Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:9]=[C:10](/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH:28]=C)[C:21](=[O:30])[CH:20]2[CH3:31])=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14].ClC1C=C(/C=C/C(N2C[CH2:48][N:47]([CH2:50][CH2:51][CH2:52][CH:53]=O)C(=O)C2)=O)C=CC=1Cl.N1CCCCC1.B.N1C=CC=CC=1.C(O)(=O)C.[OH-].[NH4+]>CC(C)=O.O.ClCCCl.C(O)C.[Os](=O)(=O)(=O)=O>[Cl:7][C:8]1[CH:9]=[C:10](/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:47]3[CH2:48][CH2:53][CH2:52][CH2:51][CH2:50]3)[C:21](=[O:30])[CH:20]2[CH3:31])=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: C=CCCCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)C(C)C1=O
Reactant: O=CCCCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CC1=O
Agent: O=[Os](=O)(=O)=O
Agent: B
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: CCO
Product: CC1C(=O)N(CCCCN2CCCCC2)CCN1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
Sodium metaperiodate (310 mg, 1.45 mmol) and osmium(VIII) oxide (2.5% solution in tert-butylalcohol, 49 μl, 48 μmol) were added at 0° C. to a solution of 4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-3-methyl-1-pent-4-enyl-piperazin-2-one (intermediate 20; 184 mg, 0.48 mmol) in acetone/water 1:1 (10 ml). The reaction mixture was stirred at 0° C. for 30 min, then allowed to reach room temperature over 45 min, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. The crude aldehyde intermediate [4-{-4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-3-methyl-2-oxo-piperazin-1-yl}-butyraldehyde] and piperidine (33 mg, 0.39 mmol) were dissolved in 1,2-dichloroethane (1.5 ml), then a freshly prepared solution of pyridine borane complex (8 M in pyridine, 71 μl, 0.78 mmol) and acetic acid (69 mg, 1.16 mmol) in ethanol (1.5 ml) was added dropwise at room temperature. The reaction mixture was stirred overnight, then 25%. aq. ammonium hydroxide solution (0.16 ml) was added, and volatile material was removed by rotary evaporation. The residue was purified by chromatography (SiO2; CH2Cl2/MeOH/NH4OH 90:10:0.25) to afford the title compound (15 mg, 11%). Light yellow solid, MS (ISP)=452.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[CH2:17]2)[CH:3]=1.[F:31][C:32]([F:44])([F:43])[O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([N:18]2[CH2:19][CH2:20][CH2:21][C@H:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]3[NH:8][C:4]3[CH:3]=[C:2]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][C:32]([F:31])([F:43])[F:44])[CH:35]=4)[CH:7]=[CH:6][N:5]=3)[CH2:17]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(Br)ccn3)C2)cc1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: O=[N+]([O-])c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(-c4cccc(OC(F)(F)F)c4)ccn3)C2)cc1

Procedure:
(1R,2R)—N1-((S)-1-(4-Nitrophenyl)piperidin-3-yl)-N2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)cyclohexane-1,2-diamine (1.6 mg, 0.003 mmol, 6.8% yield) was synthesized as described in General Procedure I using (1R,2R)—N1-(4-bromopyridin-2-yl)-N2-((S)-1-(4-nitrophenyl)piperidin-3-yl)cyclohexane-1,2-diamine (20 mg, 0.04 mmol) and 3-(trifluoromethoxy)phenylboronic acid (12.2 mg, 0.04 mmol). The desired fraction from RP prep-HPLC method D was concentrated to give the title compound as a pale yellow solid. Anal. Calcd. for C29H32F3N5O3 m/z 555.2, found: 556.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J=2.0 Hz, 1H), 7.80 (m, 2H), 7.51 (m, 1H), 7.39 (m, 1H), 7.33 (m, 2H), 6.89 (dd, J=5.6 Hz, J=1.6 Hz, 1H), 6.77 (m, 2H), 6.47 (m, 1H), 4.09 (m, 1H), 3.70 (m, 3H), 3.23 (m, 1H), 3.11 (m, 1H), 2.92 (m, 1H), 2.36 (m, 1H), 2.11 (m, 3H), 1.92 (m, 4H), 1.64 (m, 2H), 1.44 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)C1SC=C(OCCCCCCCCCC)C=1OCCCCCCCCCC)CCC>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>[N+:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCCCCOc1csc([Sn](CCCC)(CCCC)CCCC)c1OCCCCCCCCCC
Product: O=[N+]([O-])c1ccccc1
Reaction time: 0.33 h
Yield: 57 %

Procedure:
To a refluxing solution of 1-bromo-4-nitrobenzene (0.80 g, 3.98 mmol) in tolulene (200 mL) was added tetrakis(triphenylphosphine)palladium(0) (75 mg). After 20 min, 2-(tributylstannyl)-3,4-didecyloxythiophene (2.87 g, 4.19 mmol) was added via a syringe. After complete addition, the mixture was refluxed for a total of 15 h. After cooling, the mixture was filtered and evaporated to afford a solid. Filtration using hot hexane gave 1-(3,4-didecyloxy)thien-2-yl)-4-nitrobenzene, recrystallized from ethanol containing 2% acetone, 1.17 g, yield=57%, mp=40-41.5° C. IR (KBr) 3127, 2919, 1594, 1512, 1464, 1339 and 848. 1H NMR (δ ppm): 0.880 (t, J=7.2 Hz, 6H), 1.411 (m, 28H), 1.769 (m, 4H), 3.986 (t, J=7.2 Hz, 2H), 4.092 (t, J=7.2 Hz, 2H), 6.263 (s, 1H), 7.903 (d, J=10.2 Hz, 2H) and 8.208 (d, J=10.2 Hz, 2H). 13C NMR (δ ppm): 14.26, 22.69, 29.34, 29.60, 30.12, 30.64, 30.73, 31.71, 31.91, 32.37, 70.18, 73.09, 97.19, 122.46, 123.94, 126.94, 140.16, 145.08, 145.94 and 150.98. MS(EI) m/z (rel int): 517 [(M)+, 42], 377 [(M+ --C10H20), 18], 359 [(M+ --C10H22O),5], 333 [(M+ --C11H20S), 3],237 [(M+ --C20H40), 55] and 190 [(M+ --C20H41NO2), 8]. Anal. Calcd for C30H47NO4S: C, 69.59; H, 9.15; N, 2.71; S, 6.19. Found: C, 69.61; H, 9.20; N, 2.63; S, 6.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:33]([O:37][C:38]([N:40]1[CH2:46][CH2:45][CH:44]([OH:47])[CH:43]([NH2:48])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C)C=O>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH2:42][CH:43]([NH:48][C:12]([C:10]2[S:11][C:7]3[C:6]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:14])[CH:44]([OH:47])[CH2:45][CH2:46]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CCC3O)nc12
Reaction time: 16 h

Procedure:
According to scheme 10, to a stirred solution of 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester (XXX) in dichloromethane was added at −60° C. m-chloroperbenzoic acid (MCPBA). The mixture was allowed to slowly warm to room temperature overnight and 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester (XXXI) was obtained. To a solution of 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in ethanol was added water, ammonium chloride and sodium azide. The mixture was stirred at 75° C. over night, to give 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXII). 4-Azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester in methanol was hydrogenated in the presence of palladium on charcoal (10%) to yield 4-amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester (XXXIII). 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 1,1′-carbonyl-diimidazole in dimethylformamide are stirred at room temperature for about 16 hours. 4-Amino-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester was added and stirring was continued for 16 hours at room temperature. It was obtained 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester (XXXIV). To a solution of 4-hydroxy-5-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-azepane-1-carboxylic acid tert-butyl ester in dimethylsulfoxide was added triethylamine, dichloromethane and a solution of sulfur trioxide pyridine complex in dimethylsulfoxide. The mixture was stirred for 18 hours at room temperature. After purification 4-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-5-oxo-azepane-1-carboxylic acid tert-butyl ester (VIII) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][N:18]2[CH2:17][CH2:16][N:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:10][CH:11]=3)[CH2:20][CH2:19]2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Reactant: Fc1ccc(OCCCCBr)cc1
Product: Fc1ccc(Cc2ccc(N3CCN(CCCCOc4ccc(F)cc4)CC3)cc2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (10) synthesized in Example 3 and 4-(4-fluorophenyl)oxybutyl bromide to produce the above.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20].C(N(CC)CC)C.C(OCC)(=O)C>CS(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:10]2[C:11]([N+:19]([O-:21])=[O:20])=[CH:12][CH:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc(Nc2c([N+](=O)[O-])cccc2[N+](=O)[O-])cc1
Reaction time: 12 h
Yield: 98.9 %

Procedure:
0.8 g (7.4 mmol) of p-toluidine and 1.5 g of 1-chloro-2,6-dinitrobenzene were dissolved in 15 ml of dimethyl sulfoxide and 1.5 g (14.8 mmol) of triethylamine was added thereto. After stirring at 80° to 90° C. for 12 hours, ethyl acetate was added and the reaction mixture was washed with water and dried over magnesium sulfate. After concentrating, the residue was purified by silica gel column chromatography. Thus 2.0 g of N-(4-methylphenyl)-2,6-dinitroaniline was obtained. This product was dissolved in a mixture of 20 ml of methanol with 40 ml of tetrahydrofuran and hydrogenated in the presence of palladium-carbon at room temperature under atmospheric pressure. After filtering off the catalyst, the solvent was distilled off under reduced pressure. Thus 1.6 g of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=3)[O:17][CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=3)[O:17][CH:18]([CH3:23])[C:19]([OH:21])=[O:20])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)Oc1cccc(OCc2ccc3ccc(Br)cc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1cccc(OCc2ccc3ccc(Br)cc3n2)c1)C(=O)O

Procedure:
A mixture of the ester (Step 3) (861 mg), methanol (13 mL) and 5N sodium hydroxide (0.54 mL) was heated under reflux for 2 hours. The reaction mixture was evaporated to approximately 4 mL and acidified to pH 4.5 with HCl (0.5N). This gave a gum which crystallized in methanol to give the title compound. mp 178°
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:23])[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C1CN=C(c2c(F)cccc2F)c2cc(Cl)ccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Fc1cccc(F)c1C1=NCC(=S)Nc2ccc(Cl)cc21

Procedure:
A solution of 7.65 g. (0.025 mole) of 1,3-dihydro-7-chloro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepin-2-one in 500 ml. of pyridine was treated with 5.55 g. (0.025 mole) of phosphorus pentasulfide and heated under reflux in a nitrogen atmosphere for two hours. The pyridine (350 ml.) was removed in vacuo and the thus-produced residue was poured onto crushed ice. The aqueous phase was extracted with methylene chloride and then discarded. The extract was washed successively with three 200-ml. portions of water and 100 ml. of brine, and dried over anhydrous sodium sulfate. Removal of the solvent gave 7.0 g. of solid which was recrystallized from ethanol-water, to give in 2 crops 6.8 g. of crude material which, after recrystallization from ethanol-water, gave pure 1,3-dihydro-7-chloro-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepine-2-thione of melting point 222.5°-224° C.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:33][C@H:34]1[CH2:36][O:35]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:33][C@@H:34]([OH:35])[CH3:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: C[C@H]1CO1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: C[C@H](O)CN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 18.5 %

Procedure:
Following General Procedure E, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (48 mg, 0.110 mmol) and (S)-2-methyl oxirane (121 mg, 0.22 mmol) gave 7-cyclopentyl-2-{5-[4-((S)-2-hydroxy-propyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (10 mg, 16%). MS (ESI) m/z 493.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Yield: 92.3 %

Procedure:
A solution of 1-(tert-butyloxycarbonyl)-4-piperidinol (5.2 g, 25.9 mmol), tert-butyldimethylsilyl chloride (4.07 g, 1.05 equiv.) and imidazole (2.7 g, 1.5 equiv.) in DMF (20 mL) was stirred for 16 h. After dilution with Et2O, the solution was washed successively with H2O (2×), 10% aqueous citric acid, a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried (MgSO4) and concentrated to dryness. The residue was purified by HPLC using a WATERS® LC-500 preparative chromatography apparatus [2 SiO2 columns: hexane-EtOAc (19:1), Millipore Corporation, Milford, Mass., USA] to give 1-(tert-butyloxycarbonyl)-4-(tert-butyldimethylsiloxy)piperidine (7.54 g, 92%). 1H NMR (CDCl3) δ3.87 (m, 1H), 3.61 (ddd, J=3.5, 7.5, 13.0 Hz, 2H), 3.24 (ddd, J=3.7, 8.0, 13.0 Hz, 2H), 1.48 (s, 9H), 0.88 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:13]([N:15]2[CH:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])=[O:14])[CH2:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.CN1CCOCC1>CN(C=O)C>[CH:1]1([CH2:7][CH:8]([CH2:9][C:10]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:12])[C:13]([N:15]2[CH:19]([CH:20]([CH3:22])[CH3:21])[CH2:18][O:17][C:16]2=[O:23])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1COCCN1
Reactant: CC(C)C1COC(=O)N1C(=O)C(CC(=O)O)CC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C1COC(=O)N1C(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A mixture of 3-cyclohexylmethyl-4-(4-isopropyl-2-oxooxazolidin-3-yl)-4-oxobutyric acid (2.00 g, 6.14 mmol) and HBTU (2.56 g, 6.76 mmol) in DMF (20 mL) were treated with morpholine (0.591 mL, 6.76 mmol) and N-methylmorpholine (0.811 mL, 7.37 mmol). The mixture was stirred overnight at ambient temperature and then partitioned between 4:1:2:3 ethyl acetate/THF/water/brine (100 mL total). The organic phase was washed with 1M hydrochloric acid, saturated aqueous sodium bicarbonate and brine (50 mL each), dried (MgSO4) filtered and concentrated to dryness. The residue dissolved in ethyl acetate/hexane and product was crystallized out to provide 2-cyclohexylmethyl-1-(4-isopropyl-2-oxooxazolidin-3-yl)-4-morpholin-4-ylbutane-1,4-dione (1.63 g). MS (M+1): 395.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]=[C:6]2[CH2:12][C:13]([OH:15])=O.[C:16]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]=[C:6]2[CH2:12][C:13]([N:29]1[CH2:28][CH2:27][N:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:31][CH2:30]1)=[O:15]
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: COc1ccc2c(c1)C(CC(=O)O)=CC2
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CC(=O)N1CCN(c3cccc4ccccc34)CC1)=CC2
Reaction time: 1 h
Yield: 86.4 %

Procedure:
2.0 g (0.012 mol) of N,N'-carbonyldiimidazole are added in small portions to a solution of 2.45 g (0.012 mol) of 5-methoxy-1H-indene-3-acetic acid in 12 ml of tetrahydrofuran, which has been placed under an argon atmosphere, and the mixture is stirred for 1 h. A solution of 2.55 g (0.012 mol) of 1-(naphth-1-yl)piperazine in 10 ml of tetrahydrofuran is added, and the mixture is left to stand overnight. The solvent is evaporated under reduced pressure. The residual oil is taken up in water and diethyl ether, and the solid obtained is collected by filtration and dried. 4.13 g of a product are obtained which is used as it is in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1>C(O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)cc3)oc2C)cc1
Solvent: CCCCCC
Solvent: CCO
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
Ethyl 3-[{[4-({1-[5-(4-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (660 mg) which is a synthetic intermediate in Example 151 was dissolved in ethanol-hexane (1:1, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (1:1, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 13.5 min were collected, and concentrated. The obtained amorphous compound (319 mg) was dissolved in ethanol (5 mL) and tetrahydrofuran (5 mL), 1N lithium hydroxide (1.3 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (288 mg, 95%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[CH3:1])=[CH:17][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(Cc2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (106.26 g, 0.694 mol) (prepared by the method of: Wee, A. G. H.; Shu, A. Y. L.; Djerassi, C. J. Org. Chem. 1984, 49, 3327-3336) in anhydrous DMF (1.0 L), under nitrogen, was added sodium hydride (60% in oil, 30.5 g, 0.763 mol, 1.1eq.) in 5 portions over 1 hour. When gas evolution ceased, 4-fluorobenzyl bromide (131.13 g, 0.694 mol) in anhydrous DMF (0.2 L) was added via pressure equalized addition funnel over 45 minutes. The mixture was allowed to stir at room temperature for 16 hours after the addition was complete, then was poured into water (1.4 L) in a 4 L separatory funnel. The mixture was extracted with diethyl ether (5×1.0 L) and the combined organic phases were washed with brine (3.0 L) and dried (Na2SO4). Filtration, rinsing of the filter cake with diethyl ether (0.5 L) and concentration in vacuo (approx. 20 Torr) gave the crude product and DMF. Residual DMF was removed on a cold finger trap rotary evaporator at full pump vacuum in a 40° C. water bath to give the crude benzylate pyrrole as an orange oil. The crude product was purified by chromatography on a column of silica gel (125 mm OD, 1 kg 230-400 mesh, packed with hexanes-EtOAc 95:5) eluted with hexanes:EtOAc (95:5, 2.0 L) and hexanes:EtOAc (90:10, 8.0 L) while collecting 500 mL fractions, using the flash technique. Fractions 4-18 were combined to afford ethyl 1-(4-fluorobenzyl)-2-methyl-1H-pyrrole-3-carboxylate (172.3 g, 95%) as a clear, pale yellow, viscous liquid. TLC (Merck, hexanes:EtOAc 85:15, UV-+, cerium molybdate-+): Rf=0.26; LCMS (Eclipse XDB-C8, 0.8mL/min, gradient 80:20 to 5:95 H2O (+0.1% HOAc):CH3CN—5 minutes, APCl, +mode): RT-3.711 min, m/e=262.1 (base), 263.2 (30); 1H-NMR (300 MHz, CDCl3): δ=1.33 (t, J=7.06 Hz, 3H), 2.43 (s, 3H), 4.26 (q, J=7.06 Hz, 2H), 5.00 (s, 2H), 6.52 (d, J=3.20 Hz, 1H), 6.58 (d, J=3.20 Hz, 1 H), 6.92-7.04 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]([F:19])[F:18])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:27][C:28]([NH2:30])=[O:29]>CC(C)=O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:10]2[C:14](=[O:15])[N:13]([CH3:16])[C:12]([CH:17]([F:18])[F:19])=[N:11]2)=[CH:4][C:5]=1[O:9][CH2:27][C:28]([NH2:30])=[O:29]
Reactant: NC(=O)CI
Reactant: Cn1c(C(F)F)nn(-c2cc(O)c(Cl)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(C(F)F)nn(-c2cc(OCC(N)=O)c(Cl)cc2Cl)c1=O
Yield: 817.1 %

Procedure:
In a manner similar to Example 1, the reaction of 0.72 g (0.00023 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-3-difluromethyl-4,5-dihydro-4-methyl-1,2,4-triazol-5(1H)-one, 0.32 g (0.00023 mole) of potassium carbonate, and 0.47 g (0.00025 mole) of iodoacetamide in 5 mL of acetone produced 0.69 g of [2,4-dichloro-5-(3-difluoromethyl-4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]acetamide (mp 190°-193.5° C).