Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:17])=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])(=[O:8])=[O:7])(C)(C)C.Cl.[CH2:19](O)[CH3:20]>>[Cl:17][C:11]1[S:10][C:9]([S:6](=[O:7])(=[O:8])[NH2:5])=[C:13]([C:14]([O:16][CH2:19][CH3:20])=[O:15])[CH:12]=1
Reactant: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cc(Cl)sc1S(N)(=O)=O
Yield: 96 %

Procedure:
A solution of 2-(N-tert-butylsulfamoyl)-5-chlorothiophene-3-carboxylic acid (60.0 g; 0.201 mol) made by the procedure described by B. Unterhalt and S. Moghaddam, Pharmazie 49, 115-117 (1994) in 700 ml of abs. ethanol saturated with hydrogen chloride was heated with stirring at reflux for 17 h. The cooled solution was evaporated to dryness and the residue was purified by trituration with water and dried to give 52.3 g (96%) of the title compound; 1H-NMR (DMSO-d6): δ 1.31 (t, J=7 Hz, 3H, CH3), 4.32 (q, J=7 Hz, 2H, CH2), 7.55 (s, 1H), 7.77 (br. s, 2H, NH2).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[Br:33][C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=1.CN(C=O)C>CCOC(C)=O.O>[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]2)=[C:36]([C:41]([F:44])([F:42])[F:43])[CH:35]=1
Reactant: FC(F)(F)c1cc(Br)ccc1S
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCSc2ccc(Br)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
tert-Butyl 4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)piperidine-1-carboxylate (2.65 g) and potassium carbonate (2.0 g) were added to a mixture of 4-bromo-2-(trifluoromethyl)benzenethiol (1.8 g) and DMF (20 mL) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was further stirred at 80° C. for 3 hours. After the reaction mixture was cooled to room temperature, water (50 mL) and EtOAc (30 mL) were added thereto, then extraction thereof was performed using EtOAc, and the extract was washed with saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=100:0 to 80:20), whereby tert-butyl 4-(2-{[4-bromo-2-(trifluoromethyl)phenyl]sulfanyl}ethyl)piperidine-1-carboxylate (2.83 g) was obtained as a colorless oil.
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[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.Br[CH2:37][CH2:38][N:39]1[C:43](=[O:44])[C:42]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]2[C:40]1=[O:49]>>[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[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:37][CH2:38][N:39]3[C:43](=[O:44])[C:42]4=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]4[C:40]3=[O:49])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(CCN5C(=O)c6ccccc6C5=O)c4=O)CC3)c2cc1OC
Yield: 31 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 478.0 mg (1.00 mol) of Compound 24 was used and N-(2-bromoethyl)phthalimide was used in place of methyl iodide. As a result, 200 mg (yield: 31%) of Compound 33 was obtained as pale yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:22])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)Oc1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (9.3 mg, 36 μmol) in 10 mL of dichloromethane was cooled to −5° C. and a solution of phenyl chloroformate (7 mg, 45 μmol) in 1.5 mL of dichloromethane was added, with argon bubbling to facilitate mixing. The mixture was then allowed to warm to room temp. while being vortexed for 10 min. Aminomethylpolystyrene (ca. 80 mg, 1 meq/g, 100-200 mesh, Bachem) was added to quench excess chloroformate, and the mixture was refluxed and vortexed for several hours. The mixture was chromatographed through a short plug of silica gel with 10:1 dichloromethane-methanol as eluant to isolate the product as a solid. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.76 (t, J=5.6 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.45 (t, J=7 Hz, 1H), 7.34 (t, J=8.2 Hz, 2H), 7.27 (t, J=7.5 Hz, 1H), 7.18 (t, J=7.3 Hz, 1H), 7.00 (d, J=8.6 Hz, 2H), 6.65 (bs, 2H), 4.64 (t, J=7 Hz, 2H), 3.10 (q, J=6 Hz, 2H), 1.92 (quintet, J=7 Hz, 2H), 1.52 (quintet, J=7 Hz, 2H). MS (APCI) m/e 376.15 (M+H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][N:34]([CH3:37])[C:33]2=[O:38])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@@H:40]1[C:71](=[O:72])[N:42]2[C:43]([C:55]([O:57][CH:58]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])=[C:44]([CH2:47][S:48][C:49]3[N:53]([CH3:54])[N:52]=[N:51][N:50]=3)[CH2:45][S:46][C@H:41]12.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][N:34]([CH3:37])[C:33]2=[O:38])/[C:27]([NH:39][C@@H:40]2[C:71](=[O:72])[N:42]3[C:43]([C:55]([O:57][CH:58]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)=[O:56])=[C:44]([CH2:47][S:48][C:49]4[N:53]([CH3:54])[N:52]=[N:51][N:50]=4)[CH2:45][S:46][C@H:41]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CN1CCC(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1CCC(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4nnnn4C)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
1.5 g of (Z)-2-(2-tritylaminothiazol-4yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetic acid are dissolved in 50 ml of tetrahydrofuran, and 1.4 g of benzhydryl 7β-amino-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylate, 0.6 g of 1-hydroxybenzotriazole and 0.92 g of dicyclohexylcarbodiimide are added thereto. The mixture is stirred at room temperature for 2 hours. Then, the reaction mixture is treated in the same manner as described in Example 3-(1). 1.58 g of benzhydryl 7β-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetamido}-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylate are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:19][CH3:20]>>[I-:19].[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N+:10]([CH3:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: c1ccc(Cn2cc(-c3ccccc3)nn2)cc1
Product: C[n+]1nn(Cc2ccccc2)cc1-c1ccccc1
Product: [I-]
Temperature: 40 °C

Procedure:
1-benzyl-4-phenyl-1H-1,2,3-triazole (0.52 g, 2.197 mmol) prepared above and iodomethane (2 ml, 32.0 mmol) were added to a 20 mL vial. The reaction was heated at 40° C. for 3 days. The iodomethane was allowed to evaporate in the hood. The crude product was dissolved with 2 mL CH2Cl2 under reflux. The solution was precipitated into a mixture of acetone, ethyl acetate and hexane. The yellow solid was collected and dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:23][CH3:24])[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:25][CH2:26][F:27])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44].[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:23][CH3:24])[C:11]=1[N:12]1[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]1)[N:8]([CH2:25][CH2:26][F:27])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:40])[F:41])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44]
Reactant: CCOC(=O)C1CCN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(OC(F)(F)F)cc4C)cn(CCF)c3c2OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1c(N2CCC(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CCF)c12
Temperature: 25 °C

Procedure:
60 mg (0.096 mmol) of the compound of Example 4 are dissolved in 2.35 ml of dioxane, 480 μl (5 eq.) of a 1M solution of lithium hydroxide are added, and the mixture is stirred at RT until the reaction is complete (4 h). The reaction mixture is acidified with 1N hydrochloric acid and diluted with ethyl acetate and water. Following phase separation, the organic phase is washed once again with water and then with a saturated sodium chloride solution, dried over magnesium sulfate and freed from solvents on a rotary evaporator. The residue is dried under high vacuum. 54 mg (94% of theory) of the title compound are obtained.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[NH2:17][CH2:18][CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[SH:27][C:28]([CH3:33])([CH3:32])[C:29](O)=[O:30].O>C1(C)C=CC=CC=1>[OH:26][C:20]1([CH2:19][CH2:18][N:17]2[C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[S:27][CH:2]2[CH2:3][CH2:4][CH2:5][C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(S)C(=O)O
Reactant: NCCC1(O)CCCCC1
Reactant: CCOC(=O)c1ccc(CCCC=O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(CCCC2SC(C)(C)C(=O)N2CCC2(O)CCCCC2)cc1
Reaction time: 5 h

Procedure:
A solution of ethyl 4-(4-oxobutyl)benzoate (5.5 g., 0.025 mole) and 1-(2-aminoethyl)cyclohexanol (3.7 g., 0.026 mole) in toluene (40 ml.) is boiled in an open flask for 5 minutes to remove the formed water as the azeotrope. 2-Mercapto-2-methylpropionic acid (3.3 g., 0.0275 mole) is added and the solution is boiled under a Dean-Stark water separator for 5 hours. The solution is then cooled, washed with 2 N hydrochloric acid and water, and dried over sodium sulfate. The solvent is removed at reduced pressure. The residue is chromatographed on 165 g. of silica gel with 2% methanol in chloroform as the eluent. There is obtained 4.6 g. of the title ester as a light yellow, viscous oil.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[N:32]=2)[CH2:27][CH2:26]1)C1C=CC=CC=1.Cl>>[CH3:37][C:35]1[CH:34]=[C:33]([CH3:38])[N:32]=[C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:17]3[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=3[OH:15])[CH2:30][CH2:29]2)[CH:36]=1
Reactant: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3OCc3ccccc3)CC2)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])cc3O)CC2)c1
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
Trifluoroacetic acid (5 mL) was added to 1-(2-benzyloxy-4-nitro-phenyl)-4-(4,6-dimethyl-2-pyridyl)piperazine (720 mg, 1.72 mmol) at between 0 and 5° C. followed by concentrated hydrochloric acid (2 mL). The mixture was heated at reflux for 16 h then cooled to between 0 and 5° C. and quenched with saturated sodium bicarbonate solution (30 mL). Chloroform (30 mL) was added and the mixture was stirred for 15 min. The organic phase was separated and the aqueous phase was extracted with chloroform (30 mL). The combined organic phases were washed with water (2×30 mL), brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude residue. Trituration with petroleum ether afforded 2-[4-(4,6-dimethyl-2-pyridyl)piperazin-1-yl]-5-nitro-phenol (510 mg, 90%) as a brownish-yellow solid.
Reaction SMILES: [N:1]1C=CN=[CH:3][C:2]=1C(NNC(N)=N)=O.[NH:14]([NH:18][C:19]([C:21]1[C:26]([NH2:27])=[N:25][C:24]([NH2:28])=[C:23]([Cl:29])[N:22]=1)=[O:20])[C:15]([NH2:17])=N.[N-:30]=[C:31]=[S:32].ClCCN=C=S>>[NH2:27][C:26]1[C:21]([C:19]([NH:18][NH:14][CH:15]=[N:17][NH:30][C:31]2[S:32][CH2:3][CH2:2][N:1]=2)=[O:20])=[N:22][C:23]([Cl:29])=[C:24]([NH2:28])[N:25]=1
Reactant: [N-]=C=S
Reactant: N=C(N)NNC(=O)c1cnccn1
Reactant: N=C(N)NNC(=O)c1nc(Cl)c(N)nc1N
Agent: S=C=NCCCl
Product: Nc1nc(N)c(C(=O)NNC=NNC2=NCCS2)nc1Cl

Procedure:
A process of claim 5 wherein the pyrazinamidoguanidine is N-guanidino-3,5-diamino-6-chloro-2-pyrazinecarboxamide and the isothiocyanate is 2-chloroethylisothiocyanate which yields 3,5-diamino-6-chloro-N-{[(2-thiazolinylamino)iminomethyl]-amino}-2-pyrazinecarboxamide.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O=[C:15]([CH3:22])[CH2:16][C:17](OCC)=[O:18].C(=O)([O-])[O-].[K+].[K+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[C:11]3[C:10](=[CH:9][CH:8]=2)[NH:13][C:15]([CH3:22])=[CH:16][C:17]3=[O:18])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(=O)c2cc(Cn3ccnc3)ccc2[nH]1
Yield: 14.4 %

Procedure:
To a stirred and heated (100° C.) solution of 10 parts of 4-(1H-imidazol-1-ylmethyl)-benzenamine in 50 parts of poly phosphoric acid were added 15 parts of ethyl 3-oxobutanoate. The whole was stirred for 4 hours at 140° C. 100 Parts of water were added to the mixture and the whole was neutralized with potassium carbonate. The product was extracted with a mixture of ethyl acetate and methanol. The extract was dried, filtered and concentrated. The concentrate was crystallized from a mixture of 2-propanone and methanol. The product was filtered off and dried, yielding 2 parts (14.4%) of 6-(1H-imidazol-1-ylmethyl)-2-methyl-4(1H)quinolinone; mp. 245.5° C. (decomp.) (compound 77).
Reaction SMILES: CO[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=3)[N:13]=[C:12]2[CH3:31])[CH:5]=1.[OH-].[Na+].[C:35](N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:48][N:49](C)[OH:50].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:15]1[C:16](=[O:17])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[CH3:10])[C:3]([N:49]([O:50][CH3:35])[CH3:48])=[O:32])[C:12]([CH3:31])=[N:13][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[N:22]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C(F)(F)F)n3)c(Cl)c2=O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C(F)(F)F)n3)c(Cl)c2=O)c1
Temperature: 25 °C
Yield: 46.4 %

Procedure:
To a solution of 3-[5-chloro-2-methyl-6-oxo-4-(6-trifluoromethyl-pyridin-2-ylmethoxy)-6H-pyrimidin-1-yl]-4-methyl-benzoic acid methyl ester from Step A (110 mg, 0.23 mmol) in tetrahydrofuran (1 mL) was added 1N sodium hydroxide (1 mL) and the solution was stirred at ambient temperature for eighteen hours. The solution was concentrated in vacuo and the aqueous residue acidified to pH=2 using 1M HCl. The solution was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The slurry was filtered and concentrated to give a yellow solid which was used without additional purification. To a solution of the crude acid in tetrahydrofuran (2 mL) was added 1,1′-carbonyldiimidazole (56 mg, 0.35 mmol). After stirring at ambient temperature for one hour, N,N-dimethylhydroxylamine HCl (35 mg, 0.35 mmol) and triethylamine (0.06 mL, 0.46 mmol) were added. The solution continued to stir for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the amide as a colorless oil (53 mg, 46%). MS (M+H): 497
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1Br.[C:10]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])#[CH:11].C(N(CC)CC)C.C1COCC1>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[C:11]#[C:10][Si:12]([CH:13]([CH3:15])[CH3:14])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17]
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Nc1ccc(Br)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1nc(N)ccc1Br)(C(C)C)C(C)C

Procedure:
A mixture of 5,6-dibromopyridin-2-amine (60 g, 233 mmol), ethynyl-tri(propan-2-yl)silane (64 ml, 285 mmol), copper(I) iodide (1.5 g, 7.88 mmol), Dichlorobis(triphenylphosphine)-palladium(II) (4.0 g, 5.48 mmol) and triethylamine (80 ml, 577 mmol) is stirred under argon atmosphere in ACN (200 ml) with THF (100 ml) for 2 h at 50° C. The mixture is concentrated in vacuo and the product purified by NP chromatography. Yield: 76 g (92%). HPLC-MS: M+H=353/355; tR=1.79 min (*Method—1).
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:16])[CH2:4][CH:5]2[CH2:11][CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6]=12>C(#N)C.[Cu](Cl)Cl>[O:16]=[C:3]1[NH:2][N:1]=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]2=[CH:4]1
Reactant: O=C1CC2CCCc3ccccc3C2=NN1
Agent: Cl[Cu]Cl
Solvent: CC#N
Product: O=c1cc2c(n[nH]1)-c1ccccc1CCC2
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A mixture of the compound of formula (Dd), 4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one (4.7 g, 22 mmol) and anhydrous copper(II) chloride (6 g, 44 mmol) was refluxed in acetonitrile (45 mL) for 2 hours. After cooling to ambient temperature, the mixture was poured into ice-water (200 g) and the solid obtained was washed with 10% CHl solution twice (about 20 mL×2) and cold water twice (about 20 mL×2). After freeze-drying, the compound of formula (De), 3-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (4.2 g, 90%) was obtained as a white solid, 1H NMR (300 MHz, CDCl3) δ: 10.80 (bs, 1H), 7.53-7.21 (m, 4H), 6.77 (s, 1H), 2.66 (t, J=6.9 Hz, 2H), 2.45 (t, J=6.9 Hz, 2H), 2.14 (quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e): 213 (MH+).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:37][C:38]([CH3:42])=[C:39]([NH2:41])[CH:40]=1)(=[O:35])=[O:34])([CH3:31])[CH3:30]>>[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:37][C:38]([CH3:42])=[C:39]([NH:41][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:40]=1)(=[O:35])=[O:34])([CH3:31])[CH3:30]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1sc(S(=O)(=O)NC(C)(C)CO)cc1N
Product: Cc1sc(S(=O)(=O)NC(C)(C)CO)cc1NC(=O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-methyl-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.12) according to general procedure II. Yellow solid. MS (ISP) 620.3 [(M−H)−]; mp 225° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[N:8]1[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=[C:9]1[CH2:20]Cl.[CH3:22][S:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[N:8]1[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=[C:9]1[CH2:20][N:26]([S:23]([CH3:22])(=[O:24])=[O:25])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Reactant: ClCc1nc2cnc3ccsc3c2n1[C@H]1CC2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1nc2cnc3ccsc3c2n1[C@H]1CC2CCC1C2)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[(2S)-bicyclo[2.2.1]hept-2-yl]-2-(chloromethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (0.10 g, 0.31 mmol) dissolved in N,N-dimethylformamide (1 mL) was added tert-butyl (methylsulfonyl)carbamate (0.092 g, 0.47 mmol) and potassium carbonate (0.087 g, 0.63 mmol). The mixture was stirred at 50° C. overnight, then diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give crude tert-butyl ({1-[(2S)-bicyclo[2.2. l]hept-2-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}methyl)(methylsulfonyl)carbamate. LCMS calculated for C22H29N4O4S2 (M+H)+: m/z=477.2. Found: 477.1. The crude intermediate was treated with trifluoroacetic acid (0.5 mL, 6 mmol) in methylene chloride (0.5 mL) at room temperature for 30 min, then the solvent was removed in vacuo. The residue was re-dissolved in MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (30 mg, 25%). LCMS calculated for C17H21N4O2S2 (M+H)+: m/z=377.1. Found: 377.0.