Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].C([O-])([O-])=O.[Na+].[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:3]([C:2]([NH:1][C:21](=[O:22])[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:6])[CH3:5])#[N:4]
Reactant: CC(C)(N)C#N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C#N)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-2-methylpropanenitrile in water an equimolar amount of Na2CO3 and a slight excess (1.1 eq) of benzylchloroformate were added, with an external cooling. Reaction mixture was stirred o/n at room temperature, extracted in EtOAc and the organic phase was washed with NaHCO3ss, dried (Na2SO4), filtered and concentrated. Product was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:6]2[NH:13][CH:12]=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.[H][H]>CO.Cl[Pd]Cl>[N:8]1[C:7]2[CH:11]=[CH:12][NH:13][C:6]=2[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:2]=2[F:1])=[N:10][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ncnc3cc[nH]c23)c(F)c1
Agent: Cl[Pd]Cl
Solvent: CO
Product: Nc1ccc(Oc2ncnc3cc[nH]c23)c(F)c1
Yield: 72.1 %

Procedure:
A solution of 243 (263 mg, 0.966 mmol, scheme 54) in MeOH (10 mL) and PdCl2 (1.8 mg, 0.01 mmol) was stirred in the atmosphere of hydrogen for 60 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Water was added to the residue and the aqueous solution was extracted with DCM. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure, to afford title compound 247 (170 mg, 72% yield, crude) as a gray solid. MS (m/z): 243.08 (M+1).
Reaction SMILES: C(OC([C:6]1[C:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[NH:9][CH:10]=1)=O)C.[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.O>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[NH:9][CH:10]=[CH:6][C:7]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(-c2[nH]ccc2-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
15.00 g (48.3 mmol) of 4-ethoxycarbonyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in Example 1(i) above] were dissolved in a mixture of 90 ml of acetic acid, 30 ml of sulfuric acid and 60 ml of water and the resulting solution was stirred at 100° C. for 16 hours. At the end of this time, the reaction mixture was cooled to room temperature and then made alkaline with a 10% aqueous solution of sodium hydroxide. The resulting mixture was extracted with ethyl acetate and the organic extract was washed with water, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure to give 11.40 g (yield 99%) of the title compound as a pale red powder.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: NCCOc1cccc(F)c1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3cccc(F)c3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 12.2 %

Procedure:
Compound A (1.53 g, 6.25 mmol), 2-(3-fluorophenoxy)ethylamine hydrochloride (1.79 g) and sodium hydrogencarbonate (5.25 g) were added to DMSO (30 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was purified by silica gel chromatography. This was converted to hydrochloride to give the object compound of 2-(2-(3-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (308 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH3:15])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][O:26][CH2:27][C:28]([OH:30])=O)=[C:19]([C:32]([O:34]C)=[O:33])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][O:26][CH2:27][C:28]([N:3]([CH2:1][CH3:2])[C:4]2[CH:9]=[C:8]([C:10]3[CH:14]=[CH:13][O:12][CH:11]=3)[CH:7]=[CH:6][C:5]=2[CH3:15])=[O:30])=[C:19]([CH:18]=1)[C:32]([OH:34])=[O:33]
Reactant: CCNc1cc(-c2ccoc2)ccc1C
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: CCN(C(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O)c1cc(-c2ccoc2)ccc1C

Procedure:
Using the same method as in Example 15-(i), N-ethyl-5-(furan-3-yl)-2-methylaniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-(ethyl[5-(furan-3-yl)-2-methylphenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 73%).
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][CH2:16][NH2:17].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CS(C)=O>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]=2)[CH2:14][CH2:15][CH2:16][NH2:17])=[CH:21][CH:20]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: NCCCNc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: NCCCN(Cc1ccc(Br)cc1)c1ccc2ccccc2n1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
To a mixture of sodium hydride (2.64 g, 60% dispersion in mineral oil, 63.9 mmol) in dry dimethylsulfoxide (100 ml) was slowly added a solution of N-(quinolin-2-yl)propane-1,3-diamine (12 g, 56.62 mmol) in dry dimethylsulfoxide (25 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred until gas evolution was ceased. To the resulting mixture a solution of 4-bromobenzylbromide (16.27 g, 63.79 mmol) in dry dimethylsulfoxide (50 ml) was slowly added at room temperature. The reaction mixture was stirred for 4 days at room temperature poured on to ice water (800 ml) and extracted with ethyl acetate (5×150 ml). The combined organic extracts were washed with water (4×150 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue (22.27 g) was washed with n-heptane (30 ml) which afforded 20.41 g of crude N-(4-bromobenzyl)-N-(quinolin-2-yl)propane-1,3-diamine which was purified by column chromatography on silica gel (900 ml) using a mixture of dichloromethane/methanol/triethylamine 9:0.5:0.5 as eluent affording 13.9 g (63%) of N-(4-bromobenzyl)-N-(quinolin-2-yl)propane-1,3-diamine as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[OH-].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O.C(OCC)C>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(OCCCCN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3.4 g of 4-(4-aminobutoxy)benzonitrile hydrochloride (Example 52) is in 100 ml of water is treated successively with 3.5 ml of 10N NaOH and 3.5 g of 4-methylphenylsulfonyl chloride in 100 ml of diethyl ether. The mixture is stirred at room temperature for two hours, a precipitate forming. The solid is collected, washed with water and diethyl ether, dried, and recrystallized from 50% aqueous ethanol; m.p. 107°-108° C.; yield, 3.5 g.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=O)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=[C:4]3[C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])[NH:6][C:5]3=[O:11])=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=Cc1ccc2[nH]ccc2c1
Product: Cc1cccc2c1C(=Cc1ccc3[nH]ccc3c1)C(=O)N2

Procedure:
4-Methyl-2-oxindole was condensed with 1H-indole-5-carbaldehyde using method B to give 3-(1H-indol-5-ylmethylene)-4-methyl-1,3-dihydroindol-2-one as a white solid which was reduced using method C to give 20 mg (40%) of 3-(1H-indol-5-ylmethyl)-4-methyl-1,3-dihydroindol-2-one.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:18][CH:19]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccccc2n1Cc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 70.1 %

Procedure:
Ethyl 1H-indole-2-carboxylate (500 mg, 2.64 mmol) was dissolved in anhydrous DMF (8 ml), followed by 1-(chloromethyl)-4-fluorobenzene (0.380 ml, 3.17 mmol) and the addition of solid potassium carbonate (730 mg, 5.29 mmol). This was stirred at 60° C. for 20 h, at which time the reaction was allowed to cool to room temperature. Precipitate formed upon the addition of water (40 mL), was isolated over a filter, and dried under high vacuum overnight to give 550 mg of the title compound as a white solid which was recrystallized from diethyl ether. Rf=0.55 (33% EtOAc/Hex.)
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([NH2:20])[C:15]([C:21]([OH:23])=[O:22])=[C:14]2[CH2:24][CH2:25][CH2:26][NH:27]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35]>O1CCOCC1.C(Cl)Cl>[ClH:35].[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([NH2:20])[C:15]([C:21]([OH:23])=[O:22])=[C:14]2[CH2:24][CH2:25][CH2:26][NH2:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCc1c(C(=O)O)n(N)c2ccc(C(=O)OCc3ccccc3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCCc1c(C(=O)O)n(N)c2ccc(C(=O)OCc3ccccc3)cc12
Reaction time: 0.75 h

Procedure:
5-(Benzyloxycarbonyl)-amino-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid (72 mg) was dissolved in 5 mL of 4 N HCl in dioxane. Within 10 min a white crystalline solid had formed. The mixture was stirred for 45 min at which time the reaction was diluted with 10 mL of methylene chloride. The filtrate was removed with a filter-tipped cannula and the solid was washed 3×10 mL of methylene chloride and dried, providing the title compound; MS, electrospray, 369 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([CH:28]4[CH2:32][O:31]C5(CCCCC5)[O:29]4)[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[C:6]([CH3:38])[CH:5]=[CH:4][N:3]=1.[ClH:39].CCOCC>C(O)C>[ClH:39].[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([NH:22][C:23]3[S:27][N:26]=[C:25]([C@H:28]([OH:29])[CH2:32][OH:31])[N:24]=3)=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[C:6]([CH3:38])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of (S)-N-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.360 g, 0.656 mmol) in ethanol (25 mL) was added an aqueous 6N solution of HCl (2 mL). The reaction was heated at 80° C. for 2 hours, then cooled to ambient temperature, stirred for 30 minutes, then cooled to 0° C. Ether (25 mL) was slowly added to initiate precipitation/crystallization. The reaction was stirred 30 minutes, then filtered. The solids were washed with ether several times, then hexanes, and dried overnight under vacuum at 50° C. to afford (S)-1-(5-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (0.205 g, 0.406 mmol, 61.9% yield) as a light yellow powder/fine crystals. Mass Spectrum (apci) m/z=469.2 (M+H—HCl).
Reaction SMILES: [C:1]([O:5]C)(=[O:4])[C:2]#[CH:3].[OH-].[Na+].[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>O>[C:9]1([S:15]/[CH:3]=[CH:2]\[C:1]([OH:5])=[O:4])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#CC(=O)OC
Reactant: Sc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)/C=C\Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Methyl propiolate (3.37 ml, 40.0 mmol) was suspended in aqueous 2.5N NaOH (32.0 ml, 80 mmol), and the resulting mixture was cooled to 0° C. Thiophenol (4.12 ml, 40.0 mmol) was added drop wise under vigorous stirring, and the reaction was left at room temperature for 1 hour. The mixture was diluted with water (30 ml), and the pH was adjusted to 1 with aqueous 10% HCl. The aqueous solution was extracted with AcOEt (2×60 ml) and the combined organic layers were dried over Na2SO4 and evaporated to dryness (presence of two diastereoisomers, Z/E ratio about 90/10). The solid residue was suspended in CH3CN (20 ml) and heated to 40° C. to obtain complete dissolution. The solution was cooled to 0° C. and crystallization of the (Z) isomer was observed. The solid was collected by filtration and dried under vacuum affording (Z)-3-(phenylthio)acrylic acid (299a) (2.67 g, 14.81 mmol, 37% yield, MS/ESI+ 181.3 [MH]+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:27]([O:12][C:10](=[O:11])[C@@H:9]([NH2:8])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:18][CH:19]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of (S)-2-tert-butoxycarbonylamino-3-(3′-chloro-biphenyl-4-yl)-propionic acid (12.9 g, 34.3 mmol) in DMF (130 mL) were added benzyl bromide (8.16 mL, 68.6 mmol) and NaHCO3 (5.77 g, 68.6 mmol). After stirred at room temperature overnight, the reaction mixture was diluted with EtOAc. The mixture was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was treated with 4M HCl in dioxane (30 mL) and stirred for 2 hours. The reaction mixture was concentrated and the resulted residue was rinsed with iPr2O to give (S)-2-amino-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (11.2 g). 1H NMR (400 MHz, DMSO-d6) δ 3.14 (dd, 1H, J=7.7, 12.0 Hz), 3.27 (dd, 1H, J=5.9, 12.0 Hz), 4.38 (dd, 1H, J=5.9, 7.7 Hz), 5.15 (s, 2H), 7.23-7.27 (m, 2H), 7.30-7.34 (m, 5H), 7.42-7.45 (m, 1H), 7.51 (dd, 1H, J=7.6, 7.6 Hz), 7.61-7.66 (m, 3H), 7.69 (dd, 1H, J=1.8, 1.8 Hz), 8.64 (bs, 2H); MS: m/z (MH+) 366.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:20]([CH:17]1[CH2:18][CH2:19][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15][CH2:16]1)[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH3:33]
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)C1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)C1CCN(C2CCNCC2)CC1
Reaction time: 5 h

Procedure:
A suspension of 1.30 g (2.83 mmol) ethyl [(1′-benzyl-[1,4′]bipiperidinyl-4-yl)-tert-butoxycarbonyl-amino]-acetate and 0.16 g 10% Pd/C in 25 mL EtOH was hydrogenated for 5 h at 50° C. and 50 psi hydrogen pressure. The catalyst was removed by suction filtering and the filtrate was evaporated to dryness. The product was obtained as a colourless oil, which was reacted further without purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]([CH3:13])=[N+:11]([O-:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:15].[Br:16]Br>CO>[OH:1][CH2:2][C:3]1[C:12]([CH2:13][Br:16])=[N+:11]([O-:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[O-:15]
Reactant: BrBr
Reactant: Cc1c(CO)[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: CO
Product: [O-][n+]1c(CO)c(CBr)[n+]([O-])c2ccccc21
Reaction time: 48 h
Yield: 62 %

Procedure:
To a stirred suspension of 2-hyroxymethyl-3-methylquinoxaline-1,4-dioxide (10.3 g., 0.05 mole) in 100 ml. of methanol was added 1.5 ml. (0.055 mole) of bromine over a period of ten minutes at room temperature. The reaction mixture was then stirred for two days. The resulting yellow solid was collected, washed with methanol and ether, and air dried to give 8.9 g. (62 percent yield of the title compound, mp-138°-140°.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)=[C:4]([CH2:20][CH3:21])[CH:3]=1.NN>C(Cl)(Cl)Cl.C(O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH2:7])=[C:4]([CH2:20][CH3:21])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1CN
Temperature: 25 °C

Procedure:
2-(4-Bromo-2-ethyl-benzyl)-isoindole-1,3-dione (4 g, 11.7 mmol) and hydrazine (1.8 mL, 58.3 mmol) in chloroform:ethanol (1:1.5, 250 mL) were refluxed for 4 h. The mixture was cooled to room temperature and filtered through a pad of celite. The solution was diluted in water and partitioned. The organic layer was washed with water, saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and then concentrated in vacuo to a yellow oil (2.2 g, 88%). 1H NMR (300 MHz, CDCl3): δ ppm 1.23 (t, J=7.54 Hz, 3 H) 1.65 (s, 2 H) 2.66 (q, J=7.60 Hz, 2 H) 3.84 (s, 2 H) 7.19-7.23 (m, 1 H) 7.30-7.34 (m, 2 H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:20]=[C:21]3[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=2)[NH:24][CH:23]=[C:22]3[CH:31]2[CH2:36][CH2:35][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:33][CH2:32]2)[CH:15]=[CH:16][C:17]=1[F:18])[CH3:9].[CH2:42](N)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([NH:10][CH2:11][C:12]2[CH:13]=[C:14]([C:19]3[CH:20]=[C:21]4[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=3)[NH:24][CH:23]=[C:22]4[CH:31]3[CH2:32][CH2:33][N:34]([S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])[CH2:35][CH2:36]3)[CH:15]=[CH:16][C:17]=2[F:18])[CH2:42][CH2:9]1
Reactant: CCN
Reactant: CCNCc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)ccc1F
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(F)c(CNC5CC5)c4)cc23)CC1
Yield: 49.4 %

Procedure:
The title compound was prepared according to the general procedure of 5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting cyclopropylamine (32 mg, 0.46 mmol) for ethylamine to afford 23 mg of the title compound (49.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: COC(=O)C(C(=O)OC)C(Cc1c([N+](=O)[O-])cccc1C(F)(F)F)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C(=O)OC)C(Cc1c(N)cccc1C(F)(F)F)c1ccc(OC)cc1
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A suspension of 40.4 g (0.088 mol) of [2-(2-nitro-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)-ethyl] propanedioic acid, dimethyl ester (see Example 7A) in methanol was treated with a cold suspension of 5% palladium on charcoal in methanol (under nitrogen) and placed on the Parr apparatus at 58 psi of hydrogen. The mixture was heated at 50°-55° C. for 1 hour to assure that all of the starting material had dissolved. The mixture was removed from the Parr apparatus and allowed to stand at room temperature overnight. The flask was heated to dissolve the crystallized product, and the hot solution was filtered through Celite (under nitrogen) and washed with hot methanol. The colorless filtrate was concentrated on a rotary evaporator to yield 36.9 g of the title compound, melting point 111°-113° C. A sample crystallized from methanol melted at 112°-114° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23]I)[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)O[C@@H]1O[C@H](CI)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 45.1 %

Procedure:
1,2,3,4-Tetra-O-acetyl-6-deoxy-6-iodo-β-D-glucopyranose (251.6 mg, 0.549 mmol) was dissolved in 20 mL of ethanol. To this solution was added 1 mL of triethylamine and 5% palladium on carbon (50.0 mg). The reaction mixture was exposed to 60 psi of hydrogen in a Parr apparatus at room temperature for 5 hours. The palladium on carbon was filtered off and the ethanol was removed in vacuo to yield a white solid. Purification via column chromatography over silica gel yielded 82.3 mg of the title compound as a white solid. (45%). MS(FAB) calculated for C14H20O9 (M+): 332.1. Found: 331.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:36][C:37]([F:43])([F:42])[C:38]([NH:40][NH2:41])=O>CC1C=CC(C)=CC=1>[C:29]1([C:19]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)=[N:28][C:22]3[O:23][CH2:24][C:25]4[N:26]([C:38]([C:37]([F:43])([F:42])[F:36])=[N:40][N:41]=4)[C:21]=3[CH:20]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NNC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C(F)(F)F)CO4)cc2)CCC1
Yield: 21.8 %

Procedure:
A solution of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (70 mg, 0.144 mmol) and 2,2,2-trifluoroacetohydrazide (7.3 mg, 0.057 mmol) in p-xylene (1 ml) was heated to 150° C. for 30 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (7 mg, 20%). LCMS (Method D): RT=1.633 min, M+1=564. 1H NMR (500 MHz, CDCl3): 7.96 (1H, s), 7.36-7.27 (7H, m), 7.21-7.17 (2H, m), 5.63 (2H, s), 2.55-2.40 (4H, m), 2.14-1.98 (1H, m), 1.88-1.78 (1H, m), 1.37-1.20 (9H, bs).