Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrC[C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Product: Cl

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and methyl 4-(bromomethyl)benzoate to give, after deprotection by the General Procedure 1-4, the title compound as a white solid. MS (ES+) m/z: 362 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[C:5]([CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccc(CNC(=O)C(C)C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Yield: 88.3 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-2, step-3 using ethyl 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoate (1.00 g, 3.31 mmol) and NaOH (530 mg, 13.26 mmol) in THF:MeOH:H2O (3:2:1; 12 mL) to afford 800 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 14.10 (s, 1H), 8.32 (br t, 1H), 7.38-7.29 (m, 2H), 4.25 (d, J=5.1 Hz, 2H), 2.40 (m, 1H), 1.00 (d, J=6.9 Hz, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:3]1=2.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:14])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:17][C:3]1=2
Reactant: NC(=O)c1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2nc3sc(-c4ccccc4)cc3c(=O)n2c1
Yield: 82.4 %

Procedure:
From 3.2 g (0.01 mol) of 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno-[2,3-d]pyrimidine-7-carboxamide (Example 25), 90 ml of phosphorus oxychloride and 50 ml of chloroform and refluxing for twenty-four hours, following the procedure of Example 27, there is obtained 2.5 g of 4-oxo-2-phenyl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carbonitrile; mp 349°-351° C. after recrystallization from pyridine.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10].B(Br)(Br)Br.CCCCCC>C(Cl)Cl.C(OCC)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23])=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: COc1ccccc1S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a stirred suspension of N-[4-(2-methoxyphenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1.14 g, 2.8 mmol) in dry methylene chloride (30 mL) was added boron tribromide (8.5 mL of a 1.0M solution of boron tribromide in methylene chloride, 8.5 mmol). The resulting solution was stirred at room temperature for 3 hours, diluted with methylene chloride (50 mL) and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo to yield an off-white solid which was dissolved in ethyl acetate (10 mL) and dropped into hexane (300 mL). Collection of the precipitate by filtration yielded the title propanamide as a white solid (0.84 g, 77%); mp 184°-186° C. 1H-NMR (250 MHz, d6-DMSO): 1.57 (s, 3H, CH3) 6.90 (d, 1H, J=8.3 Hz, aromatic) 7.01 (t, 1H, J=7.5 Hz, aromatic) 7.50 (m, 1H, aromatic) 7.56 (s, 1H, OH) 7.85-7.97 (m, 5H, aromatic) 10.37 (s, 1H, NH) 10.74 (s, 1H, OH). MS (CI, CH4): 390 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)[C:10]2[C:15]([C:16]=1[NH:17][C:18]([NH:20][C:21]1[C:25]([C:26]([O:28]C)=O)=[CH:24][S:23][CH:22]=1)=[O:19])=[C:14]([CH3:30])[C:13]([C:31]([F:34])([F:33])[F:32])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C(OCC)(=O)C>CO>[C:1]([O:5][C:6]([C:8]1[N:9]([C:35]2[CH:39]=[CH:38][S:37][CH:36]=2)[C:10]2[C:15]([C:16]=1[N:17]1[C:26](=[O:28])[C:25]3=[CH:24][S:23][CH:22]=[C:21]3[NH:20][C:18]1=[O:19])=[C:14]([CH3:30])[C:13]([C:31]([F:34])([F:32])[F:33])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cscc1NC(=O)Nc1c(C(=O)OC(C)(C)C)n(-c2ccsc2)c2ccc(C(F)(F)F)c(C)c12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(C(F)(F)F)ccc2c1c(-n1c(=O)[nH]c3cscc3c1=O)c(C(=O)OC(C)(C)C)n2-c1ccsc1
Temperature: 100 °C

Procedure:
To a solution of 3-[3-(4-methoxycarbonyl-thiophen-3-yl)-ureido]-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1H (1.50 g, 2.59 mmol) in anhydrous methanol (10 mL) was added a 0.5 M solution of sodium methoxide (7.8 mL, 3.90 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 20 minutes. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to provide 3-(2,4-dioxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1J which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Br)[CH:15]=[CH2:16].[H-].[Na+].Cl>CN(C)C=O>[CH2:16]([O:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH:15]=[CH2:14].[CH2:16]([O:12][C:10]1[CH:11]=[C:2]([OH:1])[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6])[CH:15]=[CH2:14]
Reactant: COC(=O)c1cc(O)cc(O)c1C
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(O)c(C)c(C(=O)OC)c1
Product: C=CCOc1cc(O)cc(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 27.3 g of methyl 3,5-dihydroxy-2-methylbenzoate and 21.8 g of allyl bromide in 300 ml of dimethylformamide were added portionwise, within 30 minutes, 8.64 g of a 55% dispersion of sodium hydride in mineral oil, the temperature being held between 10° and 20° C. The mixture was stirred at room temperature for 3 hours, and then poured into ice-water. The pH was adjusted to about 3 by the addition of 3N hydrochloric acid, and the mixture was extracted with 600 ml of ethyl acetate. The organic layer was washed 5 times with 100 ml of water, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride/hexane (1:1:3, v/v/v) as eluent, and the purified products were crystallized from ethyl acetate/hexane to afford 4.1 g of methyl 3-allyloxy-5-hydroxy-2-methylbenzoate, m.p. 86°-88° C., and 5.61 g of methyl 5-allyloxy-3-hydroxy-2-methylbenzoate, m.p. 84°-87° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][N:60]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1>C(Cl)Cl>[N:42]1([CH2:47][CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([NH:58][C:59]3[N:60]=[CH:61][C:62]([NH:65][C:14](=[O:15])[C:13]4[CH:17]=[C:9]([NH:8][C:6](=[O:7])[C:5]5[CH:19]=[CH:20][CH:21]=[C:3]([C:2]([F:22])([F:23])[F:1])[CH:4]=5)[CH:10]=[CH:11][C:12]=4[Cl:18])=[CH:63][N:64]=3)=[CH:54][N:53]=2)=[O:51])[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: Nc1cnc(Nc2ccc(C(=O)NCCN3CCCC3)nc2)nc1
Reactant: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1cccc(C(F)(F)F)c1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(C(=O)NCCN4CCCC4)nc3)nc2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
Intermediate 1 (Example 2) (0.076 g, 0.222 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.047 g, 0.266 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.05 mL, 0.443 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 23 (Example 31) (0.076 g, 0.233 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.081 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C@H:14]2[CH2:22][O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])(=[O:12])=[O:11])=[C:5]([CH3:32])[CH:4]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C@H:14]2[CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:12])=[O:11])=[C:5]([CH3:32])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of (S)-tert-butyl 2-((1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)indolin-2-yl)methoxy)acetate (0.5 mmol) in dichloromethane (6 ml) was added TFA (1.5 ml) and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the crude product was used in the next step.
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2=[O:19])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH:26]=O.[O-:28][CH2:29][CH3:30].[Na+].C(O)C>C(OCC)(=O)CC>[F:18][C:16]1[CH:15]=[C:14]([C:13]([O:12][CH2:11][CH3:10])=[O:19])[C:30]2[C:29](=[O:28])[CH:26]([C:22]3[N:21]([CH3:20])[CH:25]=[CH:24][N:23]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:8][C:9]=2[CH:17]=1
Reactant: Cn1ccnc1C=O
Reactant: CC[O-]
Reactant: O=C1OCc2c(/N=C/c3ccccc3)cc(F)cc21
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1nccn1C)C(c1ccccc1)N2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (E)-4-(benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one (2 g, 7.8 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (0.949 g, 8.63 mmol) in ethyl propionate (50 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol [sodium (722 mg, 31.37 mmol) in ethanol (30 mL)] was added drop-wise. After the addition, the mixture was stirred at room temperature for 2 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10) to give the ethyl 7-fluoro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (141 mg). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.18-1.22 (t, 3H), 3.31 (s, 3H), 4.17-4.21 (q, 2H), 4.621-4.65 (d, 2H), 5.17-5.20 (d, 1H), 6.48-6.51 (dd, 1H), 6.70-6.73 (m, 2H), 6.86 (s, 1H), 7.24-7.30 (m, 3H), 7.42-7.44 (t, 2H), 7.76 (s, 1H); LC-MS (ESI) m/z: 394 (M+1)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34](O)=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3].[N:37]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([NH2:37])=[O:35])[CH2:31][N:32]=2)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)nc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A mixture of {2-[5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (210 mg), 1H-1,2,3-benzotriazol-1-ol (80 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (120 mg) and N,N-dimethylformamide (5 mL) was stirred at 50° C. for 30 min and cooled to 0° C. 10% Aqueous ammonia (1 mL) was added to the mixture, and the mixture was stirred at room temperature for 2.5 days. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and subjected to silica gel short column chromatography (eluted with ethyl acetate-methanol (95/5, volume ratio)) to give pale-yellow crystals. The crystals were recrystallized from acetone-hexane to give the title compound (130 mg, yield 62%) as pale-yellow prism crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[CH:17]=[CH:16][C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[C:13]=3[NH:12][C:11](=[O:23])[C:10]2=[O:24])[CH:6]=[CH:7][CH:8]=1)#[N:2].C([Sn]([N:38]=[N+:39]=[N-:40])(CCCC)CCCC)CCC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH:38]1[C:1]([C:3]2[CH:4]=[C:5]([N:9]3[C:18]4[CH:17]=[CH:16][C:15]5[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=5[C:13]=4[NH:12][C:11](=[O:23])[C:10]3=[O:24])[CH:6]=[CH:7][CH:8]=2)=[N:2][N:40]=[N:39]1
Reactant: N#Cc1cccc(-n2c(=O)c(=O)[nH]c3c4ccccc4ccc32)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c3ccccc3ccc2n(-c2cccc(-c3nnn[nH]3)c2)c1=O
Temperature: 110 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To an anhydrous toluene (1 mL)-anhydrous DMF (1.5 mL) solution of 4-(3-cyanophenyl)-1,4-dihydrobenzo[f]quinoxaline-2,3-dione (20 mg, 0.064 mmol) was added tri-n-butyltin azide (53 μL, 0.192 mmol), and the mixture was stirred at 110° C. for 18 hours. After cooling on standing, the reaction mixture was poured into a 1M aqueous sodium hydroxide solution, and washed with ethyl acetate. After neutralization of the aqueous layer by addition of a 1M aqueous hydrochloric acid solution, the precipitated solid was collected by filtration, washed with water, and dried to obtain the titled compound as a white crystal (15 mg, yield 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[C:14](=O)([O:23]C1C=CC([N+]([O-])=O)=CC=1)[O:15][C:16]([O:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17]>CN(C)C=O.O>[C:20]([O:19][C:16]([O:15][C:14]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:23])([CH3:18])[CH3:17])(=[O:22])[CH3:21]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(=O)OC(C)(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)OC(C)(C)OC(C)=O)cc1OC

Procedure:
A solution of 3,4-dimethoxyphenethylamine (110 mg) and acetoxyisopropyl p-nitrophenyl carbonate (0.18 g) in dimethylformamide (3 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate. The ethyl acetate extract was washed with water, ice cold 1% aqueous sodium hydroxide, 1N HCl, water and brine. The organic extract was dried over sodium sulfate and evaporated. The residue (0.11 g) was purified by preparative thin layer chromatography on silica gel plates. The title compound (75 mg) was eluted with ethyl acetate-chloroform (5:95). 1H NMR (CDCl3) δ 1.81 (6H, s), 2.05 (3H, s), 2.75 (2H, t), 3.36 (2H, m), 4.85 (1H, br, t), 6.71-6.84 (3H, m); 13C NMR (CDCl3) δ 22.05, 25.9, 35.45, 41.91, 55.76, 55.83, 105.07, 111.29, 111.87, 120.61, 131.09, 147.59, 148.91, 153.36 and 168.79; 1R (film) 3370, 2941, 1748, 1718, 1517, 1464, 1370, 1261, 1238, 1140, 1027 cm-1 ; HRMS (e/m) calculated for C16H23NO6, 325.1525; found, 325.1512.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].Cl.[CH3:13][S:14][C:15]1[N:16]=[N:17][C:18]([C:22](OCC)=[O:23])=[C:19](Cl)[N:20]=1.C(N(CC)CC)C>C(#N)C>[CH3:13][S:14][C:15]1[N:16]=[N:17][C:18]2[C:22](=[O:23])[NH:7][C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[O:2][CH3:1])=[N:6][C:19]=2[N:20]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: COc1ccccc1C(=N)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Temperature: 0 °C

Procedure:
A cooled (0° C.) solution of 2-methoxybenzamidine (from 1.97 g of the hydrochloride) in acetonitrile (17 ml) was added to a cooled solution of 3-methylthio-5-chloro-6-carboethoxy-1,2,4-triazine (prepared from 3-methylthio-5-oxo-6-carboethoxy-4,5-dihydro-1,2,4-triazine, 1.08 g, and thionyl chloride, 20 ml) in acetonitrile (17 ml). Triethylamine (0.51 g) was added and the reaction mixture was stirred with cooling (0° C.) for one hour and then at ambient temperature for 17 hours to afford a yellow solid which was washed with acetonitrile and ether to afford the crude title compound (1.39 g). A sample (0.35 g) of this was washed twice with boiling methanol to afford the title compound, 0.25 g, m.p. 267.5-268.5° C. The remaining material (1.04 g) was similarly treated with boiling methanol to afford the title compound, 0.91 g, m.p. 266-268° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].C(N(CC)C(C)C)(C)C.Br[CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>C(#N)C>[C:7]([C:6]1[CH:9]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:11]=[CH:12][C:5]=1[O:4][CH:2]([CH3:1])[CH3:3])#[N:8]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCCCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Temperature: 80 °C

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile (Example 32) (100 mg, 0.204 mmol) in acetonitrile (10 ml) was added N,N-diisopropylethylamine (0.07 ml, 0.408 mmol) and ethyl 5-bromopentanoate (0.06 mL, 0.408 mmol). The reaction mixture was heated to 80° C. overnight then was allowed to cool and the solvent evaporated. Purification of the residue by flash chromatography, eluting with (40-100% ethyl acetate in cyclohexane) gave the title compound as an off white solid (70 mg).
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.CCCCCC>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(C(F)(F)F)cc3)oc2CC)C2CCCCC2)cc1
Solvent: CCO
Solvent: CCCCCC
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (880 mg) which is a synthetic intermediate in Example 10 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 12 min were collected, and concentrated. The obtained amorphous compound (359 mg) was dissolved in ethanol (5 mL) and tetrahydrofuran (5 mL), 1N lithium hydroxide (2 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 (330 mg, 97%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:22])[C@@H:12]3[C@H:15]([O:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH3:16])[C:9]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:45][N:46]=[C:47]=[O:48].C(OCC)(=O)C>ClCCl>[CH3:45][NH:46][C:47]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C@H:13]3[N:10]([C:11](=[O:22])[C@@H:12]3[C@H:15]([O:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[CH3:16])[C:9]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[CH:5]=[CH:6][CH:7]=1)=[O:48]
Reactant: CN=C=O
Reactant: C[C@@H](O[Si](C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cccc(O)c3)C[C@H]12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1cccc(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]3C2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitrobenzyl (5R,6S)-3-(3-hydroxyphenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate prepared in the above step in dichloromethane (10 ml) was added N,N-diisopropylethylamine (catalytic amount), and thereto was added under ice cooling a solution of methyl isocyanate (57 mg) in dichloromethane (5 ml). After stirring under ice cooling for 2 hours, the temperature was raised to room temperature and the reaction mixture was poured into a mixture of ice water and ethyl acetate. The mixture was extracted and separated with a separating funnel. The organic layer was washed with cold water (twice) and a cold saturated aqueous sodium chloride solution in the order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 4-nitrobenzyl (5R,6S)-3-(3-{[(methylamino)carbonyl]oxy}phenyl)-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (276 mg).