Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[CH:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[C:21]([I:30])[CH:20]=1)[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=O)#[N:2].P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:16][C:8]1[CH:9]=[C:10]([Cl:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=1[NH:6][C:4]1[C:24]2[C:19](=[CH:20][C:21]([I:30])=[C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:23]=2)[N:18]=[CH:17][C:3]=1[C:1]#[N:2]
Reactant: COCCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{[3-iodo-4-(2-methoxyethoxy)phenyl]amino}acrylamide (1.0 g, 1.80 mmol) in 35 mL of toluene was heated to reflux and phosphorous oxychloride (1.7 mL, 18.0 mmol) was added dropwise. The mixture was heated at reflux for 2 hours, and an additional 1.7 mL of phosphorous oxychloride was added. The mixture was continued to heat at reflux for 2 hours, and an additional 1.7 mL of phosphorous oxychloride was added and the reaction mixture was heated at reflux overnight. The reaction is then cooled to room temperature and water was added followed by 10 N sodium hydroxide. The mixture was stirred in an ice-bath for 30 minutes and the precipitate was collected by filtration, washed with methylene chloride to give 870 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-iodo-6-(2-methoxyethoxy)-3-quinolinecarbonitrile as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 3.41 (s, 3H), 3.81 (t, 2H), 3.87 (s, 3H), 4.34 (t, 2H), 7.40 (s, 1H), 7.78 (s, 1H), 7.88 (s, 1H), 8.43 (s, 1H), 8.45 (s, 1H), 9.85 (s, 1H); MS (ES) m/z542.1, 544.1 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.C(N(C(C)C)C(C)C)C.Cl.[CH2:24]([O:26][C:27](=[O:32])[C:28]([NH2:31])([CH3:30])[CH3:29])[CH3:25].O>CN(C)C=O>[CH2:24]([O:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[NH:31][C:11]([C:9]1[N:10]=[C:5]2[N:6]([N:7]=[C:2]([Cl:1])[CH:3]=[CH:4]2)[N:8]=1)=[O:13])[CH3:25]
Reactant: CCOC(=O)C(C)(C)N
Reactant: O=C(O)c1nc2ccc(Cl)nn2n1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NC(=O)c1nc2ccc(Cl)nn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
1.52 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylic acid and 1.45 ml of N-ethyldiisopropylamine were suspended in 15 ml of N,N-dimethylformamide; 1.37 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 3 hours. To the reaction mixture, 1.41 g of 2-aminoisobutyric acid ethyl ester hydrochloride was added, followed by stirring at room temperature for 4 hour. Water was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the crystal precipitated was washed with ethyl ether, collected by filtration and dried to yield 1.48 g of the title compound. The filtrate was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure to yield 450 mg of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)OCC1.[OH2:20].[OH2:21].O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Tl+3].C(Cl)Cl.Cl(O)(=O)(=O)=O>CO>[O:1]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:21])=[O:20])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [Tl+3]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)Cc1ccc(N2CCC(=O)CC2)cc1
Reaction time: 3 h
Yield: 17.1 %

Procedure:
1-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-ethanone (2.61 g, 10 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) was added to a solution of thallium trinitrate trihydrate (4.44 g, 10 mmol) (McKillop, A., Swann, B. P., Taylor, E. C. J. Am. Chem. Soc., 1971, 93, 4919) in methanol (40 mL) and methylene chloride (20 mL) containing perchloric acid (70%, 10 mL). After 5 hours at room temperature the precipitated thallium (I) nitrate was removed by filtration, and the filtrate was diluted with water (100 mL). The organic phase was separated, the aqueous layer was extracted with methylene chloride, and the combined organic phases were washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in concentrated hydrochloric acid (250 mL) at room temperature. After 3 hours the solution pH was adjusted to 5 by ˜28% ammonium hydroxide. The aqueous layer was extracted with methylene chloride, and the combined organic phases were washed with water, dried over sodium sulfate and concentrated. The product was purified by chromatography on silica gel with ethyl acetate/hexanes eluant to give the title compound as a pale yellowish solid (0.4 g, 17%); 1H NMR (300 MHz, DMSO-d6) δ 2.42 (t, J=6.0 Hz, 4H), 3.41 (s, 2H), 3.56 (t, J=6.0 Hz, 4H), 6.98 (d, J=8.7 Hz, 2H), 7.12 (d, J=8.7 Hz, 2H), 12.20 (s, 1H); MS (ES) m/z: 234.3 (MH+); HRMS Calcd. for C13H15NO3 (M+): 233.1052. Found: 233.1045.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([NH2:30])[CH:27]([CH3:29])[CH3:28]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:30][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 61.3 %

Procedure:
N-tert-Butoxycarbonylalanine (2.8 g, 15 mmol) and carbonyldiimidazole (2.75 g, 17 mmol) are stirred together in 30 mL of dry THF under nitrogen for 1 h. To this is added 3 mL (30 mmol) of isobutyl amine, and the mixture is stirred for one week. It is then concentrated, dissolved in ethyl acetate, and washed successively with 1 N KHSO4, water, and brine, and dries over Na2SO4. Concentration affords the title compound as a white solid (2.25 g, 9.2 mmol, 62%). 1H NMR (CDCl3) δ 6.27 (m, 1H), 5.02 (m, 1H), 4.13 (m, 1H), 3.08 (m, 2H), 1.77 (m, 1H), 1.45 (s, 9H), 1.35 (d, J=7 Hz, 3H), 0.90 (d, J=7 Hz, 6H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([Br:13])=[C:10]([Br:12])[N:11]=1.[CH2:22]=[O:23]>C1COCC1>[Br:12][C:10]1[N:11]=[C:7]([CH2:22][OH:23])[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]=1[Br:13]
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(CO)nc(Br)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
n-BuLi (3.16 mL of a 1.6 M solution in hexanes, 4.96 mmol) was added dropwise to a −78° C. solution of 2,4,5-tribromo-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (2.16 g, 4.96 mmol) in THF (50 mL). After 30 min, paraformaldehyde (0.74 g, 24.82 mmol) was added. The reaction mixture was warmed to RT, stirred overnight, quenched by addition of sat'd NH4Cl and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (5-60% EtOAc/hex) to afford the title compound (0.57 g, 302%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.44 (d, J=0.46 Hz, 2H), 4.74-4.88 (m, 2H), 3.49-3.69 (m, 2H), 0.88-1.02 (m, 2H), −0.13-0.22 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12](O)[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:15])[N:3]=1.S(Cl)(Cl)=O.ClC1C(C(Cl)C)=CC2C(=CC=CC=2Cl)N=1.[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:11]([CH:12]([N:39]2[C:35](=[O:45])[C:36]3[C:37](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:38]2=[O:40])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:15])[N:3]=1
Reactant: CC(O)c1cc2c(Cl)cccc2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(Cl)c1cc2c(Cl)cccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(c1cc2c(Cl)cccc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 55 °C

Procedure:
Added DCM (2 mL) to 1-(2,5-dichloroquinolin-3-yl)ethanol (200 mg, 826 μmol). Added thionyl chloride (301 μl, 4131 μmol). Obtained a clear colorless solution within minutes. Concentrated reaction mixture to dryness on the rotavap to obtain an oil, which was used without further purification. LC-MS (+esi, M+H+=260.0). Dissolved 2,5-dichloro-3-(1-chloroethyl)quinoline (215 mg, 825 μmol) in DMF (2 mL) and added phthalimide (127 mg, 866 μmol) and K2CO3 (228 mg, 1650 μmol). Submerged in oil bath and began heating to 55° C. After 10 min the temperature of the oil bath was raised to 80° C. After 30 more minutes the reaction mixture was partitioned between EtOAc:H2O. The organic layer was washed with water (3×), dried with sodium sulfate, filtered, and concentrated. The crude was solid was chromatographed on 12 g silica gel column with 0-20% EtOAc:Hex. The desired fractions were combined and concentrated to yield a white crystalline solid. 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 1.99 (d, J=7.04 Hz, 3 H) 5.93 (q, J=7.17 Hz, 1 H) 7.64-7.70 (m, 2 H) 7.71-7.76 (m, 2 H) 7.77-7.83 (m, 2 H) 7.88-7.93 (m, 1 H) 8.95 (s, 1 H). LC-MS (+esi, M+H+=371.0)
Reaction SMILES: [CH2:1]([Zn]CC)C.ClCI.[Si:9]([O:16][C:17](=[CH2:55])[CH2:18][O:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]2[C:31](=[O:32])[C:30]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:36][CH:35]=3)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]3[N:51]=[C:52]([CH3:54])[N:53]=[C:27]23)[CH2:22][CH2:21]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[Cl-].[NH4+]>C(Cl)Cl>[Si:9]([O:16][C:17]1([CH2:18][O:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([N:26]3[C:31](=[O:32])[C:30]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]5[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:35]=4)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]4[N:51]=[C:52]([CH3:54])[N:53]=[C:27]34)[CH2:24][CH2:25]2)[CH2:1][CH2:55]1)([C:12]([CH3:14])([CH3:15])[CH3:13])([CH3:11])[CH3:10]
Reactant: C=C(CO[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3nc(C)nc32)CC1)O[Si](C)(C)C(C)(C)C
Reactant: CC[Zn]CC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3(O[Si](C)(C)C(C)(C)C)CC3)CC2)c2nc(C)nn12
Reaction time: 0.17 h

Procedure:
To a solution (10 mL) of diethylzinc (1.0 M hexane solution, 5.3 mL) in methylene chloride was added a solution (5 mL) of chloro(iodo)methane (0.38 mL) in methylene chloride at 0° C., and the mixture was stirred at the same temperature for 10 min. A solution (5 mL) of 4′-[(4-{trans-4-[(2-{[tert-butyl(dimethyl)silyl]oxy}prop-2-en-1-yl)oxy]cyclohexyl}-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g) in methylene chloride was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.26 g, 52%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])C=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19][C:20](O)=O.N1CCCCC1>N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:15])([CH3:17])[CH3:16])[C:12]=1[OH:13])[CH:20]=[CH:19][C:18]([O:24][CH2:25][CH3:26])=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
Ethyl 3,5-di tert.butyl-4-hydroxycinnamate was prepared by heating a mixture of 33.0 grams of 3,5-di tert.butyl-4-hydroxybenzaldehyde, 55.0 grams of ethyl hydrogen malonate, 50 milliliters of pyridine, and 3 milliliters of piperidine at 90° to 95° C. for 7 hours. The reaction mixture was cooled to room temperature and the solid which precipitated was filtered off, washed with 5 percent hydrochloric acid, and dried. Thirty grams of product was obtained which melted at 149° to 152° C. Working up the filtrate yielded an additional 5.5 grams of product.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([N+:19]([O-])=O)[C:13]=1[OH:22])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:22])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of N-benzyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (180 mg, 0.52 mmol) in ethyl acetate, was added 10% Pd/C (70 mg). The mixture was flushed with argon, then stirred under a hydrogen atmosphere at balloon pressure for 1 hour at room temperature. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated to give the desired product (140 mg, 85%). 1H NMR (DMSO-d6): δ 8.73 (t, 1H), 7.24 (m, 5H), 6.78 (d, 1H), 4.09 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CC(=O)OC(C)(C)C)c1

Procedure:
To a solution of (3-methoxyphenyl)acetylchloride (25 g, 135 mmol), in dry dichloromethane (50 ml) was added t-butanol (14 ml) slowly with stirring. After stirring at room temperature for 5 minutes, the reaction was cooled in ice, and triethylamine (20 ml) added dropwise. After stirring a further 2 hours at room temperature, the reaction was poured into saturated aqueous sodium carbonate solution, extracted with dichloromethane, dried (MgSO4), solvents evaporated, and the residue chromatographed on silica (eluted 10% diethyl ether-petroleum ether bp 60°-80°), to give t-butyl (3-methoxyphenyl)acetate. 1H NMR (250 MHz, CDCl3) δ1.38 (9H, s), 3.42 (2H, s), 3.73 (3H, s), 6.69-6.82 (3H, m), 7.17 (1H, t, J=8.4Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)[C@H](C1C=CC=CC=1)O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C@H:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(Cc1ccc([N+](=O)[O-])cc1)NCc1ccccc1
Agent: O=C(O)[C@@H](O)c1ccccc1
Product: C[C@H](Cc1ccc([N+](=O)[O-])cc1)NCc1ccccc1
Yield: 24.6 %

Procedure:
A sample of 2.0 g (7.3 mmol) of 1-(4′-nitrophenyl)-2-benzylaminopropane (43) was reacted with 1.13 g (7.3 mmol) of (S)-(+)-mandelic acid to give 486 mg (49% based on enantiomeric abundance) of the free amine after workup. 1H NMR (CDCl3) δ□ 1.60 (d, 3H, J=6.3 Hz), 2.73-2.85 (m, 1H), 3.00-3.12 (m, 2H), 3.86 (dd, 2H, J=26 Hz, J=60 Hz), 7.23-7.40 (m, 5H), 7.30 (d, 2H, J=9.0 Hz), 8.14 (d, 2H, J=8.7 Hz); MS (APCI+) m/z (rel): 271 (100); [α]D=−9.3° (c=1.0 MeOH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:3]=1.[CH:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+].O>CC(C)=O>[Cl:8][C:6]1[N:7]=[C:2]([NH:26][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:5]=1
Reactant: O=[N+]([O-])c1cccc(Nc2nc(Cl)nc(Cl)n2)c1
Reactant: NC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)c1

Procedure:
To 158a (1.0008 g, 3.5 mmol) dissolved in acetone (20 mL) was added a solution of N-cycloheptylamine (0.45 mL, 3.5 mmol) in acetone (5 mL) followed by addition of 2.5 N NaOH (1.4 mL, 3.5 mmol) and water (3.5 mL). The reaction mixture was allowed to stir at reflux for 3 hours under nitrogen. The reaction mixture was extracted 2 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. After filtering, the sample was concentrated by rotary evaporation and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded a yellow solid (158b, 991 mg, 78%), mp 82° C.; HPLC: Inertsil ODS-3V C18, 40:10:50 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 54.5 min, 99.8% purity; MS (TOF MS ES+): m/z 440 (100), 365 (20.0), 363 (M+H, 53.2).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:13]2[O:18][CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>[Pd].CO>[CH3:1][C:2]1[N:3]=[C:4]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)[NH:5][C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1nc(C2CN(Cc3ccccc3)CCO2)[nH]c1-c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1nc(C2CNCCO2)[nH]c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Palladium on carbon (0.527 g, 0.495 mmol) was added to a solution of 2-(4-methyl-5-phenyl-1H-imidazol-2-yl)-4-(phenylmethyl)morpholine (1.65 g, 4.95 mmol) and hydrochloric acid (4.12 mL, 49.5 mmol) in CH3OH (80 mL) under nitrogen, and the reaction mixture was stirred under hydrogen for 2 hours at 25° C. TLC indicated that the starting material was consumed. The mixture was filtered, washing with EtOAc (50 mL) and CH3OH (50 mL), and concentrated. Water (80 mL) was added, and the resulting mixture was lyophilized to afford the title compound (980 mg) as a brown solid. LC-MS (ES) m/z=244 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])[N:10]=[C:9]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[C:8]=2[C:7]1=[O:30]>C(O)(C(F)(F)F)=O>[F:15][C:12]1[C:13]2[CH2:14][NH:6][C:7](=[O:30])[C:8]=2[C:9]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[N:10][C:11]=1[NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4ccco4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](Nc1nc(-c2ccco2)c2c(c1F)CNC2=O)C(N)=O

Procedure:
A solution of (R)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-4-(furan-2-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (93.1 mg, 0.188 mmol) in TFA (5 mL) was heated to 65° C. for 3 h. The solvent was removed and the resulting residue was diluted in MeOH/DCM (10 mL) and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (30%, 0.035% TFA). The collected fractions were stripped to dryness via rotary evaporation to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.97 (m, 6 H), 1.52-1.87 (m, 3 H), 4.38 (s, 2 H), 4.66-4.85 (m, 1 H), 6.61 (dd, J=3.54, 1.77 Hz, 1 H), 6.92-7.07 (m, 2 H), 7.36 (br s, 1 H), 7.79 (dd, J=1.64, 0.63 Hz, 1 H), 8.04 (dd, J=3.54, 0.51 Hz, 1 H), 8.32 (s, 1 H). [M+H] calc'd for C17H19FN4O3, 347; found, 347.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][C:11]([S:14]([C:17]1[CH:34]=[CH:33][C:20]2[N:21]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[C:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:23][C:19]=2[CH:18]=1)(=[O:16])=[O:15])([CH3:13])[CH3:12])(=O)=O>CN(C=O)C>[N:1]([CH2:13][C:11]([S:14]([C:17]1[CH:34]=[CH:33][C:20]2[N:21]([CH2:29][CH:30]3[CH2:31][CH2:32]3)[C:22]([CH2:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[N:23][C:19]=2[CH:18]=1)(=[O:16])=[O:15])([CH3:10])[CH3:12])=[N+:2]=[N-:3]
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)COS(C)(=O)=O)ccc2n1CC1CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)CN=[N+]=[N-])ccc2n1CC1CC1
Temperature: 160 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
To a solution of sodium azide (176 mg, 2.70 mmol) in N,N′-dimethylformamide (5 mL) was added 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropyl methanesulfonate (Step I, 411 mg, 0.90 mmol) in N,N′-dimethylformamide (3 mL) at room temperature. The mixture was stirred at 160° C. for 24 h. The mixture was washed with ethyl acetate (20 mL×3) and water (30 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:2 as eluent) to afford the title compound (265 mg) as a white amorphous.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([CH2:20]C)[CH:17]=[C:16]([CH2:22]C)[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>O.CCO.[Pd]>[CH3:20][C:18]1[CH:19]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:15]=[C:16]([CH3:22])[CH:17]=1
Reactant: CCc1cc(CC)cc(C2=CCN(Cc3ccccc3)CC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: O=CO
Product: Cc1cc(C)cc(C2CCNCC2)c1
Reaction time: 6 h
Yield: 83.3 %

Procedure:
1.24 g of 10% Pd on activated carbon were suspended in 15 mL of water, then a solution of 4.4 g (15.86 mmol) of 1-benzyl-4-(3,5-diethylphenyl)-1,2,3,6-tetrahydropyridine in 60 mL of EtOH was added followed by 1 mL of formic acid The resulting mixture was hydrogenated at 45 p.s.i. in a Parr apparatus for 6 h, then the catalyst was filtered off and the solvent was removed in vacuo. The resulting residue was taken up in water, basified with conc. NH4OH solution and extracted with CH2Cl2. The organic phase was dried and the solvent was removed in vacuo, yielding 2.5 g of the title compound, which was used without further purification.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.[N+](C1C=CC(CC[Br:38])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[BrH:38].[F:28][C:8]([F:7])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Br
Temperature: 90 °C

Procedure:
A mixture of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (13.0 g, 0.042 mole), p-nitrophenethyl bromide (11.7 g, 0.05] mole), sodium bicarbonate (18 g, 0.21 mole) and 0.01 g of KI in DMF (100 ml) was warmed at 90° C. for six hours. The reaction mixture was cooled, filtered and concentrated to an oil which was stirred with water then extracted with ether. The ether extracts were washed with water and dried (saturated MgSO4). The solution was filtered then concentrated to an oil (20 g). The oil was passed through a silica gel dry column using ethyl acetate as the eluent. The desired produce was extracted with ethyl acetate, filtered and concentrated to an oil (16 g) which was dissolved in ether, then converted to the hydrobromide salt (8 g, 35%, m.p. 98°-108°) by the addition of ethereal HBr. A 3.0 g. sample was recrystallized from a 20:1 solution of ethyl acetate/methanol to yield 3-[2-p-nitrophenylethyl)]-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)- 3-benzazepine hydrobromide (2.4 g, d 216°-217° C.).