39][CH:40]=[CH:41][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][N:26]([CH3:37])[CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:12]3[CH:38]=[CH:39][CH:40]=[CH:41][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CO[C@H]1C(=O)N(CCN(C)CCc2ccc(OC)cc2)c2ccccc2S[C@H]1c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CCN(C)CCN2C(=O)[C@H](OCC(=O)O)[C@H](c3ccc(OC)cc3)Sc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of (+)-cis-2-(4-methoxyphenyl)-3-(ethoxycarbonylmethyl)oxy-5-{2-[N-methyl-N-(4-methoxyphenethyl)amino]ethyl}-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (5.4 g), sodium hydroxide (423 mg), water (50 ml) and methanol (50 ml) is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure, and water is added to the resulting residue. The mixture is washed with ether, and the pH value thereof is adjusted to 4 with 10% hydrochloric acid, and then extracted with a mixture of chloroform and isopropyl alcohol. The extract is washed, dried, and the solvent is distilled off to give (+)-cis- 2-(4-methoxyphenyl)-3-(carboxymethyl)oxy-5-{2-[N-methyl-N-(4-methoxyphenethyl)amino]ethyl}-2,3-dihydro-1,5-benzothiazepin-4-(5H)-one (4.57 g) as oily product.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:38])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:38])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCCC)c1
Yield: 77 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 14 eq) of sodium hydroxide and methyl 3-[3′-(3-heptyl-1-methylureido)-2-pentyloxybiphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 260 mg of 3-[3′-(3-heptyl-1-methylureido)-2-pentyloxybiphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=69° C.). Yield=77% over the two steps.