Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.Cl[C:44]([O:46][CH3:47])=[O:45]>ClCCl>[C:1]([C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([C:44]([O:46][CH3:47])=[O:45])[CH2:26][CH2:25]3)=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2ccccn2)CCN(Cc2cc(C(=O)NC3CCNCC3)c(=O)n3ccccc23)CC1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCC(NC(=O)c2cc(CN3CCC(C#N)(c4ccccn4)CC3)c3ccccn3c2=O)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-4-oxo-N-piperidin-4-yl-4H-quinolizine-3-carboxamide (0.027 g, 0.057 mmol) in 2 mL of dichloromethane was added triethylamine (0.3 mL, 2.1 mmol) followed by methyl chloroformate (0.10 mL, 1.3 mmol). After 1 h, the mixture was washed with 0.5 N aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound that gave a proton NMR spectra consistent with theory: 1H NMR (400 MHz, CDCl3) δ 9.80 (d, J=7.7 Hz, 1H), 9.40 (d, J=7.3 Hz, 1H), 8.65 (s, 1H), 8.60-8.58 (m, 1H), 8.19 (d, J=8.9 Hz, 1H), 7.76-7.66 (m, 2H), 7.62-7.59 (m, 1H), 7.32-7.23 (m, 2H), 4.24-4.21 (m, 1H), 4.03 (br s, 1H), 3.82 (s, 2H), 3.71 (s, 3H), 3.69-3.61 (m, 2H), 3.15-3.09 (m, 1H), 3.02-2.98 (m, 1H), 2.60-2.57 (m, 1H), 2.55-2.50 (m, 2H), 2.32-2.25 (m, 1H), 2.09-2.02 (m, 2H), 1.93 (br s, 1H), 1.59-1.52 (m, 1H), 1.40-1.37 (m, 2H), 1.06-1.01 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:8][C:6]1[C:5]([O:11][CH3:12])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1
Reactant: COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Br)nc1N
Temperature: 72.5 °C
Reaction time: 0.25 h

Procedure:
To a heterogeneous solution of 6-bromo-3-methoxy-2-nitropyridine (32) (2.32 g, 10 mmol) in of ethanol:water (40 mL, each) were added iron powder (2.8 g, 50 mmol), followed by ammonium chloride (2.64 g, 50 mmol) at room temperature. The resulting heterogeneous mixture was then stirred at 70-75° C. for 15 minutes, filtered through celite (when hot), washed with ethanol (2×50 mL) and solvent was then removed under reduced pressure. The residue upon dilution with water afforded a solid, which was isolated by filtration to give 2-amino-6-bromo-3-methoxypyridine (33). LCMS: purity: 95%, MS (m/z): 203 (MH+).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:12][CH:11]=1>CS(C)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C@@H:16]2[CH2:4][C@H:17]2[C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: CON(C)C(=O)/C=C/c1ccc(F)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CON(C)C(=O)[C@@H]1C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
In a 1 L three neck flask, DMSO (100 mL) was rapidly stirred as 60% sodium hydride in mineral oil (4.59 g, 115 mmol) was added in 1.5 g portions. After the foaming subsided, trimethylsulfoxonium iodide (25.2 g, 115 mmol) was added portion wise over a 1 h period, maintaining the temperature below 35° C. The reaction was stirred at rt for 30 min. A soln of (E)-3-(4-fluorophenyl)-N-methoxy-N-methyl acrylamide (8 g, 38.2 mmol) in DMSO (50 mL) was then added dropwise maintaining the temperature below 35° C. After 45 min, the reaction was then slowly quenched with sat'd ammonium chloride (25 mL). The solution was then diluted with EtOAc. The solution was washed with water, dried with brine, dried over magnesium sulfate, and concentrated to give trans-2-(4-fluorophenyl)-N-methoxy-N-methylcyclopropanecarboxamide as a clear oil (8.1 g, 95%). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.16-7.08 (m, 2H), 7.05-6.93 (m, 2H), 3.72 (s, 3H), 3.26 (s, 3H), 2.55-2.45 (m, 1H), 1.64 (ddd, J=9.2, 5.1, 4.3 Hz, 1H), 1.34-1.29 (m, 2H). LCMS: M+1=224.16.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>CN(C=O)C>[Cl:26][CH2:27][CH2:28][CH2:29][S:30]([N:23]1[CH2:24][CH2:25][CH:20]([C:11]2[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH:9]=3)[NH:13][N:12]=2)[CH2:21][CH2:22]1)(=[O:32])=[O:31]
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 5-(3-fluorophenyl)-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 15) (106 mg, 0.222 mmol) was reacted with 3-chloropropane sulfonyl chloride (34 uL, 0.275 mmol) in the presence of triethyl amine (124 uL, 0.888 mmol) in DMF (4 mL) to give 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:18][CH2:19][C:20]1[CH:36]=[CH:35][C:23]([C:24]([N:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH3:27])=[O:25])=[CH:22][C:21]=1[CH3:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:18][CH2:19][C:20]1[CH:36]=[CH:35][C:23]([C:24]([N:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH3:27])=[O:25])=[CH:22][C:21]=1[CH3:37])=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CNC(=O)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 69 %

Procedure:
3-Chlorobenzoyl chloride (61 mg, 0.35 mmol) and triethyl-amine (to pH9) were added to a solution of 4-aminomethyl-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide from Example E115.2 (100 mg, 0.35 mmol) in dichloro-methane (5 ml) at room temperature. The mixture was stirred for 1 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (101 mg, 69%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1([C:13]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(C(=O)O)CCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(C(=O)OCc2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[[[13-cyclohexyl-6-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepin-10-yl]carbonyl/amino]-cyclopentanecarboxylic acid. 1-(Tert-butoxycarbonyl)cyclopentanecarboxylic acid (3.37 g, 14.7 mmol) was dissolved in DMF (40 mL) and treated with Cs2CO3 (5.28 g, 16.2 mmol) and benzyl bromide (1.1 mL, 16.2 mmol), the mixture was stirred at rt overnight and then at 70° C. for 3 h. The reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (250 mL). The organic phase was washed with water (100 mL) and brine (100 mL); dried over Na2SO4, filtered and concentrated to afford benzyl 1-(t-butoxycarbonyl)cyclopentanecarboxylate as a white solid. A portion of the solid (1.4 g) was dissolved in CH2Cl2 (40 mL) and treated with TFA (5 mL) and stirred at rt overnight. The reaction mixture was concentrated in vacuo to afford the TFA salt of benzyl 1-aminocyclopentanecarboxylate as an off-white solid. LCMS: m/e 220 (M+H)+, ret time 1.30 min, column 3, 2 minute gradient. This solid was then dissolved in THF (20 mL) and dimethyl-4-morpholinyl]carbonyl]-N-[(methylamino)sulfonyl]-,7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-, (1.4 g, 4.2 mmol) was added followed by DMAP (1.54 g, 1.27 mmol) and HATU (2.4 g, 6.3 mmol). The mixture was stirred at rt for 48 h. Solvent was removed in vacuo. Water (100 mL) and AcOEt (100 mL) were added. The organic phase was separated, dried over Na2SO4 and purified using silica gel (AcOEt/Hex 10%-70%) to afford the benzyl protected cyclopentanecarboxylic acid, 1-[[[13-cyclohexyl-6-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepin-10-yl]carbonyl]amino]-, as a bright yellow solid (1.4 g). LCMS: m/e 700 (M+H)+, ret time 2.46 min, column 3, 2 minute gradient. The benzyl protected compound (578 mg, 0.8 mmol) was dissolved in a 1:1 mixture of THF/MeOH (10 mL) and treated with 1N NaOH (2 mL). The mixture was stirred at rt for 18 h. Same procedure was repeated with 822 mg of the benzyl protected compound and the reactions were reunited. HCl (1N) was added to pH=5 and the precipitated formed was collected by filtration to afford the title compound as a pale yellow solid (650 mg). A small portion was purified using reverse phase HPLC. 1HNMR (500 MHz, DMSO) δ 8.33 (br s, 1H), 8.30 (br s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.60-7.50 (m, 5H), 6.92 (br s, 1H), 5.15 (br s, 1H), 4.37 (br s, 1H), 4.22-3.05 (m, 6H), 2.75 (m, 1H), 2.50-1.10 (m, 24H). LCMS: m/e 610 (M+H)+, ret time 2.35 min, column 3, 2 minute gradient.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:13][OH:14])[CH2:8][CH2:7][CH2:6]2.C([Li])CCC.[CH2:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27](OC)=O)=[CH:25][CH:24]=1)[CH2:21][CH3:22].OS(O)(=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1=[N:13][O:14][C:27]([C:26]3[CH:31]=[CH:32][C:23]([CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=3)=[C:8]1[CH2:7][CH2:6]2
Reactant: CCCc1ccc(C(=O)OC)cc1
Reactant: COc1ccc2c(c1)CCCC2=NO
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2onc3c2CCc2cc(OC)ccc2-3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To 6-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 2, 0.483 g, 2.52 mmol) in 4 mL of THF, cooled to 0° C. was added butyllithium (2.5 M, 2.020 mL, 5.05 mmol) dropwise over a period of 3 min. The contents were stirred at 0° C. for 30 min. A solution of methyl 4-propylbenzoate (Preparation 9A, 0.3 g, 1.683 mmol) dissolved in 2 mL of THF was added over a period of 3 min. The pale yellow reaction mixture was allowed to come to room temperature and stirred for 20 min. at room temperature. To the reaction mixture was added 0.5 mL of conc. H2SO4 dropwise over a period of 3 min. at 0° C. The reaction was allowed to come to room temperature over a period of 10 min. and stirred at room temperature for 40 min. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (25 mL) and water (10 mL). The ethyl acetate layer was washed with sat. aq. sodium bicarbonate (15 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatography employing hexane/ethyl acetate. Product containing fractions were collected and concentrated to yield 7-methoxy-3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazole (0.355 g, 1.111 mmol, 66.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.93 (d, J=8.28 Hz, 1H) 7.69 (d, J=8.28 Hz, 2H) 7.30 (d, J=8.28 Hz, 2H) 6.83-6.91 (m, 2H) 3.86 (s, 3H) 2.95-3.06 (m, 4H) 2.61-2.68 (m, 2H) 1.62-1.74 (m, J=7.47, 7.47, 7.47, 7.47, 7.28 Hz, 2H) 0.97 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[NH2:13][CH2:14][CH2:15][OH:16]>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:13][CH2:14][CH2:15][OH:16])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: NCCO
Reactant: COC(=O)c1nc(Br)cnc1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)nc1C(=O)NCCO
Yield: 15 %

Procedure:
A solution of 3-amino-6-bromo-2-carbomethoxypyrazine (100 mg, 0.4 mmol ) and 2-aminoethanol (500 mg, 8.2 mmol ) in THF (5 mL) was heated at reflux for 2 days. The reaction mixture was cooled, diluted with ethyl acetate (20 mL), washed with water then brine, dried over sodium sulfate, filtered, and concentrated. The oily residue was purified by flash chromatography (silica gel, eluted with ethyl acetate-hexanes gradient from 15% to 80% yield) to give 3-amino-N-(2-hydroxyethyl)-6-bromo-pyrazine-2-carboxamide, a pale yellow oil, (108 mg, 96% yield) MS (EI) for C7H9BrN4O2: 262 (MH+).
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:15]2[NH:14][C:13](=S)[CH:12]([CH3:17])[N:11]=[C:10]([C:18]3[C:23]([CH2:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:26][CH3:27])[C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[OH:28][CH2:29][C:30]([NH:32][NH2:33])=O>>[CH2:1]([S:4][C:5]1[C:15]2[N:14]3[C:30]([CH2:29][OH:28])=[N:32][N:33]=[C:13]3[CH:12]([CH3:17])[N:11]=[C:10]([C:18]3[C:19]([CH2:26][CH3:27])=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][CH3:25])[C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCSc1cccc2c1NC(=S)C(C)N=C2c1c(CC)cccc1CC
Reactant: NNC(=O)CO
Product: CCCSc1cccc2c1-n1c(CO)nnc1C(C)N=C2c1c(CC)cccc1CC

Procedure:
In the manner given in Example 11, a solution of 1,3-dihydro-9-propylthio-3-methyl-5-(2,6-diethylphenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butylalchol was refluxed to give 10-propylthio-1-(hydroxymethyl)-4-methyl-6-(2,6-diethylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][C@@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C:35]3=[O:40])=[CH:30][CH:29]=2)[CH2:23]1>>[CH3:19][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[NH:20][CH2:21][C@@H:22]1[O:26][C:25](=[O:27])[N:24]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][C:35]3=[O:40])=[CH:30][CH:29]=2)[CH2:23]1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCCCC(=O)O)C(=O)OCc1ccccc1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Product: CN(CCCCC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)OCc1ccccc1

Procedure:
32 mg (0.119 mmol) of 5-[[(benzyloxy)carbonyl](methyl)amino]valeric acid are reacted as carboxyl component by General Procedure 1 with compound (B).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH2:11][N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[N:7]([C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH2:11][N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)[CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 5.7 g (14.1 mmol) [(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester, 676 mg (17 mmol) NaH (55%) in DMF was stirred for 20 minutes at room temperature and 1 h at 60° C. 3 g (21 mmol) iodomethane in DMF was added and the mixture was stirred at 60° C. for 1 h and evaporated. The residue was taken up in ethyl acetate and water, the organic layer washed with brine and back-extracted with ethyl acetate. The combined organic layers were dried with Na2SO4, filtered off and evaporated. The residue was taken up on isolute and subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 2.67 g (45%) of the title compound as light yellow oil. MS m/e: 419.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])=[C:6]([O:21][CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:5]=1.[OH-].[Li+].Cl>CO>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][CH2:22][O:21][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12])[C:3]([OH:28])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)Nc2cnc(C)cn2)c(OCCCN(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnc(NC(=O)Nc2ccc(C(=O)O)cc2OCCCN(C)C)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
To a stirred solution of 3-(3-dimethylamino-propoxy)-4-[3-(5-methyl-pyrazin-2-yl)-ureido]-benzoic acid methyl ester (1.0 gm; 3.3 mmol) in methanol (25 mL) was added lithium hydroxide (5 mL of a 2M aqueous solution). The reaction was heated to 60 degrees and stirred for 12 hours. The reaction was allowed to cool to room temperature and the pH was adjusted to 5.5 with 1N hydrochloric acid. A precipitate formed which was filtered and dried under reduced pressure to yield the desired product as a tan solid (52% yield). 1H-NMR (400 MHz, d6-DMSO) δ 8.62 (br s, 1H), 8.39 (d, 1H), 8.21 (s, 1H), 7.59 (d, 1H), 7.43 (s, 1H), 4.15 (t, 2H), 2.42 (m, 5H), 2.18 (s, 6H), 2.01 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH:9]1C)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][NH2:39])[CH:34]=[CH:35][CH:36]=1>>[CH:10]12[CH2:14][CH:13]([NH:8][CH2:9]1)[CH2:12][N:11]2[CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:39][CH2:38][CH2:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C
Reactant: NCCc1cccc(F)c1
Product: Fc1cccc(CCNc2nccc(-c3cccc(CN4CC5CC4CN5)c3)n2)c1

Procedure:
Intermediate 142 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 404. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.45 (s, 1H) 8.36 (d, 2H) 7.89 (d, 1H) 7.73 (t, 1H) 7.54 (d, 1H) 7.27 (q, 1H) 7.10 (m, 2H) 6.91 (t, 1H) 4.63 (q, 2H) 4.61 (d, 2H) 3.92 (m, 3H) 3.78 (d, 1H) 3.59 (t, 2H) 3.07 (t, 2H) 2.76 (d, 1H) 2.33 (d, 1H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)(=O)[CH3:2].[N+:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[CH2:15]2)([O-:11])=[O:10].N1CCCCC1>>[N+:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[C:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)[CH3:2])([O-:11])=[O:10]
Reactant: CC(=O)c1c[nH]cn1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Solvent: C1CCNCC1
Product: CC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
4-Acetylimidazole (0.7 g, 3.1 mmol) and 5-nitroindolin-2-one (0.56 g, 3.1 mmol) in sealed tube were heated in the presence of piperidine at 135° C. After 30 minutes, the reaction mixture was cooled to ambient temperature and concentrated. Recrystallization from ethanol afforded 0.66 g of 5-nitro-3-[1-(imidazol-4-yl)ethylidene]indolin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:18]=3[N+:25]([O-])=O)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].O1CCC[CH2:31]1.C(OCC)(OCC)OCC>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:17]4[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:18]=4[N:25]=[CH:31]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: NC(=O)c1sc(-n2cnc3ccc(C=O)cc32)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of the 1.00 g (2.49 mmole) of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2b), 40 mL of saturated aqueous ammonium chloride solution and 40 mL of tetrahydrofuran was added 1 g of zinc powder. The mixture was stirred room temperature for 15 minutes, then another 1 g of zinc powder was added. The mixture was stirred at room temperature for 15 minutes, then 1 g of zinc powder was added, and the mixture was stirred at room temperature for 15 minutes until the organic layer became straw yellow in color. Subsequent manipulations were performed under nitrogen. The mixture was filtered, and the filtrate was partitioned between 30 mL of saturated ammonium chloride solution and tetrahydrofuran (1:1). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a reddish yellow solid. The solid was mixed with 40 mL of acetic acid and 0.82 ml, (4.98 mmole) of triethyl orthoformate, and the mixture was stirred at room temperature for 30 minutes, during which time the mixture became mostly homogeneous. The mixture was filtered and the filtrate was poured into 200 mL of water. The precipitate was collected by filtration, washed with water and air-dried to give 0.73 g of 4-(3-chloro-phenyl)-2-(6-formyl-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.2a) as a pink solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:21])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18][CH3:19])([CH3:16])[CH2:8][CH:7]2O)([O-:3])=[O:2].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[N+:1]([C:4]1[C:5]([CH3:21])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH2:17][O:18][CH3:19])([CH3:16])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: COCC1(C)CC(O)c2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COCC1(C)C=Cc2c(C)c([N+](=O)[O-])c(C)c(C)c2O1
Yield: 99.1 %

Procedure:
To 10.1 g of 6-nitro-4-hydroxy-2-methoxymethyl-2,5,7,8-tetramethylchroman, 200 ml of benzene was added and 1.0 g of p-toluenesulfonic acid was added, followed by heating at reflux for 2 hours using a Dean-Stark apparatus. The reaction solution was poured into water and then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, 9.4 g of the objective oily compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[N:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(Cl)nn2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](Oc2cccnn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an argon purged solution of cis/trans-4-(6-chloro-pyridazin-3-yloxy)-cyclohexanecarboxylic acid ethyl ester (1:1) (1.30 g, 4.57 mmol) and triethylamine (0.64 ml, 4.57 mmol) in ethyl acetate (46 ml) was added palladium on charcoal 10% (0.097 g). The reaction mixture was purged with hydrogen gas and stirred under an atmosphere of hydrogen gas for 4 h at room temperature. The catalyst and the ammonium salts were removed by filtration over Decalite. The filtrate was concentrated in vacuo to give the title compound (1.09 g, 95%) as light yellow oil.