Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[CH:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1)C.[Li+].[OH-].Cl>O1CCCC1.CO.O>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([O:33][CH3:34])=[C:26]([S:23]([N:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:35])=[O:3])=[CH:6][CH:7]=4)=[O:13])[CH:22]=3)[CH:18]=[CH:19]2)(=[O:25])=[O:24])[CH:31]=1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3ccn(S(=O)(=O)c4cc(Cl)ccc4OC)c3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)n1ccc2ccc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester (70 mg, 0.14 mmol) in tetrahydrofuran (1.5 ml) and methanol (0.5 ml) was treated with a 1N solution of LiOH in water (0.5 ml). The mixture was stirred at room temperature for 4 hours, then acidified with 1N HCl (0.5 ml). Methanol and tetrahydrofuran were evaporated and the residual slurry was extracted three times with ethyl acetate. The combined organic phases were dried with Na2SO4 and evaporated, and the residue purified by flash chromatography (dichloromethane/methanol gradient), to yield 4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-1H-indole-6-carbonyl]-amino}-benzoic acid as a light yellow solid, 17 mg (25%). MS (ISP): m/e=483.0 (M−H); δH (300 MHz; d6-DMSO) 12.77 (1H, bs), 10.60 (1H, s), 8.34 (1H, s), 8.08 (1H, d), 7.91-7.97 (6H, m), 7.75-7.80 (2H, m), 7.23 (1H, d), 6.91 (1H, d), 3.70 (3H, s).
Reaction SMILES: [H-].[Na+].CCCCCC.[Si:9]([O:16][CH2:17][CH2:18][C@H:19]([OH:41])[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].CS(O[CH2:47][CH2:48][O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])(=O)=O>CS(C)=O.O>[Si:9]([O:16][CH2:17][CH2:18][C@H:19]([O:41][CH2:47][CH2:48][O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[CH2:20][O:21][C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:12]([CH3:14])([CH3:15])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCCOS(C)(=O)=O
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCO[C@@H](CCO[Si](C)(C)C(C)(C)C)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 0 %

Procedure:
Sodium hydride (2.11 g, 52.7 mmol, 60% in oil) was loaded under argon circumstance in three-necked flask and hexane (30 ml) was added thereto. After stirring for a while, it was allowed to stand and the supernatant was removed by syringe. By repeating this procedure three times, the oil of sodium hydride was removed. After drying in vacuo anhydrous dimethyl sulfoxide (DMSO) (10 ml) was added and the solution was stirred at 60° C. for 1 hour. After cooling to room temperature, (S)-4-tert-butyldimethylsilyloxy-1-trityloxy-2-butanol (20.36 g, 44.0 mol) in DMSO (12 ml) was gradually dropped at room temperature to the solution and then the solution was stirred for 30 minutes. To the solution was gradually dropped 2-tert-butyldimethylsilyloxyethyl methanesulfonate (12.28 g, 48.3 mol) in DMSO (12 ml) at room temperature and then the solution was stirred for 12 hours. To the reaction mixture was added water (40 ml) and the solution was extracted with ethyl acetate. The extract was washed with water (50 ml) twice and with saturated brine once, dried on sodium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-4-tert-butyldimethylsilyloxy-2-(2-tert-butyldimethylsilyloxyethoxy)-1-trityloxybutane (11.2 g, yield 55%).
Reaction SMILES: [N+]([O-])([O-])=O.[Ag+:5].[CH3:6][C:7]1[O:15][S:12](=[O:14])(=[O:13])[N-:11][C:9](=[O:10])[CH:8]=1.[K+]>O>[CH3:6][C:7]1[O:15][S:12](=[O:14])(=[O:13])[NH:11][C:9](=[O:10])[CH:8]=1.[Ag:5]
Reactant: [Ag+]
Reactant: CC1=CC(=O)[N-]S(=O)(=O)O1
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1=CC(=O)NS(=O)(=O)O1
Product: [Ag]
Yield: 88 %

Procedure:
A solution of 30 mmol (5.148 g) of silver(I) nitrate in 30 ml of water was added to a solution of 30 mmol (6.037 g) of acesulfame-K in 30 ml of water. After addition was complete, the colorless precipitate formed was filtered off by suction and washed twice, each time with 10 ml of water. 88% of colorless acesulfame-silver crystals resulted. The reaction and subsequent workup as described above need not be carried out in the absence of light.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:21])[N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:10]([CH3:11])=[C:6]2[C:5]([CH3:22])=[N:4][N:3]=1.[CH3:23][NH2:24].CCO>O>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]([CH3:11])=[C:6]3[C:7]([C:2]([NH:24][CH3:23])=[N:3][N:4]=[C:5]3[CH3:22])=[C:8]2[CH3:21])=[CH:13][CH:14]=1)[CH3:20]
Reactant: CCOc1ccc(-n2c(C)c3c(C)nnc(Cl)c3c2C)cc1
Reactant: CN
Solvent: CCO
Solvent: O
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(NC)c3c2C)cc1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
To a Personal Chemistry Microwave Synthesizer microwave vial was combined 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine (200 mg, 0.64 mmol), MeNH2 (1 mL, 40% in H2O), and EtOH (1 mL). The vial was sealed and heated at 120° C. for 12 min. The reaction mixture was poured into water to afford crude 6-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine. Purification by reverse phase preparative HPLC using a YMC CombiPrep Pro C1820×100 column (Gradient: 5%-100% Acetonitrile in a H2O+0.1% TFA solution over 10 min, retention time: 6.1 min) afforded pure 6-(4-ethoxyphenyl)-N,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazin-1-amine as a colorless solid: 1H NMR (CDCl3, 500 MHz) δ 7.05-7.12 (m, 4H), 4.16 (q, 2H), 3.20 (s, 3H), 2.69 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H), 1.51 (t, 3H); MS (ESI) 311 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19].CCOCC>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6])[CH3:19]
Reactant: OCCc1ccccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1ccccc1CCO
Temperature: 42.5 °C
Reaction time: 12 h

Procedure:
To a suspension of 1.00 g (7.24 mmol) of 2-hydroxyphenethyl alcohol and 1.35 g (8.68 mmol) of potassium carbonate in 15 ml of N,N-dimethylformamide was added 2.00 g (14.48 mmol) of iodoethane at 0° C. The reaction mixture was stirred at 40-45° C. for 12 h and was poured into 200 ml of ether. It was washed with water (20 ml ×3), dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 9:1 hexane/ethyl acetate to afford the 2-ethoxyphenethyl alcohol as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][S:11][CH3:12].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][S:11]([CH3:12])=[O:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCOc1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: CS(=O)COc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To an ice cooled solution of the above crude 2,4-dichloro-1-methylsulfanylmethoxy-benzene (17 g) in DCM (200 mL) was added portion wise m-CPBA (13.8 g, 79.75 mmol) during 30 min. The resulting mixture was allowed to reach room temperature and stirring was continued for 16 hrs. The organic phase was washed with water (2×100 mL), 1N NaOH until pH 6-7, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on silicagel (10 cm) using first heptane (1 L) followed by EtOAc:heptane (1:1) (1 L) and finally EtOAc as eluents. Pure fractions were collected from the pure EtOAc phase and evaporated in vacuo affording 10.1 g (69%) of 2,4-dichloro-1-methanesulfinylmethoxy-benzene as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:38][CH2:37][C:36]1[CH:35]=[CH:34][C:33]([C:29]2[N:28]([CH3:27])[CH:32]=[CH:31][N:30]=2)=[CH:40][CH:39]=1
Reactant: Cn1ccnc1-c1ccc(CN)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cn1ccnc1-c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 84.3 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (455 mg, 1.1 mmol) with 4-(1-methyl-1H-imidazol-2-yl)-benzylamine (240 mg, 1.3 mmol) in toluene (8 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to obtain 7-chloro-6-[4-(1-methyl-1H-imidazol-2-yl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (429 mg, 93%). MS (ES+) m/z: 463 (4+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][O:23]C2CCCCO2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][OH:23])[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(CCO)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of N-[2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl]-N-methylbenzamide (10.5 g) in tetrahydrofuran (100 mL) was added 6N hydrochloric acid (50 mL), and the resulting solution was allowed to stir overnight. The mixture was neutralized with 10N sodium hydroxide, diluted with water, and extracted with dichloromethane. The organic layer was dried and evaporated. The resulting yellow solid was suspended in ether and filtered to give the alcohol as a white solid (8.4 g); MS: m/z=352(M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:33])[C:15]([OH:32])=[C:16]2[C:29](=[O:30])[N:20]3[C@@H:21]([CH3:28])[CH2:22][CH2:23][N:24]([CH:25]([CH3:27])[CH3:26])[C@@H:19]3[CH2:18][N:17]2[CH:31]=1)=[O:12].N[C@@H:35]([CH3:42])[CH2:36][CH2:37]NC(C)C.[C:43](O)(=O)[CH3:44].[Cl:47][CH2:48]Cl>>[ClH:47].[ClH:47].[NH2:20][C@@H:21]([CH3:28])[CH2:22][CH2:23][NH:24][CH:25]([CH3:27])[CH3:26].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:33])[C:15]([O:32][CH2:48][C:35]2[CH:36]=[CH:37][CH:44]=[CH:43][CH:42]=2)=[C:16]2[C:29](=[O:30])[N:20]3[C@@H:21]([CH3:28])[CH2:22][CH2:23][N:24]([CH:25]([CH3:27])[CH3:26])[C@@H:19]3[CH2:18][N:17]2[CH:31]=1)=[O:12]
Reactant: ClCCl
Reactant: CC(C)N1CC[C@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3C[C@@H]12
Reactant: CC(=O)O
Agent: CC(C)NCC[C@H](C)N
Product: CC(C)N1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4F)cn3C[C@@H]12
Product: Cl
Yield: 57 %

Procedure:
[(3S)-3-Aminobutyl](1-methylethyl)amine dihydrochloride was prepared in a similar manner as described in example Z-29, 1H NMR (400 MHz, CDCl3/CD3OD) δ 1.20-1.25 (m, 9H), 1.93-2.02 (m, 2H), 2.92 (m, 2H), 3.20-3.29 (m, 2H), 8.04 (br, <1H), 8.64 (br, <1H). b) (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2, 16a (60 mg, 0.13 mmol) and free based [(3S)-3-aminobutyl](1-methylethyl)amine (55 mg, 0.42 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (40 mg, 57%) as a film. This material was hydrogenated in a second step as described in example Z-2 to give (4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (17 mg, 50%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.02 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H), 1.33 (d, J=7.2 Hz, 8H), 1.55-1.58 (m, 1H), 1.94-2.03 (m, 1H), 2.70-2.77 (m, 1H), 2.81-2.86 (m, 1H), 3.11-3.18 (m, 1H), 4.17 (dd, J=3.0, 13.8 Hz, 1H), 4.32 (dd, J=3.2, 14.0 Hz, 1H), 4.48 (m, 1H), 4.59-4.69 (m, 2H), 4.97-5.00 (m, 1H), 6.77-6.83 (m, 2H), 7.33-7.39 (m, 1H), 8.28 (s, 1H), 10.50 (m, 1H), 12.55 (s, 1H); ES+ MS: 461 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:29][C@@H:30](O)[CH2:31]C.Br[C:35]1[CH:40]=C[C:38]([S:41]([O-:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1>CN(C)C=O>[CH3:29][C:30]1([CH3:31])[CH:5]2[CH2:6][CH2:7][C@@:8]1([CH2:38][S:41]([OH:44])(=[O:43])=[O:42])[C:3](=[O:2])[CH2:4]2.[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([C@@H:35]([CH3:40])[CH2:36][CH3:37])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC[C@@H](C)O
Reactant: O=S(=O)([O-])c1ccc(Br)cc1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Product: CC[C@H](C)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 13.7 %

Procedure:
A mixture of 3.5 g of (2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-3H-1,2,4-triazol-3-one, 0.6 g of a sodium hydride dispersion 50% and 100 ml of N,N-dimethylformamide was stirred for 3 hours at 80° C. After the addition of 3.5 g of (R)-2-butanol 4-bromobenzenesulfonate (ester) (intermediate (3)), stirring was continued for 6 hours at this temperature. After cooling, waster was added. The crystallized product was filtered off and taken up in trichloromethane. The undissolved part was filtered off. The remaining solution was dried and purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and converted into the (S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate salt in 2-propanone. The salt was filtered off and recrystallized from 1-butanol. The product was filtered off and dried, yielding 1.2 g (13.7%) of (+)-(S)-2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one (S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate (1:2); mp. 192.0° C.; [α]D20 =+28.41° (conc.=1% in ethanol) (interm. 5).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>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:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:30]4[CH:29]=[N:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cncc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (65 mg, 0.151 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.7 mL). 3-(Methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (53.1 mg, 0.226 mmol), tetrakis(triphenylphosphine)palladium(0) (17.40 mg, 0.015 mmol) and potassium carbonate (62.4 mg, 0.452 mmol) were added and the mixture heated in a microwave at 120° C. for 10 min. Ethyl acetate (10 mL) was then added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-5% MeOH in DCM, and then further purified by MDAP (acidic conditions), to give the title compound (17.2 mg). LCMS (A) m/z: 460 [M+1]+, Rt 0.90 min (acidic).
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][N:20]([CH3:30])[C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:13][CH:12]=1>>[CH2:1]([NH:7][C:8]([C:19]1[N:20]([CH3:30])[C:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[N:18]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1Cl
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1C

Procedure:
Using essentially the same procedure as Example 33, but using n-hexyl isocyanate (0.040 mL, 0.30 mmol), 4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1-methylimidazole (50 mg, 0.15 mmol) from Example 32, Step C was converted to the title compound after purification twice by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=O)[NH:8][CH:7]=[N:6]2.C(N(C(C)C)CC)(C)C.O(Cl)[Cl:22].[P+3].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:22][C:9]1[C:10]2=[C:2]([Cl:1])[CH:3]=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: ClOCl
Reactant: O=c1[nH]cnn2ccc(Cl)c12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [P+3]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ccn2ncnc(Cl)c12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a solution of 5-chloropyrrolo[2,1-f][1,2,4]triazin-4 (3H)-one (5.00 g, 29.5 mmol) in toluene (100 mL) at rt under nitrogen was added diisopropylethylamine (5.14 mL, 29.5 mmol) followed by phosphorus(III) oxychloride (8.25 mL, 88.5 mmol). The mixture was heated at 100° C. for 20 h and was then cooled to rt. The reaction was slowly added to saturated aqueous sodium bicarbonate solution (500 mL) at 0° C. After the addition was complete, the mixture was stirred at rt for 30 min. The aqueous phase was extracted with ethyl acetate (3×500 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give the crude product (3.73 g, 67%) as a yellow solid which was used without further purification. 1H NMR (CDCl3) δ 8.03 (s, 1H), 7.70 (d, 1H, J=2.8 Hz), 6.84 (d, 1H, J=2.8 Hz); MS(ESI+) m/z 188.1 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:26]3[C:27]4[C:19]([CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)=O.[CH3:28][C:29]([CH3:32])([O-])[CH3:30].[K+].CO.O>CN(C)C=O>[CH3:28][C:29]1[CH:32]=[CH:4][C:3]([CH:8]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([N:9]([C:16]3[C:26]4[C:27]5[C:19]([CH2:20][CH2:21][C:22]=5[CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=2)=[CH:1][CH:30]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C=Cc2ccc(N(c3ccccc3)c3ccc4c5c(cccc35)CC4)cc2)cc1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
20.96 g (0.06 mol) of 5-[N-(4-formylphenyl)-N-phenylamino]acenaphthene prepared in Preparation Example 1 and 17.44 g (0.072 mol) of diethyl 4-methylbenzyl phosphonate were dissolved in 300 ml of N,N-dimethylformamide, and 10.1 g (0.09 mol) of potassium-tert-butoxide was added thereto at room temperature for 20 minutes. After the addition, the resultant mixture was further stirred for 2 hours. The reaction was determined to be finished when disappearance of the formyl compound was identified. The reaction product was poured into 1500 ml of methanol at a temperature of 5° C. or lower, and 150 ml of water was further dropwise added thereto to precipitate a crystal, which was then filtrated, washed with methanol and dried to obtain 22.18 g (yield: 84.5%) of a crude crystal. 21.0 g of the crude crystal thus obtained was purified by column chromatography (carrier: silica gel, eluent: toluene/hexane=1/4) to obtain 17.85 g of (purification yield: 85.0%, melting point: 148.0°-149.0° C.) of 5-{N-[4-(4-methylstyryl)phenyl]-N-phenylamino}acenaphthene (Compound No. 4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1.Cl.[NH2:14][OH:15].C(=O)([O-])O.[Na+].O>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][O:15][NH2:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(C=NON)cc1
Yield: 81 %

Procedure:
In 200 ml of methanol were dissolved 16.5 g of 4-cyanobenzoic acid methyl ester and 7.2 g of hydroxylamine hydrochloride. To the solution was added 8.82 g of sodium hydrogencarbonate at room temperature. The mixture was heated for 3 hours under reflux. The reaction mixture was cooled, to which was added 400 ml of water. Resulting crystalline precipitate was collected by filtration, which was washed with water and ether, followed by drying under reduced pressure to afford 16.1 g of the titled compound as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C1COCC1.[CH2:19]([NH2:21])[CH3:20]>ClCCl>[CH2:19]([NH:21][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:20]
Reactant: CCN
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Alternatively, 2-chloro-5-nitrobenzoyl chloride (10 g, 45.5 mmol) in anhydrous dichloromethane (250 mL) with Amberlyst A-21 ion-exchange resin (17 g) was treated with a 2M THF solution of ethylamine (45 mL). The mixture was stirred at rt under nitrogen overnight. After filtration, the filtrate was concentrated to give N-ethyl-2-chloro-5-nitrobenzamide (9.0 g, 39 mmol, 86% yield) as a yellow solid.