Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1.Cl[CH2:29][C:30]([NH2:32])=[O:31].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:24][CH2:25]4)[C:15](=[O:26])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:27]=1
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCNCC1
Reactant: NC(=O)CCl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CN1CCC(CN2CCN(S(=O)(=O)c3cc4ccc(Cl)cc4s3)CC2=O)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-piperidin-4-ylmethyl-piperazin-2-one (20 mg, 0.047 mmol) in N-methylpyrrolidinone (0.5 mL) is added 2-chloroacetamide (9 mg, 0.094 mmole) and diisopropylethylamine (0.016 mL, 0.094 mmole) and heated at 120° C. for 16 h. The reaction is concentrated and purified by column chromatography (silica, 5% methanol/dichloromethane) to provide 2-{4-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-piperidin-1-yl}-acetamide. 1H NMR (300 MHz, CDCl3) d 7.88-7.83 (m, 3H), 7.47 (dd, 1H), 6.98 (bs, 1H), 5.30 (bs, 1H), 3.86 (s, 2H), 3.46 (s, 4H), 3.28 (d, 2H), 2.95 (s, 2H), 2.82 (d, 2H), 2.06 (t, 2H), 1.69-1.50 (m, 3H), 1.33-1.25 (m, 2H); MS (Ion spray) 485 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]2=[C:16]([C:18]([OH:20])=O)[CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][C@H:46]1[CH:51]2[CH2:52][CH2:53][N:48]([CH2:49][CH2:50]2)[CH2:47]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:48]12[CH2:53][CH2:52][CH:51]([CH2:50][CH2:49]1)[C@H:46]([NH:45][C:18]([C:16]1[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[O:9][C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:7][C:6]=13)=[O:20])[CH2:47]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COc1cc(C(=O)O)c2nc(-c3ccccc3)oc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)N[C@@H]2CN3CCC2CC3)c2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A mixture of 6-methoxy-2-phenylbenzoxazole-4-carboxylic acid (50 mg, 0.18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg, 0.37 mmol), 1-hydroxybenzotriazole (50 mg, 0.37 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (46 mg, 0.23 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.10 mL, 0.72 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-6-methoxy-2-phenylbenzoxazole-4-carboxamide (55 mg, 76%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.56 (d, J=7.2 Hz, 1H), 8.21-8.17 (m, 2H), 7.79 (d, J=2.5 Hz, 1H), 7.60-7.52 (m, 3H), 7.26-7.24 (m, 1H), 4.34-4.30 (m, 1H), 3.94 (s, 3H), 3.56-3.51 (m, 1H), 3.16-3.05 (m, 2H), 2.95-2.84 (m, 3H), 2.20-2.18 (m, 1H), 2.15-2.03 (m, 1H), 1.82-1.76 (m, 2H), 1.70-1.55 (m, 1H); MS (ESI+) m/z 378 (M+H); HPLC>99% (AUC), tR=12.90 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Br)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-bromophenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 597.2 (M+H)+.
Reaction SMILES: C(OC([NH:11][C:12]([CH3:50])([CH3:49])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][CH:30]=2)[C:18]1=[O:48])=[O:15])=O)C1C=CC=CC=1.C(O)(=O)C>CO.[OH-].[Pd+2].[OH-]>[C:41]([OH:43])(=[O:42])[CH3:36].[NH2:11][C:12]([CH3:50])([CH3:49])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[C:36]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:33][CH:34]=2)[C:18]1=[O:48])=[O:15]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)C1=O)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(N)CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)C1=O
Reaction time: 4 h
Yield: 193.7 %

Procedure:
To a solution of 400 mg (0.592 mmol) of t-butyl 4'-[[3(R)[[3-benzyloxycarbonylamino-3-methyl-1-oxobutyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-carboxylate (prepared according to the procedure of Fisher et al, U.S. Pat. No. 5,206,235) in 10 mL of methanol was added 0.034 mL (0.59 mmol) of acetic acid and 80 mg (20% w/w) palladium hydroxide. The resulting mixture was stirred under a hydrogen atmosphere for 4 hours. Catalyst was removed by filtration through Celite and the solvent removed under vacuum to afford 345 mg (97%) of the product as a white solid. 1H NMR (400 MHz, CD3OD): δ1.17 (s, 9H), 1.37 (s, 3H), 1.41 (s, 3H), 1.92 (s, 3H), 2.17 (m, 1H), 2.35 (m, 1H), 2.45-2.75 (m, 4H), 4.41 (dd; 12, 8 Hz; 1H), 4.93 (d, 15 Hz, 1H), 5.37 (d, 16 Hz, 1H), 7.12-7.52 (m, 11H), 7.66 (d, 8 Hz, 1H). FAB-MS: calculated for C33H39N3O4 541; found 542 (M+H,100%).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:38][CH2:39][CH3:40])[CH:32]=4)[CH2:28][CH2:27][C:26]([C:41](O)=[O:42])=[CH:25][C:24]=3[CH:44]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:38][CH2:39][CH3:40])[CH:32]=4)[CH2:28][CH2:27][C:26]([C:41]([NH:29][C:23]4[CH:24]=[CH:44][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:42])=[CH:25][C:24]=3[CH:44]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccc(OCCC)c2)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cccc(OCCC)c2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (134 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (100 mg) and triethylamine (455 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 4.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-propoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 64) (207 mg) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[C:4]([S:10][CH3:11])[N:3]=1.C([Li])CCC.CCCCCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[N:9]2[C:5]([S:6][CH:7]=[C:8]2[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CSc1nc(C)n2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1csc2c(SC)nc(C)n12
Reaction time: 0.67 h

Procedure:
5-Methyl-7-methylthioimidazo[5,1-b]thiazole (3.34 g) was dissolved in 150 ml of THF. A 1.59 N n-butyllithium/n-hexane solution (22.8 ml) was added dropwise to the solution in an argon atmosphere at −73° C. The mixture was stirred at the same temperature for 40 min. Tri-n-butylstannyl chloride (6.39 ml) was added thereto, followed by stirring at the same temperature for one hr. An ammonium chloride solution was added to the reaction solution. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 1:1). Of two main components, the fraction, which had been eluted earlier, was collected to give 598 mg of 5-methyl-7-methylthio-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.
Reaction SMILES: [CH2:1]([C@H:5]1[O:7][C@@H:6]1[C:8]([OH:10])=O)[CH2:2][CH2:3][CH3:4].CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O.C1CCC(NC2CCCCC2)CC1.C(Cl)(=O)C(C)(C)C.[CH2:58]1[O:67][C:66]2[CH:65]=[CH:64][C:62]([NH2:63])=[CH:61][C:60]=2[O:59]1>O1CCCC1>[CH2:58]1[O:67][C:66]2[CH:65]=[CH:64][C:62]([NH:63][C:8]([C@@H:6]3[C@@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[O:7]3)=[O:10])=[CH:61][C:60]=2[O:59]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CCCC[C@H]1O[C@@H]1C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: C1CCOC1
Product: CCCC[C@H]1O[C@@H]1C(=O)Nc1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
Under ice-cooling, to 10 ml of an anhydrous tetrahydrofuran solution containing 299 mg (1.84 mmol) of (2S-trans)-3-butyl-oxiranecarboxylic acid.dicyclohexylammonium salt was added 2 ml of an anhydrous tetrahydrofuran solution containing 222 mg (1.84 mmol) of pivaloyl chloride, and the resulting mixture was stirred at the same temperature for 15 minutes. Moreover, the temperature of the reaction mixture was returned to room temperature, and the mixture was stirred for 2 hours. After insoluble material in the reaction mixture was filtred off, the filtrate was added to 10 ml of an anhydrous tetrahydrofuran solution containing 252 mg (1.84 mmol) of 3,4-methylenedioxyaniline under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. Under reduced pressure, the reaction mixture was concentrated, ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and then a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 484 mg (Yield: 100%) of the title compound.
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:29][CH:30]=[C:31]([CH2:33][CH2:34]O)[CH:32]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CS(C)=O.C(C(C)=O)C>[CH2:33]([C:31]1[CH:32]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[C:28]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:29][C:30]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)[CH3:34]
Reactant: OCCc1ccc(OCc2ccccc2)c(-c2ccc(F)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCC1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
3-(Methanesulfonyloxymethyl)-N-(tertbutoxycarbonyl)-piperidine (143 mg, 0.49 mmol) and 5-(4-fluorophenyl)-4-benzyloxy-2-hydroxyethylbenzene (150 mg, 0.47 mmol) were added to methyl ethyl ketone (7 mL) followed by potassium carbonate (113 mg, 0.82 mmol), potassium iodide (15.5 mg, 93 μmol), and dimethylsulfoxide (4 mL). The slurry was heated at reflux for 40 hours, when it was cooled, diluted with water (50 mL) and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a clear oil which was not purified but used as is in the following step. Mass Spec (EI): 537.4 (M+NH4)
Reaction SMILES: CS(C1C=CC([N:11]2C(=O)C=CC(C([O-])=O)=N2)=CC=1)(=O)=O.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([O:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[C:30]([C:49]([O:51]C)=O)=[N:29]2)=[CH:24][C:23]=1[F:53]>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:33](=[O:34])[CH:32]=[C:31]([O:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:38][CH2:37]3)[C:30]([C:49](=[O:51])[NH2:11])=[N:29]2)=[CH:24][C:23]=1[F:53]
Reactant: COC(=O)c1nn(-c2ccc(Br)c(F)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)[O-])ccc2=O)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Br)c(F)c3)nc2C(N)=O)CC1
Yield: 100 %

Procedure:
tert-Butyl 4-(1-(4-bromo-3-fluorophenyl)-3-carbamoyl-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was prepared in 100% yield according to procedures described in Example 31 (Step A) substituting methyl 441-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate for methyl 1-(4-bromo-3-fluorophenyl)-4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-6-oxo-1,6-dihydropyridazine-3-carboxylate (Example 43). MS (ESI) 511 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[CH:11]=1.ClC(Cl)C(O)=O.[I:35]N1C(=O)CCC1=O>C(#N)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[C:11]=1[I:35]
Reactant: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=C(O)C(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(I)c2=O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a suspension of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (2.53 g, 6.55 mmol) and dichloroacetic acid (0.27 mL, 3.27 mmol) in acetonitrile (20 mL) was added N-iodosuccinimide (1.62 g, 7.20 mmol). Stirred at ambient temperature for 3.5 h. Cooled reaction mixture (0° C.), filtered solid, washed with cold acetonitrile, and dried in vacuo overnight. Obtained product as white solid (2.72 g, 81%). 1H NMR (CD3OD/400 MHz) δ8.24 (s, 1H), 8.07 (m, 1H), 7.93 (s, 1H), 7.63 (q, 1H, J=8.4 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.01 (t, 2H, J=8.4 Hz), 5.57 (s, 2H), 3.90 (s, 3H), 2.19 (s, 3H). ESHRMS m/z 513.0143 (M+H calculated for C20H16F21N2O4 requires 513.0117).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.CCN=C=N[CH2:25][CH2:26][CH2:27]N(C)C>C(O)(C)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH:26]([CH3:27])[CH3:25])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Solvent: CC(C)O
Product: CC(C)OC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reaction time: 16 h

Procedure:
2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid was mixed with EDCI and isopropanol and the reaction mixture was stirred for 16 h to obtain isopropyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: Nc1ccccc1
Agent: Cl
Product: N#Cc1c(F)cccc1Nc1ccccc1

Procedure:
A mixture of 2.8 g (20 mmol) of 2,6-difluorobenzonitrile in 20 ml of aniline is refluxed for 6 hrs. The mixture is poured into diluted HCl and the acid is extracted with methylene chloride. Evaporation gives the crude product which is chromatographed on silica gel (50% hexane--CH2Cl2) to give the title compound, m.p. 97°-99° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:32]([O-])=O)[C:18]([NH:19][C@@H:20]4[CH2:24][CH2:23][N:22]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.[Ni]>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:32])[C:18]([NH:19][C@@H:20]4[CH2:24][CH2:23][N:22]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCN(Cc2ccccc2)C1
Reaction time: 2.5 h
Yield: 94.5 %

Procedure:
A mixture of (1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-((R)-1-benzyl-pyrrolidin-3-yl)-amine (2.48 g, 5.2 mmol) and Raney Ni (5.5 g) in ethyl acetate (50 mL) was hydrogenated at 25° C. for 2.5 hours. The mixture was filtered through Celite, thoroughly washing the filter cake with methanol. The filtrate and washings were combined and concentrated under vacuum, gave 2.2 g (96%) of (1-Benzenesulfonyl-5-amino-1H-pyrrolo[2,3-b]pyridin-4-yl)-((R)-1-benzyl-pyrrolidin-3-yl)-amine, which was used in the next step without further purification. LCMS (Method J, ESI): RT=0.81 min, M+H+=447.9; 1H NMR (400 MHz, CDCl3) δ: 8.07-8.05 (d, J=6.8 Hz, 2H), 7.74 (s, 1H), 7.46-7.44 (m, 2H), 7.39-7.35 (m, 3H), 7.25-7.18 (m, 6H), 6.52-6.50 (d, J=4.4 Hz, 1H), 4.30-4.40 (m, 1H), 3.56 (s, 2H), 2.79-2.76 (m, 2H), 2.69-2.59 (m, 1H), 2.36-2.25 (m, 2H), 1.60-1.70 (m, 1H).
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]/[C:4]([OH:6])=O.[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]([C:17]2[C:18]3[C:30]([NH2:31])=[N:29][CH:28]=[N:27][C:19]=3[N:20]3[C:25]=2[CH2:24][CH2:23][CH:22]([NH2:26])[CH2:21]3)[CH:8]=1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:31][C:30]1[C:18]2[C:17]([C:9]3[CH:8]=[N:7][C:16]4[C:11]([CH:10]=3)=[CH:12][CH:13]=[CH:14][CH:15]=4)=[C:25]3[N:20]([C:19]=2[N:27]=[CH:28][N:29]=1)[CH2:21][C@@H:22]([NH:26][C:4](=[O:6])/[CH:3]=[CH:2]/[Cl:1])[CH2:23][CH2:24]3
Reactant: O=C(O)/C=C/Cl
Reactant: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2CC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2C[C@@H](NC(=O)/C=C/Cl)CC1
Reaction time: 1 h
Yield: 41.4 %

Procedure:
Trans-3-chloroacrylic acid (399.5 mg) was added to a suspension of 5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizine-4,8-diamine (498.0 mg) obtained in Step 11 of Example 1 in DMF (8 ml) at room temperature. After dissolving, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (350.1 mg) was added thereto under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound as a light-yellow solid (261.2 mg).