Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:14][C:6]1[C:5]2[C:4]([C:15]([O:17][CH3:18])=[O:16])=[CH:3][C:2]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:10][C:9]=2[N:8]([CH:11]([CH3:13])[CH3:12])[N:7]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(-c2cccnc2)cc2c1c(C)nn2C(C)C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
To a stirred solution of methyl 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylate (0.5 g, 1.60 mmol) in 1,4-dioxane (25 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.39 g, 1.92 mmol) followed by PdCl2(dppf)-CH2Cl2 adduct (0.26 g, 0.32 mmol). The reaction mixture was stirred for 5 min, then sodium bicarbonate (0.4 g, 4.80 mmol) dissolved in water (8 mL) was added and the reaction mixture was stirred at 100° C. for 6 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with cold water (2×25 mL), brine solution (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product. The crude compound was purified by silica gel chromatography (eluent: 100% ethyl acetate) to afford the title compound as an off-white solid (470 mg, 94%). 1H NMR (DMSO-d6, 400 MHz): δ 1.485 (d, J=6.4 Hz, 6H), 2.601 (s, 3H), 3.945 (s, 3H), 5.121-5.186 (m, 1H), 7.523-7.554 (m, 1H), 7.902 (s, 1H), 8.232 (d, J=7.6 Hz, 1H), 8.316 (s, 1H), 8.625 (d, J=4 Hz, 1H), 9.045 (s, 1H).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1([CH3:32])[CH:22]=[C:21]([N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]2=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]#[N:31])[CH:19]=2)[O:14]1)=O)C1C=CC=CC=1.C(OC(NCC(=O)C)=O)C1C=CC=CC=1.C(C1(C)C(CN)C(=O)C2C(=CC=C(C#N)C=2)O1)(OCC1C=CC=CC=1)=O.O1C2C(=CC=CC=2)C(O)CC1.OCC1(C)C=C(N2C=CC=CC2=O)C2C(=CC=C(C#N)C=2)O1>O1CCOCC1.[Pd].[C]>[NH2:11][CH2:12][C:13]1([CH3:32])[CH:22]=[C:21]([N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]2=[O:29])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:30]#[N:31])[CH:19]=2)[O:14]1
Reactant: CC1(CNC(=O)OCc2ccccc2)C=C(n2ccccc2=O)c2cc(C#N)ccc2O1
Agent: [Pd]
Agent: CC(=O)CNC(=O)OCc1ccccc1
Agent: CC1(C(=O)OCc2ccccc2)Oc2ccc(C#N)cc2C(=O)C1CN
Solvent: C1COCCO1
Product: CC1(CN)C=C(n2ccccc2=O)c2cc(C#N)ccc2O1

Procedure:
A solution of 1 g of 2-benzyloxycarbonylaminomethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano3-chromene [obtainable from 1-benzyloxycarbonylamino-2-propanone ("1-CBZ-2-propanone") via 2-CBZ-aminomethyl-2-methyl-6-cyano-4-chromanone, the corresponding 4-chromanol, the corresponding 3-chromene and the corresponding 3,4-epoxide] in 20 ml of dioxane is hydrogenated on 0.5 g of 5% Pd-carbon at 20° C. and 1 bar until the calculated amount of H2 has been absorbed. The mixture is filtered, the solution is evaporated and 2-aminomethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano-3-chromene is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]Br)[CH:7]=1)C.BrN1[C:20](=[O:21])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CO.C[O-].[Na+].C(OCC)(=O)C>[CH3:1][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:21][CH3:20])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cccc(CBr)c1
Agent: C[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COCc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl(3-(bromomethyl)phenyl)acetate (1.78 g) in carbon tetrachloride (80 ml), 1.78 g of N-bromosuccinimide and 100 mg of benzoyl peroxide were added, and the reaction solution was heated overnight at reflux. The reaction solution was cooled, then the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-10:90)) to afford a crude product. To a solution of the crude product (304 mg) in methanol (1 ml), 0.3 ml of sodium methoxide (25% methanol solution) was added, and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution and a saturated saline solution sequentially, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., ethyl acetate/hexane (20:80)) to afford the title compound as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:18][C:19]([C:21]3[CH:42]=[CH:41][C:24]([O:25][C:26]4[CH:35]=[C:34]5[C:29]([CH:30]([C:36]([OH:38])=[O:37])[CH2:31][CH2:32][O:33]5)=[CH:28][C:27]=4[C:39]#[N:40])=[CH:23][CH:22]=3)=[O:20])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:43]>O1CCOCC1>[ClH:43].[C:39]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:26]=1[O:25][C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[NH:18][C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH2:17][NH:8][CH2:9]4)=[CH:14][CH:13]=3)=[CH:42][CH:41]=1)[O:33][CH2:32][CH2:31][CH:30]2[C:36]([OH:38])=[O:37])#[N:40]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(NC(=O)c3ccc(Oc4cc5c(cc4C#N)C(C(=O)O)CCO5)cc3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3ccc4c(c3)CNCC4)cc1)OCCC2C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a stirred solution of 7-(4-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid (40 mg, 0.070 mmol) in dioxane (1 mL) at ambient temperature was added a 4M solution of hydrogen chloride in dioxane (2 mL). The resulting solution was stirred at ambient temperature for 90 minutes. Some dark material had separated from the cloudy reaction mixture, and the supernatant was concentrated to afford 6-cyano-7-(4-(1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid hydro-chloride as a light tan solid (30 mg, 84% yield). MS (apci) m/z=470.2 (M-Cl).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][NH:10][C:11]2[C:12]3[C:17]([N:18]=[C:19]4[C:24]=2[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:16][CH:15]=[CH:14][CH:13]=3)C=CC=C[CH:2]=1.CN(C)C1C=C2C(N=C3C(=C2NOCC2SC=CC=2)CCCC3)=CC=1.S1C=CC=C1CONC1C2C(N=C3C=1CCCC3)=CC=CC=2.O1C=CC=C1CONC1C2C(N=C3C=1CCCC3)=CC=C([N+]([O-])=O)C=2.O1C=CC=C1CONC1C2C(N=C3C=1CCCC3)=CC(C(F)(F)F)=CC=2.O1C=C(CONC2C3C(N=C4C=2CCCC4)=CC=CC=3)C=C1.ClC1C=CC(CONC2C3C(N=C4C=2CCCC4)=CC=CC=3)=CC=1.C(ONC1C2C=CC=CC=2N=C2CCCC=12)C1C=CC=CC=1>>[CH3:2][CH2:1][CH2:7][CH2:8][O:9][NH:10][C:11]1[C:12]2[C:17]([N:18]=[C:19]3[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: c1ccc(CCONc2c3c(nc4ccccc24)CCCC3)cc1
Agent: CN(C)c1ccc2nc3c(c(NOCc4cccs4)c2c1)CCCC3
Agent: Clc1ccc(CONc2c3c(nc4ccccc24)CCCC3)cc1
Agent: FC(F)(F)c1ccc2c(NOCc3ccco3)c3c(nc2c1)CCCC3
Product: CCCCONc1c2c(nc3ccccc13)CCCC2

Procedure:
N-(4-chlorobenzyloxy)-1,2,3,4-tetrahydro-9-acridinamine N-(4-furylmethoxy)-1,2,3,4-tetrahydro-9-acridinamine N-(2-furylmethoxy)-1,2,3,4-tetrahydro-6-trifluoromethyl-9-acridinamine N-(2-furylmethoxy)-7-nitro-1,2,3,4-tetrahydro-9-acridinamine N-(2-thienylmethoxy)-1,2,3,4-tetrahydro-9-acridinamine 7-dimethylamino-N-(2-thienylmethoxy)-1,2,3,4-tetrahydro-9-acridinamine N-[(2-phenylethyl)oxy]-1,2,3,4-tetrahydro-9-acridinamine N-[[2-(3,4-dimethoxyphenyl)ethyl]oxyl-1,2,3,4-tetrahydro-9-acridinamine N-[(2-dimethylaminocthyl)oxy]-1,2,3,4-tetrahydro-9-acridinamine N-[(3-dimethylaminopropyl)oxy]-1,2,3,4-tetrahydro-9-acridinamine N-[(4,4-diphenylbutyl)oxy]-1,2,3,4-tetrahydro-9-acridinamine N-[(4,4-[bis(4-fluorophenyl)butyl ]oxy] -1,2,3,4-tetrahydro-9-acridinamine N-acctyl-N-benzyloxy-1,2,3,4-tetrahydro-9-acridinamine N-benzyloxy-N-methyl-1,2,3,4-tetrahydro-9-acridinamine N-hydroxy-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-amine N-methoxy-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-amine N-benzyloxy-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-amine 2,3-dihydro-N-hydroxy-1H-cyclopenta[b]quinolin-9-amine 2,3-dihydro-N-methoxy-1H-cyclopenta[b]quinolin-9-amine and 2,3-dihydro-N-benzyloxy-1H-cyclopenta[b]quinoline-9-amine
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)(C)(C)C.[Br:26][C:27]1[CH:28]=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[N:32][C:31]=2Cl.C([O-])(O)=O.[Na+]>C(O)(C)(C)C.Cl.O1CCOCC1>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:31]3[N:32]=[CH:33][CH:34]=[C:35]4[C:30]=3[N:29]=[CH:28][C:27]([Br:26])=[CH:36]4)[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:15])[F:16])[N:13]=1
Reactant: Clc1nccc2cc(Br)cnc12
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)COC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: NC1=N[C@@](c2cc(Nc3nccc4cc(Br)cnc34)ccc2F)(C(F)F)COC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
[(R)-5-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]carbamic acid tert-butyl ester (CAS registry 1262859-09-5) (250 mg, 0.696 mmol) and 3-bromo-8-chloro-[1,7]naphthyridine [Heteroaryl 1] (186 mg, 0.765 mmol) were dissolved in tert-Butanol (4 ml) in a microwave vial and HCl (0.174 ml of a 4M solution in dioxane) was added. The vial was sealed and heated to 100° C. for 1 h. The reaction mixture was cooled to rt and added to a saturated NaHCO3 solution (20 ml) and stirred at rt for 10 min.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH3:18])=[O:5].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:43])OC2C=CC=CC=2)[CH:29]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]([CH2:19][CH2:20][N:21]([CH3:22])[C:35]([NH:34][C:30]1[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=1)=[O:43])[CH3:18])=[O:5]
Reactant: CNCCN(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CCN(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12)C(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-4-[N-(2-methylaminoethyl)-N-methylamino]quinoline (130 mg), phenyl 3-pyridylcarbamate (76 mg) and triethylamine (97.9 mg) in dimethylformamide (1.5 ml) was stirred for 1 hour at ambient temperature. The mixture was diluted with ethyl acetate, washed with 1N sodium hydroxide solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (methanol-dichloromethane) to give 8-(2,6-dichlorobenzoylamino)-4-[N-[2-[l-methyl-3-(3-pyridyl)ureido)ethyl]-N-methylamino]quinoline (168 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[CH:42][CH:41]=3)[CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 29 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and (4-(morpholinomethyl)phenyl)boronic acid (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and the solution was purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and solution was purged again for 10 min. Reaction mixture was heated at 100° C. for 4 h. On completion, the mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.070 g, 29% yield). LCMS: 557.40 (M+1)+; HPLC % 98.83 (@254 nm) (Rt; 4.303; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.15 (t, 1H, J=4 Hz), 7.56 (d, 2H, J=7.6 Hz), 7.36 (d, 2H, J=8 Hz), 7.28 (s, 1H), 7.13 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.57 (m, 4H), 3.48 (s, 2H), 2.74 (t, 1H), 2.64 (s, 3H), 2.36 (m, 4H), 2.20 (s, 6H), 2.10 (s, 3H), 1.69-1.71 (m, 3H), 1.53-1.56 (m, 2H), 1.41-1.44 (m, 2H), 1.10-1.23 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[OH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.C(Cl)Cl.[Cu]I>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#Cc1cc(-n2ccccc2=O)ccc1N
Temperature: 160 °C
Yield: 11.2 %

Procedure:
A suspension of 2-amino-5-bromobenzonitrile (1 g), 2-hydroxypyridine (730 mg), CuI (190 mg), potassium carbonate (770 mg) and 8-hydroxyquinoline (150 mg) in 7 ml DMSO was heated for 1.5 h at 160° C. The reaction mixture was afterwards cooled, diluted with CH2Cl2 and filtered through decalite. The organic phase was extracted with water and brine and purified by chromatography (silica gel, AcOEt/heptane) to yield 2-amino-5-(2-oxo-2H-pyridin-1-yl)-benzonitrile as a yellow solid (120 mg). MH+=212.1
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.5 %

Procedure:
A suspension of 3-bromo-2-fluorobenzoic acid (1.009 g, 4.61 mmol) in DCM (25 mL) was stirred at rt and treated with oxalyl chloride (2.016 mL, 23.04 mmol), followed by a drop of DMF, causing gas evolution to commence. After 2.5 h, the solution was heated to boiling for 1-2 min and allowed to cool to rt. After 3 h total, the solution was concentrated to provide 3-bromo-2-fluorobenzoyl chloride as a dark yellow liquid (1.078 g, 99%). A portion of this (200 mg, 0.842 mmol) was dissolved in THF (1.5 mL) and added to a solution of dimethylamine (2 M in methanol, 2.0 mL, 4.00 mmol) in THF (2 mL). The mixture was stirred at rt for 18 h, then was concentrated. The residue was dissolved in EtOAc, washed sequentially with 1 M hydrochloric acid, NaHCO3 (aq) and brine, and dried and concentrated to provide 3-bromo-2-fluoro-N,N-dimethylbenzamide as a light yellow oil (192 mg, 93%). 1H NMR (400 MHz, chloroform-d) δ 7.60 (ddd, J=8.1, 6.5, 1.6 Hz, 1H) 7.32 (ddd, J=7.6, 5.9, 1.6 Hz, 1H) 7.09 (td, J=7.8, 0.7 Hz, 1H) 3.14 (s, 3H) 2.93 (d, J=1.5 Hz, 3H). Mass spectrum m/z 246, 248 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1(/[CH:28]=[CH:29]/[C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.CO>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:30](=[O:31])/[CH:29]=[CH:28]/[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccccc1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 90.6 %

Procedure:
Preparation of example 89 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), (E)-3-phenyl-acrylic acid (23 mg, 0.154 mmol), triethylamine (0.054 mL, 0.384 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59 mg, 0.154 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 2:1 hexane:acetone), also in an analogous manner, after a final trituration with methanol afforded the title compound (47 mg, 0.116 mmol) as a yellow powder in 90% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][NH:8][C:7]=2[CH:18]=1.O.C(=O)([O-])O.[K+].Br[CH2:26][C:27]#[N:28]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][N:8]([CH2:26][C:27]#[N:28])[C:7]=2[CH:18]=1
Reactant: N#CCBr
Reactant: COc1ccc2c(c1)NCC(c1ccccc1)O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Product: COc1ccc2c(c1)N(CC#N)CC(c1ccccc1)O2
Temperature: 70 °C
Reaction time: 16 h

Procedure:
The compound obtained in Step C (1.5 g; 6.22 mmol) is suspended in 25 ml of water (4 ml/1 mmol). Potassium hydrogen carbonate (10 eq.; 62.2 mmol; 5.22 g), tetrabutylammonium bromide (0.05 eq.; 0.31 mmol; 100 mg) and bromoacetonitrile (8 eq.; 49.7 mmol; 3.46 ml) are then added. The mixture is stirred vigorously at 70° C. for 16 hours. After returning to ambient temperature, the product formed is extracted with dichloromethane. The organic phase is dried over MgSO4, filtered, and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (eluant: PE/AcOEt (8/2)). The title product is obtained in the form of a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:30])=[O:29].[CH:32]1([S:37]([C:40]2[S:41][C:42](Br)=[CH:43][CH:44]=2)(=[O:39])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:32]1([S:37]([C:40]2[S:41][C:42]([C:14]3[CH:15]=[C:16]4[C:11](=[C:12]([C:26]([NH2:28])=[O:27])[CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:6]3[CH2:5][CH2:4][S:3](=[O:29])(=[O:30])[C:2]([CH3:1])([CH3:31])[CH2:7]3)=[CH:43][CH:44]=2)(=[O:39])=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)C(C)(C)C4)c3c2)OC1(C)C
Reactant: O=S(=O)(c1ccc(Br)s1)C1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(S(=O)(=O)C5CCCC5)s4)cc23)CCS1(=O)=O
Temperature: 100 °C

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (75 mg, 0.17 mmol), 5-bromo-2-thienyl cyclopentyl sulfone (60 mg, 0.20 mmol), PdCl2(dppf)-CH2Cl2 adduct (20 mg, 0.024 mmol, 0.15 eq), and potassium carbonate (100 mg, 0.72 mmol, 4.3 eq) were diluted in a mixture of 1,4-dioxane (3 mL) and water (1.5 mL) in a 2-5 mL microwave tube. The mixture was degassed by bubbling argon through for 5 minutes, then was heated in a biotage microwave at 100° C. for 5 minutes. The crude reaction mixture was filtered through a thiol SPE cartridge (polymer labs) to remove palladium, and was concentrated. The residue was re-diluted in ˜3 mL of dmso, and filtered through a syringe filter. The crude product was purified by ammonium hydroxide Gilson HPLC, and the desired fractions were evaporated to afford 5-[5-(cyclopentylsulfonyl)-2-thienyl]-3-(2,2-dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide as an off white solid (22.4 mg, 24%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:3]=12.[H-].[Na+].Cl.Cl[CH2:20][CH2:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[CH3:27]>CN(C)C=O.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[N:12]([CH:21]([C:22]3[N:23]=[CH:24][NH:25][C:26]=3[CH3:27])[CH3:20])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1[nH]cnc1CCCl
Reactant: Cc1c2n(c3ccccc13)C(=O)NCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]cnc1C(C)N1CCc2c(C)c3ccccc3n2C1=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-dihydro-5-methylpyrimido[1,6-a]-indol-1(2H)-one (1.88 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in mineral oil 1.12 g) at 5° C. After being stirred at 5° C. for 30 minutes, 4-(2-chloroethyl)-5-methyl-1H-imidazole hydrochloride (2.17 g) in N,N-dimethylformamide (30 ml) was added dropwise over 20 minutes. The mixture was stirred at 5° C. for 30 minutes and at ambient temperature for 16 hours. The reaction mixture was diluted with chilled water and extracted with a mixture of ethyl acetate and tetrahydrofuran (2:1, 30 ml×2). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (3%-methanol-chloroform) to give 3,4-dihydro-5-methyl-2-[1-(5-methyl-1H-imidazol-4-yl)ethyl]pyrimido[1,6-a]indol-1(2H)-one as a powder.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7].[Br:11][C:12]([Br:17])([Br:16])[C:13](Br)=[O:14].C(N(CC)CC)C>ClC(Cl)C.O.C(O)C>[Br:11][C:12]([Br:17])([Br:16])[C:13]([O:1][CH:2]([CH3:10])[CH2:3][NH:4][C:5](=[O:9])[C:6]([CH3:8])=[CH2:7])=[O:14]
Reactant: O=C(Br)C(Br)(Br)Br
Reactant: C=C(C)C(=O)NCC(C)O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(Cl)Cl
Product: C=C(C)C(=O)NCC(C)OC(=O)C(Br)(Br)Br
Temperature: 0 °C

Procedure:
N-(2-Hydroxypropyl)methacrylamide (7.15 g) was dissolved in dichloroethane (150 ml) in a 500 ml three-necked round-bottomed flask, fitted with a stirrer, two dropping funnels and a nitrogen supply. The flask was cooled to 0° C. by means of an ice/salt freezing mixture, stirring was started and the reaction was blanketed with dry nitrogen. `Topanol OC`, a butylated hydroxy toluene stabilizer, (0.1 g) was added. Tribromoacetylbromide (18 g) was added dropwise, simultaneously with triethylamine (5.1 g) over a period of 30 minutes, keeping the temperature between 0° and -5° C. While stirring the mixture was then slowly allowed to come to room temperature. After four hours the precipitated salts were filtered off, washed with dichloroethane, and the washings and filtrate were combined. The solvent was removed under vacuum by a rotary evaporator leaving an oil residue. This was dissolved in a mixture of water and ethanol and on standing the product crystallized as a colorless solid. It was recrystallized from the same solvent mixture. Yield (13 g) m.p. 104°-105° C.