Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](N1CCCC(CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)C1)[CH3:2].[CH2:29]([O:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:55][CH3:56])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[C:36]([NH2:57])[N:35]=1)[CH2:30][CH2:31][CH3:32].ICC>>[CH2:29]([O:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:55][CH3:56])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]2[CH2:50][CH2:51][N:52]([CH2:1][CH3:2])[CH2:53][CH2:54]2)=[C:36]([NH2:57])[N:35]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCC3CCNCC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CCI
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-(butyloxy)-8-(methyloxy)-9-[6-(4-piperidinyl)hexyl]-9H-purin-6-amine and 2-iodoethane.
Reaction SMILES: [CH3:1][N:2]([S:28]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)(=[O:30])=[O:29])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25](O)=[O:26])[CH2:20][CH2:19]3)=[CH:15][N:16]=1)=[CH:8]2.[N:36]1(O)[C:40]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN.C(=O)([O-])O.[Na+]>CN(C)C=O.C1COCC1>[CH3:40][NH:36][C:25](=[O:26])[CH2:24][N:21]1[CH2:20][CH2:19][N:18]([CH2:17][C:14]2[S:13][C:12]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[N:2]([CH3:1])[S:28]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)(=[O:30])=[O:29])=[N:16][CH:15]=2)[CH2:23][CH2:22]1
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(-c3ncc(CN4CCN(CC(=O)O)CC4)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)CN1CCN(Cc2cnc(-c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.2 %

Procedure:
To a solution of {4-[(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)methyl]piperazin-1-yl}acetic acid (0.200 g) in N,N-dimethylformamide (10 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.061 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.087 g) and 2.0 mol/L solution of N-methylamine in THF (0.25 ml), and the mixture was stirred at room temperature for 15 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol), and recrystallized from ethyl acetate-hexane to give the title compound (0.150 g, yield 67%) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[H][H]>[C].[Pd].O1CCOCC1>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)(=[O:3])=[O:4]
Reactant: [H][H]
Reactant: CS(=O)(=O)Oc1ccc(N(Cc2ccc(OCc3ccccc3)cc2)S(C)(=O)=O)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CS(=O)(=O)Oc1ccc(N(Cc2ccc(O)cc2)S(C)(=O)=O)cc1
Yield: 92.3 %

Procedure:
A mixture composed of 350 mg of 4-[N-(4-benzyloxybenzyl)-N-methylsulfonylamino]phenyl methanesulfonate, 350 mg of 10% palladium-carbon, and 10 ml of dioxane was stirred for 2 days under an atmospheric pressure of hydrogen. The reaction mixture was filtered to remove any insoluble matter, and the solvent was distilled off from the filtrate. Thus, there was obtained 260 mg of 4-[N-(4-hydroxybenzyl)-N-methylsulfonylamino]phenyl methanesulfonate.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]=[CH:13][C:7]=3[C:6]=2[CH:14]=1.[CH:15]1[C:27]2[N:26]([C:28]3[CH:29]=[CH:30][C:31]4[NH:32][C:33]5[C:38]([C:39]=4[CH:40]=3)=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[K]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C(C)=CC=CC=1>[CH:14]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[O:9][C:5]=2[CH:4]=[CH:3][C:2]=1[N:32]1[C:31]2[CH:30]=[CH:29][C:28]([N:26]3[C:27]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:20]4[C:25]3=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2
Reactant: Ic1ccc2oc3c(c2c1)C=CCC3
Reactant: c1ccc2c(c1)[nH]c1ccc(-n3c4ccccc4c4ccccc43)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)oc1ccc(-n3c4ccccc4c4cc(-n5c6ccccc6c6ccccc65)ccc43)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
The 100 mL round bottom flask, equipped with magnetic stirrer and refluxed condenser, was charged with 8-iodo-3,4-dihydrodibenzo[b,d]furan (332 mg, 1 mmol), 3-(9-carbazolyl)carbazole (294 mg, 1 mmol), Pd(OAc)2 (23 mg, 10 mol %), P(t-Bu)3 (1 mL of 1M solution in toluene, 1 mmol), potassium tert-buthoxide (150 mg, 1.5 eq) and 100 ml of xylene. The flask was filled with nitrogen, and the reaction mixture was heated to reflux and stirred under nitrogen atmosphere for 24 hours. Then reaction was cooled down to room temperature, filtered through silica plug and evaporated. The residue was subjected to column chromatography on silica gel, eluent hexane/ethyl acetate mixture 9:1, providing 410 mg of 9-(dibenzo[b,d]furan-2-yl)-9H-3,9′-bicarbazole as white solid. The structure was confirmed by NMR and MS spectroscopy.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:13][C:12]=1[N+:24]([O-])=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7]>CO.[Pd]>[C:20]([O:19][C:17]([C:14]1[CH:13]=[C:12]2[C:11]([CH2:10][CH:4]([CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:3](=[O:2])[NH:24]2)=[CH:16][CH:15]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)CC(=Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1Cc2ccc(C(=O)OC(C)(C)C)cc2NC1=O

Procedure:
A solution of 2-(4-tert-butoxycarbonyl-2-nitro-benzylidene)-succinic acid dimethyl ester (5.0 g, 13.2 mmol) in methanol (40 mL) with 10% Pd/C was hydrogenated at 50 psi and 25° C. for 20 h. The reaction mixture was filtered to afford after evaporation in vacuo the title compound as a gray solid (3.56 g, 85%). NMR (dmso-d6, 200 MHz) : δ1.5 (s, 9H, tert-butyl), 2.7-3.4 (m, 5H, CH2CHCH2), 3.6 (s, 3H, CH3), 7.2-7.5 (m, 3H, ArH), 10.3 (s, 1H, NH).
Reaction SMILES: B[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.I[C:58]1[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[NH:60][N:59]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.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].O1CCCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([S:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[C:58]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[NH:60][N:59]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Ic1n[nH]c2ccccc12
Reactant: Bc1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2n[nH]c3ccccc23)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
A 25 mL scintillation vial was charged with N-(2-boranyl-4-chloro-phenyl)-4-tert-butyl-benzenesulfonamide (90 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (24 mg, 0.05 mmol), 3-iodo-1H-indazole (65 mg, 0.27 mmol), saturated aqueous sodium bicarbonate (1 mL), and tetrahydrofuran (1.5 mL). The reaction was stirred at 80° C. under nitrogen overnight. The following day, the reaction was cooled to room temperature and diluted with 10 mL of ethyl acetate. The solution was subsequently washed with saturated aqueous NaHCO3 and brine, and then concentrated to dryness. The crude product was purified by flash chromatograph to yield 23 mg of product: MS (ES) M+H expected 441.1, found 441.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)=O)[C:5](=[O:16])[N:4]2[C:17]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[NH:18][C:19](=[O:20])[C:3]=12.O.[NH2:27][NH2:28]>C(O)C.C(O)(=O)C.O>[N:27](=[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][N:11]=1)[C:6]1[C:5](=[O:16])[N:4]2[C:17]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[NH:18][C:19](=[O:20])[C:3]2=[C:2]([CH3:1])[CH:7]=1)[NH2:28]
Reactant: NN
Reactant: Cc1cc(C(=O)c2ccncn2)c(=O)n2c1C(=O)NC21CCCCC1
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(=NN)c2ccncn2)c(=O)n2c1C(=O)NC21CCCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 8′-methyl-6′-(pyrimidine-4-carbonyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3, 0.7 g, 2.07 mmol) in ethanol (4 mL), acetic acid (4 mL) and water (4 mL) is added hydrazine hydrate (0.13 g, 4.14 mmol). The reaction is stirred at 80° C. overnight. The reaction is cooled to room temperature and concentrated. The crude is resuspended in dichloromethane and is washed with saturated aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude is purified via column chromatography to afford 6′-(hydrazono(pyrimidin-4-yl)methyl)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (4).
Reaction SMILES: [Li]CCCC.[CH:6]1([S:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:11])=[O:10])[CH2:8][CH2:7]1.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25]Cl>C1COCC1>[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:6]1([S:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])(=[O:11])=[O:10])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Reactant: COCCOCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
BuLi 2.5 M in hexanes (7.53 ml) was added dropwise to the solution of tert-butyl (cyclopropylsulfonyl)carbamate (1.81 g) in THF (40 ml) at −78° C. This solution was stirred at −78° C. for 1 hour then 2-methoxyethoxymethyl chloride (1.85 ml) was added dropwise. The reaction was allowed to warm to room temperature and was stirred for 3 days. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate. At this point, HCl (1 M) was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (ISCO, 0 to 100% ethyl acetate in hexanes) to give the desired product (0.630 g) as a clear oil. LRMS (ES+) m/z 332.2 (M+Na)+.
Reaction SMILES: [C:1]1([C:7]2([C:10](O)=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[CH2:14][N:15]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN>CN(C=O)C.CO>[CH3:14][NH:15][CH2:10][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][CH2:8]1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: CNCC1(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.1 %

Procedure:
1-Phenylcyclopropanecarboxylic acid (2.95 g) was dissolved in DMF (120 mL). To the solution, EDC.HCl (5.2 g), HOBt (3.2 g), and a solution of methylamine in methanol (40%, 1.94 mL) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (50% ethyl acetate/hexane). An aliquot (1.1 g) of the obtained amide compound (2.9 g) was dissolved in THF (60 mL). To the solution, a solution of LAH in THF (2.4 M, 7.9 mL) was added dropwise at 0° C., and the mixture was heated to reflux at 80° C. for 12 hours. To the reaction mixture, water (4.0 mL) was gradually added dropwise at 0° C. The precipitate was removed by filtration and washed with THF (60 mL). Then, the combined filtrate was concentrated under reduced pressure to obtain the title compound (1.0 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]#[C:26][C:27](OC)=[O:28])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[NH2:31][OH:32].[OH-].[Na+].Cl>CO.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]4[O:32][N:31]=[C:27]([OH:28])[CH:26]=4)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C#Cc1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc2c(Cc3cccc(-c4cc(O)no4)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 45.1 %

Procedure:
To a solution of methyl [6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridin-2-yl]propynoate (73 mg) and hydroxylamine (50% aqueous solution, 18.2 mg) in methanol (1 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.166 mL), and this mixture was stirred at room temperature for 64 hours. To the reaction mixture were added water, ethyl acetate, and 2 mol/L hydrochloric acid (0.230 mL). The organic layer was separated. This organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (33 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 4.34 (2H, s), 6.51 (1H, s), 6.60-6.68 (1H, m), 6.87 (1H, d, J=2.3 Hz), 7.24-7.43 (3H, m), 7.44-7.54 (2H, m), 7.64-7.73 (1H, m), 7.76-7.87 (3H, m), 11.16 (1H, s), 11.47 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#N)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:24].[Na].[BH4-].[Na+]>CO.C(O)(=O)C.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:24])=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)c1ccc(Cl)nc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(CO)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.6 g (20 mmol) of 2-(6-chloro-pyrid-3-yl)-2-methylpropionitrile are introduced into 50 ml of toluene, and 25 ml of a diisobutylaluminum hydride solution (1M in toluene) is added dropwise without cooling, by means of which the internal temperature rises to 45° C. The mixture is stirred for 2 hours at room temperature. 10 ml of methanol, 50 ml of water and 90 ml of 2N sulfuric acid are then cautiously added successively, and the mixture is stirred for 2 hours at room temperature and finally for 2 hours at 50° C. The toluene phase is separated off and the solvent is removed. The residue is dissolved in 10 ml of methanol and a solution of 0.1 g of sodium and 0.4 g (10.6 mmol) of sodium borohydride in 10 ml of methanol are added. The mixture is stirred for 1 hour at room temperature and acidified with 0.7 g of acetic acid, and the solvent is removed. The residue is boiled with ethyl acetate, the ester phase is boiled off and the solvent is removed in vacuo. The oily crude product is distilled in a bulb tube; 0.15 mbar, apparatus temperature 170° C. Yield 2.5 g (67% of theory) of a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[Cl:22].O>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:23][C:18]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(Oc2ccc(Br)cn2)cc1Cl
Temperature: 90 °C
Yield: 99.5 %

Procedure:
To a solution of 2,5-dibromopyridine (2.412 g, 10.18 mmol) in DMF (50 mL) was added K2CO3 (5.22 g, 37.8 mmol) and 3,4-dichlorophenol (2.66 g, 16.3 mmol). The mixture was heated at 90° C. for 18 h then allowed to cool to room temperature (rt). Water was added and the mixture was extracted with DCM. Purification by FCC provided the desired product (3.23 g, 100%). 1H NMR (400 MHz, CDCl3): 8.21 (dd, J=2.5, 0.8 Hz, 1H), 7.81 (dd, J=8.3, 3.0 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.26 (d, J=1.5 Hz, 1H), 7.00 (dd, J=9.0, 2.5 Hz, 1H), 6.88 (dd, J=8.8, 0.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:32][C:33]#[N:34]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:33]#[N:34])=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCn1cc(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
To a stirred solution of 40 mg (0.101 mmol) of 1-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (the preparation of which has been described in example 18) in 5 ml DMF was added 4.2 mg (0.105 mmol) NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 8.3 mg (0.11 mmol) of chloro-acetonitrile was added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Preparative HPLC afforded 6 mg (14%) of {6-Chloro-3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetonitrile as a white solid.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[NH2:11]
Reactant: Nc1cccc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Br)ccc2ccccc12

Procedure:
To a solution of naphthalen-1-amine (10 g, 69.8 mmol) in N,N-dimethylformamide (50 mL) at 0° C. was added N-bromosuccinimide (12.4 g, 69.8 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture stirred for 1 hour before the addition of water (400 mL). The product was extracted with ethyl acetate (3×200 mL), and the combined ethyl acetate washes were extracted with brine (3×50 mL). The ethyl acetate was concentrated, and the crude material was purified by flash chromatography (0-20% ethyl acetate/hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.15-8.24 (m, 1 H) 7.73-7.82 (m, 1 H) 7.40-7.52 (m, 3 H) 7.07 (d, J=8.82 Hz, 1 H) 5.87 (s, 2 H); MS (APCI+) m/z 222.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=O.[K+].[Br-]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: COc1ccccc1C(=O)O
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1nc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 76 %

Procedure:
Prepared from 4-nitrophenylenediamine and 2-methoxybenzoic acid, in a manner similar to that of Example 9b. Yield: 76%; Rf (6/4 toluene/ethyl acetate): 0.43; IR (KBr): 3005, 1515, 1335, 750 cm−1.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:37][NH2:38]>CCCCCC>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:38][CH2:37][C:36]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:34]([O:33][CH3:32])[CH:35]=2)=[N:9][CH:10]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Solvent: CCCCCC
Product: COc1ccc(CNc2cc(C(Sc3ccc(Cl)cc3)c3cc(F)ccc3F)c(Cl)cn2)cc1OC
Temperature: 25 °C
Yield: 49 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (218 mg, 0.523 mmol) obtained in Example 54 and 3,4-dimethoxybenzylamine (400 μl) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (140 mg, 0.256 mmol, 49%) as an amorphous substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[C:18]3=[O:33])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:4][CH2:3]1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[N:19]([CH2:25][C:26]([OH:28])=[O:27])[C:18]3=[O:33])[S:11]([CH3:14])(=[O:13])=[O:12])[CH2:6][CH2:7]1
Reactant: CN1CCN(CCN(c2ccc3c(c2)C(=O)N(CC(=O)OC(C)(C)C)C3=O)S(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CCN(c2ccc3c(c2)C(=O)N(CC(=O)O)C3=O)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
To a solution of tert-butyl 2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (140 mg, 0.291 mmol) in dry DCM (4 ml) cooled to 0° C., TFA (0.449 ml, 5.83 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The volatiles were removed under vacuum and the crude residue was dried affording 2-(5-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid 2,2,2-trifluoroacetic acid salt (152 mg, 0.282 mmol, 97% yield, MS/ESI+ 424.8 [MH]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([O:25][C:26](=[O:29])[CH2:27]Br)[CH3:24]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:29])[N:11]=[C:10]([C:13]([F:14])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: FC(F)(F)c1cc(-c2ccc(Br)cc2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(Br)cc1
Temperature: 80 °C
Yield: 25.7 %

Procedure:
To 6 g of 34a in acetonitrile (150 mL) was added cesium carbonate (13.5 g, 41 mmol) followed by ethylbromoacetate (1.3 mL, 30 mmol) and the reaction mixture heated to 80° C. for 6 h. On completion, the solvent was removed, water (100 mL) added and the crude reaction mixture extracted with ethyl acetate (50 mL×3). Combined organic layer was washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using 10% ethyl acetate in hexane to afford 35 (2 g, 26%).