Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])P(=O)(OCC)OCC.[CH:20]([C@@:22]1([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:26][CH2:25][C@H:24]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:29][CH:28]=2)[CH2:23]1)=O>C1COCC1>[CH2:17]([O:16][P:12](/[CH:3]=[CH:20]/[C@@:22]1([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:26][CH2:25][C@H:24]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:31][CH:32]=2)[CH2:23]1)([O:13][CH2:14][CH3:15])=[O:19])[CH3:18]
Reactant: CCCCCCCCc1ccc([C@H]2CC[C@@](C=O)(NC(=O)OC(C)(C)C)C2)cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc([C@H]2CC[C@@](/C=C/P(=O)(OCC)OCC)(NC(=O)OC(C)(C)C)C2)cc1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
Sodium hydride (0.020 g, 0.498 mmol) (Aldrich) was stirred in THF (3.32 ml) under nitrogen to give a colorless suspension. Tetraethyl methylenediphosphonate (0.124 ml, 0.498 mmol) (ALDRICH) was added and the reaction stirred for about 30 min. Tert-butyl (1R,3S)-1-formyl-3-(4-octylphenyl)cyclopentylcarbamate (0.2 g, 0.498 mmol) was added in small portions and the reaction stirred for about 16 h. Solvents were removed under reduced pressure. Ethyl acetate (50 mL) and water (10 mL) were added and the layers separated and extracted with ethyl acetate (2×10 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to a yellow oil. The residue was purified by flash column chromatography (40 g Redi-Sep) eluting with ethyl acetate/heptane and the product fractions combined. The solvent was removed under reduced pressure to provide tert-butyl (1R,3S)-1-((E)-2-(diethoxyphosphoryl)vinyl)-3-(4-octylphenyl)cyclopentylcarbamate (0.237 g, 0.442 mmol, 89% yield) as an orange oil: LC/MS (method f) Rt=3.12 min.; MS m/z: 553.42 (M+H2O)+.
Reaction SMILES: [CH:1]1[C:15]2=[C:16]3[C:8]([C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3](B(O)O)[CH:2]=1.Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24]2.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH:1]1[C:15]2=[C:16]3[C:8]([C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[C:3]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24]3)[CH:2]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccc2c3c(cccc13)-c1ccccc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Oc1ccc2cc(-c3ccc4c5c(cccc35)-c3ccccc3-4)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A flask was charged with 2.7 g of fluoranthene-3-boronic acid, 2.0 g of 6-bromo-2-naphthol, 0.31 g of tetrakis(triphenylphosphine)palladium(0), 27 mL of 1,2-dimethoxyethane, and 13.5 mL of a 2 M sodium carbonate aqueous solution in an argon atmosphere. The mixture was heat refluxed with stirring for 4 hours. After cooling the reaction solution to room temperature, 2 M hydrochloric acid was added to the reaction solution so that the reaction solution had a pH in the acidic region. The reaction solution was then extracted with dichloromethane. After removing the aqueous phase, the organic phase was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering the organic phase, the solvent was evaporated under reduced pressure. The residue was dispersed and washed in dichloromethane to obtain 2.75 g of the target 6-(fluoranthen-3-yl)-2-naphthol (yield: 89%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a stirred solution of tert-butyl trans-4-hydroxycyclohexylcarbamate (2.0 g, 9.3 mmol) in 100 mL of dichloromethane was added PCC (3.0 g, 14 mmol) and celite (5.0 g). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a celite pad and the residue concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:1, v/v) to give tert-butyl 4-oxocyclohexylcarbamate (1.6 g, 80%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 4.52 (brs, 1H), 3.94 (brs, 1H), 2.45-2.40 (m, 4H), 2.20-2.27 (m, 2H), 1.74-1.63 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[NH:15][CH:16]=[CH:17][N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[CH:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Brc1ccc2c(c1)OCCn1cc(-c3ncc[nH]3)nc1-2
Product: Brc1ccc2c(c1)OCCn1cc(-c3nccn3CCN3CCOCC3)nc1-2
Yield: 51 %

Procedure:
9-Bromo-2-(1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was alkylated with 4-(2-chloroethyl)morpholine to give 9-bromo-2-[1-(2-morpholinoethyl)-1H-imidazol-2-yl]-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (yield 51%. MS: 444.2) which was coupled under Suzuki palladium coupling conditions of Example 182 with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate to give 209. Yield 24%. MS: 432.1. 1H NMR (400 MHz, DMSO) δ 12.95 (s, 1H), 8.56 (d, J=2.3, 1H), 8.09 (s, 1H), 7.87 (s, 1H), 7.72 (s, 1H), 7.51 (dd, J=8.4, 2.3, 1H), 7.21 (d, J=1.0, 1H), 7.04 (d, J=8.4, 1H), 6.89 (d, J=1.0, 1H), 4.72 (t, J=7.1, 2H), 4.50 (q, J=5.6, 4H), 3.48-3.40 (m, 4H), 2.73 (t, J=7.1, 2H), 2.46-2.36 (m, 4H)
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([N:8]([CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CNCc2ccccc2)cc1
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(C(=O)CN(Cc2ccccc2)Cc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a solution of 2-benzylamino-1-(4-methoxy-phenyl)-ethanone (12.0 g, 47.0 mmol, see Preparation 60) and 3-methoxy benzaldehyde (6.09 g, 44.8 mmol) in 1,2 DCE (250 ml) was added NaB(OAc)3H. The reaction mixture was stirred at RT overnight. The reaction was poured into sat. NaHCO3 (150 ml) and extracted with CH2Cl2 (3×100 ml). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography (SiO2, gradient elution 20% to 50% EtOAc/hexanes) gave the title product (13.85 g, 36.9 mmol, 83% yield).
Reaction SMILES: [CH2:1]1[C:10](=[O:11])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][CH:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][C:10]1=[O:11]
Reactant: COC(=O)CBr
Reactant: O=C1CCc2ccccc2C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC1C(=O)CCc2ccccc21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A three-neck, round-bottomed flask equipped with a dropping funnel and a septum, was charged with 6.6 mL (50 mmol) of beta-tetralone and 100 mL of THF under a nitrogen atmosphere. The solution was cooled to -30° C. and 36.6 mL (55 mmol) of LDA (1.5M in cyclohexane) was added dropwise. The solution was stirred for 30 minutes and warmed to 0° C. To this solution, 5.7 mL (60 mmol) of methyl bromoacetate was added. The solution was stirred at 0° C. for 1 h. The reaction was quenched with 3N HCl until pH of the mixture was <3. THF was removed in vacuo and the concentrate was extracted with methylene chloride (2×500 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. This oil was purified by liquid chromatography on 560 g silica gel 60 (230°-400 m), eluting with hexane-ethyl acetate (4:1) and collecting 40 mL fractions. Fractions homogeneous by TLC were combined and concentrated in vacuo. The resulting oil needed the second chromatography to afford 8.22 g (75.4%) of >95% pure product as a near colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][OH:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.CN1CCCN(C)C1=O>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH:15]=[O:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: OCc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CN1CCCN(C)C1=O
Solvent: ClCCl
Product: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
With ice-cooling, 1.9 g of manganese dioxide (85%) are added to a suspension of 715 mg (2.6 mmol) of 4-(3-chloroanilino)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidine in 170 ml of methylene chloride and the mixture is stirred at RT for 20 h. 20 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) are then added to the reaction mixture, and it is stirred for 1 h and then filtered through Hyflo. The filtration residue is again stirred (1 h) in 50 ml of methylene chloride/DMPU (1:1) and again filtered. The two filtrates are combined, evaporated and taken up in ethyl acetate/THF and water. The aqueous phases are extracted twice with ethyl acetate; the organic phases are washed 4 times with water and brine, dried (MgSO4) and evaporated down to a residual volume of ≈20 ml. Addition of diethyl ether and filtration yields 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=10.1; TLC-Rf=0.24 (CH2Cl2/methanol [10:1]).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:18])[N:33]([CH2:32][C:29]4[CH:30]=[CH:31][C:26]([C:25]([O:24][CH3:23])=[O:34])=[CH:27][CH:28]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(C(=O)OC)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 4-(aminomethyl)benzoic acid methyl ester (0.28 g, 1.4 mmol). Purification using silica gel, eluting with 4:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 110 as a white solid (m.p. 244-246° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][CH:8]([NH:15][C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C:9](N(OC)C)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].OS([O-])(=O)=O.[K+]>C(OCC)C>[C:1]([O:5][C:6](=[O:33])[CH2:7][CH:8]([NH:15][C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CC(C=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a suspension of 3-(9H-Fluoren-9-ylmethoxycarbonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (4.57 g, 10.04 mmol) in Ethyl ether (30 mL) at −5° C. was added dropwise 0.5 equiv of 1.0M Lithium aluminum hydride (LAH) in ethyl ether (5.02 mL, 5.02 mmol). After stirring at −5° C. to room temperature for 1 hr, the reaction mixture was treated with 5% KHSO4 (200 mL), stirred for 5 min and then partitioned between EtOAc/water. The organic phase was washed with saturated NaCl solution (200 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by flask column chromatography on silica gel eluting with EtOAc/Hexane (20%) to give the title compound (2.18 g, 55%) as a clear oil. TLC (30% EtOAc/Hexane) Rf=0.35; 1HNMR (CDCl3) δ 9.65 (s, 1H), 7.77 (d, J=7.2 Hz, 2H), 7.50 (d, J=7.5 Hz, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.33 (dt, J=7.5, 1.2 Hz, 2H), 5.88 (d, J=7.2 Hz, 1H), 4.50–4.36 (m, 2H), 4.24 (t, J=6.6 Hz, 1H), 3.54–3.45 (m, 1H), 3.00–2.93 (dd, J=17.4, 4.8 Hz, 1H), 2.82–274 (dd, J=17.7, 5.1s Hz, 1H), 1.45 (s, 9H). MS(ES) for C23H25NO5 (MW=395.45): positive 396 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([N:18]1[C@@H:30]2[C@@H:21]([C@H:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:20][CH2:19]1)=[O:17])=[O:8].O.[NH2:38][CH2:39][CH2:40][OH:41]>>[OH:41][CH2:40][CH2:39][NH:38][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([N:18]1[C@@H:30]2[C@@H:21]([C@H:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:20][CH2:19]1)=[O:17])=[O:8]
Reactant: NCCO
Reactant: O=C(CCCCCBr)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Solvent: O
Product: O=C(CCCCCNCCO)N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Yield: 73 %

Procedure:
6-Bromo-N-((1R,2S)-2-{[(3aR,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexyl)hexanamide (150 mg, 0.27 mmol) was stirred in 2-aminoethanol (3 ml) at 60° C. for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography and eluted with ethyl acetate-methanol (5:1, v/v) to give the title compound (106 mg, 73%) as a white solid.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=2)[C:12]([OH:14])=[O:13])=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[O:8]=[C:9]1[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[CH:15]=[CH:16][NH:17]1
Reactant: COc1ccc(COc2cc(C(=O)O)ccn2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
Compound 1 (20.4 g, 84.0 mmol) obtained in Reference Example 12 was dissolved in trifluoroacetic acid (168 mL), and anisole (91.1 mL, 0.840 mol) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was reslurried with ethyl acetate to afford 2-oxo-1,2-dihydropyridine-4-carboxylic acid (6.99 g, 60%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[Cl:9][C:10]([Cl:14])([Cl:13])[S:11]Cl.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[CH3:1][N:2]1[CH2:8][C:6](=[O:7])[N:5]([S:11][C:10]([Cl:14])([Cl:13])[Cl:9])[C:3]1=[O:4]
Reactant: CN1CC(=O)NC1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC(=O)N(SC(Cl)(Cl)Cl)C1=O
Yield: 91.1 %

Procedure:
A mixture of 11.4 g (0.1 mole) 1-methylhydantoin, 1.2 g Aliquat® 336 and 19.5 g (0.1 mole) trichloromethylsulfenyl chloride in 100 ml methylene chloride was stirred vigorously and cooled in an ice bath. To that mixture, 25 g of 20% pre-cooled aqueous sodium hydroxide was added at once; the temperature of the reaction mixture increased from 5° C. to 21° C. Stirring was continued; the ice bath was removed after 5 minutes. The methylene chloride layer was washed with water, dried over magnesium sulfate and stripped to give 24 g of sticky solids. Crystallization from toluene with charcoal treatment gave 8.4 g of the above-identified product, as a white solid, melting point 110°-112° C.
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]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.[BH4-].[Na+]>[OH-].[K+].O>[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]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCC(O)c1ccc(-c2ccccc2F)cc1

Procedure:
45.9 gm (0.169 mol) of 4-(2'-fluoro-4-biphenylyl)-4-oxo-butyric acid were dissolved in a solution of 11.2 gm of potassium hydroxide in 450 ml of water at 35° C. While stirring, a solution of 6.4 gm (0.169 mol) of sodium borohydride in water was added. After stirring for about 3 hours, the mixture was acidified and extracted with ethyl acetate. From the washed and dried organic phase, the cyclohexylamine salt was precipitated by addition of cyclohexylamine. Yield: 41 gm (65% of theory); m.p. 174°-175° C.; melting point of the free acid: 120°-122° C. (from benzene); melting point of the isobutylamine salt: 125°-127° C. (from isopropanol); melting point of the morpholine salt: 108°-110° C. (from isopropanol); melting point of the sodium salt: 222°-224° C. (from ethanol).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH3:41])=[C:10]([CH:40]=2)[C@@H:11]([C:28]2[C:37]([CH3:38])=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][C:29]=2[CH3:39])[O:12]C(=O)[C@@H](NS(C2C=CC(Cl)=CC=2)(=O)=O)C)[CH:5]=[CH:4][N:3]=[CH:2]1>CN(C)C=O>[OH:12][C@H:11]([C:28]1[C:29]([CH3:39])=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:36][C:37]=1[CH3:38])[C:10]1[CH:40]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=[CH:8][C:9]=1[CH3:41]
Reactant: COC(=O)c1cc(C)c([C@@H](OC(=O)[C@H](C)NS(=O)(=O)c2ccc(Cl)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccnc2)cc1[C@H](O)c1c(C)cc(C(=O)O)cc1C

Procedure:
The compound obtained in Example 3 was treated in the same manner as in Example 2 to give 2.4 g of (S)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, melting point 286-288° C. (decomposition), optical rotation [α]D21 -261.5° (c=1.0, dimethylformamide).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[NH:18][N:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[CH:15]=[CH:16][N:17]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: c1ccc(CO[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: c1ccc(CO[C@H]2CCC[C@@H]2c2ccn(C3CCCCO3)n2)cc1
Yield: 92.6 %

Procedure:
A solution of the 5-[(1R,2S)-2-(benzyloxy)cyclopentyl]-1H-pyrazole (322 mg, 1.33 mmol) prepared in Example 148c, 3,4-dihydro-2H-pyran (0.728 mL, 7.98 mmol) and p-toluenesulfonic acid hydrate (50 mg, 0.266 mmol) in dichloromethane (5.0 mL) was stirred for 3 hours under reflux. After allowing to cool, the reaction solution was vacuum concentrated, and the residue was purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (402 mg, 93%) in the form of a diastereomeric mixture as a colorless oil.
Reaction SMILES: [C:1]([C:5]([C:7]1[S:11][C:10]([NH2:12])=[N:9][C:8]=1[C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:8]1[N:9]=[C:10]([NH:12][C:18]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[O:25])[S:11][C:7]=1[C:5](=[O:6])[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)c1sc(N)nc1-c1ccco1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 79.3 %

Procedure:
Compound 399 (102 mg, 0.408 mmol) was dissolved in DMF (5 mL), and isonicotinic acid (199 mg, 1.63 mmol), EDC hydrochloride (309 mg, 1.61 mmol) and 1-hydroxybenzotriazole monohydrate (245 mg, 1.60 mmol) were added thereto, followed by stirring at 60° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to afford the entitled Compound 400 (115 mg, 79%) as a pale yellowish green solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]1[CH:25]([CH:26](O)C#N)[CH2:24]1.C([BH3-])#N.[Na+].C(O)(=O)C.[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15]2[C:20]([NH:21][CH2:26][CH:25]3[CH2:23][CH2:24]3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(c1ncccc1N)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#CC(O)C1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CN(c1ncccc1NCC1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h

Procedure:
1-tert-Butyloxycarbonyl-4-[N-methyl-N-(3-amino-2-pyridinyl)amino]piperidine (1.64 g, 5.37 mmol) is dissolved in methanol (0.2M) and cooled to 0°. Cyclopropylcarboxaldehyde (0.40 ml, 5.37 mmol) is added. After stirring 5 min, sodium cyanoborohydride (337 mg, 5.37 mmol) is added. The reaction is refluxed one hour, then stirred overnight at 20°-25°. Acetic acid (53.7 mmol) is added and the reaction refluxed 3 hr. After cooling to 20°-25°, cyclopropylcarboxaldehyde (820 mg, 2.68 mmol) and sodium cyanoborohydride (168 mg 2.68 mmol) are added and the reaction stirred 16 hr at 20°-25°. The mixture is diluted with water, adjusted to pH 9 with sodium hydroxide (1N) and extracted with chloroform. The extract is filtered and concentrated. The concentrate is chromatographed (silica gel; ethyl acetate/hexane (20/80) to give the title compound; NMR (300 MHz, CD3OD) 7.39, 6.79, 3.79, 3.07, 2.80, 2.63, 2.44, 1.52, 1.33, 1.27, 0.93, 0.35 and 0.05δ.