Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=1)[CH2:9][C:8]2([CH3:29])[CH3:28])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:28][C:8]1([CH3:29])[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=2)[CH2:9]1
Reactant: COC(=O)c1cc(C)c2c(c1)C(C)(C)CC(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)cc2c1NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
To a stirred mixture solution of 4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.4 g, 3.55 mmol) in methanol (5 mL) and tetrahydrofuran (10 mL) was added 30% sodium hydroxide in water (5 mL). The reaction mixture was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.9 g, 66%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=381.0.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH:34]=[O:35]>C1COCC1>[Cl:31][C:32]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:33]=1[CH:34]([OH:35])[CH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][S:13]([C:16]([F:18])([F:19])[F:17])(=[O:15])=[O:14])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1
Reactant: Cc1cc(=O)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1cc(CC(O)c2ccc(Cl)cc2Cl)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Reaction time: 1 h

Procedure:
To a solution of Trifluoro-methanesulfonic acid 4-methyl-2-oxo-2H-chromen-7-yl ester (340 mg, 1.1 mmol) in dry THF (8 mL0 at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (1.2 mL). After 30 minutes 2,4-dichloro-benzaldehyde (130 μL) was added slowly into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, concentrated and purified on silica gel eluted with 30% ethyl acetate in hexanes to yield trifluoro-methanesulfonic acid 4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromen-7-yl ester as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:15])[NH:10]1>C1(C)C=CC=CC=1>[CH3:8][C@H:9]1[CH2:14][NH:13][CH2:12][C@@H:11]([CH3:15])[N:10]1[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccn1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: Cc1ccccc1
Product: C[C@@H]1CNC[C@H](C)N1c1ncccn1

Procedure:
A solution of 820 mg 2-chloropyrimidine and 1.6 g cis-2,6-dimethylpiperazine in 25 mL toluene was heated at reflux temperature for 12 hours. The solvent was evaporated, the residue was basified with 5% sodium hydroxide and extracted with 2×100mL of dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give cis-2,6-dimethyl-1-(2-pyrimidyl)-piperazine. This amine was then used to prepare 2-phenyl-4(5)-[(4-(2-pyrimidinyl)-cis-2,6-dimethylpiperazin-1-yl)-methyl]yl)-methyl]-imidazole (Compound 140), m.p.130°-135° C., according to the procedures described in Example VIII.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([NH2:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:31](Cl)(=[O:33])[CH3:32].O>CN(C)C(=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([NH:24][C:31](=[O:33])[CH3:32])=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(N)cc12
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A solution of tert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (synthesized according to the method similar to that in Example 82 (2)) (0.21 g, 0.5 mmol) and acetyl chloride (0.04 ml, 0.6 mmol) in N,N-dimethylacetamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl{6-(acetylamino)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.19 g, 80.8%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:34]1>>[CH2:38]([N:35]1[CH2:36][CH2:37][CH:33]([NH:32][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)[CH:19]=2)[CH2:34]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NC1CCN(Cc2ccccc2)C1
Product: O=C(NC1CCN(Cc2ccccc2)C1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-amino-1-benzylpyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z=604.99 (M+H+); retention time=0.63 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]#[N:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2.C1C(=O)N([Cl:22])C(=O)C1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:13]#[N:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[Cl:22]
Reactant: N#Cc1cc(Br)cc2ccc(O)cc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12

Procedure:
The title compound was prepared by reacting 3-bromo-7-hydroxy-1-naphthonitrile (0.32 g, 1.28 mmol) with NCS (0.24 g, 1.8 mmol) in THF (25 mL) at 45° C. for 3 hr according to method C to yield 0.30 g (83%) of a yellow solid. An analytical sample was prepared by preparative reverse phase HPLC to yield the title compound as a white solid: mp 148-150° C.; 1H NMR (DMSO-d6): δ 7.47 (1H, d, J=8.98 Hz), 7.95 (1H, d, J=9.02 Hz), 8.32 (1H, d, J=2.08 Hz), 8.55 (1H, d, J=2.08 Hz), 11.33 (1H, s); MS (ESI) m/z280/282/284 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].CN1CCOCC1.O>C(#N)C>[CH2:28]([O:27][C:25]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[CH3:23])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(C)c(-c2c3ccccc3nc3ccc(N)cc23)c1
Solvent: O
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCOC(=O)Nc1ccc2nc3ccccc3c(-c3cc(C)ccc3C)c2c1
Reaction time: 0.25 h

Procedure:
1.42 pbw of the compound 1d and 2.78 pbw of ethyl chloroformate were dissolved in 100 pbv of acetonitrile at 25° C. and 4.85 pbv of N-methylmorpholine were added. The temperature rose to 38° C. during this process. Stirring of the yellow solution was continued for 15 minutes, then it was poured into 400 pbv of water, and the mixture was stirred for 2 hours and the precipitated residue filtered off by suction. Yield: 1.3 pbw (72% of theory). Mp.: 200°-202° C.
Reaction SMILES: [NH2:1][C:2]12[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:3]1([OH:22])[O:4][C:5]1[C:10]2=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1.C(N([CH2:28][CH3:29])CC)C.[C:30](Cl)(=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[C:30]([NH:1][C:2]1([C:10]2[CH:9]=[CH:8][C:7]([CH:11]([CH3:12])[CH3:13])=[CH:6][C:5]=2[O:4][C:3](=[O:4])[CH2:2][CH2:10][CH2:9][CH2:8][CH2:28][CH3:29])[C:3](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21])(=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(C)c1ccc2c(c1)OC1(O)c3ccccc3C(=O)C21N
Solvent: ClCCl
Product: CCCCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCCCC)C(=O)c2ccccc2C1=O
Reaction time: 3 h
Yield: 120.6 %

Procedure:
A solution of 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]inden-10-one (0.20 g, 0.67 mmol) in anhydrous methylene chloride (10 ml) was added triethylamine (0.20 g, 2.01 mmol) and heptanoyl chloride (0.25 g, 1.69 mmol) and then stirred for 3 hrs. The reaction mixture was concented and extracted with ethylacetate. The concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:6 to 1:4) to afford the title compound as a syrup (0.21 g, 60%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13](C3CCCCO3)[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([NH:27][C:28]2[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]([F:47])([CH3:46])[C:43](O)=O.CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(O)(=O)C>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:27]2[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]=[C:43]2[C:42]([F:47])([F:41])[CH3:46])[N:15]=3)[CH2:7][CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(F)(F)C(=O)O
Reactant: CC(C)(C)N1CCN(Cc2nc3c(N4CCOCC4)nc(Nc4ccccc4N)nc3n2C2CCCCO2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)[nH]c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
N1-(8-((4-tert-butylpiperazin-1-yl)methyl)-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl)benzene-1,2-diamine (0.085 g, 0.15 mmol) and 2,2-difluoropropanoic acid (0.019 g, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 mL, 0.02 mol). N,N-Diisopropylethylamine (0.054 mL, 0.31 mmol) was added. The resulting solution was cooled at 0° C. for 20 minutes. N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.070 g, 0.00018 mol) was added and the reaction stirred overnight at room temperature. The reaction mixture was concentrated to dryness. Acetic acid (3.0 mL, 0.053 mol) was added to the crude residue and the reaction mixture was heated at 90° C. for 18 hours. The reaction mixture was cooled, filtered and concentrated to dryness. The crude was purified by reverse phase HPLC to give 457 (15.3 mg, 18%). [M+H]+=540.3
Reaction SMILES: [C:1]([O:6]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].[N+:8](=[CH2:10])=[N-:9].[CH3:11]COCC>>[CH3:11][CH:10]1[CH2:3][C:2]([CH3:4])([C:1]([OH:6])=[O:5])[N:9]=[N:8]1
Reactant: C=C(C)C(=O)OC
Reactant: CCOCC
Reactant: C=[N+]=[N-]
Product: CC1CC(C)(C(=O)O)N=N1

Procedure:
A solution of 10 g of methyl methacrylate in 100 ml of ether is treated with an excess of ethereal diazomethane for about 16 hours. The ether is removed in vacuo to give 12.5 g of the title compound as an oil. Examination of the oil on thin layer chromatography silica gel plates using 40% ethyl acetate/hexane shows a single spot at Rf =0.34, visualized with phosphomolybdic acid plus heat. The oil has the following spectral characteristics: NMR(13C,CDCl3 ppm), 170.9(C-1), 94.1(C-2), 28.0(C-3), 77.1(C-4), 21.1(C-5), 52.3(C-6), IR(neat), 5.78μ(CO2CH3), 6.5μ(N=N). ##STR23##
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[Cl:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[N:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=[N:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc(Cl)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: Clc1cccc(C#CCCn2nc3ccccc3n2)n1
Reaction time: 0.25 h
Yield: 5300 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2,6-dichloropyridine (150 mg, 1.01 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (0.17 g, 1.00 mmol, Example 109(D)). Microwave conditions: 120° C. for 15 min. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 15 mg (53 mmol, 5%) of 2-(4-(6-chloropyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([O:14][CH3:15])[S:10]([CH3:13])(=[O:12])=[O:11])=[N:6][CH:7]=1.[F:16][CH:17]([F:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@H:22]([OH:33])[C:23]1[CH:28]=[CH:27][C:26]([Sn](C)(C)C)=[CH:25][CH:24]=1)=[O:19].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][CH:17]([F:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@H:22]([OH:33])[C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:7]=[N:6][C:5]([CH2:8][N:9]([S:10]([CH3:13])(=[O:12])=[O:11])[O:14][CH3:15])=[CH:4][CH:3]=2)=[CH:27][CH:28]=1)=[O:19]
Reactant: CON(Cc1ccc(Br)cn1)S(C)(=O)=O
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CON(Cc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 16 %

Procedure:
To a stirred solution of N-(5-Bromo-pyridin-2-ylmethyl)-N-methoxy-methane sulfonamide (0.2 g, 0.678 mmol) in N-Methyl-2-pyrrolidone (8 mL) is added and 2,2-Difluoro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)ethyl]-acetamide (0.27 g, 0.678 mmol). Reaction mixture is degassed with nitrogen for 15 minutes then added tris(dibenzylideneacetone)dipalladium(0) (0.06 mg, 0.068 mmol) and Tri-2-furylphosphine (0.03 g, 0.136 mmol) simultaneously. The resulting reaction mixture is stirred at 80° C. for 5 hours. Diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash using 50% ethyl acetate in hexane as an eluent to afford the title compound (0.05 g). 1HNMR (400 MHz, DMSO-d6) δ: 3.16 (s, 3H), 3.49 (s, 3H), 4.30-4.37 (m, 1.5H), 4.41-4.46 (m, 0.5H), 4.46 (s, 2H), 4.54-4.56 (m, 0.5H), 4.65-4.68 (m, 0.5H), 4.89 (m, 1H), 5.94 (d, J=4.2 Hz, 1H), 6.20 (t, J=53.76 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.16 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 8.14-8.16 (dd, J1=2.32 Hz, J2=8.16 Hz, 1H), 8.86 (d, J=8.72 Hz, 1H), 8.91 (d, J=2.08 Hz, 1H). LCMS (m/z): [M+H]=461.9.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: BrCCBr
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 ml) at r.t. The mixture was stirred for 1 hour at this temperature and 1,2-dibromethane (5 ml) was added. The reaction mixture was stirred overnight and ethyl acetate (100 ml) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 ml) and brine (20 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 ml) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 ml) to remove the excess of 1,2-dibromoethane; the crude product was washed from the silica with acetone (120 ml). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 628 mg (43%). 1H-NMR (400 MHz, d6-DMSO) δ=3.61 (t, J=6.2 Hz, 2H), 4.30 (t, J=6.4 Hz, 2H), 6.64 (d, J=9.0 Hz), 7.74 (d, 9.0 Hz, 2H), 8.97 (s, 2H). LRMS (FAB+):292.0 (100, [M+H]+)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=[C:11]([N+:31]([O-])=O)[CH:10]=1)=[O:8]>CN(C=O)C.C(O)(=O)C.[Pd]>[NH2:31][C:11]1[CH:10]=[C:9]([C:7](=[O:8])[NH:6][C:2]2[NH:3][CH:4]=[CH:5][N:1]=2)[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:20])[NH:14][C:13]=2[CH:12]=1
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cc([N+](=O)[O-])cc2[nH]1)c1cc2ccccc2cn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Reaction time: 3 h
Yield: 103.1 %

Procedure:
0.1 g (0.2 mmol) of isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-6-nitro-1H-benzoimidazol-2-yl]-amide (Example 129) was suspended in a mixture of 2 mL of DMF and 5 mL of acetic acid. To this stirring solution, −20 mg of 10% Pd on carbon was added, and the resulting mixture was hydrogenated at 42 psi of H2 at room temperature for 3.0 h. The reaction mixture was filtered, and the solid was washed with 5 mL of DMF. The filtrate and washings were combined and evaporated to reduce the volume to 10 mL, then diluted with saturated NaHCO3 (10 mL), and extracted with ethyl acetate. The organic layer was washed with water and brine and evaporated to provide 85 mg (91%) of isoquinoline-3-carboxylic acid [6-amino-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 413 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(=O)C.[K+].O>CO.Cl[Pd]Cl>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:4]=[CH:3][C:2]([F:6])([F:5])[F:1])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(F)(F)F
Reactant: Ic1ccc(OCc2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: FC(F)(F)C=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
At 130° C., 96 g of 3,3,3-trifluoropropene, 155 g of 1-benzyloxy-4-iodobenzene, 68.5 g of potassium acetate and 0.85 g of PdCl2 in 750 ml of methanol were reacted in an autoclave for 20 hours. After cooling to room temperature, the reaction mixture was mixed with water and extracted with ether. The combined organic phases were washed with water, dried and concentrated to give the title product as a colourless crystalline powder, which was reacted further without any purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:11]2([CH2:32]O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=3)[C:24]([O:26][CH3:27])=[O:25])[C:12]2=[O:31])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[O:31]=[C:12]1[C:11]2([C:3]3=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=[C:2]3[O:1][CH2:32]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[CH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1cccc(CN2C(=O)C(CO)(c3cc4c(cc3O)OCO4)c3ccccc32)c1
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: COC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)c1
Yield: 73 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using methyl 3-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained as a white powder in 73% yield; 1H NMR (300 MHz, CDCl3) δ 7.97-7.95 (m, 2H), 7.53-7.50 (m, 1H), 7.45-7.40 (m, 1H), 7.21-7.15 (m, 2H), 7.04-6.99 (m, 1H), 6.73-6.71 (m, 1H), 6.52 (s, 1H), 6.20 (s, 1H), 5.86 (s, 1H), 5.18 (d, 1H), 4.72 (d, 1H), 4.80 (d, 1H), 4.69 (d, 1H), 3.89 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 177.7, 166.6, 156.0, 149.0, 142.4, 141.7, 136.1, 132.2, 131.7, 130.9, 129.2, 128.1, 124.0, 123.7, 119.4, 109.2, 103.1, 101.6, 93.7, 80.5, 64.3, 58.3, 52.3, 43.7; MS (ES+) m/z 430 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][C@@H:7]1[CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2].[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.C(OCC)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C:9]2([O:19][CH2:18][CH2:17][O:12]2)[CH2:8][C@H:7]1[CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2]
Reactant: CCCC[C@H]1CC(=O)CC[C@H]1C(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: CCCC[C@@H]1CC2(CC[C@@H]1C(=O)OCC)OCCO2

Procedure:
cis-2-Butyl-4-oxocyclohexane carboxylic acid ethyl ester (9.0 g; 40 mmole), ethylene glycol (2.73 g; 44 mmole) and p-toluenesulphonic acid (100 mg) were refluxed in benzene 80 ml) using a Dean-Stark water trap. After 12 hours the mixture was cooled, diluted with diethyl ether and washed with saturated aqueous sodium bicarbonate followed by water. Drying over MgSO4 and evaporation gave a liquid (10.80 g; 100%) which was pure enough to use directly. Found: C, 66.71; H, 9.79. C15H26O4 requires C, 66.64; H, 9.69%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl.[CH3:44][NH:45][O:46][CH3:47]>C(Cl)Cl>[CH3:44][N:45]([O:46][CH3:47])[C:12](=[O:14])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CNOC
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CC(=O)N(C)OC)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.1 %

Procedure:
(3,4-Dimethoxyphenyl)acetic acid (13.0 g, 66.4 mmol) was suspended in anhydrous CH2Cl2 followed by addition of EDCI (15.3 g, 79.7 mmol), HOBt (20.6 g, 152 mmol), triethylamine (8.06 g, 79.7 mmol), and N,O-dimethylhydroxylamine hydrochloride (6.48 g, 66.4 mmol). The reaction was stirred 3 days at ambient temperature after which the solvent was evaporated at reduced pressure. The residue was partitioned between EtOAc and water. The organic layer was washed with aq. HCl, sat NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo to give 10.5 g (66%) of N-methyl-N-methoxy-(3,4-dimethoxyphenyl)acetamide as a pale brown oil.