Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.COP([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(OC)=O.[H-].[Na+].[CH:22]([C:25]1[CH2:26][C@@H:27]2[C@H:30]([CH:31]=1)[C:29](=O)[CH2:28]2)([CH3:24])[CH3:23]>O>[CH:22]([C:25]1[CH2:31][C@@H:30]2[C@H:27]([CH:26]=1)[C:28](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:29]2)([CH3:24])[CH3:23]
Reactant: CC(C)C1=C[C@@H]2C(=O)C[C@@H]2C1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A tetrahydrofuran (15 mL) solution of tert-butyl dimethylphosphonoacetate (3.70 g, 16.5 mmol) was added dropwise at 0° C. over 20 minutes to a tetrahydrofuran (15 mL) suspension of sodium hydride (0.68 g, 63%, 18.0 mmol), and the mixture was stirred at 0° C. for 20 minutes. To this solution, a tetrahydrofuran (15 mL) solution of (±)-(1S,5R)-3-isopropylbicyclo[3.2.0]hept-3-en-6-one (2.25 g, 15.0 mmol) was added dropwise at 0° C. over 15 minutes, and the mixture was stirred at room temperature for 2 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (3.00 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]([CH3:35])([CH3:34])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:25][C:26]([CH3:35])([CH3:34])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Yield: 51.3 %

Procedure:
A solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.323 mmol), tert-butyl 2-amino-2-methylpropanoate hydrochloride (82 mg, 0.42 mmol), HATU (160 mmol, 0.42 mmol) and DIPEA (66 mg, 0.51 mmol) in 6 mL of DMF was stirred at room temperature for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:1, v/v) to give tert-butyl 2-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-2-methylpropanoate (75 mg, 51.8%) as a white solid. MS: (M+H)+=453; 1H NMR (300 MHz, DMSO): δ 13.93 (s, 1H), 9.13 (s, 1H), 8.57-8.52 (m, 1H), 8.48 (s, 1H), 8.30 (s, 1H), 7.72 (dd, 1H, J=9.8, 2.1 Hz), 7.21-7.15 (m, 1H), 4.18 (s, 3H), 1.63 (s, 6H), 1.25 (s, 9H).
Reaction SMILES: O=S(Cl)Cl.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:17]O>>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1
Reactant: CO
Reactant: O=C(O)CCc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Neat SOCl2 (25.7 g, 216.7 mmol) was added dropwise to a −60° C. solution of MeOH (100 mL). Upon completion of the addition, 3-(4-chlorophenyl)propanoic acid (10.0 g, 54.1 mmol) was added in several portions. Upon completion of the addition, the cooling bath was removed, and the reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was then concentrated to dryness, and the resulting residue was dissolved in DCM (100 mL), washed with saturated NaHCO3, dried (MgSO4), filtered, and concentrated to give methyl 3-(4-chlorophenyl)propanoate as an oil (10.48 g, 97%).
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].C1O[C@@H]2[C@H](O)CO[C@@H]2[C@@H]1O.C1O[C@@H]2[C@@H](O)CO[C@@H]2[C@H]1O.[OH:31][CH2:32][C@@H:33]([C@H:35]([C@@H:37]([C@@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[OH:36])[OH:34].C(O)[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@H:2]1[OH:10].[O:31]=[CH:32][C@@H:33]([C@H:35]([C@@H:37]([C@H:39]([CH2:41][OH:42])[OH:40])[OH:38])[OH:36])[OH:34]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Isohexide starting materials can be obtained by known methods of making respectively isosorbide, isomannide, or isoidide. Isosorbide and isomannide can be derived from the dehydration of the corresponding sugar alcohols, D-sorbitol and D mannitol. As a commercial product, isosorbide is also available easily from a manufacturer. The third isomer, isoidide, can be produced from L-idose, which rarely exists in nature and cannot be extracted from vegetal biomass. For this reason, researchers have been actively exploring different synthesis methodologies for isoidide. For example, the isoidide starting material can be prepared by epimerization from isosorbide. In L. W. Wright, J. D. Brandner, J. Org. Chem., 1964, 29 (10), pp. 2979-2982, epimerization is induced by means of Ni catalysis, using nickel supported on diatomaceous earth. The reaction is conducted under relatively severe conditions, such as a temperature of 220° C. to 240° C. at a pressure of 150 atmosphere. The reaction reaches a steady state after about two hours, with an equilibrium mixture containing isoidide (57-60%), isosorbide (30-36%) and isomannide (5-7-8%). Comparable results were obtained when starting from isoidide or isomannide. Increasing the pH to 10-11 was found to have an accelerating effect, as well as increasing the temperature and nickel catalyst concentration. A similar disclosure can be found in U.S. Pat. No. 3,023,223, which proposes to isomerize isosorbide or isomannide. More recently, P. Fuertes proposed a method for obtaining L-iditol (precursor for isoidide), by chromatographic fractionation of mixtures of L-iditol and L-sorbose (U.S. Patent Publication No. 2006/0096588; U.S. Pat. No. 7,674,381 B2). L-iditol is prepared starting from sorbitol. In a first step sorbitol is converted by fermentation into L-sorbose, which is subsequently hydrogenated into a mixture of D-sorbitol and L-iditol. This mixture is then converted into a mixture of L-iditol and L-sorbose. After separation from the L-sorbose, the L-iditol can be converted into isoidide. Thus, sorbitol is converted into isoidide in a four-step reaction, in a yield of about 50%. (The contents of the cited references are incorporated herein by reference.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[CH3:10]OS(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-5-methylphenol (14.2 g, 1 equiv), Me2SO4 (10.5 mL, 1.1 equiv) and K2CO3 (27.6 g, 2 equiv) in 150 mL of THF was stirred at rt overnight. Ethyl acetate and water were added and the organic layer was dried over sodium sulfate, filtered and evaporated to give 2-chloro-5-methylanisole as a crude product.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)[C:5]([F:22])=[C:4]([F:23])[N:3]=1.[Cl:24]C(OCCCl)=O>ClCCCl>[ClH:24].[F:23][C:4]1[C:5]([F:22])=[C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:7]([F:8])=[C:2]([F:1])[N:3]=1
Reactant: Fc1nc(F)c(F)c(N2CCN(Cc3ccccc3)CC2)c1F
Reactant: O=C(Cl)OCCCl
Solvent: ClCCCl
Product: Cl
Product: Fc1nc(F)c(F)c(N2CCNCC2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To an ice bath cooled, stirred solution of 1-(2,3,5,6-tetrafluoropyridin-4-yl)-4-benzylpiperazine (Method 20; 4.59 g, 14.1 mmol) in 1,2-dichloroethane (40 ml) was added chloroethyl chloroformate (1.6 ml, 14.7 mmol) over five minutes. The solution was heated to reflux and stirred for two hours and allowed to cool to ambient temperature. Volatile material was removed by evaporation. The residue was dissolved in methanol, heated to reflux and stirred for 2.5 hours, allowed to cool to ambient temperature. Volatile material was removed by evaporation. The residue was purified by chromatography eluting with 5-10% MeOH in DCM to give a solid which was triturated with ether to give the title compound (2.57 g) as a solid. NMR 3.05 (m, 4H), 3.53 (m, 4H); m/z 236.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:27][CH:28]2[CH2:30][CH2:29]2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: BrCC1CC1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCC4CC4)nc3N21
Reaction time: 3 h
Yield: 67.1 %

Procedure:
To a solution of 1.2 g (37.6 mmol) (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 30 ml N,N-dimethylformamide was added 0.18 g (41.4 mmol) sodium hydride. After 30 min 0.72 ml (1.01 g, 75.2 mmol) (bromomethyl)cyclopropane was added and the reaction was stirred for 3 h. The reaction mixture was poured into 10% aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (0.032–0.063 mm) with a gradient of ethyl acetate:n-hexane (1:1 to 100:0) as eluant to afford the compound as a light yellow oil (67.1%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:20][C:21]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([NH:34][NH2:35])=O)=[C:27]2[C:22]=1[CH2:23][CH2:24][CH2:25][O:26]2>>[Cl:31][C:30]1[C:21]([NH2:20])=[C:22]2[C:27](=[C:28]([C:32]3[O:14][C:12]([CH2:11][CH:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[N:35][N:34]=3)[CH:29]=1)[O:26][CH2:25][CH2:24][CH2:23]2
Reactant: O=C(O)CC1CCN(C2CCC2)CC1
Reactant: NNC(=O)c1cc(Cl)c(N)c2c1OCCC2
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1c(Cl)cc(-c2nnc(CC3CCN(C4CCC4)CC3)o2)c2c1CCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To the (1-cyclobutyl piperidin-4-yl) acetic acid (725 mg, 3.52 mmol, obtained in preparation 4) was added phosphoryl chloride (4 mL). The mixture was stirred for 15 minutes and 5-Amino-6-chloro-chroman-8-carboxylic acid hydrazide (500 mg, 2.0 mmol) was added. The reaction mixture was gradually heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, triturated with hexanes (2×20 mL) and the crude mass was basified with aqueous sodium bicarbonate solution. The basified mixture was extracted with 10% methanol in dichloromethane. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure and was purified by silica gel column to obtain 6-chloro-8-[5-(1-cyclobutyl piperidin-4-ylmethyl)-[1,3,4]oxadiazol-2-yl]chroman-5-yl amine (250 mg). Yield: 30%.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15]CC3C=CC=CC=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[Cl:31])[NH2:27].Cl>C(O)(C)C.C(OCC)C.C(#N)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:3]2[C:12]3[C:7](=[CH:8][C:9]([OH:15])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: CC#N
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Temperature: 25 °C
Yield: 94.1 %

Procedure:
4-Chloro-6-(methyloxy)-7-[(phenylmethyl)oxy]quinazoline hydrochloride (22.91 g, 67.9 mmol) was suspended in isopropanol followed by addition of 3,4-dichloroaniline (13.2 g, 81.5 mmol) and concentrated aqueous hydrochloric acid (1 mL). The mixture was brought to reflux over 12 hours and diluted with ethyl ether (150 mL). The solid was collected by filtration, washed with additional ethyl ether and dried. The material was then taken into trifluoroacetic acid (150 mL) and brought to reflux over 1 hour. The solution was cooled to room temperature then concentrated in vacuo to give a crystalline residue. The residue was suspended in acetonitrile (100 mL) followed by addition of ethyl ether (100 mL). The solid was collected by filtration and washed with additional ethyl ether then dried in vacuo to give 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (21.49 g, 64% yield) as a tan solid. 1H NMR (400 MHz, d6-DMSO): 11.09 (br s, 1H), 8.87 (s, 1H), 8.07 (d, 1H), 8.00 (s, 1H), 7.23 (s, 1H), 3.98 (s, 3H); MS (EI) for C15H11N3O2Cl2: 337 (MH+).
Reaction SMILES: [C:1]([O:4][CH:5](P(OCC)(OCC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Li+].[Cl-].CN(C)C(N(C)C)=N.[CH3:29][Si:30]([CH3:61])([CH3:60])[CH2:31][CH2:32][O:33][CH2:34][N:35]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[C:36]1[N:41]2[N:42]=[CH:43][CH:44]=[C:40]2[N:39]=[C:38]([CH:45]2[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]2)[CH:37]=1>C1COCC1.C(Cl)Cl>[C:1]([O:4][C:5](=[C:48]1[CH2:49][CH2:50][CH:45]([C:38]2[CH:37]=[C:36]([N:35]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[CH2:34][O:33][CH2:32][CH2:31][Si:30]([CH3:61])([CH3:29])[CH3:60])[N:41]3[N:42]=[CH:43][CH:44]=[C:40]3[N:39]=2)[CH2:46][CH2:47]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(OC(C)=O)P(=O)(OCC)OCC
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(OC(C)=O)=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 100 mL roundbottom flask was charged ethyl 2-acetoxy-2-(diethoxyphosphoryl)acetate (1121 mmol, 3.16 g), LiCl (11.21 mmol, 475 mg), and THF (25 mL). The flask was then flushed with argon, sealed, and cooled to −78° C. in a dry ice/IPA bath. Added dropwise to this solution was a solution of 1,1,3,3-tetramethylguanidine (11.21 mmol. 1.41 g) in THF (5 mL). The resulting solution was allowed to stir at −78° C. for 30 minutes. At 30 minutes, 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone (5.09 mmol, 2.50 g) was added in THF (3 mL). The reaction was then allowed to slowly warm to room temperature and then stirred for 48 hours. After 48 hours, the reaction was diluted with DCM (100 mL) and washed with H2O (50 mL). The organic layer was collected, dried over Na2SO4, and reduced in vacuo. The resulting residue was purified via flash chromatography to yield the title compound.
Reaction SMILES: [O:1]1CCC[CH2:2]1.[CH2:6]([SH:8])[CH3:7].C([Li])CCC.BrCC([C:18]([N:30]([CH2:33][CH3:34])[CH2:31]C)=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=O>C(Cl)(Cl)Cl>[CH2:6]([S:8][C:34]1[C:2](=[O:1])[C:19]([C:20]2[CH:21]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:24][CH:25]=2)=[CH:18][N:30]([CH3:31])[CH:33]=1)[CH3:7]
Reactant: CCS
Reactant: CCN(CC)C(=Cc1cccc(C(F)(F)F)c1)C(=O)CBr
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Product: CCSc1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 10 ml. of anhydrous tetrahydrofuran at -20° C. were added 1.3 g. of ethanethiol and 13 ml. of 1.6 M n-butyllithium solution and the mixture was stirred under nitrogen for 15 minutes. The solution was allowed to warm to room temperature and a solution of 7.24 g. of α-bromoacetyl-β-diethylamino-3-trifluoromethylstyrene in 10 ml. of tetrahydrofuran was added. The mixture was stirred and heated under reflux overnight. The tetrahydrofuran was stripped off to leave an oil which was dissolved in chloroform and the solution was washed with 1 N hydrochloric acid, 0.1 N sodium hydroxide and saturated sodium chloride. Removal of the chloroform left an oil. One gram of this oil was removed and the remainder was heated under reflux with 25 ml. of N,N-dimethylformamide dimethylacetal for 3 days. The excess dimethylformamide acetal was stripped off and a solution of 5.0 grams of methylamine hydrochloride in 50 ml. of ethanol was added. This solution was heated under reflux for 24 hours. The reaction was poured into methylene chloride and the resulting solution was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and saturated sodium chloride, then dried over magnesium sulfate, filtered, and the solvent stripped. The residue was triturated under diisopropyl ether to give crystalline 3-ethylthio-1-methyl-5 -(α,α,α-trifluoro-m-tolyl)-4(1H)-pyridone, m.p. 84°-85° C. The overall yield was 2.5 g. (40%).
Reaction SMILES: C(OC([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[CH:13][C:14]([C:20](=[O:22])[CH3:21])=[CH:15][C:16]=32)[CH2:9]1)=O)(C)(C)C.[ClH:23].CCOC(C)=O>>[ClH:23].[CH:17]12[CH2:19][CH:10]([CH2:9][NH:8][CH2:18]1)[C:11]1[CH:12]=[CH:13][C:14]([C:20](=[O:22])[CH3:21])=[CH:15][C:16]2=1
Reactant: CC(=O)c1ccc2c(c1)C1CC2CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(c1)C1CNCC2C1
Temperature: 70 °C

Procedure:
4-Acetyl-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (190 mg, 0.63 mmol) was treated with excess 3N HCl EtOAc and warmed to 70° C. for 1 hour then concentrated and dissolved in a minimum of MeOH. The resulting solution was saturated with Et2O and stirred. After 18 hours the white crystalline product was collected by filtration (81 mg, 54%). 1H NMR (400 MHz, DMSO-d6) δ9.75 (br s, NH), 7.89 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.74 (br s, NH), 7.44 (d, J=8.0 Hz, 1H), 3.33 (br s, 2H), 3.22 (br s, 2H), 3.00 (br m, 2H), 2.5 (s, 3H), 2.17 (m, 1H), 2.02 (d, J=11.0 Hz, 1H). GCMS m/e 201 (M+). mp 198-202
Reaction SMILES: [C:1]1([CH:7]([C:9]2[C:18]3[C:13](=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:23]([F:26])([F:25])[F:24])[CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:30].O>C1COCC1>[CH3:30][O:8][CH:7]([C:9]1[C:18]2[C:13](=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:23]([F:26])([F:24])[F:25])[CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: OC(c1ccccc1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(c1ccccc1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 81.9 %

Procedure:
A solution of α-phenyl-2,8-bis(trifluoromethyl)quinoline-4-methanol (50 mg, 0.13 mmol) in anhydrous THF (4 mL) was treated with NaH (18 mg, 60% dispersion in oil, 0.44 mmol), stirred at room temperature for 2 min, treated with iodomethane (0.8 mL, 1.2 mmol) and stirred for 15 min. The solution was then treated with water (10 mL), extracted with ether (2×10 mL), the extracts washed with water (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; heptane-EtOAc (10:1)] to give the title compound (41 mg, 79%) as a pale solid: mp 115-117° C.; IR νmax (liquid film)/cm−1 3070, 2929, 2854, 1589, 1588, 1517, 1491, 1456, 1429, 1378, 1210, 1276, 1211, 1184, 1164, 1129 and 1101; NMR δH (400 MHz, CDCl3) 3.47 (3H, s), 5.90 (1H, s), 7.29-7.35 (5H, m), 7.60-7.64 (1H, t J 8 Hz) and 8.25 (1H, d J 8 Hz).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)=[O:4].[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=2)=[O:4])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CS(=O)(=O)Nc1ccc(NC(=O)CCl)cc1
Solvent: CCCCCC
Product: CS(=O)(=O)Nc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-methanesulfonylamino-phenyl)-acetamide and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 102-106° C. (hexane)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:31])([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[SH:33][CH:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:28]([N:17]1[C:16](=[O:32])[C:15]([NH:14][CH2:13][CH2:12][S:33][CH:34]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]2)=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18]1(=[O:26])=[O:27])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(S)C1
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(SCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)C1
Temperature: 120 °C
Yield: 84 %

Procedure:
2-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (150 mg, 0.313 mmol) was dissolved in dry MeCN (3 mL) under nitrogen atmosphere. tert-Butyl 3-mercaptopyrrolidine-1-carboxylate (10 mg, 0.345 mmol) was added followed by potassium carbonate (217 mg, 1.567 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. Potassium carbonate was filtered off and the reaction mixture was evaporated to dryness in a vacuum centrifuge. The crude product was purified by preparative HPLC affording the title compound (134 mg, 83.4%). The product is a mixture of cis and trans isomers. 1H NMR (CDCl3, 500M): δ 1.47 (s, 9H), 1.73 (s, 10H), 2.05 (s, 1H), 2.46-2.51 (m, 2H), 2.88 (bs, 1H), 3.01-3.13 (m, 3H), 3.29 (s, 1H), 3.41-3.57 (m, 2H), 5.65 (bs, 1H), 7.43-7.46 (m, 3H), 7.49-7.53 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 27.83, 28.73, 31.29, 32.33, 32.86, 41.74, 42.41, 43.23, 44.86, 45.09, 52.27, 52.53, 61.86, 79.79, 108.04, 125.15, 129.04, 130.04, 131.65, 134.81, 154.41, 159.66; Mass Spectrum: M+H+ 509.9.