Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Cl.[CH:9]([N:12]([CH2:16][CH2:17]Cl)[CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:17][CH2:16][N:12]([CH:13]([CH3:15])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(CCSc1nnc(N)s1)C(C)C
Yield: 78.1 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (4.0 g), diisopropylaminoethylchloridehydrochloride (6.0 g), and potassium hydroxide (3.4 g) were stirred in methanol (100 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 6.1 g of the aimed compound.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].F[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.O>C1COCC1>[N+:22]([C:21]1[C:16]([O:14][CH:12]2[CH2:13][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11]2)=[N:17][CH:18]=[CH:19][CH:20]=1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=[N+]([O-])c1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ncccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
Sodium hydride (60% dispersion in oil, 2.30 g, 57.64 mmol) was added portionwise into a solution of 1-Boc-3-(hydroxy)azetidine (9.94 g, 57.64 mmol) in anhydrous THF (110 mL) at 0° C. and stirred for 0.5 hour. A solution of 2-fluoro-3-nitro-pyridine (7.80 g, 54.9 mmol) in anhydrous THF (15 mL) was added drop wise and the mixture allowed to warm to ambient temperature overnight. The mixture was cooled in an ice-bath and water (50 mL) added. The product was extracted with EtOAc, washed with water, brine and dried (Na2SO4). The product was purified by flash-column chromatography (petroleum ether (40-60° C.)/DCM) to yield the title compound as a yellow solid (4.37 g, 27%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:21]#[N:22].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([C:3]1[C:2]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[CH:26][CH:25]=2)=[N:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:20])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[CH2:9]2)=[CH:5][N:4]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CN(C)C(=O)N(C)[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN(C)C(=O)N(C)[C@@H]1CCCN(c2cnc(C#N)c(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)C1
Temperature: 115 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
The mixture of (R)-1-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,3,3-trimethylurea (294, 390 mg, 1.21 mmol), tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (670 mg, 2.42 mmol), fine-powder cesium carbonate (1600 mg, 4.84 mmol), Pd(OAc)2 (134 mg, 0.60 mmol), BINAP (374 mg, 0.60 mmol) in 60 mL dioxane was degassed with nitrogen stream for 5 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 120 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 20 to 100% EtOAc in DCM to isolate (R)-tert-butyl 4-(4-(3-cyano-6-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)piperidine-1-carboxylate (295) in >80% yield. It was dissolved in 40 mL MeOH and 10 mL DMSO. To it were added two NaOH solid bead (about 200 mg) and then 2 mL 30% H2O2. The mixture was stirred at RT for 3 hours, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 120 mL EtOAc, washed with water ×2, concentrated, and subjected to silica flash column using 0 to 7% MeOh in DCM to give crude (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)piperidine-1-carboxylate (296). It was treated with 30 mL commercial 4N HCl in dioxane for 90 min, and concentrated in vacuo to afford crude (R)-3-(4-(piperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide (297) hydrochloride.
Reaction SMILES: [O:1]1[C:5]2([CH2:11][CH2:10][CH2:9][N:8](C(OCC)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH-].[K+]>CC(O)C>[O:1]1[C:5]2([CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)N1CCCC2(CC1)OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C1CNCCC2(C1)OCCO2
Yield: 62.7 %

Procedure:
A mixture of intermediate (4) (0.585 mol) and KOH (5.85 mol) in 2-propanol (1200 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was stirred in water and this mixture was extracted with DCM. The separated organic layer was dried, filtered, and the solvent evaporated, yielding 57.7 g of 1,4-dioxa-8-azaspiro[4.6]undecane (intermediate 5).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2/[CH:23]=[CH:24]\[CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.[F:30][C:31]1[C:36](O)=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.O>[F:30][C:31]1[C:32]([F:41])=[C:33]([F:40])[C:34]([F:39])=[C:35]([F:38])[C:36]=1[O:19][C:18]([C:17]1[CH:21]=[CH:22][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[C:15](/[CH:23]=[CH:24]\[CH3:25])[CH:16]=1)=[O:20]
Reactant: C/C=C\c1cc(C(=O)O)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C/C=C\c1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 94.3 %

Procedure:
(Z)-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-3-(prop-1-en-1-yl)benzoic acid (108 mg, 0.267 mmol) was dissolved in ethyl acetate:acetone=4:1 (5.7 mL). At room temperature, pentafluorophenol (59 mg, 0.320 mmol) and N,N′-dicyclohexylcarbodiimide (66 mg, 0.320 mmol) were added sequentially, and the mixture was stirred at room temperature for 10 hours. The reaction solution was added water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (129 mg (yield 95%)) was obtained as a white crystal.
Reaction SMILES: [C:1]([NH:9][C:10]([NH2:12])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[N:12]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:11][CH:14]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)NC(=O)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1csc(NC(=O)c2ccccc2)n1

Procedure:
A solution of 19.02 g. of benzoylthiourea and 19.12 g. of ethyl bromopyruvate in 300 ml. of ethanol was refluxed for 2 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (1 liter) and 20% aqueous sodium carbonate (400 ml.). The organic layer was separated, washed successively with 20% aqueous sodium carbonate (3×400 ml.), water (2×400 ml.) and a brine solution (2×400 ml.) and dried over sodium sulfate. The solution was concentrated to about 50 ml. and the precipitated solids filtered and dried, 20.16 g., m.p. 146-147° C.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][C:5]1([C:18]([O:20]CC)=[O:19])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.O.[OH-].[Li+].CCO.Cl>O>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([CH2:4][CH2:3][N:2]([CH3:23])[CH3:1])([C:18]([OH:20])=[O:19])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C1(CCN(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)CCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
1-tert-Butyl 4-ethyl 4-(2-(dimethylamino)ethyl)piperidine-1,4-dicarboxylate from step A (328 mg, 1.0 mmol) was treated overnight with lithium hydroxide monohydrate (210 mg, 5 mmol) in 1:1 EtOH:H2O (5 mL) at 60° C. The reaction was cooled to room temperature, neutralized to pH 6 with 1 N aq. HCl, and concentrated under vacuum. The residue was purified by prep HPLC and lyophilized twice to give the title compound (191 mg, 64%) as a white solid. MS (ES+) [M+H]+=301.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].I[CH2:18][CH3:19].[H-].[Li+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][CH3:19])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccccc2)nn1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a 0° C. mixture of the above-prepared 5-phenyl-2H-pyrazole-3-carboxylic acid ethyl ester (350 mg, 1.62 mmoles) and iodoethane (260 μL, 3.23 mmoles) in DMF (3 mL) was added neat LiH (spatula tip, excess) under a nitrogen atmosphere. The resulting mixture was warmed up to room temperature and stirred overnight. The crude reaction was cooled to 0° C., quenched with aqueous NH4Cl, diluted with ethyl acetate and enough water to dissolve all solids. The phases were separated, and the organic phase was washed sequentially with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The regioisomeric products separated and purified by flash chromatography (silica gel, hexanes/ethyl acetate gradient) to give the title compound (167 mg, 42% yield, higher Rf in hexanes/ethyl acetate) and the undesired regioisomer (175 mg, 44% yield) as white solids. 1H NMR (CDCl3, 400 MHz): 7.81 (d, 2H); 7.40 (dd, 2H); 7.29 (dd, 1H); 7.13 (s, 1H); 4.63 (q, 2H); 4.37 (q, 2H); 1.47 (t, 3H); 1.41 (t, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].[C:18]1([CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH:31]=[CH:32][CH:33]=[O:34])[CH2:27][CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C1CCCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:33]([OH:34])[CH:32]=[CH:31][CH:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:30][CH2:29]1
Reactant: O=CC=CC1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2scnc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: OC(C=CC1CCN(Cc2ccccc2)CC1)c1nc2ccccc2s1
Reaction time: 0.25 h

Procedure:
A solution of benzothiazole (0.243 g, 1.8 mmol) in 5 ml of dry THF was treated with 1.5M lithium diisopropylamide in cyclohexane (1.45 ml) at -78° C. and stirred at that temperature for 15 minutes. A solution of 3-[1-(phenylmethyl)-4-piperidinyl]propenal (452 mg, 1.97 mmol) in 3 ml of dry THF was added at -78° C. and stirred at that temperature for 30 minutes. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give a thick yellow oil in a quantitative yield.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH:10]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(O)C.S(=O)(=O)(O)O.[OH-].[Na+]>O>[C:19]1([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:12])[CH:10]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:8][OH:7])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C(CCOC1CCCCO1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The evaporation residue obtained in step (b) is dissolved in a mixture containing 400 ml of absolute ethanol, 10 g of concentrated sulfuric acid and 75 ml of water. The mixture is stirred for 2 h at room temperature. The solution is neutralized with 2M sodium hydroxide solution, after which the ethanol is evaporated. Water is added to the residue. Then the product is extracted in ethyl acetate. The ethyl acetate solution is dried over sodium sulfate, and the solvent is evaporated. The product is recrystallized from toluene. The yield is 16.5 g (52% from desoxybenzoin) and m.p. 185°-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[Mg].C1O[C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12]C1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:16]1[CH2:17][CH2:18][C:13](=[O:12])[CH2:14][CH:15]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Clc1ccccc1I
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C1CC=C(c2ccccc2Cl)CC1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 7, using 9.5 grams (0.040 mole) of 1-chloro-2-iodobenzene, 1.1 grams (0.044 mole) of magnesium turnings, 6.2 grams (0.040 mole) of 1,4-cyclohexanedione mono-ethylene ketal, and about 100 mL of aqueous 10% hydrochloric acid in about 95 mL of tetrahydrofuran, yielding 1-(2-chlorophenyl)-1-cyclohexen-4-one.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:15])[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].CN([CH:24]=[O:25])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+]>>[C:1]([NH:4][C:5]1[S:6][C:7]([CH:24]=[O:25])=[C:8]([CH3:15])[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c(C)csc1NC(C)=O
Reactant: CN(C=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(NC(C)=O)sc(C=O)c1C
Reaction time: 1.5 h

Procedure:
A mixture of 22.7 parts of 2-acetylamino-3-ethoxycarbonyl-4-methylthiophene, 261 parts of N-methylformanilide and 28.4 parts of phosphoryl chloride is stirred for 90 minutes at 90° - 95° C. 300 Parts of a 4N aqueous solution of sodium acetate are added and the mixture stirred for 10 minutes at 90° C. The oily solid is separated from the liquid and crystallised from ethanol to give 2-acetylamino-3-ethoxycarbonyl-4-methyl-5-formylthiophene (m.pt 174° - 176° C).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:14]3[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=3[N:12]=2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2oc(-c3ccc(Cl)c(Cl)c3)nc2c1

Procedure:
3,4-Dichlorobenzoyl chloride (4.6 g, 0.022 mol) is added to 2-amino-4-nitrophenol (3.4 g, 0.022 mol) in toluene (250 ml) and the mixture is refluxed for 24 hours. para-Toluenesulfonic acid (1.0 g) is added, the mixture is refluxed for 24 hours and cooled, and the product is filtered off. It is recrystallized from isopropyl ether. Yield: 6.8 g; IR (KBr): 3100, 1531, 1350 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[N:5]([CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[CH2:6][C:7]1[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH3:2].[OH2:38]>CO.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:37])[N:5]([CH2:22][C:23]1[CH:24]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:28]=1)[CH2:6][C:7]1[C:8]([S:18]([CH2:19][CH2:20][CH3:21])=[O:38])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH3:2]
Reactant: CCCSc1nc2c(C)cccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OCC
Reactant: O
Solvent: ClCCl
Solvent: CO
Product: CCCS(=O)c1nc2c(C)cccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
(3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-carbamic acid ethyl ester (Example 135) (116 mg, 0.18 mmol) was dissolved in methanol (2 mL) and water (2 mL) followed by the addition of magnesium bis(mono peroxy phthalate hexahydrate) (MMPP) (267.1 mg, 0.54 mmol). The resulting mixture was stirred at room temperature overnight. The sample was diluted with methylene chloride and washed one time with water andone time with brine. The organic phase was dried, filtered and concentrated by rotary evaporation. The resulting sample was dried overnight under vacuum. (Biotage Horizon HPFC chromatography system, SiO2, 70:80 hexanes: ethyl acetate) gave a whit solid (80 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:21])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:29][OH:30].C(N(CC)CC)C>C(Cl)Cl.C1COCC1.O>[OH:30][NH:29][C:11](=[O:12])[C:10]([S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(SC(C)(Cc2ccccc2)C(=O)O)cc1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(SC(C)(Cc2ccccc2)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(4methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid (0.5 g, 1.65 mmol) and DEF (2 drops) in CH2Cl2 (100 ml) at 0° C., oxalyl chloride (1.0 gm, 8 mmol) was added in a drop-wise manner. After the addition, the reaction mixture was stirred at room temperature for 1 hour. Simultaneously, in a separate flask a mixture of hydroxylamine hydrochloride (2.0 gm, 29 mmol) and triethylamine (5 ml, excess) was stirred in THF:water (5:1, 30 ml) at 0° C. for 1 hour. At the end of 1 hour, the oxalyl chloride reaction mixture was concentrated and the pale yellow residue was dissolved in 10 ml of CH2Cl2 and added slowly to the hydroxylamine at 0° C. The reaction mixture was stirred at room temperature for 24 hours and concentrated. The residue obtained was extracted with chloroform and washed well with water. The product obtained was purified by silica gel column chromatography and eluted with ethyl acetate. The N-hydroxy-2-(4-methoxyphenylsulfanyl)-2-methyl-3-phenyl-propionamide was isolated as a colorless solid. mp 88° C.; Yield, 300 mg, 57%; MS: 318 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.32 (s, 3H), 3.07 (d, J =11 Hz, 1H), 3.23 (d, J=11 Hz, 1H), 3.79 (s, 3H), 6.83-7.36 (m, 9H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[NH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CS(C)=O>[N:26]1([C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: C1CCCNCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCCC3)nc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500 mg, crude) in DMSO (6 mL) was added DIEA (543 mg, 4.20 mmol) and azepane (208 mg, 2.10 mmol). The solution was stirred overnight at 90° C. Then the reaction was quenched by the addition of water (50 mL), extracted with ethyl acetate (5×20 mL) and the organic layers were concentrated under vacuum to give a residue, which was purified by a silica gel column with 1%-5% ethyl acetate in petroleum ether to afford methyl 3-(azepan-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (165 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2C(OC(C)(C)C)=O)[CH:7]=1.[Cl:26][C:27]([O:29][CH3:30])=[O:28].Cl>N1C=CC=CC=1>[ClH:26].[CH:23]([S:20]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27](=[O:28])[O:29][CH3:30])=[CH:7][C:6]=1[C@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)(=[O:21])=[O:22])([CH3:24])[CH3:25]
Reactant: CC(C)S(=O)(=O)c1ccc(N)cc1[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(S(=O)(=O)C(C)C)c([C@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1F (0.1 g, 0.27 mmol) in pyridine (1 mL) at 0° C. was added methyl chloroformate (57 (μL, 0.54 mmol). After 2.0 h of stirring at rt the reaction was acidified with 1M HCl to pH 3-4. The product was extracted with ethyl acetate and was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was redissolved in ethyl acetate (1.5 mL) and hydrogen chloride (2 mL, 4M in dioxane) was added. The reaction was stirred for 3 h at rt. The solvent was removed and placed on the lyophilizer to give 0.15 g white solid 1G. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.25 (t, J=7.09 Hz, 3H) 1.37 (d, J=6.85 Hz, 3 H) 2.13-2.31 (m, 1H) 2.31-2.47 (m, 2H) 2.47-2.63 (m, 1H) 3.36-3.56 (m, 3H) 3.73-3.91 (m, 3H) 5.43 (t, J=7.70 Hz, 1H) 7.66 (dd, J=8.80, 2.20 Hz, 1H) 7.97 (d, J=8.80 Hz, 1H) 8.11 (d, J=1.96 Hz, 1H).
Reaction SMILES: [ClH:1].Cl.CO[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH:10]([NH2:22])[CH2:9][CH2:8]2.[C:23]([C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:31][CH2:30][N:29]([CH2:32][C:33]([OH:35])=O)[CH2:28][CH2:27]1)(=[O:25])[CH3:24].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[ClH:1].[ClH:1].[C:23]([C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:27][CH2:28][N:29]([CH2:32][C:33]([NH:22][C@H:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][CH:14]=[CH:5][CH:6]=3)[C@H:11]2[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:35])[CH2:30][CH2:31]1)(=[O:25])[CH3:24]
Reactant: CC(=O)C1(c2ccccc2)CCN(CC(=O)O)CC1
Reactant: COc1ccc2c(c1)CCC(N)C2Cc1cccnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)C1(c2ccccc2)CCN(CC(=O)N[C@H]2CCc3ccccc3[C@H]2Cc2cccnc2)CC1
Yield: 179.6 %

Procedure:
1,2,3,4-Tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenamine bis-hydrochloride 4 (0.75 g, 2.41 mmol) was reacted with 2-(4-acetyl-4-phenyl-piperidin-1-yl)acetic acid (0.86 g, 2.65 mmol), N,N-diisopropylethylamine (2.0 mL, 11.3 mmol) and HBTU (1.01 g, 2.65 mmol) in N,N-dimethylformamide (15 mL) at room temperature for 2 h as described above in EXAMPLES 7–8. The product was collected by filtration from the aqueous work-up. This material was dissolved in isopropanol (˜30 mL) and treated with a saturated solution of hydrochloric acid in isopropanol (˜5 mL). The solvent was evaporated in vacuo, and the residue was triturated with diethyl ether to give 4-acetyl-4-phenyl-N-[cis-1,2,3,4-tetrahydro-1-(3-pyridinylmethyl)-2-naphthalenyl]-1-piperidineacetamide bis-hydrochloride 21 as an amorphous pale yellow solid (1.2 g, 90%): MS m/e 482 (MH+) (FIG. 7).