Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:15].[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].BrCC1C=C(OC)C=CC=1C1C=CC(Cl)=CC=1>>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=2[CH3:15])=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1Br
Agent: COc1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1-c1ccc(C#N)cc1
Yield: 83.8 %

Procedure:
(Step 1) A solution of tert butyl 4-bromo-3-methylbenzoate (3.3 g, 12.2 mmol) was reacted with 4-cyanophenylboronic acid (2.15 g, 14.6 mmol) according to the procedure described for compound 14. The crude product was purified by column chromatography (silica gel, 3:2 hexanes/methylene dichloride) to afford tert-butyl 4′-cyano-2-methyl-1,1′-biphenyl-4-carboxylate as a white solid (3.0 g, 84% yield). ESI-MS m/e 294.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.[N:25]1N=CN(N)C=1.C(N(CC)CC)C.[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.CO.CC(C)=O>[NH2:25][CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:5]2[N:4]([CH2:3][C:2]([CH3:24])([CH3:23])[CH3:1])[C:8]3[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=3[CH:6]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)Cn1c(CN2CCC(=O)CC2)cc2cnc(C#N)nc21
Reactant: Nn1cnnc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Cn1c(CN2CCC(N)CC2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 86.8 %

Procedure:
To the mixture of 100 mg (0.30 mmoles) of 7-(2,2-Dimethyl-propyl)-6-(4-oxo-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile, 40 mg (0.60 mmoles) of [1,2,4]triazol-4-ylamine and 0.16 ml (1.1 mmoles) of triethylamine in 5 ml of CH2Cl2, 58 mg (0.48 mmoles) of MgSO4 is added at ambient temperature and the mixture is stirred for 17.5 hours at ambient temperature. The reaction mixture is filtered to remove MgSO4 and concentrated under reduced pressure to give crude imine. To a solution of crude imine in 5 ml of MeOH, 13 mg (0.33 mmoles) of NaBH4 is added at −10-−20° C., and the reaction mixture is stirred at 0° C. for 1 h. After addition of 5 ml of acetone, the mixture is concentrated, diluted with H2O, and then extracted with CH2Cl2. The combined extrats are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 85 mg of desired 6-(4-amino-piperidin-1-ylmethyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 85% yield.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:20]2[CH:15]([CH2:16][CH:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:19]2)[CH2:14][CH2:13][C:12]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:20]2[CH:15]([CH2:16][CH:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:19]2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCC2CC(Cc3ccccc3)CCC2N1Cc1nc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CC2CCC3C(CCCN3Cc3nc4ccccc4[nH]3)C2)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 0.15 g of 1-(1H-benzimidazol-2-ylmethyl)-6-benzyl-octahydro-quinolin-2-one in 20 mL of dry THF containing 0.1 g of lithium aluminum hydride was heated to reflux overnight, cooled in an ice bath, and quenched with 0.1 mL of 5N NaOH, then 1 mL of water. After stirring and warming to room temperature for 2 h, the mixture was filtered through a glass frit and the filtrate concentrated to dryness under reduced pressure. Chromatography using 10% methanol in chloroform gave 1-(1H-benzimidazol-2-ylmethyl)-6-benzyl-decahydro-quinoline in four bands.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14](=[O:17])[CH2:15][SH:16].CCN(CC)CC.O>CS(C)=O>[CH3:12][O:13][C:14]([C:15]1[S:16][C:2]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=2[CH:4]=1)=[O:17]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: COC(=O)CS
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc2ccc(OC)cc2s1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
To a solution of 2-fluoro-4-methoxy-benzaldehyde (4.0 g, 26 mmol) in DMSO (200 mL) was added mercapto-acetic acid methyl ester (3.6 mL, 3.9 g, 39 mmol) and Et3N (10.8 mL, 7.8 g, 78 mmol) and the reaction mixture was heated (80° C., 12 h). The reaction mixture was cooled (rt) and treated with H2O (100 mL). The suspension was filtered to afford the title compound as a yellow solid (4.1 g, 71%). MS (ESI): mass calcd. for C11H10O3S, 222.0; m/z found, 223.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.97 (d, J=0.6, 1H), 7.74 (d, J=8.8, 1H), 7.28 (d, J=2.3, 1H), 7.02 (dt, J=8.7, 4.3, 1H), 3.92 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])=[O:40])([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C.ClCCl>[C:34]([O:38][C:39](=[O:40])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: CC(C)(C)OC(=O)NCCCCCN
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCNC(=O)OC(C)(C)C)c23)cc1
Temperature: 80 °C
Yield: 71 %

Procedure:
Dissolve 1.00 g (3.0 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 5 ml DMF and add 1.15 g (8.9 mmol) DIEA. Add 1.20 g (5.9 mmol) 5-[(tert.-butyloxycarbonyl)amino]-1-pentylamine [obtainable from 1,5-diaminopentane according to J. Med. Chem. 47 (20), 4933-4940 (2004)] and then heat the mixture to 80° C. for 3 h. After cooling, dilute the mixture with dichloromethane and wash successively with water and saturated sodium chloride solution. Dry the organic phase over magnesium sulphate and concentrate by evaporation. Purify the residue by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). A total of 1.07 g (67% of theor.) of tert.-butyl-(5-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}pentyl)carbamate is obtained in two fractions, in the form of beige crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[C:10]([O:17][CH3:18])[C:9]=1[O:19][CH3:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=1I.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([F:21])=[C:27]([C:11]2[CH:12]=[CH:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[C:9]([O:19][CH3:20])[C:10]=2[O:17][CH3:18])[CH:26]=1
Reactant: COc1c(B(O)O)ccc(-c2ccccc2F)c1OC
Reactant: Fc1ccc(Br)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1c(-c2ccccc2F)ccc(-c2cc(Br)ccc2F)c1OC
Temperature: 25 °C
Yield: 80.1 %

Procedure:
In the atmosphere of argon, 15.2 g of 2′-fluoro-2,3-dimethoxybiphenyl-4-boronic acid, 16.5 g of 2-fluoro-5-bromoiodobenzene, 1.27 g of tetrakistriphenylphosphine palladium (0), 180 mL of toluene and 90 mL of an aqueous 2M sodium carbonate solution were placed in a flask. The resulting solution was stirred with heating under reflux for 8 hours. After cooling to room temperature, the reaction solution was extracted with toluene. An aqueous phase was removed, and an organic phase was washed with saturated saline. The organic phase was dried with magnesium sulfate, and concentrated. Residues were purified by means of silica gel column chromatography, whereby 17.8 g (yield: 80%) of 5-bromo-2-fluoro-2′,3′-dimethoxy-2″-fluoro-p-terphenyl was obtained.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[C:12]([C:15]1[C:19]([CH3:20])=[C:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[NH:17][CH:16]=1)(=[O:14])[CH3:13].C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O>[C:12]([C:15]1[C:19]([CH3:20])=[C:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[NH:17][C:16]=1[N+:8]([O-:11])=[O:9])(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1c[nH]c(-c2ccncc2)c1C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1c([N+](=O)[O-])[nH]c(-c2ccncc2)c1C
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 14 %

Procedure:
To a cooled (−10˜−20° C.) acetic anhydride (1.2 mL) was added fuming nitric acid (0.13 mL) and sulfuric acid (1 drop). After stirring for 3 minutes, 3-acetyl-4-methyl-5-(4-pyridyl)-1H-pyrrole (0.2 g, 1 mmol) was added to the mixture. The resulting mixture was allowed to warm to room temperature and stirred for additional 1 hour. The mixture was poured into saturated aqueous NaHCO3. The whole was extracted with ethyl acetate (30 mL×4), the combined organic layers washed with brine, dried over MgSO4, and concentrated in vacito. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (2:1) to provide the title compound (35 mg, 14% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[K+].C1(Br)CC1.[Br:11][C:12]1[CH:13]=[C:14]([SH:18])[CH:15]=[CH:16][CH:17]=1.O>CS(C)=O>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH:5]2[CH2:2][CH2:1]2)[CH:13]=1
Reactant: Sc1cccc(Br)c1
Reactant: CC(C)(C)[O-]
Agent: BrC1CC1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1cccc(SC2CC2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
Potassium t-butoxide (4 g) and cyclopropyl bromide (7.6 mL) were added to a solution of 3-bromothiophenol (6 g) in dimethyl sulfoxide (30 mL), and the mixture was stirred at 80° C. for five hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and brine, dried over sodium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→7:3) to give the title compound as a light yellow oil (1.6 g, 23%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH3:13])=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:14][NH:15][CH3:16]>O1CCOCC1>[Br:1][C:2]1[C:3]([O:11][CH2:12][CH3:13])=[CH:4][C:5]([N:15]([CH3:16])[CH3:14])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CCOc1cc(F)c(C#N)cc1Br
Reactant: CNC
Solvent: C1COCCO1
Product: CCOc1cc(N(C)C)c(C#N)cc1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of 5-bromo-4-ethoxy-2-fluoro-benzonitrile (2 g, 8.2 mmol) in 16.5 mL of dioxane was added dimethylamine (16.5 mL, 33 mmol, 2.0 M in tetrahydrofuran). The reaction was stirred at 80° C. overnight. The reaction mixture was concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 5-bromo-2-dimethylamino-4-ethoxy-benzonitrile (1.95 g, 88%). LC-MS: 269.2 [(M+H)+].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:23][N:24]([CH:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:25]1[O:26][C:27]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][C:28]=2[N:29]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:23][N:24]([CH:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:25]1[O:26][C:27]2[CH:33]=[CH:32][C:31]([NH:34][C:17](=[O:19])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([O:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:15]=3)=[CH:30][C:28]=2[N:29]=1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCC(N(C)c2nc3cc(NC(=O)c4cccc(Oc5ccccc5)c4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
Add oxalyl chloride (0.20 mL, 2.30 mmol) and 3 drops of DMF to a stirring suspension of 3-phenoxy-benzoic acid (0.247 g, 1.15 mmol) in CH2Cl2 (5.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 3-phenoxy-benzoyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.200 g, 0.768 mmol) and pyridine (0.06 mL) in CH2Cl2 (5.0 mL). Shake the reaction mixture overnight at room temperature. Wash the mixture with saturated NaHCO3 (aqueous) (3×25 mL), dry the organic phase over Na2SO4, filter, and concentrate the mixture in vacuo. Subject the residue to silica gel flash column chromatography (5×4 g columns, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product as a white solid (0.163 g, 46%). mass spectrum (m/e): 457.0 (M+1), 455.0 (M−1). 1H NMR (400 MHz, CD3OD): δ 7.72-7.67 (m, 2H), 7.60-7.57 (m, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.44-7.38 (m, 2H), 7.35-7.28 (m, 2H), 7.22-7.15 (m, 2H), 7.09-7.05 (m, 2H), 4.18-4.09 (m, 1H), 3.12 (s, 3H), 3.06-3.00 (m, 2H), 2.35 (s, 3H), 2.24 (dt, J=12.4, 2.4 Hz, 2H), 2.03-1.92 (m, 2H), 1.87-1.80 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([CH2:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([S:29][CH3:30])=[CH:24][CH:23]=2)([OH:18])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([F:17])[CH:9]=1)([CH3:7])[CH3:6].I([O-])(=O)(=O)=[O:34].[Na+]>CO.[Cl-].[Na+].O>[F:32][C:2]([F:1])([F:31])[C:3]([CH2:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([S:29]([CH3:30])=[O:34])=[CH:24][CH:23]=2)([OH:18])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([F:17])[CH:9]=1)([CH3:7])[CH3:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc2[nH]c(CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc2[nH]c(CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cc2c1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(5-methylsulfanyl-1H-indol-2-ylmethyl)pentan-2-ol (25 mg, 0.053 mmol) in 10 mL of methanol was added sodium periodate (150 mg, 0.70 mmol). After 1 hour, the mixture was diluted with brine and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with three 7 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative TLC on silica gel eluting with ethyl acetate to afford 19.8 mg (77% yield) of the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[O:10])[CH2:5][CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[C:22]([O:1][N:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[O:10])[CH2:5][CH2:4]1)(=[O:24])[CH3:23]
Reactant: O=C1CCc2cc(C(=O)N3CCC(=NO)CC3)ccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)ON=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 Grams of 6-(4-hydroxyimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril, 11.4 ml of acetic anhydride and 31.8 ml of triethylamine in 300 ml of methylene chloride solution were mixed together and stirred at room temperature overnight. The reaction mixture was poured into ice-water, and extracted with chloroform. The chloroform extract was dried with anhydrous sodium carbonate, then the solvent was removed by evaporation to yield 16.5 g of 6-(4-acetyloxyimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][P:13](=[C:15]([CH2:17][N+:18]([CH3:21])([CH3:20])[CH3:19])[OH:16])=[O:14])=O)(C)(C)C.[ClH:22]>C(Cl)(Cl)Cl>[ClH:22].[ClH:22].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][P:13](=[C:15]([CH2:17][N+:18]([CH3:19])([CH3:21])[CH3:20])[OH:16])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCO[P+]([O-])=C(O)C[N+](C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C[N+](C)(C)CC(O)=[P+]([O-])OCCCN
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a solution of 0.200 g (0.586 mmol) of 48 in 2 ml of chloroform was added 1 ml of HCl-saturated ether. The solution was shaken at room temperature for 20 minutes then concentrated to afford 0.190 g (96%) of the title compound as a colorless glass.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]1([CH:17]=CC=C(O)[C:11]=1O)[OH:10]>>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:11][C:9]([CH3:17])=[O:10]
Reactant: Oc1cccc(O)c1O
Agent: Oc1cccc(O)c1
Product: CC(C)=O

Procedure:
The procedure of Production Example 1 was repeated except that resorcinol was used in-place of the pyrogallol, to give a resorcinol-acetone condensate with a melting point of 170°-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C@@H:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C@@H:8]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:9]([OH:11])=[O:10])=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](CC(C)C)NCc1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NCc1ccc(Br)cc1)C(=O)O
Reaction time: 8 h

Procedure:
To methyl (2S)-2-[(4-bromobenzyl)amino]-4-methylpentanoate (2.198 g, 7.0 mmol) in MeOH (30 mL) was added an aqueous solution of LiOH (2 M, 17.5 mL, 35 mmol) and the reaction was stirred overnight. The reaction was neutralized with aqueous 10% HCl (pH of 6–7) and the product crystallized out of solution and was filtered and dried in vacuo to afford (2S)-2-[(4-bromobenzyl)amino]-4-methylpentanoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:34][C@H:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[C:20]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:43]([S:46]([NH2:49])(=[O:48])=[O:47])[CH2:44][CH3:45].N12CCCN=C1CCCCC2>CN(C)C=O.C(OCC)(=O)C>[CH:28]1([O:27][C:20]2[CH:19]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][N:8]([CH2:34][C@H:35]([OH:42])[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:13][CH:14]=3)[CH:23]=[CH:22][C:21]=2[C:24]([NH:49][S:46]([CH2:43][CH2:44][CH3:45])(=[O:48])=[O:47])=[O:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCCS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
To a solution of 4′-[3-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]propyl]-3-(cyclohexyloxy)-4-biphenylcarboxylic acid (133 mg) in N,N-dimethylformamide (1.3 ml) was added N,N′-carbonyldiimidazole (41.3 mg) and the mixture was stirred at room temperature for 5 hours. To the mixture were added 1-propanesulfonamide (31.4 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (41.6 μl) and the mixture was stirred at 50° C. for 14 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml×2) and brine (10 ml). The solution was dried over magnesium sulfate then concentrated in vacuo to give a crude solid which was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give tert-butyl [3-[3′-(cyclohexyloxy)-4′-[[(propylsulfonyl)amino]carbonyl]-4-biphenylyl]propyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (63.5 mg) as a white solid.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.Cl.C(N=C=NCCCN(C)C)C.[CH2:28]([O:35][C:36]([N:38]1[CH2:42][C@@H:41]([OH:43])[C@H:40]([C:44](O)=[O:45])[CH2:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH:12]1([NH:15][C:44]([C@H:40]2[C@H:41]([OH:43])[CH2:42][N:38]([C:36]([O:35][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[CH2:39]2)=[O:45])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CC1)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: 25 °C
Yield: 48.9 %

Procedure:
17.9 g of 1-hydroxybenzotriazole hydrate (117 mmol), 16.9 mL of cyclopropylamine (244 mmol) and 22.4 g of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (117 mmol) were successively added to a solution of (3R,4S)-1-benzyloxycarbonyl-4-hydroxypyrrolidine-3-carboxylic acid (25.9 g, 97.5 mmol) in 259 mL of dehydrated tetrahydrofuran under stirring at room temperature. The mixture was further stirred at room temperature for 5 hours. Subsequently, the reaction mixture was concentrated under reduced pressure, followed by addition of 130 mL of ethyl acetate and 260 mL of 1 mol/L hydrochloric acid and subsequent stirring for 30 minutes. The resulting crystals were collected by filtration and washed with 26 mL of ethyl acetate. The organic layer was collected and washed with 130 mL of a 10% aqueous sodium bicarbonate solution and 130 mL of 28% brine. To this layer, 39.0 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The insoluble material was separated by filtration and washed with 52 mL of ethyl acetate. The filtrate was concentrated under reduced pressure. To the resulting residue, 156 mL of diisopropyl ether was added and the product was tritulated. The precipitated powder was collected by filtration and washed with 39 mL of diisopropyl ether. The washed product was dried by air-blowing at room temperature for 30 minutes. 25.6 g of the resulting crystals were added to 308 mL of ethyl acetate. The mixture was heated at an external temperature of 80° C. for 25 minutes under stirring, then allowed to cool in the air for 40 minutes under stirring, then cooled in a water bath for 5 minutes under stirring at an internal temperature of 40° C., and then stirred at room temperature for 5 minutes at an internal temperature of 25° C. The precipitated powder was collected by filtration and washed with 52 mL of diisopropyl ether. The washed product was dried for 1 hour by air-blowing. Further drying the product by air-blowing at 60° C. for 16 hours gave 14.5 g of the title compound as fluffy colorless crystals (43% yield in the 3 steps).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:2]([Br:1])=[C:3]([CH:4]=[O:5])[CH:6]=1)[CH3:19]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
A mixture of 3.5 g (17.4 mmol) of 2-bromo-5-hydroxybenzaldehyde, 3.7 g (19 mmol) of ethyl 4-bromobutyrate, 5.5 g (40 mmol) of anhydrous, granular potassium carbonate, and 40 mL of dry dimethyl sulfoxide was stirred at room temperature for 5 hr and then kept at room temperature overnight. The resulting slurry was poured into ice-water and worked-up with ether in the usual manner giving an oil product which was flash-chromatographed on silica gel. Elution with 2:1 hexane-ether afforded 4.4 g (80.3%) of 4-(4-bromo-3-formylphenoxy)butanoic acid ethyl ester as an oil.