Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:21][C:22]1[CH:23]=[C:24]([CH3:29])[C:25](F)=[N:26][CH:27]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([C:25]2[C:24]([CH3:29])=[CH:23][C:22]([Br:21])=[CH:27][N:26]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCOCC1
Reactant: Cc1cc(Br)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2ncc(Br)cc2C)CCOCC1
Reaction time: 1 h
Yield: 45.5 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-carboxylic acid methyl ester (759 mg) in toluene (5 ml) was added dropwise a 1.0 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (5.26 ml) under ice-cooling, and stirred at the same temperature for 1 hour. Then, a solution of 5-bromo-2-fluoro-3-methylpyridine (1 g) in toluene (5 ml) was added dropwise thereto, and stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added thereto, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 4-(5-bromo-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid methyl ester (753 mg) as a pale yellow oil. MS (ESI) m/z: 314, 316 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][C:4](=[S:8])[N:3]1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C)C=O.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C([O-])([O-])=O.[K+].[K+].O>[CH2:9]([N:3]1[C:4]([S:8][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][CH2:6][CH2:7][N:2]1[CH3:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCNC(=S)N1Cc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN=C(SCc2ccccc2)N1Cc1ccccc1
Temperature: 35 °C
Reaction time: 2 h

Procedure:
Seven grams of tetrahydro-1-methyl-2-(phenylmethyl)-1,2,4-triazine-3(2H)-thione was dissolved in 30 ml. of dimethyl formamide. Three grams of finely ground potassium carbonate (K2CO3) was added to the solution. Benzyl bromide (5.43 grams) was added in several additions at room temperature. The mixture was heated to 60°-65° C and held at that temperature for 2 hours. The mixture was chilled and diluted with additional K2CO3 (10 g.) and water (200 ml). The product was extracted with trichloromethane and washed with brine. The mixture was dried with magnesium sulfate. The mixture was diluted with ethyl ether and the insoluble particles filtered off. The filtrate was heated to 35° C to concentrate the solution. Upon chilling 2-benzyl-3-(benzylthio)-1,2,5,6-tetrahydro-1-methyl-1,2,4-triazine crystallized from the liquid reaction mass. This product was recrystallized from isopropanol-hexane. The product was found to have a melting point at 45° C. The structure was confirmed by IR, NMR and elemental analysis.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1F)[CH:17]=[O:18]>>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1)[CH:17]=[O:18]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C1CCN(CC2CCNCC2)C1
Product: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c(F)c1

Procedure:
Prepared from the product of Example 4 and 3,4-difluorobenzaldehyde.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1>O=[Pt]=O.C(O)C>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[N:5]=[C:6]2[C:11]([CH2:10][CH2:9][CH2:8][NH:7]2)=[CH:12][CH:13]=1
Reactant: COC(OC)c1ccc2cccnc2n1
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(OC)c1ccc2c(n1)NCCC2
Temperature: 23 °C
Reaction time: 8 h

Procedure:
The procedure described in J. Org. Chem., 2004, 69 (6), pp 1959-1966 was used. Into a 5-l pressure tank reactor (5 atm) was placed 2-(dimethoxymethyl)-1,8-naphthyridine (intermediate 5, 200 g, 979 mmol), ethanol (3 l), PtO2 (12 g). The reactor was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The mixture was stirred overnight at 23° C. under an atmosphere of hydrogen. This reaction was repeated four times. The solids were filtered out and the resulting mixture was concentrated under vacuum to give the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14](=[O:21])[NH:15]2)[CH:3]([NH:6][CH:7]([CH3:9])[CH3:8])[CH2:4][CH3:5].[CH3:22][O-:23].[Na+]>CO>[OH:1][CH:2]([C:10]1[CH:19]=[CH:18][C:17]([O:20][C:22](=[O:23])[C:17]2[CH:18]=[CH:19][C:10]([CH3:2])=[CH:11][CH:16]=2)=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14](=[O:21])[NH:15]2)[CH:3]([NH:6][CH:7]([CH3:9])[CH3:8])[CH2:4][CH3:5]
Reactant: CCC(NC(C)C)C(O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(NC(C)C)C(O)c1ccc(OC(=O)c2ccc(C)cc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5.8 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril was dissolved in 150 ml of methanol, and a 15% methanolic solution of sodium methylate was added to the solution in an equimolar amount relative to the starting carbostyryl compound. The mixture was concentrated to dryness and the resulting residue was dissolved in 100 ml of dimethylformamide. 3.0 g of p-toluylic acid chloride was added to the solution while cooling with ice-water, and the resulting mixture was stirred for 1.5 hours at room temperature. The precipitate formed was separated by filtration, and washed successively with dimethylformamide and diethyl ether to obtain 4.2 g of 5-(1-hydroxy-2-isopropylaminobutyl)-8-p-methylbenzoyloxycarbostyril having a melting point of 197°-198° C. (after recrystallization from chloroform-diethyl ether).
Reaction SMILES: [C:1]([O:13][CH2:14][CH:15]=[CH2:16])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]CC=C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O)(=O)C>O1CCCC1>[O:8]=[C:6]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:1]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12]
Reactant: C=CCOC(=O)CCCCC(=O)OCC=C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1CCCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A stirred solution of diallyl adipate (4.53 g, 20 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to 0° C. and treated with lithium bis(trimethylsilyl)amide (40 mL, 1.0 N in THF, 40 mmol). After the addition was complete, the solution was warmed to room temperature and stirred for 2 h. The solution was then recooled to 0° C. and treated with acetic acid (2.53 mL, 44 mmol) in a dropwise manner. The turbid mixture was warmed to room temperature and filtered. The filtrate was concentrated, dissolved in minimal dichloromethane and purified by flash column chromatography (silica gel, dichloromethane) to afford allyl 2-oxocyclopentanecarboxylate (2.62 g, 78%) as a colorless oil. Characterization data is same as that observed from method A.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].ClCCl.[CH2:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH:29]=[CH:28]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:19]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH:29]=[CH:28]2)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: O=c1ccc2cc(OCCCCNCc3ccccc3)ccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ccc2cc(OCCCCN(Cc3ccccc3)S(=O)(=O)CCCCl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6.6 ml of 3-chloropropanesulfonyl chloride was dropwise added, at 0° C., to a dichloromethane solution containing 8 g of 6-(4-benzylaminobutoxy)carbostyril and 7.6 ml of triethylamine. The mixture was stirred at room temperature for 1 day. The reaction mixture was washed with 10% hydrochloric acid and water in this order and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was dissolved in 30 ml of dioxane. To the solution was added 10.ml of a 10% potassium hydroxide solution, followed by stirring at room temperature for 30 minutes. The reaction mixture was neutralized with 10% hydrochloric acid, followed by extraction with chloroform. The extract was dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was crystallized from diethyl ether to obtain 7.3 g of 6-{4-[N-(3-chloro-propylsulfonyl)-N-benzylamino]butoxy}carbostyril.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:10]1=[O:24])=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[NH2:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:10]1=[O:24]
Reactant: COC(=O)CN1C(=O)[C@H](NC(=O)OC(C)(C)C)Cc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CN1C(=O)[C@H](N)Cc2ccccc21

Procedure:
(R)-3-t-butyloxycarbonylamino-1-carbomethoxymethyl-3,4-dihydrocarbostyril (20 mg) was dissolved in 4 M hydrogen chloride in 1,4-dioxane solution (5 mL) at room temperature. After 1 h the solvent was evaporated under vacuum, and the residue was twice taken up in toluene (10 mL) and evaporated under vacuum to provide (R)-3-amino-1-carbomethoxymethyl-3,4-dihydrocarbostyril hydrochloride, a white solid (21 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([F:17])=[C:5]([C:9]([N+:14]([O-:16])=[O:15])=[C:10](F)[C:11]=1[F:12])[C:6]([OH:8])=[O:7].[OH-].[NH4+:19]>>[NH2:19][C:10]1[C:9]([N+:14]([O-:16])=[O:15])=[C:5]([C:4]([F:17])=[C:3]([O:2][CH3:1])[C:11]=1[F:12])[C:6]([OH:8])=[O:7]
Reactant: COc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Reactant: [NH4+]
Agent: [OH-]
Product: COc1c(F)c(N)c([N+](=O)[O-])c(C(=O)O)c1F
Yield: 80 %

Procedure:
2.0 g (8 mmol) of 3-methoxy-6-nitro-2,4,5-trifluoro-benzoic acid was treated with ammonium hydroxide to produce 1.6 g (6.45 mmol, 80%) of 3-amino-4,6-difluoro-5-methoxy-2-nitro-benzoic acid. LCMS: 249 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[OH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-]>CC(=O)CC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: BrCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OCCCCBr)cc1
Reaction time: 24 h

Procedure:
A mixture of 1,4 dibromobutane (50 ml), methyl 4-hydroxy-benzoate (15.2 g, 0.1 mole), potassi-m carbonate (40 g) in 2-butanone (500 ml) was refiuxed for 24 hours. The mixture was filtered, solvent removed and the residue was chromatographed on silica gel eluted with chloroform/petrol and recrystallised from pentane to give methyl 4-(4-bromobutyloxy)benzoate (19.26 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:8]1([S:18](Cl)(=[O:20])=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>C(#N)C>[C:8]1([S:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7])(=[O:20])=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: NCCCCCN
Solvent: CC#N
Product: NCCCCCNS(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Under ice cooling, 7.91 g of 1,5-diaminopentane was added dropwise with 240 mL of acetonitrile solution in which 1.75 g of 1-naphthalenesulfonyl chloride was dissolved, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the residue was added with 500 mL of water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.90 g of 5-(1-naphthalenesulfonyl)aminopentylamine.
Reaction SMILES: OC1(C2C=CC=CC=2)CCN(C2N=CN(CC3SC(C(F)(F)F)=CC=3)C(=O)N=2)CC1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2(O)[CH2:43][CH2:42][N:41]([C:44]3[N:49]=[CH:48][N:47]([CH2:50][C:51]4[S:52][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:54][CH:55]=4)[C:46](=[O:60])[N:45]=3)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH2:43][CH2:42][N:41]([C:44]3[N:49]=[CH:48][N:47]([CH2:50][C:51]4[S:52][C:53]([C:56]([F:57])([F:58])[F:59])=[CH:54][CH:55]=4)[C:46](=[O:60])[N:45]=3)[CH2:40][CH:39]=2)=[CH:36][CH:37]=1
Reactant: O=c1nc(N2CCC(O)(c3ccc(Cl)cc3)CC2)ncn1Cc1ccc(C(F)(F)F)s1
Agent: O=c1nc(N2CCC(O)(c3ccccc3)CC2)ncn1Cc1ccc(C(F)(F)F)s1
Product: O=c1nc(N2CC=C(c3ccc(Cl)cc3)CC2)ncn1Cc1ccc(C(F)(F)F)s1

Procedure:
The synthesis was performed using the mixture (21 mg) of 4-(4-hydroxy-4-phenylpiperidin-1-yl)-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one and 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one that were synthesized in Reference Synthesis Example 91 in a similar manner to Synthesis Example 68. The resultant residue was purified by preparative high performance chromatography to obtain the title compound of Synthesis Example 70 (3.0 mg, yield: 16%) and the title compound of Synthesis Example 71 (7.5 mg, yield: 37%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:17][CH3:18])[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2.[Al+3].[Cl-].[Cl-].[Cl-].CCS>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:17][CH3:18])[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2
Reactant: CC[C@H](C(=O)OC)[C@@H]1CCc2cc(OC)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CC[C@H](C(=O)OC)[C@@H]1CCc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a cold solution (ice water bath) of the compound prepared in Example 6 (233 g, 0.94 mol) in 2.5 L CH2Cl2, was added AlCl3 (630 g, 4.7 mol) slowly under Ar. The pot temperature was kept below 20° C., and the color of the reaction turned purple. EtSH (345 mL, 4.7 mol) was added slowly via an addition funnel to the reaction mixture, and the inside temperature was kept below 15° C. After 2 hours of stirring at below 20° C., the reaction went to completion by NMR analysis. The pot mixture was slowly poured into 2.5 L ice water with a strong agitation. The organic layer was separated, and the aqueous layer was extracted with 1 L CH2Cl2. The combined CH2Cl2 layers were washed with water (4×1 L) until pH 6.0-7.0, and then dried over Na2SO4. The product (216 g, 98%) was obtained as a white solid after solvent removal and vacuum drying. 1H NMR (DMSO-d6) δ 9.10 (s, 1H), 6.78 (d, 1H), 6.58 (d, 1H), 6.50 (dd, 1H), 3.60 (s, 3H), 3.20 (q, 1H), 2.70 (m, 2H), 2.40 (m, 1H), 2.08 (m, 1H), 1.80 (m, 1H), 1.50 (m, 2H), 0.80 (t, 3H).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][CH:20]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:29][CH3:30])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl>CO.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:29][CH3:30])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(c3ccc(OCOC)cc3)=C1c1ccc(OC)cc1C2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC12CCC(=O)C(c3ccc(O)cc3)=C1c1ccc(OC)cc1C2
Temperature: 60 °C
Yield: 108.6 %

Procedure:
A suspension of 9a-butyl-7-methoxy-4-(4-methoxymethoxy-phenyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (813 mg, 2 mmol) in methanol (12 mL) was warmed in an oil bath at 60° C. and treated with aqueous 2N HCl (4 mL). The resulting mixture was stirred and heated at 60° C. for two hours, then cooled to room temperature and evaporated under vacuum to leave a yellow semi-solid. The residue was dissolved in EtOAc, washed with water and brine, dried over MgSO4, filtered, evaporated under vacuum, and stripped with toluene to afford 9a-butyl-4-(4-hydroxy-phenyl)-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (787 mg, ca. 92% weight pure) as a yellow foam.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[CH:19]([C:20](O)=[O:21])[NH:18][CH:17]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]32[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[NH:29][C:28]3=[O:37])[CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][CH3:73]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:20]([CH:19]2[NH:18][CH:17]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[C:16]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:15]2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[C:10]=2[F:38])=[O:21])=[C:65]([O:72][CH3:73])[CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(C#N)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Br)c1F
Yield: 40.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 97 (0.4 g, 0.66 mmol), was reacted with diisopropylethylamine (0.43 g, 3.3 mmol), diphenylphosphinic chloride (0.31 g, 1.3 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.29 g, 2.0 mmol) to give rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a white foam (Yield 0.17 g, 40%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[O:7][C:8]=1[CH:9]([OH:11])[CH3:10])([CH3:3])[CH3:2].[CH3:23][O:24][C:25](=[O:36])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][C:29]=1[CH3:35].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25](=[O:36])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:11][CH:9]([C:8]2[O:7][C:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:21])([F:22])[F:20])=[CH:14][CH:13]=3)=[N:5][C:4]=2[CH:1]([CH3:2])[CH3:3])[CH3:10])=[CH:30][C:29]=1[CH3:35]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: CC(C)c1nc(-c2ccc(OC(F)(F)F)cc2)oc1C(C)O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(OC(F)(F)F)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.4 %

Procedure:
A solution of 1-[4-isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethanol (140 mg, 0.446 mmol) and 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (122 mg, 0.624 mmol) in toluene (15 mL) is degassed and filled with nitrogen for 3 times. Tributylphosphine (144 mg, 0.713 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of of 1,1′-(azodicarbonyl)-dipiperidine (169 mg, 0.669 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The mixture is loaded directly on silica gel column chromatography with 10–25% EtOAc/Hexanes to afford the title compound (25 mg, 11%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[O:11][CH2:12][C:13](=[O:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.[OH-].[Na+]>C(O)C.Cl>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[OH:1])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: CCOC(=O)C1=C(Nc2ccc(C)cc2O)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(C)cc2O)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 18.5 %

Procedure:
To a solution of ethyl 2-[(2-hydroxy-4-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.061 g, 0.42 mmol) in ethanol (2.5 mL), 2M hydrochloric acid in ethanol (0.56 mL, 1.1 mmol) was added at ambient temperature. The mixture was refluxed for 19 h. Cooled with ice bath, 2M sodium hydroxide solution (0.49 mL, 0.97 mmol) was added dropwise to neutralize, and ethanol (8.0 mL) was added and the mixture was refluxed for 30 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.027 g, y. 18%).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:22]=[CH:21][C:9]([CH2:10][C:11]2[S:12][C:13](/[CH:16]=[CH:17]/[N+:18]([O-:20])=[O:19])=[CH:14][CH:15]=2)=[CH:8][CH:7]=1.C(O)(=O)C.[BH4-].[Na+]>O>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][C:11]2[S:12][C:13]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])=[CH:14][CH:15]=2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(Cc2ccc(/C=C/[N+](=O)[O-])s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(Cc2ccc(CC[N+](=O)[O-])s2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.4 %

Procedure:
To a dimethyl sulfoxide (20.0 mL) solution of 2-(4-methyl-benzyl)-5-((E)-2-nitro-vinyl)-thiophene (1.20 g, 4.63 mmol) described in Manufacturing Example 92-1-3 and acetic acid (1.20 mL) was added sodium borohydride (280 mg, 7.41 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 20 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was crystallized with a tetrahydrofuran-ethyl acetate-heptane system and filtered to obtain the title compound (525 mg, 43.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:19])[C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11]
Reactant: C=C(C(=O)c1ccc(=O)[nH]c1)c1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Product: CC(C(=O)c1ccc(=O)[nH]c1)c1ccc(Cl)cc1Cl
Yield: 27.5 %

Procedure:
5-[2-(2,4-Dichloro-phenyl)-acryloyl]-1H-pyridin-2-one (840 mg) was hydrogenated in EtOAc using 5% Pd/Alox as a catalyst to give the title compound (233 mg) as a light brown solid. MS (m/e, ISP neg. ion)=293.8 [M−H+].
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CO>[C:23]1([NH:29][C:30]([N:14]2[CH2:15][CH:11]([NH:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH2:12][CH2:13]2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=S(=O)(NC1CCNC1)c1ccccc1
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N1CCC(NS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2S,4R)-2-[(E and Z)-5-carboxy-1-pentenyl]-4-phenylsulfonylaminopyrrolidine (169 mg), triethylamine (0.070 ml) and phenyl isocyanate (0.060 ml) in methanol (5 ml) was stirred at room temperature overnight and water was added to the solution. The solution was extracted with chloroform and organic phase was washed with brine. After the solution was dried over magnesium sulfate, the solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column with a mixture of chloroform and methanol (40:1) as an eluent to give (2S,4R)-2-[(E and Z)-5-carboxy-1-pentenyl]-1-phenylcarbamoyl-4-phenylsulfonylaminopyrrolidine (51 mg) as an oil.