Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[O:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH+:7]([O-:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.[CH2:17]1[CH2:21]OC[CH2:18]1>>[CH2:18]([O:12][N:7]1[C:6]([CH3:14])([CH3:13])[CH2:5][CH:4]([O:3][Si:2]([CH3:1])([CH3:15])[CH3:16])[CH2:9][C:8]1([CH3:10])[CH3:11])[CH2:17][CH3:21]
Reactant: C1CCOC1
Reactant: CC1(C)CC(O[Si](C)(C)C)CC(C)(C)[NH+]1[O-]
Product: CCCON1C(C)(C)CC(O[Si](C)(C)C)CC1(C)C

Procedure:
In another reaction vessel, 96.2 g (394 mmol) of 4-trimethylsilyloxy-2,2,6,6-tetramethylpiperidine-N-oxide was dissolved in 100 ml of dehydrated THF, and the Grignard reactant prepared was dropped at 0° C. After a reaction for 3 hours, the solution was concentrated by a rotary evaporator. 500 mL of water was added to the residue and an extraction was carried out using 500 mL in total of ethyl acetate, and the organic layer was concentrated by a rotary evaporator. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate=20/1, volume ratio) to obtain 38.5 g of 1-(1-propyl)oxy-2,2,6,6-tetramethyl-4-trimethylsilyloxypiperidine.
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22](OCC)=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>CO.CN(C)C=O>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([NH:30][CH2:29][CH2:27][OH:28])=[O:23])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccccc3)nc1-2
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1nc(C(=O)NCCO)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Temperature: 65 °C
Yield: 60 %

Procedure:
To a suspension of 0.30 g (0.86 mmol) of ethyl 8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate in a mixture of 10 mL of methanol and 10 mL of dimethylformamide, 5 mL of ethanolamine were added. The mixture was heated in a close bottle under stirring at 65° C. After 5 hours the solvent was removed, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and evaporated. The residue was triturated with diethyl ether and the product collected by filtration (60% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[C@H:3]([NH:12][C:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]=1)[C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].[F:20][C:21]([F:42])([F:41])[C:22]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:42][C:21]([F:20])([F:41])[C:22]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][CH:28](/[CH:31]=[C:17]2/[C:13]([NH:12][C@H:3]([C:4]([N:6]3[CH2:7][CH2:8][O:9][CH2:10][CH2:11]3)=[O:5])[CH:2]([CH3:19])[CH3:1])=[N:14][C:15](=[O:18])[S:16]/2)[CH2:27][CH2:26]1
Reactant: CC(C)[C@H](NC1=NC(=O)SC1)C(=O)N1CCOCC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N1CCOCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of 4-{[(2S)-3-methyl-1-(morpholin-4-yl)-1-oxobutan-2-yl]amino}-1,3-thiazol-2(5H)-one (371 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (441 mg) in 2-propanol (10 mL) was added piperidinium acetate (189 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (416 mg).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH:20]1[CH2:24][CH2:23][CH2:22][O:21]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH:20]3[CH2:24][CH2:23][CH2:22][O:21]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CCCO1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OCC1CCCO1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-hydroxymethyl-tetrahydrofuran, there is obtained 2-tetrahydrofurylmethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 322 (14), 237 (66), 194 (100), 85 (36), 71 (12);
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:13])=[C:4]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)[N:5]=[N:6][CH:7]=1.[CH:14](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:3]2[N:13]=[CH:14][N:8]([CH:9]3[CH2:12][CH2:11][CH2:10]3)[C:4]=2[N:5]=[N:6][CH:7]=1
Reactant: Nc1c(Cl)cnnc1NC1CCC1
Reactant: CCOC(OCC)OCC
Product: Clc1cnnc2c1ncn2C1CCC1
Temperature: 140 °C
Yield: 54 %

Procedure:
A mixture of 5-chloro-N3-cyclobutylpyridazin-3,4-diamine (Preparation 98, 140 mg, 0.70 mmol) and triethyl orthoformate (4 mL) was heated at 140° C. for 4 hours. After evaporation in vacuo, the crude residue was purified by silica gel column chromatography eluting with CH2Cl2:MeOH 99:1 to afford the title compound as an off white solid in 54% yield, 80 mg.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][N:33]=[C:34]=[O:35]>CCCCCC>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:34]([NH:33][CH3:32])=[O:35])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN=C=O
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: CCCCCC
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)NC
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (0.30 g, 0.0007 mol) in hexane (15 mL) was added methylisocyanate (0.06 mL, 0.057 g, 0.001 mol) and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed with 1:1 hexane-ethyl acetate . The resulting oil was triturated with hexane to give the title compound (0.23 g, 0.00047 mol) as a white solid, mp 93°-96°.1H NMR (CDCl3) δ 7.6-7.2(m, 11H), 4.35-2.7(m, 9H), 1.9-1.2(m, 16H), 0.9(t,3H, J=8 Hz).
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH:23]=O)[CH2:6]1)(=[O:3])[CH3:2].[CH2:25]([SH:28])[CH2:26][SH:27].B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([CH:23]2[S:28][CH2:25][CH2:26][S:27]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@H]1C[C@@H](C=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: SCCS
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)S[C@H]1C[C@@H](C2SCCS2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-formyl-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (1.00 g) and 1,2-ethanedithiol (0.36 ml) in dichloromethane (20 ml) was added boron trifluoride etherate (0.1 ml), and the solution was stirred for 14 hours at ambient temperature. To the mixture was added saturated aqueous sodium hydrogen carbonate and the organic layer was separated, and washed with brine. The organic layer was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (50 ml) and eluted with a mixture of acetone and dichloromethane (2:98, V/V) to give (2S, 4S)-4-acetylthio-2-(1,3-dithiolan-2-yl) -1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][C:6]([CH2:7][N:8]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:32][N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=[CH:5][CH:4]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[F:29][C:27]1[CH:28]=[C:23]([NH:22][C:21]2[C:16]([C:11]3[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([N:8]([CH2:7][C:6]4[CH:55]=[CH:56][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:46][C:47]4[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=4)[N:10]=3)=[CH:17][C:18]([CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:19][N:20]=2)[CH:24]=[N:25][C:26]=1[O:30][CH3:31]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCNCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slightly cooled stirred solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (8.77 g, 11.45 mmol) in DCM (25.00 mL, 389 mmol) was treated with TFA (15.00 mL, 195 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residual sticky material was taken up in DCM (100 mL) and carefully quenched with saturated NaHCO3(aq) until slightly basic. The aqueous layer was extracted with DCM (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine as a yellow solid. A portion of this solid (0.349 g, 0.524 mmol) was dissolved in DCM (5.00 mL, 78 mmol) and Et3N (0.365 mL, 2.62 mmol) at −15° C. The mixture was treated slowly with dimethylcarbamic chloride (0.169 g, 1.573 mmol) and stirred for 1 h before warming up to room temperature overnight. The reaction mixture was concentrated, the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (10 to 100% EtOAc in hexanes) to give 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N,N-dimethylpiperazine-1-carboxamide (0.3555 g, 92%) as a yellow solid (ESI, +ve ion) 736.7 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:11][CH2:10]2)[O:8][C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:18]=2)[C@@H:6]1[O:32][C:33](=[O:35])[CH3:34])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[O:42]1[CH2:46][CH2:45][C@@H:44](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:43]1>CN(C=O)C.O>[C:33]([O:32][C@@H:6]1[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C:9]2([CH2:10][CH2:11]2)[O:8][C@H:7]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C@H:44]3[CH2:45][CH2:46][O:42][CH2:43]3)=[CH:29][CH:30]=2)[CH:18]=1)(=[O:35])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc(O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc(O[C@H]3CCOC3)cc2)c1
Temperature: 60 °C

Procedure:
To a solution of Acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester (120 mg, 0.22 mmole) in DMF (3 mL), cesium carbonate (85 mg, 0.27 mmole), Toluene-4-sulfonic acid (R)-(tetrahydro-furan-3-yl)ester (65 mg, 0.27 mmole) was added at room temperature and heated at 60° C. for 6 hours. The reaction mixture was diluted with water (20 mL), and extracted with dichloromethane (2×50 mL). Crude (5S,6S,7R,8S)-5-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)phenyl)-4-oxaspiro[2.5]octane-6,7,8-triyl triacetate obtained after the removal of solvent used for next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:19])([C:14]#[C:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([F:13])([F:12])[F:11].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:20](=[O:21])[O:19][C:9]([C:14]#[C:15][CH:16]3[CH2:18][CH2:17]3)([C:10]([F:13])([F:11])[F:12])[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(O)(C#CC1CC1)C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C(C#CC2CC2)(C(F)(F)F)O1
Yield: 100.4 %

Procedure:
A solution of 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (15.00 g, 0.0518 mol) and 41.98 g (0.259 mol) of 1,1'-carbonyldiimidazole in 250 mL of dry THF was stirred under argon at 55° C. for 24 hours. The solvent was removed on a rotary evaporator and the residue was partitioned between 500 mL of ethyl acetate and 400 mL of water. The layers were separated and the aqueous phase was extracted once more with ethyl acetate. The combined ethyl acetate extracts were washed with 2×200 mL of 2% aqueous HCl, saturated aqueous NaHCO3, and brine. Drying over MgSO4, filtration, and removal of the solvent in vacuo provided 16.42 g of the title compound as a solid. Recrystallization from ethyl acetate-hexane afforded 12.97 g of analytically pure (±)6-chloro-4-cyclo-propylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white crystals. mp: 178°-180° C. 1H-NMR (CDCl3): 0.85 (m, 2H), 0.94 (m, 2H), 1.40 (m, 1H), 6.81 (d, J=8.5 Hz, 1H), 7.37 (dd, J=2.5, 8.5 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H), 8.87 (br s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[CH:55]=[C:54]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)[CH:53]=[N:52][CH:51]=1>CN(C=O)C>[N:50]1[CH:55]=[C:54]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)[CH:53]=[N:52][CH:51]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cncnc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cncnc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 61.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyrimidin-5-yl-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.015 g of product in 62% yield: LCMS (ESI) m/z 374 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[N:29]=[C:30]2[N:34]([C:35]=1[S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:32][S:31]2>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:36]([C:35]2[N:34]3[C:30]([S:31][CH:32]=[CH:33]3)=[N:29][C:28]=2[Cl:27])(=[O:37])=[O:38])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1c(Cl)nc2sccn12
Yield: 67.7 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride (Maybridge, 132 mg, 0.52 mmol) in THF. 172 mg (65%) of 102 was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28]>O1CCCC1>[CH2:1]([N:10]1[CH2:11][CH2:12][N:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:27]1=[S:28])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: S=C(Cl)Cl
Reactant: C(=C/c1ccccc1)\CNCCNc1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a solution of 5.37 g of (E)-N-cinnamyl-N'-(3-pyridyl)ethylenediamine dissolved in 100 ml of tetrahydrofuran, 4.5 g of triethylamine was added and the mixture was ice-cooled. To the mixture was added dropwise 20 ml of a tetrahydrofuran solution containing 5.12 g of thiophosgene over 5 minutes, and subsequently the mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 2 hours. The solvent was distilled off, and the residue was dissolved in chloroform, washed with water and dried, followed by distillation of the solvent. The residue was purified by silica gel column chromatorgraphy (solvent: chloroform-methanol=20:1) to give 2.86 g of (E)-1-cinnamyl-3-(3-pyridyl)imidazolidine-2-thione as caramel.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:34]1[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:41])[F:40])=[CH:38][C:33]=1[F:32])=[N:3][CH:4]=[CH:5]2)(=[O:14])=[O:13]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4F)nccc3c2)c(OC)c1
Temperature: 90 °C
Yield: 85.5 %

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO; 0.250 g, 0.525 mmol), (2-fluoro-4-(trifluoromethyl)phenyl)boronic acid (0.164 g, 0.788 mmol), Pd(PPh3)4 (0.061 g, 0.053 mmol), and potassium carbonate (0.363 g, 2.63 mmol). Dioxane (2.63 mL) and Water (0.875 mL) were added, the vial was flushed with argon and sealed, and heated in a microwave reactor at 90° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 50% EtOAc:Heptane) to afford N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.271 g, 0.449 mmol, 85% yield) as a white solid. N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (35 mg, 0.058 mmol) was dissolved in 1 mL of DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated, dissolved in methanol, and passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford 1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.92 (br. s., 1H), 8.77 (d, J=5.7 Hz, 1H), 8.62 (d, J=1.6 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H), 7.99-7.91 (m, 2H), 7.89-7.77 (m, 3H), 7.27 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H). m/z (ESI) 454.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH:7]1[CH2:16][CH2:15][CH2:14][CH:8]12.[C-:24]#[N:25].[K+].C1OCCOCCOCCOCCOCCOC1>>[OH:13][C:11]1[CH:10]=[C:9]2[C:4]([CH2:5][CH:6]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)[CH:7]3[CH2:16][CH2:15][CH2:14][CH:8]32)=[C:3]([CH2:2][C:24]#[N:25])[CH:12]=1
Reactant: [C-]#N
Reactant: Oc1ccc(C2Cc3c(CBr)cc(O)cc3C3CCCC23)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Product: N#CCc1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21

Procedure:
Combine 6-Bromomethyl-4-(4-hydroxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-8-ol (0.037 g, 0.1 mmol), KCN (0.010 g, 0.15 mmol), and 18-crown-6 (0.043 g, 0.16 mmol) and heat at 80° C. for 2 hours. Cool, add ice and extract with ethyl acetate. Wash organic layer with sodium bicarbonate solution sat., then water. Dry over anhydrous sodium sulfate and concentrate to a residue which yields, after separation on silica gel with 33% EtOAC/hexanes, the titled compound (0.022 g, 70%). 1H NMR (DMSO-d6) 9.27(s, 1H), 9.18 (s, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.73 (d, J=7.9 Hz, 2H), 6.66 (s, 1H), 6.59 (s, 1H), 3.95 (s, 2H), 3.4 (m, 1H presumed), 3.0 (m, 1H), 2.76 (m, 1H), 2.65 (m, 1H), 2.45(m, 1H) 2.15 (m, 1H), 1.6-1.2 (m, 5H). MS m/z 318 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C@:7]23[CH2:14][C@H:13]([NH2:15])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[C:8]3=[O:25])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@:7]23[CH2:14][C@H:13]([NH:15][C:28](=[O:30])[CH3:29])[CH2:12][N:11]2[C:10](=[O:16])[N:9]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[C:8]3=[O:25])=[CH:26][CH:27]=1
Reactant: N[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@@]2(Cc2ccc(Br)cc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@@]2(Cc2ccc(Br)cc2)C1
Reaction time: 5 h

Procedure:
To a solution of (5R,7S)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-7-amino-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.103 g) in THF (4 mL) was added acetic anhydride (0.031 mL). After 5 hours, the reaction mixture was concentrated and purified by chromatography (silica gel: CH2Cl2, Chromatotron) to afford the titled compound (0.125 g). MS (m/z) 510 (MH+). mp 140.7° C.