Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11](I)=[C:10]2[C:5]([CH2:6][C@@H:7]([C:13]([OH:15])=[O:14])[NH:8][CH2:9]2)=[CH:4][C:3]=1I.CCN(CC)CC>O.[Pd]>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C@@H:7]([C:13]([OH:15])=[O:14])[NH:8][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1Cc2cc(I)c(O)c(I)c2CN1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)[C@@H]1Cc2ccc(O)cc2CN1
Reaction time: 4 h

Procedure:
(S)-7-Hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2.0 g, 4.5 mmol) and 5% Pd/C (0.48 g, 0.22 mmol) were suspended in H2O (24 mL) and Et3N (2.1 mL, 15 mmol). EtOH (73 mL) purged with H2 was then syringed into a reaction flask. The reaction mixture was topped with a balloon of H2 and stirred for 4 h. The reaction mixture was filtered through CELITE®, washing with MeOH, and concentrated in vacuo to give crude (S)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid which was used directly in the next step. MS (ESL) m/z 193.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](B(O)O)=[CH:5][C:6]2[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=2[CH:20]=1.Cl[C:25]1[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]2[CH2:37][C:36]([CH3:39])([CH3:38])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]2)=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[C:4]([C:25]2[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]3[CH2:37][C:36]([CH3:38])([CH3:39])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]3)=[CH:27][CH:26]=2)=[CH:5][C:6]2[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=2[CH:20]=1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc2c(cc1B(O)O)nc(C)n2COCC[Si](C)(C)C
Product: COc1cc2c(cc1-c1ccc(N(C)C3CC(C)(C)NC(C)(C)C3)nn1)nc(C)n2COCC[Si](C)(C)C
Yield: 89 %

Procedure:
The mixture of (6-methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)boronic acid and the pinacol ester (78 mg, 0.139 mmol), and Intermediate 1-1 (26 mg, 0.092 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. 6-(6-Methoxy-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine was obtained after flash column chromatography purification (44 mg, 89% yield). MS (M+1)=539.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C@H:12]1[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)[CH:7]=[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]2=[O:30].Cl.O1CCOCC1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1)[CH:7]=[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]2=[O:30]
Reactant: CCOC(=O)c1cn([C@H]2CCCN(C(=O)OC(C)(C)C)C2)c2ncc(Br)cc2c1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1cn([C@H]2CCCNC2)c2ncc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-ethyl 6-bromo-1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 30, 10.847 g, 22.58 mmol) was taken up in dichloromethane (10 mL) and added HCl 4M in Dioxane (113 mL, 451.63 mmol) while stirring at RT for 1 h. The solvent was removed in vacuo and the residue was triturated with DCM, ether and EtOAc to give the desired product as a yellow solid. (S)-ethyl 6-bromo-4-oxo-1-(piperidin-3-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate (8.50 g, 90%) was recovered as the HCl salt. MS (ES)(M+H)+: 381 for C16H18BrN3O3.[HCl].
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Cl:11])[CH:5]=1.CON(C)[C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]>C1COCC1>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[CH:7]=1)[C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc(F)cc(Cl)c2)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 108.1 %

Procedure:
In a 2 L three-necked bottle flushed with N2, Mg (26.5 g, 1.1 mol) was warmed to 50° C., 1-bromo-3-chloro-5-fluorobenzene (157 g, 0.75 mol) solution in anhydrous THF (1 L) was added dropwise, then the mixture was stirred at r.t. for 2 hr. To a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (120 g, 0.441 mol) in anhydrous THF (1.1 L) at −78° C. under nitrogen was added dropwise the above Grignard reagent. The reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with EtOAc (3×400 mL). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate (163 g), which was used immediately without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:40])[N:22]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:16]([O:20][C:21](=[O:40])[N:22]([CH2:29][C:30]1[CH:39]=[CH:38][C:33]2[O:34][CH2:35][CH2:36][O:37][C:32]=2[CH:31]=1)[CH:23]1[CH2:28][CH2:27][N:26]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[N:6]=[CH:7][C:8]2=[O:15])[CH2:25][CH2:24]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cnc2ccc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To 20 mL of a chloroform solution containing 355 mg of (7-fluoro-2-oxoquinoxalin-1(2H)-yl)acetaldehyde and 553 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 98 μL of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 549 mg of sodium triacetoxyborohydride was added, and stirred for 1 hour. Aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=1:1] to give 655 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)[N:9]=1.[Br:23][CH:24]([CH3:28])[C:25](Cl)=[O:26]>C(Cl)(Cl)Cl>[Br:23][CH:24]([CH3:28])[C:25]([NH:7][C:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[N:9]=1)=[O:26]
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Reactant: CC(Br)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Br)C(=O)NC1=NN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
To 100 ml. of chloroform with stirring is added 2.75 g. of potassium carbonate and 5.3 g. of 3-amino-1-(α,α,α-trifluoro-m-tolyl)-2-pyrazoline, then 5.0 g. of α-bromopropionylchloride is added dropwise. After the addition is complete the reaction mixture is refluxed on a steam bath for 4 hours. Then the solvent is removed in vacuo and water is added to give a gum. The gum is extracted with dichloromethane. The extracts are combined and dried over anhydrous magnesium sulfate. The solution is passed through a short column of a hydrous magnesium silicate, then is evaporated leaving a gummy solid. The solid is triturated with ether to give 1.13 g. of a yellow solid. The solid is recrystallized from acetone-hexane to give the desired product as yellow crystals, m.p. 54°-56° C.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:11]([F:21])[CH2:10]1)=O)(C)(C)C>CCOCC.C(Cl)Cl>[F:21][CH:11]1[CH:12]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH2:13][CH2:14][NH:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCOCC2)C(F)C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: FC1CNCCC1N1CCOCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
2.0 N HCl in Et2O (15 mL) was added to a solution of 3-Fluoro-4-morpholin-4-yl-piperidine-1-carboxylic acid tert-butyl ester (1.28 g, 4.44 mmol) in DCM (2 mL) and the resulting suspension was stirred at room temperature 4 days. The precipitate was filtered off and tritured with Et2O (2×5 mL) Na2CO3 saturated solution (10 mL) was added and the resulting solution was concentrated under reduced pressure. EtOH (15 mL) was added and precipitate was filtered off.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C[N:14](C)C=O.C1(C)C=CC=CC=1.N>O>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:14])=[O:12])=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)Cc1ccc(CBr)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 393 %

Procedure:
To a solution of (4-bromomethyl-phenyl)-acetic acid (9.23 g, 40.30 mmol) and N,N-dimethylformamide (0.5 ml, 6.47 mmol) in toluene (100 ml) thionyl chloride (3.1 ml, 42.31 mmol) was added. The mixture was heated at 80° C. for 1 h. At 0° C., this mixture was added to a solution of ammonia in water (25%, 200 ml). After stirring for 30 min the precipitate was collected, washed with water and pentane, and dried in a vacuum oven at 50° C. to give the product as white crystals (5.8 g, 63%).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]=[C:10]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Br)(=[O:19])[CH3:18].C(N(CC)CC)C>CC(C)=O>[C:17]([N:11]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]1[CH3:16])(=[O:19])[CH3:18]
Reactant: CC1=NC=CC(=O)C1OCc1ccccc1
Reactant: CC(=O)Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)n1ccc(=O)c(OCc2ccccc2)c1C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
3-Benzyloxy-2-methylpyrid-4-one (4 g) is dissolved in dry acetone (100 ml). Acetylbromide (3 g) and triethylamine (2.7 g) are added and the resulting mixture is mechanically stirred overnight. The mixture is then filtered and the filtrate is rotary evaporated to dryness. The residue is dissolved in methylene chloride and washed with dilute hydrochloric acid (pH 3.0), then twice with water, and is dried over Na2SO4 and rotary evaporated to yield a solid residue. Recrystallisation of this residue from an ethylacetate/hexane mixture gives 1-acetyl-3-benzyloxy-2-methylpyrid-4-one as an oil (3.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[O:22][CH3:23])[C:10]([CH3:12])([CH3:11])[C:6]=2[C:5]([F:25])=[C:4](Cl)[N:3]=1.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@@H:29]1[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[O:22][CH3:23])[C:10]([CH3:12])([CH3:11])[C:6]=2[C:5]([F:25])=[C:4]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@@H:29]2[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[N:3]=1
Reactant: COc1ccc(CN2C(=O)c3c(Cl)nc(Cl)c(F)c3C2(C)C)c(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN2C(=O)c3c(Cl)nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c3C2(C)C)c(OC)c1
Temperature: 95 °C
Yield: 55.5 %

Procedure:
In a 10 mL sealed cap glass vial, 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1,1-dimethyl-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (50 mg, 0.125 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (53.2 mg, 0.250 mmol) were dissolved in ACN (2 mL). N-ethyldiisopropylamine (0.033 mL, 0.188 mmol) was added, the cap was sealed, and the reaction mixture heated at 95° C. for 72 h. The reaction mixture was subsequently purified by preparative HPLC and basified to give the title compound as a light yellow solid (40 mg, 55%). [M+H] calc'd for C29H38ClFN4O5, 578.1. found, 577.4.
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@H](CCl)COc1cccc(Br)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3cccc(Br)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 3-bromophenyl (2S)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:41])[C:7]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:16]3=[N:17][CH:18]=2)[CH:10]=[CH:9][C:8]=1[NH2:40])(C)(C)C.ClCCl.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[NH2:40][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]4[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=4)(=[O:31])=[O:32])[C:16]3=[N:17][CH:18]=2)=[CH:12][C:7]=1[C:6]([OH:41])=[O:5]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N)c(C(=O)OC(C)(C)C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N)c(C(=O)O)c3)cc12

Procedure:
2-Amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid tert-butyl ester (1.13 g, 1.98 mmol) was treated with 10 mL of dichloromethane/trifluoracetic acid (1:1) for 24 h. The solution was dried in vacuo to afford 2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid trifluoroacetate (quantitative). MS: m/z 514 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH2:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12][NH:13][C:21](=[O:23])[CH3:22])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1c[nH]c2cc(F)ccc12
Reaction time: 1 h

Procedure:
To a solution of 2-(6-fluoro-1H-indol-3-yl)-ethylamine (0.88 g) and NEt3 (2.27 ml) in CH2Cl2 (8 ml) was added acetic acid anhydride (0.43 ml) and stirring was continued at 22° C. for 1 h. The mixture was washed with 1 N aqueous HCl, the organic layer was dried and evaporated. The residue was chromatographed on silica using CH2Cl2/MeOH (25:1) to give the title compound as a pale yellow oil. MS: 219.1 ([M−H]−).
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:7]=2[C:6]1=O)C.C([O-])([O-])=O.[K+].[K+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:35][C:36]([NH2:38])=[NH:37])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34].Cl>CCO.O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:35][C:36]2[N:38]=[CH:4][C:5]3[CH2:11][C:10](=[O:12])[NH:9][C:8]4[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:7]=4[C:6]=3[N:37]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1ccc(NC(=N)N)cc1OC
Reactant: CN(C)C=C1CC(=O)Nc2ccc(I)cc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(I)ccc2NC(=O)C3)cc1OC
Temperature: 80 °C

Procedure:
To a solution of 4-dimethylaminomethylene-7-iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-a) (1.64 g, 4.6 mmol) in 50 mL EtOH was added K2CO3 (1.82 g, 11.04 mmol) and 1-(3,4-dimethoxyphenyl)guanidine (1.31 g, 5.06 mmol), and the reaction was heated to 80° C. for 12 h. The reaction was then cooled to 22° C., diluted with H2O, and treated with 1 M HCl to pH 3. The resulting solid was filtered and washed with H2O, followed by EtOH and Et2O. The crude product was dried in vacuo to give I-26 (1.8 g, 81%): HRMS Calcd. for C20H17IN4O3: 489.0423, Found 489.0431.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Ca+2].[Br-:24].[Br-:25].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>CO.ClCCl>[NH2:1][C:2]1[C:7]([Br:24])=[CH:6][C:5]([Br:25])=[CH:4][C:3]=1[N:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12]
Reactant: [Br-]
Reactant: CCOC(=O)N(CCN(C)C)c1ccccc1N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N(CCN(C)C)c1cc(Br)cc(Br)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.4 %

Procedure:
To a solution of N-(2-aminophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine (1.60 g) in methanol (20 ml) and dichloromethane (30 ml) were added calcium carbonate (1.29 g) and benzyltrimethylammonium tribromide (5.05 g), and the reaction mixture was stirred at room temperature for 24 hours. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure. To the residue were added 5% aqueous sodium hydrogen sulfite solution and 1N aqueous sodium hydroxide solution to make the solution alkaline and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=30:1) to give 0.87 g of N-(2-amino-3,5-dibromophenyl)-N-ethoxycarbonyl-N',N'-dimethylethylenediamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[C:30]3[O:29][C:28]([C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=4)=[C:27]([CH3:40])[C:26](=[O:41])[C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:11][CH2:10]1>C(O)C.C(O)(=O)C.[Ni]>[NH2:37][C:34]1[CH:33]=[CH:32][C:31]([C:28]2[O:29][C:30]3[C:21]([C:19](=[O:20])[NH:18][CH2:17][CH2:16][CH2:15][N:12]4[CH2:13][CH2:14][N:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])[CH2:10][CH2:11]4)=[CH:22][CH:23]=[CH:24][C:25]=3[C:26](=[O:41])[C:27]=2[CH3:40])=[CH:36][CH:35]=1
Reactant: COc1ccccc1N1CCN(CCCNC(=O)c2cccc3c(=O)c(C)c(-c4ccc([N+](=O)[O-])cc4)oc23)CC1
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccccc1N1CCN(CCCNC(=O)c2cccc3c(=O)c(C)c(-c4ccc(N)cc4)oc23)CC1
Reaction time: 6 h

Procedure:
2.22 g of compound of Example 113 and 0.56 g of Raney-Nickel in 96 ml of ethanol and 4.8 ml of acetic acid was hydrogenated in a Parr apparatus (pH2 =1 atm) at room temperature. After 6 hours shaking, the catalyst was filtered off and the filtrate was alkalinized with 3N aqueous sodium hydroxide solution and diluted with water. After standing for 2 days at 0° C., the precipitated title compound was collected by suction, washed with water, desiccated and recrystallized firstly from ethyl acetate then from ethanol yielding 1.5 g of the title compound (m.p. 192°-194° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH2:8][CH2:7]2.[CH3:18][Mg]Br.C(OCC)C>C1COCC1.[Cu]I>[F:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9]([CH:11]([C:12]#[N:13])[C:14]#[N:15])([CH3:18])[CH2:8][CH2:7]2
Reactant: C[Mg]Br
Reactant: COc1ccc2c(c1F)C(=C(C#N)C#N)CC2
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1F)C(C)(C(C#N)C#N)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 38.2 (260 mg, 1.1 mmol) in THF (7.0 mL) was added copper(I) iodide (260 mg, 1.4 mmol) followed by a 3.0M solution of methylmagnesium bromide in diethyl ether (0.45 mL, 1.4 mmol). The mixture was heated to reflux and stirred for one hour. The reaction was then cooled to room temperature and quenched with a saturated ammonium chloride solution. The mixture was extracted with EtOAc (2×) and the combined organic layers were dried over magnesium sulfate. The residue was purified by medium pressure chromatography (silica, 25 to 50% EtOAc:hexanes) to yield 38.3 (190 mg, 68% yield). MS ESI (neg.) m/e: 243.1 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][C:5]([F:21])=[CH:4][N:3]=1.O1CCCC1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1>CN(C)C=O>[F:21][C:5]1[CH:6]=[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=4)=[CH:16][CH:15]=3)[CH:9]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Fc1ccc(CCl)nc1
Reactant: Nc1ncc(F)cc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ncc(F)cc1-c1cc(Cc2ccc(OCc3ccc(F)cn3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To 4-(5-(2-amino-5-fluoro-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (20.0 mg, 0.07 mmol) described in Manufacturing Example 174-1-1 were added tetrahydrofuran (3 mL) and a 5 N sodium hydroxide aqueous solution (14.0 μL, 0.07 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. Next, the reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of this solid and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-5-fluoro-pyridine (11.2 mg, 0.08 mmol) described in manufacturing Example 41-1-2, which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (24.7 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:10]([O:12][CH2:13][C:14](N)=[NH:15])[CH3:11]>>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:14]([CH2:13][O:12][CH2:10][CH3:11])[N:15]=1
Reactant: CCOCC(=N)N
Reactant: N#Cc1nccnc1N
Product: CCOCc1nc(N)c2nccnc2n1

Procedure:
A mixture of 36.0 g (0.30 mole) of 3-amino-2-pyrazinecarbonitrile [prepared according to A. Albert and K. Ohta, J. Chem. Soc. C, 1970, 1540] and 46.7 g of 2-ethoxyacetamidine in 700 ml of absolute control is refluxed for 2 hours 30 minutes under a nitrogen atmosphere. After cooling, the precipitate obtained is isolated by filtration. It is purified by recrystallization from ethanol. Yld: 52.0 g (84%), m.p. 152°-154° C.