Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C)CC1C=CC=CC=1.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C#N>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([C:1]#[N:2])=[O:18])=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN(C)Cc1ccccc1
Agent: C#N
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)C#N)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
A solution of 135 g (1 mole) of dimethylbenzylamine in 100 ml of toluene was added dropwise, at -20° C, while cooling, in the course of 30 minutes to a mixture of 170 g (1 mole) of para-methoxybenzoyl chloride and 50 g of anhydrous hydrocyanic acid in 400 ml of toluene at such a rate that the internal temperature did not rise above -20° C during the addition. When the addition was complete, the mixture was stirred for a further 10 minutes at -20° C and excess hydrocyanic acid was then distilled, under a waterpump vacuum, into a cooled receiver. The residue was recrystallized from a mixture of benzene and ligroin. In this way 128 g (77% of theory) of para-methyoxybenzoyl cyanide with a melting point of 63° C were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC=CC=1CCCC(OC)=O)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=1
Reactant: COC(=O)CCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: COC(=O)CCCc1ccccc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)CCCc1ccc(N)cc1
Yield: 41 %

Procedure:
A mixture of methyl 4-(4-nitrophenyl)butanoate and methyl 4-(2-nitrophenyl)butanoate (2.24 g, 10.03 mmol) and 0.2 g of 10% Pd/C in 40 mL of methanol was vigorously stirred under hydrogen air. The mixture was stirred for 4 h at room temperature (monitored by TLC), and filtered through Celite. The solvent was evaporated. The residue was purified by chromatography to give the title compound (0.80 g, 41%): NMR (400 MHz in CDCl3, Bruker AVANCE-400): δ 1.89 (m, 2H, CH2), 2.31 (t, 2H, CH2—CH2—COOMe), 2.53 (t, 2H, CH2), 3.58 (br, 2H, NH2), 3.65 (s, 3H, OMe), 6.61 (d, 2H, J=3.5 Hz, Ar—H), 6.95 (d, 2H, J=3.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[CH3:10].[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[CH2:18][Cl:17])=[C:3]([C:9]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)([OH:11])[CH3:10])[CH:4]=1
Reactant: CC(O)(c1ccco1)c1cc(Br)ccc1N
Reactant: O=C(Cl)CCl
Product: CC(O)(c1ccco1)c1cc(Br)ccc1NC(=O)CCl

Procedure:
Prepared from 1-(2-amino-5-bromophenyl)-1-(2-furyl)ethanol and chloroacetyl chloride generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.84 (s, 1H), 8.07 (d, J=8.76 Hz. 1H), 7.57 (bs, 1H), 7.50 (dd, J=2.33, 8,76 Hz, 1H), 7.12 (s, 1H), 7.09 (d, J=2.31 Hz, 1H), 6.46-6.42 (m, 2H), 4.35 (d, J=1.69 Hz, 2H), 1.85 (s, 3H); MS (ES) m/z 356/358 ([M−H]−, 100%).
Reaction SMILES: [Cs].[C:2]1([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][N:20]1[C:24](=[O:25])[C:23]2[C:26]([O:33][CH2:34][CH3:35])=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[CH:29][C:22]=2[S:21]1(=[O:37])=[O:36]>CN(C=O)C>[CH2:34]([O:33][C:26]1[C:23]2[C:24](=[O:25])[N:20]([CH2:19][O:13][C:12]3[N:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[N:9]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:11]=3)[S:21](=[O:37])(=[O:36])[C:22]=2[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[CH:27]=1)[CH3:35]
Reactant: CCOc1cc(OCC)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccccc1
Agent: [Cs]
Solvent: CN(C)C=O
Product: CCOc1cc(OCC)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 714.4 %

Procedure:
The cesium salt of 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole [prepared from 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole (0.714 g, 0.312 mmol) and Cs2CO3 (0.509 g, 0.156 mmol)] was suspended in DMF (20 ml) and treated with 2-chloromethyl-4, 6-diethoxy-1,2-benzisothiazol-3 (2H)-one 1,1-dioxide (0.5 g, 0.156 mmol). The reaction mixture was stirred at room temperature for 24 hours, then was poured onto ice-water and was extracted with ethyl acetate (300 mL). The organic layer was washed with water, then brine and then was dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography on silica gel eluting with CH2Cl2 to afford 0.57 g (71%) of 4,6-diethoxy-2-[1-phenyl-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CF3 ; R3 =H; R4 =OEt; R5 =6-OEt), m.p. 159°-160° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([NH:21][C@H:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:24]1[CH2:25][CH2:26][CH2:27][C@H:22]([NH:21][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[C:11]([C:9]4[NH:10][C:6]5[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=5[CH:8]=4)[CH:12]=[CH:13][CH:14]=3)[N:19]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(N[C@H]5CCCNC5)nc34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
A mixture of (S)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)amino)piperidine-1-carboxylate (78.0 mg, 0.169 mmol) and TFA (0.30 mL, 3.894 mmol) in DCM (1.5 mL) was stirred at 25° C. for 1 h. The mixture was concentrated in vacuo, and the residue was taken up in DMSO (2.0 mL) and purified by reversed-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) to provide (S)-2-(2-(piperidin-3-ylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (41.1 mg, 0.086 mmol, 51% yield) as a yellow-orange solid: 1H NMR (400 MHz, MeOH-d4) δ ppm 8.16 (1H, br. s.), 7.84 (1H, dd, J=7.5, 1.1 Hz), 7.69 (1H, d, J=7.6 Hz), 7.35-7.46 (1H, m), 7.25-7.34 (1H, m), 6.97-7.09 (1H, m), 4.33-4.45 (1H, m), 3.74 (1H, dd, J=12.3, 3.3 Hz), 3.64 (2H, t, J=7.1 Hz), 3.41 (1H, dt, J=12.7, 3.8 Hz), 3.04-3.16 (2H, m), 3.01 (2H, t, J=7.0 Hz), 2.26-2.35 (1H, m), 2.08-2.19 (1H, m), 1.90-2.04 (1H, m), 1.70-1.84 (1H, m). 19F NMR (377 MHz, MeOH-d4) δ ppm −77.49 (3F, s). m/z (ESI, +ve) 362.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[C:13]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:12][NH:11][N:10]=1)=[O:8].C=O.S([O-])([O-])(=O)=O.[Mg+2].[C:39]([BH3-])#N.[Na+].[OH-].[Na+].[Cl-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[C:13]([N:14]([CH3:39])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[CH:12][NH:11][N:10]=1)=[O:8]
Reactant: [BH3-]C#N
Reactant: COc1ccc(CNC(=O)c2n[nH]cc2NCc2cccc([N+](=O)[O-])c2)c(OC)c1
Agent: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)O
Product: COc1ccc(CNC(=O)c2n[nH]cc2N(C)Cc2cccc([N+](=O)[O-])c2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A solution of 1.61 g of 4-(3-nitrobenzylamino)-1H-pyrazole-3-carboxylic acid 2,4-dimethoxybenzylamide, 1.25 g of paraformaldehyde and 0.94 g of anhydrous magnesium sulfate in 70 ml of glacial acetic acid is stirred at room temperature for 4 hours. 1.23 g of sodium cyanoborohydride are then added portionwise to this solution. The reaction medium is stirred for 2 hours at room temperature, and then poured onto 300 ml of aqueous 5N sodium hydroxide solution and 120 g of crushed ice, the pH being adjusted to 11. 300 ml of saturated sodium chloride solution are then added. This solution is filtered and the solid is washed three times with 60 ml of distilled water. The solid thus collected is air-dried. 1.51 g of 4-[methyl(3-nitrobenzyl)amino]-1H-pyrazole-3-carboxylic acid 2,4-dimethoxybenzylamide are obtained in the form of a pale yellow solid. ([M+H]+): 426). RT: 3.87 min (Method A).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](O)=[O:30])([O-:21])=[O:20]>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N+:19]([O-:21])=[O:20])[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Product: O=C(Cc1ccccc1[N+](=O)[O-])Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2-nitrophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.30 (d, J=7.7, 1H), 8.09-7.95 (m, 4H), 7.94-7.87 (m, 1H), 7.73 (dt, J=7.6, 3.8, 1H), 7.63 (d, J=6.7, 1H), 7.59 (dd, J=11.2, 4.4, 1H), 4.13 (s, 2H), 3.86-3.79 (m, 4H), 3.14-3.04 (m, 4H); MS (ESI+) M/Z 410 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Br[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CN(C)C=O.C(OCC)(=O)C>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][O:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[CH:8][CH:9]=1
Reactant: BrCc1nc2ccccc2s1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 83.7 %

Procedure:
0.24 g of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 133.9 mg of 4-acetamidophenol in 2.7 ml of dimethylformamide, followed by the addition of a solution of 205.6 mg of 2-bromomethylbenzothiazole in 2 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 7 hours, after which the reaction mixture was diluted with ethyl acetate, washed with water, tried over sodium sulfate and the solvent removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 221.1 mg (yield 84%) of the title compound as a solid having a melting point of 168 to 170° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[N:34][C:33]([C@H:36]5[CH2:40][O:39]C(C)(C)[O:37]5)=[CH:32][N:31]=4)[C:26](=[O:43])[N:25]([CH3:44])[N:24]=3)[C:18]=1[CH2:45][OH:46])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl-].[NH4+]>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[N:34][C:33]([C@H:36]([OH:37])[CH2:40][OH:39])=[CH:32][N:31]=4)[C:26](=[O:43])[N:25]([CH3:44])[N:24]=3)[C:18]=1[CH2:45][OH:46])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cnc([C@H]3COC(C)(C)O3)cn2)c1=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cnc([C@H](O)CO)cn2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
To a solution of (S)-6-tert-butyl-2-(3-(5-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one (99 mg, 0.16 mmol) in tetrahydrofuran (4 mL) was added hydrochloric acid (1.0 N, 4 mL) and the resulting mixture stirred at room temperature overnight. The reaction mixture was poured into a saturated ammonium chloride solution and extracted with dichloromethane (2×50 mL). The combined organic layers were dried over magnesium sulfate. The mixture was filtered and evaporated and the residue recrystallized from dichloromethane and isopropyl acetate to give 6-tert-butyl-2-(3-{5-[5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-8-fluoro-2H-phthalazin-1-one (15.4 mg, 17%) as an off white solid: Mp. 218-224° C.; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (s, 10H) 3.44-3.95 (m, 5H) 4.32-4.82 (m, 4H) 5.40 (d, J=4.91 Hz, 1H) 7.22-7.99 (m, 5H) 8.16-8.65 (m, 3H) 8.78 (s, 1H) 9.81 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([CH:14]2[CH2:18][O:17]C(C)(C)[O:15]2)=[O:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1>C(O)(=O)C>[OH:15][CH:14]([CH2:18][OH:17])[C:12]([NH:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([NH2:1])[CH:3]=1)=[O:13]
Reactant: CC1(C)OCC(C(=O)Nc2cc(N)cc([N+](=O)[O-])c2)O1
Solvent: CC(=O)O
Product: Nc1cc(NC(=O)C(O)CO)cc([N+](=O)[O-])c1

Procedure:
A mixture of 0.915 g (3.3 mmole) of N-(3-amino-5-nitrophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxamide in 20 ml of 50% acetic acid was heated on a steam bath for 1 hour then stored over a weekend. The solvents were removed in high vacuum to afford the product, N-(2,3-dihydroxypropionyl)-3-amino-5-nitroaniline, as an oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH:18]([CH3:20])[CH3:19])[CH2:13][C@H:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH3-][C:36]#N.[Na+]>CO.O>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([CH:18]([CH3:20])[CH3:19])[CH3:36])[CH2:13][C@H:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)c2ccc(Br)cc2)C1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)c2ccc(Br)cc2)C1
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
The above derivative (118ba) (1.96 g) was dissolved in MeOH (15 ml) prior to the addition of 37% formaldehyde in water (1.41 ml). After 10 min, NaBH3CN (708 mg) was added. After 2 h, the reaction was concentrated. EtOAc was added and the organic layer was washed with H2O, brine, dried, filtered, and concentrated to give [(1S,2R,4R)-2-(4-Bromo-benzenesulfonylmethyl)-4-(isopropyl-methyl-amino)-cyclohexyl]-carbamic acid benzyl ester (1.9 g), MS found: (M+H)+=539.3
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH2:3][NH2:4].[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]>>[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[CH3:26])=[CH:22][CH:23]=1)([O:14][CH3:15])=[O:13]
Reactant: COC(=O)/C=C/c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Product: COC(=O)/C=C/c1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1

Procedure:
This was prepared in an identical manner to the compound described in Example 1 using 2-hydroxy-2-(3-chlorophenyl) ethanamine (5.45 g) and 4-{(E)-2-carbomethoxyethenyl}phenylpropan-2-one (7.11 g). The resulting oil was chromatographed on Kieselgel 60. Elution with 5% methanol-chloroform gave the title compound, 9.8 g τ (CDCl3) 8.9 (3H, d, J=6 Hz), 6.8-7.5 (7H, m, 2H disappears with D2O), 6.25 (3H, s), 5.4 (1H, m), 3.6 (1H, d, J=16 Hz), 2.5-2.9 (8H, m), 2.35 (1H, d, J=16 Hz).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:31])[C:5]2[N:6]=[CH:7][N:8]([C@@H:11]3[O:15][C@H:14]([CH2:16][CH:17]([P:25](=[O:28])([OH:27])[OH:26])[S:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@H:13]([F:29])[C@H:12]3[OH:30])[C:9]=2[N:10]=1.OO.S([O-])([O-])=[O:35].[Na+].[Na+]>O>[NH2:1][C:2]1[NH:3][C:4](=[O:31])[C:5]2[N:6]=[CH:7][N:8]([C@@H:11]3[O:15][C@H:14]([CH2:16][CH:17]([P:25](=[O:27])([OH:26])[OH:28])[S:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:35])[C@@H:13]([F:29])[C@H:12]3[OH:30])[C:9]=2[N:10]=1
Reactant: O=S([O-])[O-]
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CC(Sc3ccccc3)P(=O)(O)O)[C@@H](F)[C@H]2O)c(=O)[nH]1
Agent: OO
Agent: [Na+]
Solvent: O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CC(S(=O)c3ccccc3)P(=O)(O)O)[C@@H](F)[C@H]2O)c(=O)[nH]1
Temperature: 90 °C
Yield: 76.9 %

Procedure:
Compound 35.17 (15 mg, 0.032 mmol) was suspended in 3 mL water, and treated with 30% hydrogen peroxide (100 mL). The mixture was heated to 90° C. for 3 h and sodium sulfite (113 mg, 0.9 mmol) was added to quench the peroxide. The solvent was removed under reduced pressure and the residue was subjected to a reverse phase HPLC to give compound 35.18 (12 mg, 77% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11].CC(C)([O-])C.[K+].[Cl-].[NH4+]>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:18][CH2:17][C:16]2[CH:15]=[CH:14][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:20][CH:19]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)c1ccc(CO)cc1
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(COc2ccc(Br)cn2)cc1
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 30.7 %

Procedure:
A solution of 2,5-dibromopyridine (474 mg, 2.00 mmol) and 4-(methanesulfonyl)benzyl alcohol (372 mg, 2.00 mmol) in tetrahydrofuran (5 mL) was cooled to −15° C. under N2 and potassium tert-butoxide (1.0M in tetrahydrofuran, 2.2 mL, 2.20 mmol) was added dropwise over 10 minutes. The mixture was stirred at 0° C. for 5.5 hours, poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (210 mg, yield 31%).
Reaction SMILES: [N:1]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH:2]1[C:14]([O:16][CH3:17])=[O:15].C[Si](C)(C)N[Si](C)(C)C.[K].FC(F)(F)S(O[CH2:44][CH3:45])(=O)=O>C1COCC1>[CH2:44]([C:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:3][N:4]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[CH2:5][CH2:6][N:1]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH3:45]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Product: CCC1(C(=O)OC)CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
Following the procedure according to WO 2005/079799 (the disclosure of which is hereby incorporated by reference with respect to this synthesis), 1-benzyl 4-tert-butyl 2-methyl piperazine-1,2,4-tricarboxylate (II-JJ, 1.1 g, 2.9 mmol) was dissolved in 6 mL of dry THF and cooled to −78° C. Potassium hexamethyldisilazane (0.5M solution in toluene, Aldrich, 10 mL, 5.0 mmol) was added by syringe, and the reaction mixture stirred at −78° C. for 75 min. Ethyl trifluoromethanesulfonate (0.65 mL, 5.0 mmol) was added dropwise by syringe to this mixture, and then the reaction was allowed to warm to rt for 5 h. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted twice with ethyl acetate. The combined organics were dried with MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (0-10% methanol/DCM gradient elution) gave 1-Benzyl 4-tert-butyl 2-methyl 2-ethylpiperazine-1,2,4-tricarboxylate (compound III-JJ) as a yellow oil, approximately 5:1 ratio of methyl and ethyl esters (1.06 g): LCMS: [M+Na]+=429.2 (60%); [M-Boc+H]+=307.1 (100%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[N:19]=[C:18]([CH:31]([CH3:33])[CH3:32])[CH:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:17]1[C:18]([CH:31]([CH3:33])[CH3:32])=[N:19][N:20]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)[C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cc(-c2ccc(F)cc2)n(-c2ccc3ccccc3n2)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(-c2ccc3ccccc3n2)c(-c2ccc(F)cc2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
N-bromosuccinimide (21.03 g, 118 mmoles) was added in one portion to a solution of 2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]quinoline (39.16 g, 118 mmoles) in 400 mL DMF at 0° C. under an inert atmosphere. The mixture was warmed to room temperature and stirred for 16 hours, then poured into 500 mL H2O and the resulting precipitate was collected. The precipitate was air dried on a vacuum filter for 16 hours to give 47.20 g (97%) of the title compound as a white solid, mp 110°-114° C.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=4)=[O:51])[CH2:46][CH:45]3[CH3:63])=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=3)=[O:51])[CH2:46][CH:45]2[CH3:63])=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3C)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 100.2 %

Procedure:
23 ml of trifluoroacetic acid, followed by 0.57 ml of trifluoromethanesulfonic acid, were added dropwise to a solution of 2.26 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[2-methyl-4-(4-nitrobenzyloxycarbonyl)piperazin-1-yl-carbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (iii) above] in 3.48 ml of anisole, and the resulting mixture was worked up and purified by the same procedure as described in Preparation 4(ii), to give 1.88 g of the title compound, as an amorphous solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH:22]=[O:23])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH2:22][OH:23])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C=O)cc2ccccc2c1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(CO)cc2ccccc2c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-formylnaphthalen-2-yl)acetate (12 mg, 0.0283 mmol) in DCM/EtOH (1/1, 1 mL) at 0° C., was added NaBH4 (2 mg, 0.053 mmol) and the reaction mixture stirred at 0° C. for 2 h. The reaction was quenched by adding sat. NH4Cl. The resulting mixture was extracted with DCM, dried over MgSO4, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 8 mg of the desired product. 1H-MNR 400 MHz (CDCl3) δ: 7.85 (s, 1H), 7.78 (d, J=4.0 Hz, 1H), 7.46-7.38 (m, 4H), 7.30-7.26 (m, 1H), 7.20-7.15 (m, 2H), 5.13 (s, 1H), 5.02 (d, J=6.2 Hz, 1H), 4.54 (d, J=6 Hz, 1H), 4.12-4.02 (m, 2H), 3.82 (bs, 1H), 1.14 (t, J=7 Hz, 3H), 1.01 (s, 9H).