Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].Cl.[NH2:28][CH2:29][C:30]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[OH:36][C:30]1([CH2:29][NH:28][C:24]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:23])[F:22])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)=[O:26])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NCC1(O)CCCCC1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Agent: Cl
Product: N#Cc1ccc2c(c1)cc(C(=O)NCC1(O)CCCCC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 1-aminomethyl-1-cyclohexanol hydrochloride in a manner similar to that described in Example 11.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[C:9]([OH:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[CH3:19]O>>[F:5][C:6]1[CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[C:9]([OH:15])=[C:10]([CH:14]=1)[C:11]([O:13][CH3:19])=[O:12]
Reactant: CO
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Thionyl chloride (5.88 g, 49.4 mmol) was added dropwise to anhydrous methanol (45 mL) at 5° C. The mixture was stirred at this temperature for 30 min. Then 5-fluoro-2-hydroxy-3-nitrobenzoic acid was added to the mixture and the resulting mixture was heated to reflux for 24 hr. Solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with water (100 mL×3), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 5:1) to give methyl 5-fluoro-2-hydroxy-3-nitrobenzoate (3.4 g, yield 80% for two steps). 1H-NMR (400 MHz, CDCl3-d) δ 4.04 (s, 3H), 7.88-7.90 (dd, J1=7.6 Hz, J2=3.2 Hz, 1H), 7.93-7.96 (dd, J1=7.6 Hz, J2=3.2 Hz, 1H), 11.74 (s, 1H); LC-MS (ESI) m/z 216 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20]([OH:30])[C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:10])=[O:9]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2ccc3c(c2)OCO3)sc2ncccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(=O)c2ccc3c(c2)OCO3)sc2ncccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[α-hydroxy-3,4-(methylenedioxy)benzyl]thieno-[2,3-b]pyridine-3-sulfonamide (0.15 g, 0.27 mmoles) in CH2Cl2 (3 ml) was added manganese dioxide (72 mg, 0.83 mmoles). The black mixture was stirred 24 hours at ambient temperature then filtered and concentrated to collect 0.15 g (96%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)[NH2:7])(=[O:3])[CH3:2].Cl[C:15]1[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[N:16]=1.Cl>O>[C:1]([C:4]1[CH:5]=[C:6]([NH:7][C:15]2[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[N:16]=2)[CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: CC(=O)c1cc(N)cc(C(C)=O)c1
Agent: Cl
Solvent: O
Product: CC(=O)c1cc(Nc2nc(N)nc(N)n2)cc(C(C)=O)c1
Yield: 62.5 %

Procedure:
Compound No. 13: A suspension of 3,5-diacetylaniline (1.95 g) in water (10 mL) was treated with 2-chloro-4,6-diamino-1,3,5-triazine (1.455 g) and concentrated HCl (0.1 mL) and heated at reflux for 20 min. After cooling the hydrochloride of Compound No. 13 separated as a white powder. This was filtered out, dissolved in 60 mL of boiling aqueous 75% methanol and treated with triethylamine (1.5 mL). On cooling, off-white flakes separated. Filtration and drying gave 1.79 g of 2-(3,5-diacetylphenyl)amino-4,6-diamino-1,3,5-triazine, mp 271°-2° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.CN1CCCN(C)C1=O.[C:20]1([CH:26]2[CH2:28][O:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:28][CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[OH:27])[CH:8]=[CH:7]2
Reactant: c1ccc(C2CO2)cc1
Reactant: Brc1cccc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: OC(Cn1ccc2cccc(Br)c21)c1ccccc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a mixture of 7-bromoindole (3.3 g) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (33 mL) were added 2-phenyloxirane (2.5 mL) and cesium carbonate (11 g) at room temperature, followed by stirring at 80° C. for 12 hours. To the reaction mixture were added ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 2-(7-bromo-1H-indol-1-yl)-1-phenylethanol (5.1 g).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[S:16])=[C:13]([CH2:20][CH3:21])[N:12]=[C:11]([CH3:22])[N:10]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:28][CH2:29][NH2:30].O>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:28][CH2:29][NH:30][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[S:16])=[C:13]([CH2:20][CH3:21])[N:12]=[C:11]([CH3:22])[N:10]=2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CCOC(=S)c1c(Cl)nc(C)nc1CC
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=S)c1c(CC)nc(C)nc1NCCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50.7 %

Procedure:
Triethylamine (0.17 g, 1.68 mmol) was added to a solution of ethyl 4-chloro-6-ethyl-2-methylthiopyrimidine-5-carboxylate (0.21 g, 0.81 mmol) in toluene (4 ml), followed by addition of 3,4-dimethoxyphenethylamine (0.18 g, 0.99 mmol). The mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, extracted with ethyl acetate and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(3,4-dimethoxyphenyl)ethylamino)-6-ethyl-2-methylthiopyrimidine-5-carboxylate (0.16 g, 49%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:12]([O:16][C:17]([N:19]1[C:24]([CH3:26])([CH3:25])[CH2:23][CH2:22]OS1(=O)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([NH:19][C:24]([CH3:25])([CH3:26])[CH2:23][CH2:22][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)CCOS1(=O)=O
Reactant: O=Cc1ccc2[nH]ccc2c1
Product: CC(C)(CCn1ccc2cc(C=O)ccc21)NC(=O)OC(C)(C)C

Procedure:
Prepared analogously to Component V(a) by alkylation of indole-5-carbaldehyde with N-tert-butoxycarbonyl-4,4-dimethyl-[1,2,3]oxathiazinane-2,2-dioxide (Component XI).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:41]=[CH:40][C:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38]C)=[O:37])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[C:1]1([CH2:7][CH2:8][N:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]3[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:32][CH:33]=3)=[CH:40][CH:41]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(-c4ccccc4)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
A mixture of methyl 3-[4-[[4-[[(2-phenylethyl)(4-phenyl-1,3-thiazol-2-yl)amino]methyl]benzyl]oxy]phenyl]propanoate (270 mg, 0.480 mmol), tetrahydrofuran (15 mL), methanol (10 mL), water (10 mL) and lithium hydroxide monohydrate (60.4 mg, 1.44 mmol) was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (162 mg, yield 62%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:26].[K+].[K+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:22])=[O:26])=[CH:19][CH:20]=2)[O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CF)cc1
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: CCO
Product: CS(=O)c1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CF)cc1
Temperature: 0 °C
Reaction time: 10 h
Yield: 63.7 %

Procedure:
To a solution of (4R,5R)-4-Fluoromethyl-2,2-dimethyl-5-(4-methylsulfanyl-phenyl)-oxazolidine-3-carboxylic acid tert-butyl ester (6 g, 16.91 mmol) in ethanol (300 mL) is cooled to 0° C. followed by addition of K2CO3 (4.665 g, 33.80 mmol) and m-CPBA (2.90, 16.90 mmol) at 0° C. and resulting reaction mixture is stirred at 0° C. for 10 h. After completion, reaction mixture is quenched with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by CombiFlash using 120 g column with 100% ethyl acetate in hexane as an eluent to afford title compound (4 g) as colorless oil. 1H-NMR (400 MHz, DMSO): δ 1.43 (s, 9H), 1.50 (s, 3H), 1.62 (s, 3H), 2.74 (s, 3H), 3.82-3.89 (m, 1H), 4.46-4.57 (m, 1H), 4.81 (m, 1H), 5.15 (d, J=7.28 Hz, 1H), 7.65-7.72 (m, 4H). LC-MS (m/z): M+H=372.3.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].C(Cl)Cl>C1COCC1>[CH3:9][C:5]1[C:3]2[NH:4][C:10](=[O:11])[O:1][C:2]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc(O)c1N
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc2oc(=O)[nH]c12
Temperature: 70 °C
Reaction time: 20 h
Yield: 83.1 %

Procedure:
To a solution of 2-hydroxy-6-methylaniline (583 mg) in THF (8 mL) was added 1,1′-carbonyldiimidazole (1.14 g). The reaction mixture was stirred at 70° C. for 20 h. After cooling down, DCM was added and the mixture was washed three times with 2N NaOH. The aq. phases were combined, cooled down to 0° C. and the pH was brought to 6 by addition of 2N HCl. The suspension was filtered, the resulting powder was washed with cold water and dried in high vacuo to afford 587 mg of beige solid. LC-MS (B): tR=0.64 min. 1H-NMR (DMSO-d6): 11.7 (s, NH); 7.09 (m, 1H); 6.97 (m, 2H); 2.29 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][C:9]1[CH:13]=[C:12]([Cl:14])[S:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].[CH3:19][CH:20]([CH3:26])[CH2:21][CH2:22][N:23]=[C:24]=[S:25]>CN(C)C=O>[NH2:8][C:9]1[CH:13]=[C:12]([Cl:14])[S:11][C:10]=1[S:15]([NH:18][C:24]([NH:23][CH2:22][CH2:21][CH:20]([CH3:26])[CH3:19])=[S:25])(=[O:16])=[O:17]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CC(C)CCN=C=S
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCNC(=S)NS(=O)(=O)c1sc(Cl)cc1N
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
Potassium tert-butoxide (0.49 g, 4.4 mmol) was added to a solution of 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride (0.5 g, 2.0 mmol) in dry N,N-dimethylformamide (5 ml) with stirring on an ice bath. After 10 min, 3-methylbutyl isothiocyanate (0.31 g, 2.4 mmol) was added dropwise to the resulting suspension, and the mixture was stirred for 3.5 h at 0 to 20° C. Most of the solvent was evaporated at 40° C., and the residue was taken up in 25 ml of water, treated with decolourising charcoal, and filtered. Acidification of the filtrate with acetic acid to pH 3-4 and filtration afforded 0.21 g (29%) of the title compound; mp 114-115° C. decomp., 1H-NMR (DMSO-d6): δ0.85 (d, 6H, 2×CH3), 1.40 (q, 2H, CH2), 1.50 (m, 1H, CH), 3.45 (q, 2H, CH2), 6.45 (br, 2H, NH2), 6.65 (s, 1H, H4), 8.30 (br t, 1H, NH), 11.3 (br s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:16]2([CH3:23])[CH3:22])=[CH:10][N:9]=1)(C)(C)C.Cl>O1CCOCC1.CO>[CH3:22][C:16]1([CH3:23])[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][N:15]1[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[N:9][CH:10]=1
Reactant: CN1CCN(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(C)(C)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(Cc2ccc(N)nc2)C(C)(C)C1
Yield: 75 %

Procedure:
A mixture of [5-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 110.2) (1.94 g, 5.8 mmol), a 4 N solution of HCl in dioxane (20 mL) and MeOH (5 mL) was stirred for 12 h at rt and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 95:4:1) to afford 1.02 g of the title compound as a white solid. Title compound: ESI-MS: 235.2 [M+H]+; TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:10][C@H:11]([C:15]([OH:18])([CH3:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[F:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:10][C@H:11]([C:15]([OH:18])([CH3:17])[CH3:16])[C:12]([NH:28][NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:30][CH:29]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)C(C)(C)O)ccc(C#N)c1Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of (R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoic acid (4.0 g, 14.2 mmol) in THF (100 mL) were added 4-fluorobenzoic hydrazide (2.40 g, 15.6 mmol), HOBt (1.91 g, 14.1 mmol), EDC (4.07 g, 21.2 mmol) and Et3N (3.0 mL, 21.5 mmol) at −20° C. sequentially. After addition, the mixture was stirred at −20° C. for 30 min., then room temperature overnight. The reaction was quenched by adding ice-water. After removal of the THF, the residue was extracted with EtOAc (300 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. The filtrate was concentrated and purified by flash chromatography to give the title compound (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)-4-fluorobenzohydrazide (4.28 g, 72%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 9.61 (b, 2H), 8.00 (dd, J=5.5, 9.0 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.25 (t, J=9.0 Hz, 2H), 6.71 (d, J=8.6 Hz, 1H), 5.53 (d, J=7.4 Hz, 1H), 4.06 (d, J=7.4 Hz, 1H), 2.35 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:5]2.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>N1C=CC=CC=1.ClCCl>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([CH2:11][NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:5]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)NCC1Cc2ccc(N)cc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NCC1Cc2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cc2C1
Temperature: 5 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
N-(5-Amino-indan-2-ylmethyl)-propionamide (0.93 g, 4.26 mmol) was dissolved in pyridine-dichloromethane (1:2, 60 mL) and cooled to 5° C. 4-Isopropylbenzenesulfonyl chloride (0.98 g, 4.48 mmol) was added and the solution stirred at 5° C. for 3 h. Solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give the product as a brown oil (1.69 g, 99%).
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10]CC)=[O:9])=[CH:4][S:3]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)C.O>[O:1]=[C:2]1[S:6][C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([OH:10])=[O:9])=[CH:4][S:3]1
Reactant: CCOC(=O)C(=NOC)c1csc(=O)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)O)c1csc(=O)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.6 %

Procedure:
To a solution of ethyl 2-(2-oxo-1,3-dithiol-4-yl)-2-methoxyiminoacetate (syn isomer, 1 g.) in tetrahydrofuran (10 ml.) and ethanol (20 ml.) was added a solution of sodium carbonate 10 hydrate (1.3 g.) in water (20 ml.), and the mixture was stirred at room temperature for 3 hours. After the solvent was removed in vacuo; the residue was washed with diethyl ether, adjusted to pH 2 and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give 2-(2-oxo-1,3-dithiol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 0.2 g.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:22]=[C:21]2[C:12]([O:13][C:14]3[CH:15]=[CH:16][C:17]([C:24](OCC)=[O:25])=[CH:18][C:19]=3[C:20]2=[O:23])=[CH:11][CH:10]=1.O.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[OH:23][CH:20]1[C:19]2[CH:18]=[C:17]([CH2:24][OH:25])[CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:21]1=[CH:22][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2
Reactant: CCOC(=O)c1ccc2oc3ccc(OC)cc3c(=O)c2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(O)c1cc(CO)ccc1O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
Lithium aluminum hydride (500 mg) was added to a stirred solution of ethyl 7-methoxy-9-oxoxanthene-2-carboxylate (1g) in THF (100 ml). The reaction mixture was stirred at room temperature under nitrogen for 5 hours. Water and MgSO4 were added. The inorganic solids were filtered off and washed with ethyl acetate. The filtrate and washings were combined and evaporated to give the crude product. Recrystallization from ethyl acetate gave white crystals (0.82 g, 84%), mp. 142°-143°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH3:25])[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Cc1ccccc1N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1ccccc1N1CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Methylphenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.14 (m, 2H), 6.98 (m, 2H), 5.37 (s, 2H), 3.60 (m, 4H), 2.89 (m, 2H), 2.81 (m, 2H), 2.27 (s, 3H), 2.20 (s, 3H) ppm; MS (ES) M+H expect=401.1, found=401.1.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([NH:16][C:17](=[O:19])[CH3:18])=[CH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[OH-].[Na+].Cl.C>O.CO>[C:17]([NH:16][C:4](=[CH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[C:3]([OH:20])=[O:2])(=[O:19])[CH3:18]
Reactant: COC(=O)C(=Cc1c[nH]c2cc(Cl)ccc12)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)NC(=Cc1c[nH]c2cc(Cl)ccc12)C(=O)O
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A 2-l. three-necked flask, equipped with thermometer mechanical stirrer and reflux condenser was charged with 90.4 g (0.31 moles) of alpha-acetamido-6-chloro-3-indoleacrylic acid methylester, 200 ml (0.40 moles) of 2N aqueous sodium hydroxide and 400 ml of methylalcohol. The mixture was stirred and heated at an internal temperature of 55-58° for 90 minutes. 800 ml of distilled water was added and the brown slightly turbid solution filtered through a Buchner funnel. The clear filtrate was acidified with 90 ml (0.54 moles) of 6N aqueous hydrochloric acid. The precipitate was collected on a Buchner funnel and washed with distilled water. The wet cake was transferred into flask and suspended in 180 ml of dimethylformamide and 600 ml of methyl alcohol. The mixture was heated on a steam bath to reflux until a brown, slightly turbid solution was formed. 6 g of charcoal was added and reflux was continued for 10 minutes. The hot mixture was quickly filtered through a bed of Celite. The deep yellow, clear filtrate was transferred into a 2-l. flask, equipped with reflux-condenser and dropping funnel and brought again to reflux under an atmosphere of nitrogen. 240 ml of distilled water was added over a 5 minute period while reflux was maintained. The mixture was allowed to stand overnight under an atmosphere of nitrogen at room temperature. The product was collected by suction filtration, washed with methyl alcohol-water 1:1 and dried at 85°/0.5 mmHg, to constant weight to give 78.6 g (86%) of product, as yellow crystals, m.p. 255°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH:15]=O)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH3-]C#N.[Na+]>CO>[CH2:1]([N:8]1[CH2:14][CH2:13][CH:12]2[C:10]([CH2:15][NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=CC12CC1CCN(Cc1ccccc1)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CN2CCC3CC3(CNc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-Benzyl-3-aza-bicyclo[4.1.0]heptane-1-carbaldehyde (174) (300 mg, 1.39 mmol) in 5%HOAc in MeOH (2 ml) was added aniline (0.38 ml, 4.18 mmol) and NaCNBH3 (250 mg, 3.97 mmol). The mixture was stirred at room temperature 2 hrs. MeOH was removed by evaporation. Water (5 mL) was added to the residue. The mixture was neutralized with 2N KOH to pH=10. Extraction with CH2Cl2 (2×10 ml) followed by standard work-up provided crude 175 which was purified by silica gel chromatography (1% MeOH in CH2Cl2). LRMS (calculated for C20H25N2, M+1) 293, found 293.