Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.F[C:9]1[C:10]([C:16]#[N:17])=[N:11][C:12]([F:15])=[CH:13][N:14]=1.C([O-])(=[O:20])C.[Na+].Cl>C(OCC)(=O)C.O.CS(C)=O>[F:15][C:12]1[N:11]=[C:10]([C:16]#[N:17])[C:9]([OH:20])=[N:14][CH:13]=1
Reactant: N#Cc1nc(F)cnc1F
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1nc(F)cnc1O
Temperature: 50 °C
Reaction time: 7 h

Procedure:
To 19.92 g of a toluene solution of 3,6-difluoropyrazine-2-carbonitrile with a concentration of 12.7% were sequentially added 18 ml of dimethyl sulfoxide, 9 ml of water, and 2.95 g of sodium acetate. The resulting mixture was heated to 50° C., and stirred at 50° C. for 7 hours. The mixture was then cooled to room temperature, and 9 ml of water and concentrated hydrochloric acid were added to adjust the pH to 2.5. 54 ml of ethyl acetate was added and a separation was performed. The separated organic layer was washed with 18 ml of water, and then washed with a 10% saline solution. Each of the aqueous layers was extracted with 18 ml of ethyl acetate, and the thus obtained organic layers were combined with the original organic layer. The ethyl acetate was then removed by distillation under reduced pressure, yielding 3.45 g of an oily 6-fluoro-3-hydroxypyrazine-2-carbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])=[O:32])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccccc1F
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccccc4F)cc3)c2cc1OC
Yield: 66 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinazoline (100 mg) was dissolved in toluene (10 ml) with heat, 2-fluorophenyl isocyanate (0.30 ml) was added, and the admixture was refluxed with heat for 40 minutes. The separated solid was filtered and washed with toluene to obtain 96 mg of the title compound (yield: 66%).
Reaction SMILES: [CH3:1][C:2]1[O:10][C:9]2[CH2:8][CH2:7][N:6]=[C:5]([CH3:11])[C:4]=2[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][C:2]1[O:10][C:9]2[CH2:8][CH2:7][NH:6][CH:5]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC1=NCCc2oc(C)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cc2c(o1)CCNC2C
Yield: 45 %

Procedure:
In close analogy to the procedure described above, 2,4-Dimethyl-6,7-dihydro-furo[3,2-c]pyridine is reacted with sodium triacetoxyborohydride to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH2:20][CH2:21][OH:22]>CN(C=O)C.CCOC(C)=O>[OH:22][CH2:21][CH2:20][NH:19][C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(NCCO)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 98.8 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.10 g, 3.85 mmol) was dissolved in dry DMF (10 mL) under nitrogen atmosphere. 2-Aminoethanol (0.28 g, 4.62 mmol) was added followed by TEA (0.58 g, 5.77 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, dried with Na2SO4, filtered and evaporated. The residue was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant and TEA as additive affording the title compound (1.18 g, 99.1%). 1H NMR (500 MHz, CDCl3): δ 1.59 (d, 6H), 3.02 (q, 2H), 3.57 (t, 2H), 4.38-4.46 (m, 1H), 5.71 (bs, 1H), 7.43-7.46 (m, 3H), 7.50-7.53 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 20.38, 46.11, 47.76, 60.78, 107.46, 125.22, 128.96, 129.89, 131.70, 135.84, 158.67; Mass Spectrum: M+H+ 311.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]([C:22]2[N:23]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[N:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)=[O:21])=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2)=[O:9])([CH3:6])[CH2:3][S:4][CH3:5].ClC1C=CC=C(C(OO)=[O:46])C=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:5][S:4]([CH2:3][C:2]([NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]([C:22]2[N:23]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=3)[N:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=2)=[O:21])=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][N:16]=[CH:15]2)=[O:9])([CH3:1])[CH3:6])=[O:46]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC(C)(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cn[nH]c12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)CC(C)(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cn[nH]c12
Temperature: 25 °C
Yield: 65.4 %

Procedure:
To a mixture of 144 mg (0.26 mmol) of 6-{[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl]-amino}-1H-indazole-7-carboxylic acid (1,1-dimethyl-2-methylsulfanylethyl)-amide, prepared in example 7 in 2.88 mL of methylene chloride at 0° C. is added dropwise 64 mg (0.26 mmol) of m-chloroperbenzoic acid dissolved in 0.5 mL of methylene chloride. The mixture is stirred and let warm-up to ambient temperature within 1 hour. The reaction is quenched by the addition of an aqueous saturated sodium carbonate solution. The product is extracted with ethyl acetate (3 times) and the combined organic extracts are dried on Na2SO4, filtrated and evaporated. After a flash chromatography with hexanes and ethyl acetate as eluents, 111 mg (0.17 mmol, 75%) of a white solid are obtained; LC/MS: 568/570 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=[O:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.CC(=CC)C.[O-:27]Cl=O.[Na+].[OH-].[Na+]>CC(O)(C)C.O>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[CH2:17][C:18]([OH:27])=[O:19])=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: CC(C)(C)CN(CC=O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)CN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 91.6 %

Procedure:
To a stirred slurry of 4-[(2,2-dimethylpropyl)(2-oxoethyl)amino]-2-(trifluoromethyl)benzonitrile (1.20 g, 4.03 mmol) and 2-methyl-2-butene (4.3 mL, 40 mmol) in t-BuOH (30 mL) at rt was added a solution of NaClO2 (0.591 g of 80% tech. grade; 5.2 mmol) in NaH2PO4 buffer (6 mL, 1.5 M NaH2PO4, adjusted to pH 3.5 with 1 N HCl), dropwise over 5 min (slightly exothermic). After complete dissolution of slurried solids, the flask was stoppered with a rubber septum and placed under balloon pressure of nitrogen for 3 h. Water (100 mL) was added, the whole was adjusted to ca. pH 11 by addition of 15 wt % NaOH, and partially concentrated in vacuo. The aqueous residue was extracted with Et2O (×2), adjusted to ca. pH 1 by addition of 2 N HCl and extracted with EtOAc (×3). The combined EtOAc extracts were washed (brine), dried over Na2SO4, filtered and concentrated to dryness, affording 1.16 g of the title compound as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J=8.9 Hz, 1H), 7.01 (d, J=2.2 Hz, 1H), 6.79 (dd, J=8.9, 2.5 Hz, 1H), 4.24 (s, 2H), 3.31 (s, 2H), 1.02 (s, 9H).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)C.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)C>[C:25]([N:29]1[C:12]2[C:11](=[CH:16][C:15]([F:17])=[C:14]([F:18])[CH:13]=2)[C:10](=[O:20])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cn(C(C)(C)C)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of ethyl 3-(dimethylamino)-2-(2,4,5-trifluorobenzoyl)acrylate (64 g, 212 mmol) in a mixed solvent of Ethanol (150 mL)/Diethyl ether (300 mL) was added tert-Butylamine (44.6 mL, 425 mmol), and the reaction mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure, the resulting oily residue was dissolved in N,N-Dimethylformamide (DMF) (250 mL) and potassium carbonate (88 g, 637 mmol) was added. LCMS showed completion of the reaction after being stirred at 100° C. for 2 h. Cold water was added to the mixture, and the precipitates were collected by filtration and dried to afford ethyl 1-(tert-butyl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (60 g, 194 mmol, 91% yield) as pale yellow solid. LCMS: (M+H)+: 310.1
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[S:4][C:5]([CH3:28])([CH3:27])[CH:6]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:26])[C:22](C)(C)[CH3:23])=[CH:16][CH:15]=1)=[O:11].NC1C(=O)N2C1SC(C)(C)C2C(OCC1C=CC(OC(=O)CCC)=CC=1)=O>>[NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[S:4][C:5]([CH3:27])([CH3:28])[CH:6]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:26])[CH2:22][CH3:23])=[CH:16][CH:15]=1)=[O:11]
Reactant: CC(C)(C)C(=O)Oc1ccc(COC(=O)C2N3C(=O)C(N)C3SC2(C)C)cc1
Agent: CCCC(=O)Oc1ccc(COC(=O)C2N3C(=O)C(N)C3SC2(C)C)cc1
Product: CCC(=O)Oc1ccc(COC(=O)C2N3C(=O)C(N)C3SC2(C)C)cc1

Procedure:
6-Amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, p-(pivaloyloxy)benzyl ester; and 6-Amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, p-(butyryloxy)benzyl ester.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:19][C@H:18]3[N:14]([CH2:15][CH2:16][CH2:17]3)[C:13]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=3[C:11]2=[O:26])[CH:5]=1.[CH:28](OCC)(OCC)OCC>>[O:1]1[CH:28]=[N:27][C:3]([C:4]2[CH:5]=[C:6]([N:10]3[CH2:19][C@H:18]4[N:14]([CH2:15][CH2:16][CH2:17]4)[C:13]4[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:12]=4[C:11]3=[O:26])[CH:7]=[CH:8][CH:9]=2)=[N:2]1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(N)=NO)c1)C2=O
Reactant: CCOC(OCC)OCC
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3ncon3)c1)C2=O
Temperature: 80 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
(S)—N′-Hydroxy-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzamidine (180 mg, 0.47 mmol) obtained in Step 1 of Example 75 was suspended in triethyl orthoformate (6.0 mL), and the mixture was stirred at 80° C. for 2 days. The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-5-[3-(1,2,4-oxadiazol-3-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (144 mg, 78%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22](=O)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1.[BH3-]C#N.[Na+]>CCO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Reactant: CCOC(=O)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CCN(C(C)c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-(6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)ethanone (200 mg, 0.62 mmol) and ethyl 4-piperidinecarboxylate (146 mg, 0.93 mmol, 1.5 eq) in anhydrous EtOH (5 mL) was stirred at room temperature for 15 min, then Ti(OEt)4 (356 mg, 1.23 mmol, 2 eq) was added. The reaction mixture was stirred at reflux for 16 h under N2. After cooling to room temperature, the mixture was concentrated and the residue was dissolved in EtOH (3 mL) and NaBH3CN (125 mg, 1.85 mmol, 3 eq) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated and purified by silica gel (PE/EA=4/1) to give ethyl 1-(1-(6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)ethyl)piperidine-4-carboxylate as yellow oil (140 mg, yield: 53%). ESI-MS (M+H+): 466.4. 1H NMR (400 MHz, CDCl3) δ: 7.71-7.65 (m, 2H), 7.60 (s, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.14-7.11 (m, 2H), 4.29-4.24 (m, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.56 (br, 1H), 3.07 (br, 1H), 2.84 (br, 1H), 2.29-2.20 (m, 3H), 2.08-2.01 (m, 4H), 1.90-1.81 (m, 5H), 1.45-1.38 (m, 5H), 1.26-1.09 (m, 6H), 0.89 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[O:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[CH:22][CH:23]=2)[O:18][CH2:17]1>>[O:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][N:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:13]([CH:10]3[C:11]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=4)[CH2:7][CH2:8][CH2:9]3)=[O:15])=[CH:22][CH:23]=2)[O:18][CH2:17]1
Reactant: COc1ccc(NCc2ccc3c(c2)OCO3)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc(N(Cc2ccc3c(c2)OCO3)C(=O)C2CCCc3ccc(OC)cc32)cc1
Yield: 9.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.75 g) and [(1,3-dioxaindan-5-yl)methyl](4-methoxyphenyl)amine (0.93 g) as starting materials, N-[(1,3-dioxaindan-5-yl)methyl]-N-(4-methoxyphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.15 g) was obtained.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11](CCCCN2C(=O)C3C=CC=C4C=3C(=CC=C4)C2=O)[CH2:10][CH2:9]1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[C:48](=[O:49])[C:47]2[CH:50]=[CH:51][CH:52]=[C:45]3[C:46]=2[C:41](=[CH:42][CH:43]=[CH:44]3)[C:40]1=[O:53].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]2[C:48](=[O:49])[C:47]3[CH:50]=[CH:51][CH:52]=[C:45]4[C:46]=3[C:41](=[CH:42][CH:43]=[CH:44]4)[C:40]2=[O:53])[CH2:12][CH2:13]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCN1CCN(c2ccccn2)CC1

Procedure:
Following the procedure of part (b) of example 46 but substituting 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, one obtains 2-[5-[4-(2-pyridinyl)-1-piperazinyl]pentyl]-1H-benz[de]isoquinoline-1,3(2H)-dione, hydrochloride (1:2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]2=1.[CH3:16][CH:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18]>N1C=CC=CC=1>[O:15]=[C:11]1[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][S:19]([CH:17]([CH3:18])[CH3:16])(=[O:21])=[O:20])[C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1cccc2c3c([nH]c12)C(=O)CCC3
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1cccc2c3c([nH]c12)C(=O)CCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To a mixture of 8-amino-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.35 g) and pyridine (8 mL) was added propane-2-sulfonyl chloride (0.24 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.94 g, yield 19%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate. melting point 267-268° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[N:5][C:6]2[C:7](=O)[NH:8][CH:9]=[CH:10][C:11]=2[CH:12]=1.C1(C)C=CC=CC=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:34]>O.CCOC(C)=O>[Cl:34][C:7]1[N:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:12]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2cc(C(F)(F)F)cnc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cnc2c(Cl)nccc2c1
Temperature: 115 °C
Reaction time: 6 h
Yield: 95.7 %

Procedure:
A pressure vial was charged with 3-(trifluoromethyl)-1,7-naphthyridin-8(7H)-one (Anichem) (75 mg, 0.350 mmol), toluene (1401 μl), and Hunig's base (184 μl, 1.051 mmol). To this mixture was added POCl3 (98 μl, 1.051 mmol), and the vial was sealed. The reaction was heated at 115° C. for 2 h. After 6 h, some unreacted starting material remained. The temperature was increased to 125° C. and the reaction was stirred overnight. Upon cooling to RT, EtOAc and water were added, and the layers were separated. The aqueous portion was extracted with additional EtOAc, and the combined organic portions were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography using a gradient of 0-50% EtOAc in heptane to provide 8-chloro-3-(trifluoromethyl)-1,7-naphthyridine (78 mg, 0.335 mmol, 96%) as a tan solid. LC/MS (ESI+) m/z=233.1 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[K+]>CO>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(C2CC2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C2CC2)cn1
Temperature: 50 °C

Procedure:
To a reaction vial were added methyl 5-cyclopropylpicolinate (370 mg, 2.088 mmol) and potassium hydroxide (258 mg, 4.59 mmol) in MeOH (7 ml). The reaction mixture was heated to 50° C. for 1 h. It was concentrated and was treated with small amount of water, and acidified by 6N HCl until pH 2. Then the mixture was concentrated and MeOH was added. The white salt was filtered out and the filtrate was passed through silica plug to yield desired product as yellow solid which still contains some salt. It was used directly for next step. MS m/z=164.2 (M+H).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Br[CH2:16][N:17]1[C:21](=[O:22])[C:20]2[C:23]([CH:29]([CH3:31])[CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=2[S:18]1(=[O:33])=[O:32]>CN(C=O)C>[CH:29]([C:23]1[C:20]2[C:21](=[O:22])[N:17]([CH2:16][O:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[CH:9][CH:10]=3)[S:18](=[O:33])(=[O:32])[C:19]=2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=1)([CH3:31])[CH3:30]
Reactant: O=C1CC=NN1c1ccccc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1ccnn1-c1ccccc1)C2=O
Yield: 30.5 %

Procedure:
To a mixture of 2,4-dihydro-2-phenyl-3H-pyrazol-3-one (378 mg; 2.36 mmol) in DMF (6 ml) was added under nitrogen at room temperature 249 mg (4.3 mmol) of KF with stirring followed by 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (750 mg, 2.15 mmol). The resulting mixture was stirred at room temperature for 2 hours and then quenched with saturated ammonium chloride solution. The above mixture was extracted with ether (3×30 ml) and the organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue (yellow solid) was purified by flash chromatography (silica gel; 5% ethyl acetate in methylene chloride) to afford 280 mg (31%) of 4-isopropyl-6-methoxy-2-(1-phenylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =R3 =H; R4 =CH(CH3)2 ; R5 '6-OCH3) as a white solid, m.p. 118°-1190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:20]4[CH2:21][C:22]5[S:23][CH:24]=[CH:25][C:26]=5[C:19]=4[N:18](COCC[Si](C)(C)C)[N:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Cl>CO>[S:23]1[CH:24]=[CH:25][C:26]2[C:19]3[NH:18][N:17]=[C:16]([C:13]4[CH:12]=[CH:11][C:10]([NH:9][C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[CH:15][CH:14]=4)[C:20]=3[CH2:21][C:22]1=2
Reactant: COc1ccc(Nc2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sccc3-4)cc2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(Nc2ccc(-c3n[nH]c4c3Cc3sccc3-4)cc2)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
(4-Methoxy-phenyl)-{4-[4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-amine (0.24 g, 0.5 mmol) was dissolved in MeOH and treated with concentrated HCl (0.16 mL, 5 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding [4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenyl]-(4-methoxy-ph enyl)-amine (0.14 g, 0.40 mmol) as brown solid in 80% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[CH2:13][CH2:12][N:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].Cl>O1CCOCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:27]([F:29])([F:30])[F:28])[CH2:13][CH2:12][N:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 70.7 %

Procedure:
To the solution of methyl 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoate (1.24 g) in 1,4-dioxane was added 2N aqueous sodium hydroxide (5.4 mL), and the mixture was heated with stirring at 80° C. The mixture was cooled to room temperature and then acidified with 2N hydrochloric acid before the mixture was extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure to yield 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoic acid (0.85 g). 1H-NMR (DMSO-d6) δ: 2.58-2.72 (1H, m), 2.91-3.04 (1H, m), 3.47-3.57 (2H, m), 3.87 (1H, d), 4.32 (1H, d), 6.86 (1H, dd), 7.04 (1H, d), 7.65 (2H, d), 7.71 (1H, t), 7.78 (1H, d)