Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([C:27]#[N:28])[CH:34]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: N#Cc1cccc(B(O)O)c1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(C#N)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure of Example 93, Suzuki coupling of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-cyanophenylboronic acid gave 199. MS: (ESI+) 471.1
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)OCC

Procedure:
A mixture of 97% chlorobenzaldehyde (51.5 g, 41.3 ml, 0.35 mole), diethyl malonate (57 g, 54 ml, 0.35 mole), acetic acid (1 ml) and piperdine (2 ml) in benzene (150 ml) was heated under reflux with azeotropic removal of water overnight. Benzene was removed by distillation, the residue was diluted with ethyl acetate (200 ml), washed with 10% hydrochloric acid, saturated potassium bicarbonate, brine and dried over anhydrous magnesium sulfate and concentrated in vacuo to yield 100 g of the title A compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:18])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].N1C=CC=CC=1.[C:25]([O:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])(=[O:27])[CH3:26]>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:17]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[NH:18][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=2[O:28][C:25](=[O:27])[CH3:26])=[N:11][CH:12]=1
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(=O)Oc1cc(F)ccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Fluoro-2-amino-N-(5-chloropyridin-2-yl)benzamide (5.32 g, 20 mmol) was added to a solution of 2 mL dry pyridine and 2-acetoxy-4-fluorobenzoyl chloride (21 mmol) in 100 mL dry methylene chloride under dry nitrogen with magnetic stirring. The reaction was allowed to stir overnight at room temperature and then was diluted with 500 mL of methylene chloride. The methylene chloride solution was washed with cold 1 M HCl, cold saturated NaHCO3, and brine; and then was dried over sodium sulfate. The solvent was evaporated, and the crude product was crystallized from acetone to give 2:92 g of off-white product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.N[C:27]1[C:28]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:29]([C:35]([F:38])=[CH:36][CH:37]=1)[CH2:30][O:31][C:32](=[O:34])[CH3:33]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:10]1[N:39]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:28]2[C:29]([CH2:30][O:31][C:32](=[O:34])[CH3:33])=[C:35]([F:38])[CH:36]=[CH:37][C:27]=2[N:11]=1)[CH3:9])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: CC(=O)OCc1c(F)ccc(N)c1Nc1ccccc1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC(=O)OCc1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester 3.94 g, 20.9 mmol) in DCM (20 mL) was added triethyloxonium tetrafluoroborate (3.35 g, 17.6 mmol) and the reaction mixture stirred at RT for 2 hours, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (20 mL). Acetic acid 3-amino-6-fluoro-2-phenylaminobenzyl ester (2.3 g, 8.38 mmol) was added and the reaction heated at 75° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to give the title compound as an off white solid. LCMS (Method C): RT=3.37 min, [M+H-tBu]+=372, 100%, [M+H]+=428, 40%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1>[Ni].N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:11])[CH2:9][NH2:10])=[CH:6][CH:7]=1
Reactant: CC(C#N)c1ccc(Br)cc1
Agent: [Ni]
Agent: N
Product: CC(CN)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 34 h

Procedure:
A mixture of 3.00 g (14.3 mmol) 2-(4-bromo-phenyl)-propionitrile and 40 mL ammonia solution (7N in methanol) is charged with 0.30 g Raney nickel. The mixture is stirred under an atmosphere of hydrogen (50 psi) at r.t. for 34 h. The mixture is filtered and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[C:16]1([C:3]2[C:2]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(C(F)(F)F)cc3)nc2c1

Procedure:
A suspension of methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (100 mg, 0.33 mmol, 1.00 equiv), 4-(trifluoromethyl)phenylboronic acid (69.9 mg, 0.37 mmol, 1.10 equiv), K3PO4 (142 mg, 0.67 mmol, 2.00 equiv), Pd(PPh3)4 (11 mg, 0.01 mmol, 0.03 equiv) in toluene (1 mL) was placed in a 10-mL sealed tube under an inert atmosphere allowed to react, with stifling, overnight at 100° C. in an oil bath. The reaction was quenched by the addition of 20 mL of water, and the solids were collected by filtration, resulting in 80 mg (59%) of methyl 2-phenyl-3-(4-(trifluoromethyl)phenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C=O.[F:3][C:4]1[CH:23]=[C:22]([NH:24][CH:25]2[C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][C:28]=3[CH2:27][CH2:26]2)[N:35]=[C:34]([CH3:38])[N:33]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C:32]4=[O:47])[CH:21]=[CH:20][C:5]=1[C:6]([O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19])=[O:7].[C:48]([BH3-])#N.[Na+].O>C(O)(=O)C>[F:3][C:4]1[CH:23]=[C:22]([N:24]([CH3:48])[CH:25]2[C:29]3[CH:30]=[C:31]4[C:36](=[CH:37][C:28]=3[CH2:27][CH2:26]2)[N:35]=[C:34]([CH3:38])[N:33]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:43])([CH3:45])[CH3:44])[C:32]4=[O:47])[CH:21]=[CH:20][C:5]=1[C:6]([O:8][C:9]1[C:10]([F:19])=[C:11]([F:18])[C:12]([F:17])=[C:13]([F:16])[C:14]=1[F:15])=[O:7]
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1)CC3
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(N(C)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1)CC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An aqueous solution of formaldehyde (37% weight/volume, 17.55 ml) was added dropwise during 15 minutes to a stirred solution of pentafluorophenyl o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoate (13 g), prepared as described in Example 1, in glacial acetic acid (100 ml). The mixture was stirred at ambient temperature for 1 hour. Sodium cyanoborohydride (1.36 g) was added portionwise during 30 minutes and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was poured onto a mixture of ice and water (500 ml) and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The product was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluant. There was thus obtained pentafluorophenyl o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoate (11 g);
Reaction SMILES: [C:1]([CH:3]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])#N.CC(C[AlH]CC(C)C)C.[OH2:33].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:1]([CH:3]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[O:33]
Reactant: O
Reactant: CC(C)(C)[Si](C)(C)OCCC(C#N)CCO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCC(C=O)CCO[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 73 %

Procedure:
Following a published procedure,24 a solution of 3 (3.65 g, 10.2 mmol) in dry toluene (52 mL) at −78° C. under argon was treated with DIBALH (12 mmol, 8.3 mL, 1.5 M solution in toluene), and the reaction was allowed to proceed for 1 h. Water (2.6 mL) was added, and the mixture was allowed to reach room temperature. Aqueous NaOH (2.6 mL, 4.0 M solution) was added, and stirring was continued for 15 min. Water (7.8 mL) was added and the suspension was stirred for a further 15 min. The sample was dried (Na2SO4), concentrated at reduced pressure, and chromatographed [silica, petroleum ether/diethyl ether (20:1)], affording a colorless liquid (2.70 g, 73%): IR (film, νmax cm−1) 2955, 2859, 1729, 1708, 1472; 1H NMR δ 0.01 (s, 12H), 0.87 (s, 18H), 1.64-1.74 (m, 2H), 1.85-1.96 (m, 2H), 2.50 (m, 1H), 3.57-3.68 (m, 4H), 9.65 (d, J=2.4 Hz, 1H); 13C NMR δ −5.27, 18.45, 26.09, 32.15, 46.40, 60.80, 204.74; EI-MS 171/172, 141, 97, 75, calcd 360.2516 (C18H40O3Si2); Anal. Calcd C, 59.94; H, 11.18. Found: C, 58.15; H, 11.16.
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=O.[CH2:16]([OH:19])[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:16]1[O:19][C:10]([O:12][CH2:13][CH3:14])([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH3:15])[O:18][CH2:17]1
Reactant: CCOC(=O)CCCCCCCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC1(CCCCCCCC(C)=O)OCCO1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A solution containing 77.5 g (362 mmol) of ethyl 9-oxodecanoate (prepared described in J. Amer. Chem. Soc., 68: 832 [1946]), 22.4 g (362 mmol) of ethylene glycol and 438 mg of p-toluenesulfonic acid in 150 ml of dry benzene was refluxed for 4.5 hr with a Dean Stark trap. A 7.0 ml portion of water (theoretical=6.5 g) collected in the trap. The solution was cooled to room temperature and then was washed with saturated aqueous sodium bicarbonate. The aqueous phase was back-extracted twice with ether. The combined ether extracts were dried over Na2SO4 and evaporated in vacuo and distilled in vacuo to give a 83.5% yield of the title compound. The product had the following physical characteristics:
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:29][N:30]([NH2:32])[CH3:31]>O1CCCC1>[CH3:29][N:30]([CH3:31])[NH:32][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CN(C)N
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)NN(C)C

Procedure:
690 mg (3 meq) of myristic acid and 486 mg (3 meq) of carbonyl diimidazole are reacted in a minimum volume of tetrahydrofuran at room temperature for 1 hour. Unsym-dimethylhydrazine (0.23 ml, 3 meq) is added and reacted overnight at room temperature. The reaction mixture is evaporated under reduced pressure, dried in vacuo and purified on a silica gel column using CH2Cl2 :CH3OH (5:1). The fractions having R6 0.76 on TLC S.G. CH2Cl2 :CH3OH (5:1) chlorine-peptide spray are combined, evaporated under reduced pressure and dried in vacuo to yield 185 mg of title compound having a m.p. of 63.5°-64.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][C:9]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH3:31])[CH2:28][CH2:29][NH2:30])[CH2:23][CH2:22]3)([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:32][C:33]1[C:38]([C:39](O)=[O:40])=[C:37]([CH3:42])[N:36]=[CH:35][N:34]=1>>[F:1][C:2]1[C:7]2[CH2:8][C:9]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH3:31])[CH2:28][CH2:29][NH:30][C:39]([C:38]4[C:33]([CH3:32])=[N:34][CH:35]=[N:36][C:37]=4[CH3:42])=[O:40])[CH2:23][CH2:22]3)([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(CCN)N1CCC(C2(c3ccc(C(F)(F)F)cc3)Cc3c(F)cccc3O2)CC1
Reactant: Cc1ncnc(C)c1C(=O)O
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(C2(c3ccc(C(F)(F)F)cc3)Cc3c(F)cccc3O2)CC1
Yield: 40.1 %

Procedure:
Using general procedure E, 3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 251) (60 mg, 0.14 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (42 mg, 0.28 mmol) afforded COMPOUND 257 as a white solid (32 mg, 41%). 1H NMR (CDCl3) δ 0.62-0.92 (m, 2H), 0.92-0.97 (m, 3H), 1.09-1.23 (m, 1H), 1.50-1.55 (m, 1H), 1.69-1.78 (m, 2H), 1.84-2.02 (m, 2H), 2.24-2.45 (m, 1H), 2.50 (s, 6H), 2.61-2.86 (m, 3H), 3.17-3.47 (m, 3H), 3.70-4.00 (m, 1H), 6.51-6.57 (m, 1H), 6.84, 6.89 (d, 1H, J=8.1 Hz), 7.10-7.17 (m, 1H), 7.36-7.43 (m, 2H), 7.58-7.62 (m, 2H), 8.44, 8.59 (m, 1H), 9.04, 9.09 (s, 1H). 13C NMR (CDCl3) δ 14.55, 14.95, 23.47, 27.69, 28.14, 28.30, 29.01, 31.91, 32.79, 38.48, 38.90, 41.46, 41.67, 45.53, 45.79, 48.46, 48.52, 53.92, 54.00, 61.60, 62.16, 94.67, 94.84, 107.08, 109.15, 109.42, 113.35, 113.62, 123.78, 126.91, 127.05, 127.16, 127.39, 131.29, 131.40, 131.48, 132.30, 150.24, 150.40, 158.92, 159.20, 162.19, 162.56, 164.50, 167.87, 168.26. ES-MS m/z 571 (M+H). Anal. Calcd. for C31H34N4O2F4.0.5H2O: C, 64.24; H, 6.09; N, 9.67. Found: C, 64.25; H, 6.00; N, 9.68.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][NH2:29]>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:29][CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Reactant: CN
Agent: Cl
Product: CNc1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 99 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using methylamine hydrochloride as a reagent, the same procedure of Example 264 gave the titled compound (yield, 99%).
Reaction SMILES: Br[C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[CH:32][C:33]([CH:36]=[O:37])=[N:34][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.O.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>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:30]2[CH:35]=[N:34][C:33]([CH:36]=[O:37])=[CH:32][CH:31]=2)[C:3]([O:20][CH3:21])=[C:4]([CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:5]=1
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1Br
Reactant: CC1(C)OB(c2ccc(C=O)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1-c1ccc(C=O)nc1
Temperature: 100 °C
Yield: 74.1 %

Procedure:
To a mixture of tert-butyl [1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate (200 mg, 0.5 mmol, from Example 113, Step 1 peak 2) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbaldehyde (150 mg, 0.63 mmol, Frontier Scientific, catalog# F2110) in 1,4-dioxane (4 mL) was added potassium carbonate (200 mg, 2 mmol) in water (2 mL). The reaction was degassed with N2 and tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol) was added and degassed again with N2. The reaction was heated at 100° C. overnight. The reaction was allowed to cool to room temperature and was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude product. The product was purified by chromatography on silica gel eluting with a hexane:EtOAc gradient to give tert-butyl {1-[5-chloro-3-(6-formylpyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}carbamate as a yellow oil (0.15 g, 70%). LCMS calculated for C21H26ClN2O4(M+H)+: m/z=405.2. found: 405.1.
Reaction SMILES: [N+](=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[O:5][CH2:4]1)=[N-].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][CH2:4][CH:3]([O:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[C:12]2=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=C1COc2ccc(OCc3ccccc3)cc2C1=O
Reactant: COc1ccc(O)cc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(OC2COc3ccc(OCc4ccccc4)cc3C2=O)cc1
Temperature: 25 °C
Yield: 5.4 %

Procedure:
A solution of 76 g of 3-diazo-6-benzyloxy-4-chromanone and 76 g of p-methoxyphenol in 450 ml of toluene was heated to 110° C. in an oil bath. Rhodium (II) acetate dimer (225 mg) was added in one portion. After nitrogen evolution ceased (5 minutes), the reaction was allowed to cool to room temperature, diluted with ethyl acetate and washed with 10% sodium hydroxide to remove excess phenol. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude product, which was purified by column chromatography on silica gel eluting with dichloromethane to give 5.5 g of present title product; mp 98°-100° C.; 1H-NMR (CDCl3) delta (ppm) 3.85(s, 3H), 4.45-4.65 (m, 2H), 5.0-5.2 (m, 3H), 6.5-7.6 (m, 12H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH2:13][CH:12]3[CH2:16][CH2:17][S:18][C:19]4[S:23][CH:22]=[CH:21][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1.CS(C)=O>Br.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]3[CH2:16][CH2:17][S:18][C:19]4[S:23][CH:22]=[CH:21][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2N=C3c4ccsc4SCCC3CC2=O)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COc1ccc(-n2nc3c(cc2=O)CCSc2sccc2-3)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 14.8 g of 2-(4-methoxyphenyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in 100 ml of 30% hydrogen bromide-acetic acid is added 6.1 ml of dimethylsulfoxide with stirring at room temperature. The mixture is stirred for 4 hours at room temperature, poured into ice-cold water and extracted with chloroform. The extract is washed with water, dried and concentrated under reduced pressure. The resulting crystals are recrystallized from a mixed solvent of toluene and isopropyl ether to give 10 g of 2-(4-methoxyphenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 126°-128° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:19])[NH:6]2.FC1C=C(C(=O)C)C=C2C=1CC(=O)N2.COC1C=C(C(=O)C2C=CC=CC=2)C=C2C=1CC(=O)N2.COC1C=C(C(=O)CCC)C=C2C=1CC(=O)N2.C1(C(C2C=C3C(CC(=O)N3)=CC=2)=O)SC=CC=1.C1SC=CC=1C(C1C=C2C(CC(=O)N2)=CC=1)=O.CC1C=C(C(=O)C2SC=CC=2)C=C2C=1CC(=O)N2.CSC1C=C(C(=O)C2C=CSC=2)C=C2C=1CC(=O)N2.FC1C=C(C(=O)C2SC=CC=2)C=C2C=1CC(=O)N2>>[C:11]([C:9]1[CH:8]=[C:7]2[C:3]([CH2:4][C:5](=[O:19])[NH:6]2)=[CH:2][CH:10]=1)(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1Cc2c(Cl)cc(C(=O)c3ccccc3)cc2N1
Agent: CC(=O)c1cc(F)c2c(c1)NC(=O)C2
Agent: CCCC(=O)c1cc2c(c(OC)c1)CC(=O)N2
Agent: COc1cc(C(=O)c2ccccc2)cc2c1CC(=O)N2
Product: O=C1Cc2ccc(C(=O)c3ccccc3)cc2N1

Procedure:
In a similar manner, starting with the appropriate reagent 6-n-butyryloxindole, 4-chloro-6-benzoyloxindole, 4-fluoro-6-acetyloxindole, 4-methoxy-6-benzoyloxindole, 4-methoxy-6-butyryloxindole, 6-(2-thenoyl)oxindole, 6-(3-thenoyl)oxindole, 4-methyl-6-(2-thenoyl)oxindole, 4-methylthio-6-(3-thenoyl)oxindole and 4-fluoro-6-(2-thenoyl)oxindole are prepared.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[I:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.O>CN(C)C=O>[I:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:8][C:9]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1CBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1COc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Potassium carbonate (1.30 g, 9.41 mmol) was added to a solution of tert-butyl 2-(bromomethyl)-5-(trifluoromethyl)benzoate (2.00 g, 5.90 mmol) obtained in Example (2-2) and 4-iodophenol (1.30 g, 5.91 mmol) in N,N-dimethylformamide (20 ml) under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (three times). After the organic layer was successively washed with water (three times) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=100/1-50/1) to give tert-butyl 2-[(4-iodophenoxy)methyl]-5-(trifluoromethyl)benzoate as a colorless solid (2.65 g, yield: 94%).