Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[N:14][C:15]([C:17](=[N:19]O)[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:5][CH:4]=1.[Cl-].[NH4+]>CO.CC(O)=O.[Zn]>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[N:14][C:15]([CH:17]([NH2:19])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cnc3cc(C(C)=NO)ncc32)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(Cn2cnc3cc(C(C)N)ncc32)cc1
Temperature: 60 °C
Yield: 65.6 %

Procedure:
A mixture of 1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethanone oxime (320 mg, 1.08 mmol), zinc (3.53 g, 54.00 mmol), and ammonium chloride (2.89 g, 54.00 mmol) in MeOH (10 mL) and HOAc (2 mL) was heated at 60° C. for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added an aqueous solution of ammonia (50 mL) and the resulting mixture was extracted with DCM (50 mL×3). The combined extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with CH2Cl2:MeOH:Et3N (10:1:0.2) to afford 200 mg (66%) of 1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethanamine as a colorless oil. MS (ESI): m/z=283.2[M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:20]([O:22]CC)=[O:21])=[CH:5]2.CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:20]([OH:22])=[O:21])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(C)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.5 %

Procedure:
To a mixed solution of ethyl 5-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.80 g) in tetrahydrofuran (15 mL)-methanol (15 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (0.65 g), and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (735 mg, yield 99%) as pale-yellow crystals. melting point>280° C. (decomposition).
Reaction SMILES: [CH:1]([NH2:3])=[O:2].C[O-].[Na+].CO.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[CH:23][N:22]([C:25]4[S:29][C:28](C(OC)=O)=[C:27]([O:34][C@@H:35]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]([F:46])([F:45])[F:44])[CH3:36])[CH:26]=4)[C:21]=3[CH:47]=2)[CH2:12][CH2:11]1>C1COCC1.C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[CH:23][N:22]([C:25]4[S:29][C:28]([C:1]([NH2:3])=[O:2])=[C:27]([O:34][C@@H:35]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]([F:45])([F:44])[F:46])[CH3:36])[CH:26]=4)[C:21]=3[CH:47]=2)[CH2:12][CH2:11]1
Reactant: NC=O
Reactant: COC(=O)c1sc(-n2cnc3ccc(CN4CCN(C)CC4)cc32)cc1O[C@H](C)c1ccccc1C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](Oc1cc(-n2cnc3ccc(CN4CCN(C)CC4)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Temperature: 20 °C

Procedure:
Formamide (1.08 mL, 26.5 mmol) followed by 25% w/w sodium methoxide in MeOH (1.82 mL, 7.6 mmol) are added to a solution of methyl 5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (5.0 g, 8.95 mmol) in THF (50 mL) and toluene (10 mL) at room temperature. The reaction mixture is heated at ca 65° C. for about 18 h and then cooled to ca 30° C. The reaction mixture is diluted with EtOAc (25 mL) and H2O (25 mL) and then the biphasic mixture is separated. The organic phase is washed sequentially with H2O (25 ml), saturated aqueous Na2CO3 and finally H2O (2×25 mL). The organic phase is then concentrated by rotary evaporation and the concentrate diluted with EtOAc (30 mL) and then heated at ca 70° C. for about 1 h. The resulting suspension is then cooled to about 20° C. and stirred at this temperature for ca 18 h. The suspension is then stirred at 0-5° C. for 2 h and the product, isolated by filtration, washed with EtOAc (5 mL) and dried under vacuum at ca 25° C. to constant weight (2.93 g, 60.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[C:14]([F:23])=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>N1C=CC=CC=1>[Cl:12][C:13]1[C:14]([F:23])=[C:15]([S:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8](=[O:9])(=[O:10])[NH2:11])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(Cl)c1F
Reaction time: 12 h
Yield: 19.6 %

Procedure:
2-Aminobenzenesulfonamide (54 mg, 0.31 mmol) and 3-chloro-2-fluoro-benzenesulfonyl chloride (47 mg, 0.21 mmol) were dissolved in pyridine (1 ml) and the reaction mixture was stirred for 12 h. The solvent was removed in vacuo and the residue was purified by HPLC to give the product (15 mg, 19%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[N:12][C:11]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(Cl)Cl>[CH2:15]([O:14][C:11]1[N:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=1)[CH:16]=[CH2:17]
Reactant: C=CCOc1cnc(NC(=O)OC(C)(C)C)cn1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1cnc(N)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A solution of 5-allyloxy-pyrazin-2-yl-carbamic acid tert-butyl ester (400 mg, 1.59 mmol) in methylene chloride (2 mL) was treated with a 25% solution of trifluoroacetic acid in methylene chloride (5 mL). The mixture was stirred at 25° C. for 90 min, poured with stirring into a saturated aqueous sodium bicarbonate solution (50 mL) and then sodium chloride (3 g) was added. The resulting mixture was extracted with methylene chloride (3×25 mL), and each of the organic extracts was washed with a small portion of a saturated aqueous sodium chloride solution. The combined organic extracts were dried over potassium carbonate, filtered, and concentrated in vacuo to afford 5-allyloxy-pyrazin-2-ylamine (240 mg, 100%) as pale yellow crystals.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:31]([CH3:32])=[CH:30][C:18]2[N:19]=[C:20]([O:22]CC3C=CC=CC=3)[S:21][C:17]=2[C:16]=1[Br:33])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]>CCOC(C)=O.CCO.[Pd]>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:31]([CH3:32])=[CH:30][C:18]2[N:19]=[C:20]([OH:22])[S:21][C:17]=2[C:16]=1[Br:33])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: Cc1cc2nc(OCc3ccccc3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc2nc(O)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of (S)-2-(2-(benzyloxy)-7-bromo-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (67A), Pd/C (800 mg) in EtOAc/EtOH (10 ml, 1:1) was charged into a flask with H2 balloon, and stirred at rt for 1 h. The reaction mixture was filtered over celite, concentrated down, purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give 67B (850 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:30]2[CH2:31][CH2:32][N:27]([C:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:26])[CH2:28][CH2:29]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 25 °C
Yield: 1362.5 %

Procedure:
A solution of N-benzyl-5-bromo-2-nitrobenzenamine (50 mg, 0.16 mmol) and phenyl(piperazin-1-yl)methanone (93 mg, 0.48 mmol) in NMP (1 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish (4-(3-(benzylamino)-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (520 mg, 2.18 mmol), 92% yield. 1H NMR (500 MHz, CDCl3) d (ppm) 8.85 (m, 1H), 8.14 (d, J=9.5 Hz, 1H), 7.51-7.3 (m, 10H), 6.24 (dd, J=2.5 Hz, 10 Hz, 1H), 5.88 (d, J=2.5 Hz, 1H), 4.55 (d, J=5 Hz, 2H) 3.9-3.2 (m, 8H).+ESI HRMS (calcd for C24H24N4O3Na, M+Na) 439.1746, found 439.1741
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:30][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[C:14]([CH3:15])=[C:13]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:28])([F:27])[F:29])(=[O:24])=[O:25])=[CH:19][CH:18]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(Cc2ccc(S(=O)(=O)C(F)(F)F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1Cc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reaction time: 15 h
Yield: 89.5 %

Procedure:
To a solution of [6-fluoro-3-methyl-4-(4-trifluoromethanesulfonyl-benzyl)-naphthalen-2-yl]-acetic acid methyl ester (395 mg, 0.87 mmol) in tetrahydrofuran (15 mL) was added a solution of lithium hydroxide monohydrate (208 mg, 8.7 mmol) in water (3 mL) at room temperature. The resulting clear solution was stirred for 15 hours. Then, the tetrahydrofuran was removed under vacuum and the residue was diluted with water (10 mL). The aqueous solution was acidified with 1.0 N hydrochloric acid and the organic compound was extracted into ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (50 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum provided 343 mg (90%) of [6-fluoro-3-methyl-4-(4-trifluoromethanesulfonyl-benzyl)-naphthalen-2-yl]-acetic acid as a white solid. mp=200-201° C.: 1H NMR (300 MHz, DMSO-d6) δ ppm 12.45 (br. s, 1 H), 8.04 (d, J=8.4 Hz, 2 H), 7.96 (dd, J=9.1, 6.0 Hz, 1 H), 7.81 (s, 1 H), 7.69-7.80 (m, 1 H), 7.48 (d, J=8.4 Hz, 2 H), 7.29-7.43 (m, 1 H), 4.71 (s, 2 H), 3.84 (s, 2 H), 2.30 (s, 3 H). ES(+)-HRMS cald. for C21H16F4O4S [(M+Na)+] 463.0597, obsd. 463.0598.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3]C1.C1(N)CCC1>>[CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Agent: NC1CCC1
Product: Cc1nc(NCc2ccccn2)nc(NC2CCC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using cyclobutanamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.60-1.68 (m, 2H), 1.83-1.96 (m, 5H), 2.108-2.15 (m, 2H), 2.20 (s, 3H), 4.26-4.32 (m, 1H), 4.62 (bs, 2H), 7.28 (t, J=6.4 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.76 (t, J=5.9 Hz, 1H), 8.47 (d, J=4.4 Hz, 1H); MS (ESI) m/z 284.2 (M+1)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11](Cl)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)([OH:3])=[O:2].[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N1CCNCC1)C1C=CC=CC=1.Br.BrCCN.CC(C)([O-])C.[K+]>C(O)C.O.C(N(CC)CC)C>[C:1]([CH2:4][CH2:5][NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([NH:34][CH2:33][CH2:32][N:29]2[CH2:30][CH2:31][N:26]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)([OH:3])=[O:2]
Reactant: NCCN1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)CCNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: NCCBr
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)CCNC(=O)c1ccc(NCCN2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1

Procedure:
8.2 g of 4-chloro-3-nitro-benzoic acid-[N-(2-carboxy-ethyl)-amide](prepared from 4-chloro-3-nitro-benzoylchloride and β-alanine-methylester and subsequent saponification with 48% hydrobromic acid), 6.6 g of 2-(4-benzyl-piperazino)-ethylamine (prepared from 1-benzyl-piperazine and 2-bromo-ethylamine-hydrobromide in ethanol with the addition of potassium tert.butoxide), 4.2 ml of triethylamine and 25 ml of water are heated over a steam bath for 8 hours. The mixture is evaporated down and purified by column chromatography (silica gel; methylene chloride/methanol/glacial acetic acid=8:2:0.1 to 2:1:0.1). Yield: 9.2 g (67% of theory), Rf value: 0.47 (silica gel; methylene chloride/methanol/conc. ammonia=8:2:0.1)
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][C:18]([C:20]1[N:21]=[C:22]2[N:27]([C:28](=[O:38])[C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:25][O:24][C:23]2([CH3:40])[CH3:39])=[O:19])(=O)=O.[CH3:41][S-:42].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:10]([CH2:16][NH:17][C:18]([C:20]2[N:21]=[C:22]3[N:27]([C:28](=[O:38])[C:29]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][CH2:25][O:24][C:23]3([CH3:39])[CH3:40])=[O:19])=[C:9]([C:8]#[C:7][CH2:6][S:42][CH3:41])[CH:14]=1
Reactant: C[S-]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCOS(C)(=O)=O)c(OCc1ccccc1)c2=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCC#Cc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of intermediate 183, 3-[2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenyl]prop-2-ynyl methanesulfonate (0.160 g, 0.28 mmol) in N,N-dimethylformamide (3 ml) was treated at 0° C. with sodium thiomethoxide (0.026 g, 0.37 mmol) and the resulting mixture stirred for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.114 g (78% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.64 (6H, s, 2×CH3), 2.28 (3H, s, SCH3), 3.45 (2H, s, SCH2), 4.05 (4H, m, 2×CH2), 4.69 (2H, d, J=6.1 Hz, NCH2), 5.31 (2H, s, OCH2), 6.98 (1H, m, aromatic), 7.15 (1H,dd, J=3 Hz and J=9.1 Hz, aromatic), 7.32–7.38 (4H, m, aromatics), 7.50–7.53 (2H, m, aromatics), 7.80 (1H, broad t, NH). HRMS (ESI+) calculated for C28H29FN3O4S [M+H+]: 522.1863. found: 522.1844.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:12][C:13]2[C:14]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=3)(=[O:26])=[O:25])=[N:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1.CCO.C(O)=O.C([O-])=O.[K+]>C1COCC1>[NH2:33][C:29]1[CH:28]=[C:27]([S:24]([NH:23][C:14]2[C:13]([NH:12][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([NH2:9])[CH:6]=3)=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Agent: O=C[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=CO
Solvent: C1CCOC1
Product: COc1cc(N)cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(N)c2)c1
Temperature: 60 °C
Yield: 93.3 %

Procedure:
N-(3-(3-Methoxy-5-nitrophenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide (400 mg, 0.81 mmol), prepared as described above in Example 115, was dissolved in 1:1 THF:EtOH (4 mL), to which was added formic acid (938 μl, 2.42 mmol) and potassium formate (203 mg, 2.42 mmol). The system was flushed with nitrogen, and then 10% wt Pd/C (50 mg) was added. The reaction was then heated to 60° C. Once the reaction was determined complete by LC-MS, it was allowed to cool, and DMF was added for solubility. The solution was then filtered through a nylon frit to remove the catalyst. The filtrate was diluted water and the pH adjusted to 7 and extracted with DCM (2×) and EtOAc (2×). All organic layers were combined and evaporated to dryness to give 3-amino-N-(3-(3-amino-5-methoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide (330 mg, 93%). MS (EI) m/z for C21H20N6O3S: 437.06 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:4].[CH3:34][NH:35][NH2:36]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[CH:24]=[C:25]([CH:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[N:35]([CH3:34])[N:36]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(=O)C1CCOCC1
Reactant: CNN
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CCOCC2)n(C)n1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-[3-oxo-3-(tetrahydro-pyran-4-yl)-thiopropionyl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with methylhydrazine (CAS Reg. No. 60-34-4) to give the title compound as colorless foam. MS (ESI): m/z=502.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]2[N:20]=[CH:19][C:18]([CH:21]([CH2:24][C:25]3([CH:28]([F:30])[F:29])[CH2:27][CH2:26]3)[CH2:22][NH2:23])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][CH:21]([C:18]1[CH:19]=[N:20][C:15]([CH:12]2[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH2:24][C:25]1([CH:28]([F:29])[F:30])[CH2:27][CH2:26]1)=[O:6]
Reactant: NCC(CC1(C(F)F)CC1)c1ccc(C2CC2)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(CC1(C(F)F)CC1)c1ccc(C2CC2)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-3-(1-difluoromethyl-cyclopropyl)-propylamine. LCMS (MH+): m/z=439.1, tR (minutes, Method G)=2.09
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:16][CH:15]([NH:17][C:18](=[O:34])[CH2:19][NH:20][C:21]3[C:25]4[CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:24]=4[O:23][N:22]=3)[CH2:14]2)[CH2:9][CH2:8]1)(C)(C)C.Cl>C1COCC1>[OH:6][CH:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH2:14][CH:15]([NH:17][C:18](=[O:34])[CH2:19][NH:20][C:21]3[C:25]4[CH:26]=[C:27]([C:30]([F:32])([F:33])[F:31])[CH:28]=[CH:29][C:24]=4[O:23][N:22]=3)[CH2:16]2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(O)CC2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-{1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-azetidin-3-yl}-2-(5-trifluoro-methyl-benzo[d]isoxazol-3-ylamino)-acetamide (as prepared in Example 8, 20 mg, 0.033 mmol) in THF (2 mL) was added 1 N HCl (200 L) and stirred at RT for 1.5 hours. The reaction was quenched with 1 N NaOH to pH=10 and then extracted with EtOAc and dried over anhydrous Na2SO4, filtered and concentrated to give the title product.
Reaction SMILES: CC([S@@]([NH:7][C@H:8]([C:10]1[CH:24]=[CH:23][C:13]2[N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:15]=[N:16][C:12]=2[CH:11]=1)[CH3:9])=O)(C)C.[ClH:25].CCOC(C)=O>CCOC(C)=O>[ClH:25].[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N:14]1[C:13]2[CH:23]=[CH:24][C:10]([C@@H:8]([NH2:7])[CH3:9])=[CH:11][C:12]=2[N:16]=[CH:15]1
Reactant: C[C@H](N[S@@](=O)C(C)(C)C)c1ccc2c(c1)ncn2C1CCCCO1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](N)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 124 (3 g, 8.58 mmol) in EtOAc (10 mL) was added HCl/EtOAc (25 mL, 2 M in EtOAc) dropwise and stirred at RT. When the reaction was complete the reaction mixture was filtered, the solid was collected and washed with EtOAc to afford 2 g (83%) of (1S)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanamine hydrochloride (126) as a white solid.
Reaction SMILES: [C:1]([N:11]1[CH2:31][CH2:30][C:14]2[N:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][C:21]=3[C:13]=2[CH2:12]1)(OCC1C=CC=CC=1)=O.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:43][CH2:42]C(O)[O:40]2)=[CH:35][CH:34]=1>>[CH:37]1[C:36]([CH:39]([OH:40])[CH2:43][CH2:42][CH2:1][N:11]2[CH2:12][C:13]3[C:21]4[CH:20]=[C:19]([F:22])[CH:18]=[CH:17][C:16]=4[N:15]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[C:14]=3[CH2:30][CH2:31]2)=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=1
Reactant: OC1CCC(c2ccc(F)cc2)O1
Reactant: O=C(OCc1ccccc1)N1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1
Product: OC(CCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1)c1ccc(F)cc1

Procedure:
A process of claim 4 which further comprises hydrogenation of said 2-carbobenzoxy-8-fluoro-5-(p-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole over a noble metal catalyst in the presence of substantially one molar equivalent of 2-(p-fluorophenyl)-5-hydroxytetrahydrofuran, at 0°-75° C. in a reaction-inert solvent to form flutroline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: Cc1cc(N)ccn1
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Cc1cc(Nc2nc(-c3cc(Br)ccc3F)nc3nccnc23)ccn1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-amino-2-methylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.