Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([NH2:18])=[O:17])[CH2:11]1)=O)(C)(C)C.S(=O)(=O)(O)O>CO.O1CCOCC1>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([NH2:18])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCCN(C(N)=O)C1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CO
Product: NCC1CCCN(C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
3-(tert-Butoxycarbonylaminomethyl)piperidine-1-carboxamide (150 mg, 0.583 mmoles) (prepared as described in Preparative Example 241, Step A above) was dissolved in methanol (3 mL). 10% conc. sulfuric acid in 1,4-dioxane (7.9 mL) was added and the mixture was stirred at 25° C. for 1 h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH− form) was added until the pH was basic. The resin was filtered off, washed with methanol, evaporated to dryness and chromatographed on a silica gel column (15×2 cm) using dichloromethane followed by 15% (10% conc, ammonium hydroxide in methanol)-dichloromethane as the eluant to give the 3-(aminomethyl)piperidine-1-carboxamide (80 mg, 87%): FABMS: m/z 158.1 (MH+); HRFABMS: m/z 158.1294 (MH+). Calcd. for C7H16N3O: m/z 158.1293; δH (CDCl3+drop CD3OD) 1.20 (1H, m, CH2), 1.48 (1H, m, CH2), 1.60 (1H, m, CH), 1.68 (1H, m, CH2), 1.83 (1H, m, CH2), 2.64 (bm, 2H, —CH2NH2), 2.82 (1H, m, CH2), 3.02 (1H, m, CH2), 2.98 (2H, m, CH2), 3.70 (1H, m, —CH2NH2), 3.78 (1H, m, —CH2NH2) and 5.24 ppm (1H, bs, NH); δc (CDCl3+drop CD3OD) CH2: 24.1, 28.6, 44.0, 44.8, 47.9; CH: 38.3; C: 159.0.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]([OH:11])=O)[N:5]=[N:4][N:3]=1.Cl.[CH3:13][O:14][NH2:15].C(N(CC)CC)C.Cl>CN(C)C=O>[CH3:13][O:14][NH:15][C:9](=[O:11])[CH2:8][CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: CON
Reactant: O=C(O)CCn1nnnc1S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CONC(=O)CCn1nnnc1S
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
To an ice cold and stirred solution of 5-mercapto-1H-tetrazole-1-propionic acid (1.04 g) in N,N-dimethylformamide (60 ml) is added N,N'-carbonyldiimidazole (1.16 g). After stirring for 15 minutes at 0° C., the mixture is mixed with a solution of methoxyamine hydrochloride (600 mg) and triethylamine (720 mg) in N,N-dimethylformamide (6 ml) and stirred for 1 hour at 0° C. The reaction mixture is poured into diluted hydrochloric acid and extracted with a mixture of ethyl acetate and methyl ethyl ketone (2:1). The solvent is evaporated from the extract to leave crystalline 5-mercapto-1H-tetrazole-1-propionohydroxamic acid methyl ester (1.2 g). mp. 170°-171° C. (decomp.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:43])=[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[O:25])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[C:44](Cl)(=[O:46])[CH3:45].ClCC(NC1N=C2C(C3C=CC=C(C(F)(F)F)C=3)=C(C)C(C3N(C4C=CC(C#N)=CC=4)N=CC=3)=CN2N=1)=O>>[C:44]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:24]([NH:23][C:21]2[N:22]=[C:17]3[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=4)=[C:15]([CH3:43])[C:14]([C:13]4[N:9]([C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=5)[N:10]=[CH:11][CH:12]=4)=[CH:19][N:18]3[N:20]=2)=[O:25])[CH2:32][CH2:31]1)(=[O:46])[CH3:45]
Reactant: CC(=O)Cl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCNCC3)nc2c1-c1cccc(C(F)(F)F)c1
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Product: CC(=O)N1CCC(NC(=O)Nc2nc3c(-c4cccc(C(F)(F)F)c4)c(C)c(-c4ccnn4-c4ccc(C#N)cc4)cn3n2)CC1

Procedure:
The title compound was prepared from 1-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-piperidin-4-yl-urea (Ex. 50, 50 mg, 0.085 mmol) and acetyl chloride (80 mg, 0.102 mmol) using a similar method to that employed for Intermediate 17 (30 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16](=O)/[CH:17]=[CH:18]/[N:19](C)C)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.Cl.[F:25][C:26]([F:32])([F:31])[CH2:27][CH2:28][NH:29]N>CCO>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[N:29]([CH2:28][CH2:27][C:26]([F:32])([F:31])[F:25])[N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Reactant: NNCCC(F)(F)F
Agent: Cl
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1ccnn1CCC(F)(F)F
Temperature: 80 °C
Yield: 76 %

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude above, 1.73 g, 5.41 mmol, 1 eq.) in EtOH (10 mL) was added (3,3,3-trifluoropropyl)hydrazine dihydrochloride (1.30 g, crude above, 6.49 mmol, 1.2 eq.) at rt. The mixture was heated at 80° C. for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO3(sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridine (1.58 g; 76% for 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J=4.7, 1.6 Hz, 1H), 7.96-7.88 (m, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.29 (dd, J=7.9, 4.7 Hz, 1H), 6.34 (d, J=1.9 Hz, 1H), 4.62 (s, 2H), 4.45-4.33 (m, 2H), 2.82-2.61 (m, 2H), 0.85 (s, 8H), −0.00 (s, 5H). LRMS (M+H+) m/z 386.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(C(C)C)CC)(C)C.CO[C:18]1[CH:25]=[C:24](OC)[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C(#N)C>[CH2:20]([NH:21][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2])[C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:18]=1
Reactant: C=CCCCBr
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCNCc1ccccc1
Yield: 40.2 %

Procedure:
0.397 ml of 5-Bromo-1-pentene (3.35 mmol) and 0.67 ml of diisopropyl ethylamine (3.96 mmol) were added to the reaction solution containing 0.74 ml of benzylamine (a) (4.93 mmol) dissolved in acetonitrile with stirring and the mixture was stirred at room temperature for overnight. The reaction mixture was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with EtOAc solvent as an eluant to give 236 mg of the pure title compound (b) (yield: 44%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH2:19])[CH2:14]1)[C:8]([CH3:20])=[N:7]2.[CH3:21][C@@H:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[NH2:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][C@H:13]([NH:12][C:9]2[C:8]([CH3:20])=[N:7][C:6]3[C:11]([N:10]=2)=[C:2]([C:28]2[NH:27][C:26]4[C@@H:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=4[CH:29]=2)[CH:3]=[CH:4][CH:5]=3)[CH2:14]1
Reactant: Cc1nc2cccc(Br)c2nc1N[C@H]1CCC[C@@H](N)C1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1N[C@H]1CCC[C@@H](N)C1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
A mixture of (1S,3R)—N1-(8-bromo-3-methylquinoxalin-2-yl)cyclohexane-1,3-diamine (483b, 1.62 g, 4.83 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705, 2.53 g, 9.65 mmol), dichlorobis(p-dimethylaminophenylditbutylphosphine)palladium (II) (0.171 g, 0.24 mmol), and potassium phosphate (3.07 g, 14.48 mmol) in 1,4-dioxane (38.6 mL)/water (9.65 mL) was sparged with nitrogen for 3 min and was stirred at 80° C. for 45 min. The reaction mixture was diluted with water (200 mL), added to a separatory funnel, and extracted with 3:2 chloroform/IPA (5×100 mL); the combined organic layers were separated, dried over Na2SO4, and concentrated. The crude product in 10% MeOH/DCM was loaded onto the column and was purified via automated flash chromatography (silica gel) with 100% DCM to 50% 2 M ammonia in MeOH/DCM to give (R)-2-(3-4(1S,3R)-3-aminocyclohexyl)amino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (483, 1.59 g, 4.07 mmol, 84% yield) as a brown amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.16 (m, 1H) 1.29-1.42 (m, 3H) 1.43 (d, J=6.65 Hz, 3H) 1.82 (d, J=11.15 Hz, 2H) 1.99-2.18 (m, 3H) 2.55 (s, 3H) 2.82 (t, J=10.27 Hz, 1H) 3.33 (br. s., 1H) 4.04-4.14 (m, 1H) 4.56 (q, J=6.52 Hz, 1H) 7.03 (s, 1H) 7.13 (br. s., 1H) 7.34 (t, J=7.82 Hz, 1H) 7.60 (dd, J=7.92, 1.08 Hz, 1H) 7.64 (s, 1H) 7.86-7.91 (m, 1H) 12.08 (br. s., 1H). MS (ESI, pos. ion) m/z: 391.1 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[NH:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[CH2:23][C:24]1[N:25]([CH3:29])[N:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:29][N:25]1[C:24]([CH2:23][O:20][C:13]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]3[CH:9]=[N:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]=3[N:12]=2)=[N:28][CH:27]=[N:26]1
Reactant: Cn1ncnc1CCl
Reactant: O=c1[nH]c2c(cnn2-c2ccccc2)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(cnn2-c2ccccc2)c2ccccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture of 3,4-dihydro-3-phenyl-5H-pyrazolo[3,4-c]isoquinolin-5-one (0.10 g, 0.38 mmol), 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (0.10 g, 0.57 mmol) and cesium carbonate (0.37 g, 1.14 mmol) in dry DMF (2 ml) was stirred at 60° C. under nitrogen for 3 h. Water (30 ml) was added and the mixture was filtered. The solids were washed with diethyl ether (5 ml) and dried in vacuo to give the title compound (0.10 g, 74%) as an off-white powder, m.p. 149-151° C. Found: C, 66.19; H, 4.46; N, 23.71. C20H16N6O.0.25(H2O) requires C, 66.56; H, 4.61; N, 23.29%. δH (400 MHz; CDCl3) 3.98 (3H, s), 5.82 (2H, s), 7.36 (1H, dd, J=7 and 7), 7.52-7.57 (3H, m), 7.83 (1H, dd, J=7 and 7), 7.94 (1H, s), 8.15-8.20 (3H, m), 8.33 (1H, d, J=8), 8.42 (1H, s); m/z (ES+) 356 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O-])=O.Cl.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[N:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)cc1N1CCNCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(N2CCCC2)cc1N1CCNCC1

Procedure:
A mixture of 1-nitro-2-piperazinyl-4-pyrrolidinylbenzene (4.57 g), ethanol (110 ml), hydrochloric acid (1.2 N, 6 ml) and palladium on carbon (10%, 1 g) is exposed to hydrogen 51 psi at 20°-25° in a Parr flask. After 16 h (49 psi total uptake) the mixture is filtered. Basic workup (chloroform, potassium carbonate) and column chromatography silica gel (50 g) eluting with chloroform/methanol (4/1) gives the title compound as an oil, IR (nujol) 3315, 2947, 2816, 1512, 1258, 1001 and 753 cm-1 ; NMR (CDCl3) 1.8-2.0, 2.9-3.2, 6.52 and 6.6-6.8 δ; MS (electron impact) 246, 204 and 189.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:18])[C:15]([CH3:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:22][NH2:23]>CCO>[Br:18][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][C:15]=1[CH3:17])[O:10][CH2:9][C:8]1[N:7]2[CH:5]([CH3:6])[C:4](=[O:3])[NH:22][N:23]=1
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2cc(C)c(Br)cc21
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cc1Br)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Yield: 90.2 %

Procedure:
To a solution of 2-(6-bromo-7-methyl-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.192 g, 0.536 mmol) in EtOH (3 mL) was added anhydrous hydrazine hydrate (0.107 g, 2.144 mmol) and the mixture was heated at reflux for 4 h. The reaction mixture was cooled to ambient temperature and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 25% EtOAc in petroleum ether) to give 6-bromo-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as white solid (0.15 g, 90%). 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 7.46 (s, 1H), 7.02 (s, 1H), 4.86 (q, J=6.8 Hz, 1H), 4.60 (dd, J=12.8 Hz, 2H), 2.26 (s, 3H), 1.27 (d, J=6.8 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([NH:10][CH:11]([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)NC(=O)C1CCC(O)CC1
Product: CC(C)NC(=O)C1CCC(Oc2cccc(N)c2C#N)CC1

Procedure:
Prepared as in Example 22b from 4-hydroxy-N-isopropylcyclohexanecarboxamide (Example 45c) and 2-amino-6-fluorobenzonitrile as an off-white solid (17%). 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=6.4 Hz, 6H), 1.47-1.57 (m, 4H), 1.67-1.77 (m, 2H), 1.89-1.93 (m, 2H), 2.08-2.15 (m, 1H), 3.75-3.84 (m, 1H), 4.57 (brs, 1H), 5.93 (s, 2H), 6.19 (d, J=8.0 Hz, 1H), 6.28 (d, J=8.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H). MS 302 (MH+).
Reaction SMILES: [OH-].[K+].Cl[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][CH:5]=1.[F:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:20]=1[OH:27]>>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[O:16][CH3:17])[N:7]=[CH:6][CH:5]=[C:4]2[O:27][C:20]1[CH:21]=[C:22]([OH:26])[C:23]([CH3:25])=[CH:24][C:19]=1[F:18]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc(F)c(O)cc1O
Agent: [K+]
Agent: [OH-]
Product: COc1cc2nccc(Oc3cc(O)c(C)cc3F)c2cc1OC
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 22.2 %

Procedure:
Powdered potassium hydroxide (55 mg, 0.98 mmol) followed by 4-chloro-6,7-dimethoxyquinoline (200 mg, 0.89 mmol), (prepared as described for the starting material in Example 2), was added to 2-fluoro-5-hydroxy-4-methylphenol (600 mg, 4.2 mmol) heated at 130° C. and the mixture then stirred for 1.5 hours at 145° C. The mixture was allowed to cool then partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7 with 5M hydrochloric acid. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by preparative reverse-phase HPLC eluting with water/methanol (90/10 to 30/o) to give 6,7-dimethoxy-4-(2-fluoro-5-hydroxy-4-methylphenoxy)quinoline (65 mg, 22%) as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21](C=O)C.[CH2:25]([N:27]([CH2:50][CH3:51])[CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[C:34]([Cl:40])[CH:35]=[C:36](I)[CH:37]=2)[C:32]([OH:48])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])[C:31]1=[O:49])[CH3:26].C1(C)C=CC=CC=1>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2]>[CH2:25]([N:27]([CH2:50][CH3:51])[CH2:28][CH2:29][N:30]1[C:38]2[C:33](=[C:34]([Cl:40])[CH:35]=[C:36]([C:20]#[N:21])[CH:37]=2)[C:32]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:47])([OH:48])[C:31]1=[O:49])[CH3:26]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Cl)cc(I)cc21
Agent: [C-]#N
Agent: [Zn+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Cl)cc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To Pd2(dba)3CHCl3 (5.69 mg, 5 mol %) and triphenyIphosphine (5.76 mg, 20 mol %) under a nitrogen atmosphere was added anhydrous DMF (0.5 mL). The mixture was stirred at room temperature for 30 minutes to give orange/yellow mixture. To this was then added 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-chloro-6-iodooxindole (57.0 mg, 1.1×10−4 mol) followed by Zn(CN)2 (17.2 mg, 0.8 eq., 60%). The resulting suspension was heated to 60° C. (bath temperature) and stirred at that temperature for 3 hours. The mixture was allowed to cool and diluted with EtOAc:toluene (10 mL, 1:1). The mixture was washed with H2O (2×10 mL) and dried (anhydrous MgSO4). After filtration the solvent was removed in vacuo to give the crude title compound.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:27])[CH2:4][CH:5]([S:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C(O)C>C(Cl)Cl>[OH:1][NH:2][C:3](=[O:27])[CH2:4][CH:5]([S:16]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:36])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)NO)cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(S(=O)C(CCCCc2ccccc2)CC(=O)NO)cc1OC
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
To a solution of (±)-N-hydroxy-3-(3,4-dimethoxyphenyl)sulfanyl-7-phenylheptanamide (1.26 g, 3.24 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. is added m-CPBA (0.56 g, 3.24 mmol) in one portion. The mixture is stirred for 10 minutes after which TLC analysis indicated complete reaction. Ethanol (2 mL) is added and the mixture is partitioned between water (100 mL) and EtOAc (100 mL). Aqueous layer is extracted with EtOAc (2×50 mL) and combined organic phases are washed successively with 5% aqueous Na2S2O3 (50 mL), water (50 mL), 5% aqueous NaHCO3 (50 mL), water (50 mL) and brine (50 mL) then dried over MgSO4 and concentrated. The resulting yellow oil is chromatographed on silica gel (CH2Cl2 →2% MeOH/CH2Cl2 →5% MeOH/CH2Cl2) to afford 0.5 g of (±)-N-hydroxy-3-(3,4-dimethoxyphenyl)sulfinyl-7-phenylheptanamide (38%) as a mixture (2:1) of diastereomers in the form of a white foam. TLC analysis [CH2Cl2 /MeOH, 19:1, Rf (sulfide)=0.20, Rf (sulfoxide)=0.10]. 1H NMR (300 MHz, d6 -DMSO) δ 1.35-1.72 (m, 6H), 1.88-2.20 (m, 2H), 2.49 (m, 2H), 3.05 (m, 1H), 3.78 (br s, 6H), 7.0-7.18 (m, 6H), 7.22 (m, 2H), 8.80 (m, 1H), 10.49 (m,1H) ppm. Mass spectrum (FAB) m/z 406 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]3[CH:14]([CH2:15][CH2:16][CH:17]([O:30]C(=O)C)[CH2:18]3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+]>CO.ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[CH:19]3[CH:14]([CH2:15][CH2:16][CH:17]([OH:30])[CH2:18]3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C2=NC3CCC(OC(C)=O)CC3c3cc(OC)c(OC)cc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Product: CCCCOc1ccc(C2=NC3CCC(O)CC3c3cc(OC)c(OC)cc32)cc1
Reaction time: 19 h
Yield: 83 %

Procedure:
717 mg of (±)-acetic acid (2RS,4aRS,10bRS)-6-(4-butoxy-phenyl)-8,9-dimethoxy-1,2,3,4,4a,10b-hexahydrophenanthridin-2-yl ester (compound 14) are dissolved in 8 ml of methanol and 1 ml of dichloromethane, 259 mg of cesium carbonate are added and the mixture stirred for 19 h. The solvent is removed and the crude product is purified by flash chromatography (silica, ethyl acetate/triethylamine=9:1) to give 540 mg of the title compound as a colorless foam.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](O)=O)=[CH:5][C:4]([CH3:17])=[N:3]1.O=P(Cl)(Cl)[Cl:20].[NH4+].[OH-]>>[CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:9]([C:10]([Cl:20])=[C:5]2[C:4]([CH3:17])=[N:3]1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Nc2ccccc2C(=O)O)n(C)n1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nn(C)c2nc3ccccc3c(Cl)c12
Temperature: 0 °C

Procedure:
A mixture of N-(1,3-dimethyl-pyrazol-5-yl) anthranilic acid (7 g, 0.03 mol) and POCl3 (40 ml) is heated on a steam bath for 3 hours. The reaction mixture is then poured into ice water (600 ml) and then basified with NH4OH. The mixture is extracted with ether (3×200 ml), and the combined ether layers are dried over MgSO4 and evaporated to afford 7.0 g of 1,3-dimethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline, m.p. 127°-129° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](O)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[CH3:26][NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:26][N:27]([C:21](=[O:22])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:24])([F:25])[F:1])[CH:4]=3)=[CH:13][CH:12]=2)[CH2:15][CH2:16]1)[CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: CNCC(=O)OC
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Temperature: 25 °C

Procedure:
To a 20 mL scintillation vial was added the product from Example 26C (30 mg, 0.085 mmol), methyl 2-(methylamino)acetate (10.0 mg, 0.097 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30.0 μL 0.176 mmol). Following 4, hours of stirring at room temperature, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. The NMR spectrum includes a mixture of rotamers, with the major rotamer being reported. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.98-1.20 (m, 2 H), 1.38-1.55 (m, 2 H), 1.70-1.93 (m, 5 H), 2.20-2.33 (m, 2 H), 2.78-2.88 (m, 1H), 3.01-3.10 (m, 3 H), 3.64 (s, 3 H), 4.08 (s, 2 H), 7.03-7.19 (m, 1 H), 7.28-7.41 (m, 2 H), 7.66-7.76 (m, 2 H), 13.80-14.09 (m, 1H); MS (ESI) m/z 438 [M+H]f;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20]>>[CH:22]1([O:21][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)OC4CCCC4)cc23)CC1
Yield: 93.5 %

Procedure:
Beginning with 13 mg (0.0567 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 9.27 mg (0.062 mMol) cyclopentyl chloroformate, 18.1 mg (93%) of the title compound were recovered.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1.O.[NH2:19][NH2:20]>N1C=CC=CC=1>[NH:19]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1)[NH2:20]
Reactant: NN
Reactant: FC(F)(F)c1cccc(-c2cnc(Cl)nn2)c1
Solvent: O
Solvent: c1ccncc1
Product: NNc1ncc(-c2cccc(C(F)(F)F)c2)nn1
Temperature: 60 °C

Procedure:
A solution of 5.1 g. of 3-chloro-6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine in 30 ml. of pyridine is cooled to 0° C. and 3.5 ml. of hydrazine hydrate is added. The mixture is heated to 60° C., maintained at 60° C. for one hour, cooled and poured into ice-water. The resulting slurry is filtered and the solid is washed with ethanol giving 3-hydrazino-6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine as a yellow solid.