Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH:19]([CH:24]([CH3:26])[CH3:25])[C:18]=3[CH:27]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:28]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH:19]([CH:24]([CH3:25])[CH3:26])[C:18]=3[CH:27]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: CC(C)C1OC(=O)Nc2ccc(OCCCSc3ccc(Cl)c(Cl)c3)cc21
Product: CC(C)C1OC(=O)Nc2ccc(OCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[3-(3,4-dichloro-phenylmercapto)-propoxy]-4-isopropyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](=[O:12])[CH:5]2[C:13](=[O:19])[C:14]1[S:18][CH:17]=[CH:16][CH:15]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O.ClS(NC=O)(=O)=O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C:20]([NH2:21])=[O:26])[C:6](=[O:12])[CH:5]2[C:13](=[O:19])[C:14]1[S:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Nc2cc(Cl)c(Cl)nc2C1C(=O)c1cccs1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CS(C)=O
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2nc(Cl)c(Cl)cc21

Procedure:
The title compound was prepared from 5,6-dichloro-3-(2-thenoyl)-4-azaoxindole (Example 6B) according to the procedure of Example 2C, using 5,6-dichloro-3-(2-thenoyl)-4-azaoxindole (194 mg, 0.62 mmol), N-chlorosulfonyl isocyanate (81 L, 0.93 mmol) acetonitrile (10 mL), and a temperature of 50° C. The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in DMSO in a flask open to the air. After dilution with water, the solid was collected by filtration and recrystallized from acetic acid. Yield: 129 mg (58%).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[Cl-].[Al+3:7].[Cl-].[Cl-]>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Al+3:7].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Al+3:7]
Reactant: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Product: O=S(=O)([O-])[O-]
Yield: 1289.9 %

Procedure:
Concentrated sulphuric acid (8 g) was added to an aqueous solution of aluminium chloride (136 g). After standing, aluminium sulphate crystals precipitated from the over-saturated slurry obtained. The crystals were filtered off into a crystal cake (24 g), leaving d saturated solution of aluminium sulphate (120 g) as a mother liquor.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[C@H:41]1[CH2:46][CH2:45][C@H:44]([O:47][CH2:48][CH:49]([OH:54])[C:50]([F:53])([F:52])[F:51])[CH2:43][CH2:42]1>O.C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([C@H:41]4[CH2:46][CH2:45][C@H:44]([O:47][CH2:48][CH:49]([OH:54])[C:50]([F:52])([F:53])[F:51])[CH2:43][CH2:42]4)[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:22][CH:23]=2)[NH:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(F)(F)F)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C(F)(F)F)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.098 g), sodium hydrogen carbonate (0.15 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min, 4′-({5-oxo-7-propyl-4-[trans-4-(3,3,3-trifluoro-2-hydroxypropoxy)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.054 g) was added, and the mixture was stirred at 90° C. for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.016 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.015 mL) were added, and the mixture was stirred at room temperature for 2.5 hr. N,N′-Carbonyldiimidazole (0.016 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.015 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, adjusted to pH 4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.035 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C([C:19]1[C:20]([N:28]=[CH:29][N:30]([CH3:32])C)=[N:21][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)#N.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]3[C:32]([NH:1][C:2]4[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:3]=4[O:4][C:5]4[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=4)=[N:30][CH:29]=[N:28][C:20]=3[N:21]=2)[CH2:26][CH2:27]1
Reactant: Cc1ccc(Oc2ccc(O)cc2)c(N)c1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Cc1ccc(Oc2ccc(O)cc2)c(Nc2ncnc3nc(C4CC4)ccc23)c1

Procedure:
The product from Example 122b was reacted with the product from Example 119A using the procedure from Example 102 substituting the product from Example 122b for the product from Example 6c and substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.03-1.18 (m, J=6.25 Hz, 4H), 2.20-2.35 (m, 1H), 2.30 (s, 3H), 6.57-6.85 (m, 5H), 7.03 (dd, J=8.27, 1.65 Hz, 1H), 7.36 (d, J=1.84 Hz, 1H), 7.52 (d, J=8.46 Hz, 1H), 8.50 (s, 1H), 8.65 (d, J=8.46 Hz, 1H), 9.18 (s, 1H), 9.70 (s, 1H); MS (ESI)+ m/z 385 (M+H)+.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.C([CH:15]([C:23]([NH2:25])=[O:24])[CH:16](CC=C)[C:17]([NH2:19])=[O:18])C=C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][C:3]([CH:15]([C:23]([NH2:25])=[O:24])[CH2:16][C:17]([NH2:19])=[O:18])=[N:2]1
Reactant: C=CCC(C(N)=O)C(CC=C)C(N)=O
Reactant: C1=Cc2ccccc2NN=C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CC(C(N)=O)C1=NNc2ccccc2C=C1

Procedure:
Following the procedures described for the synthesis of 11, diallylsuccinamide intermediate 16 was prepared from 14 in reasonable yield. 14 (2.5 g, 5.9 mmol), p-chloro-BZD (2.34 g, 6.2 mmol) and DIPEA (1 ml, 5.8 mmol) in 30 ml DMF was heated to 40-50 degree overnight.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[Cl:18][S:19](O)(=[O:21])=[O:20]>>[F:17][C:2]([F:1])([F:16])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]1[CH:15]=[CH:14][C:13]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:12][CH:11]=1)=[O:4]
Reactant: O=C(N1CCCC1c1ccccc1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(N1CCCC1c1ccc(S(=O)(=O)Cl)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
At 0° C., 2,2,2-trifluoro-1-(2-phenylpyrrolidin-1-yl)ethanone (2.0 g, 8.2 mmol) was added to chlorosulfonic acid (10 mL) and allowed to warm to 25° C. over 30 min. Then the mixture was poured into ice water and extracted with EtOAc. The organic layer was concentrated to obtain 4-(1-(2,2,2-trifluoroacetyl)pyrrolidin-2-yl)benzene-1-sulfonyl chloride as a clear oil which was used in the next reaction step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]([Mg]Br)=[CH2:16].O>ClCCl>[CH:15]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[CH2:16]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: O
Solvent: ClCCl
Product: C=CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02 mmol) in 20 mL of dichloromethane at 0° C. under an atmosphere of nitrogen was added vinylmagnesium bromide (0.7 M dichloromethane solution, 9.32 mL, 6.52 mmol) dropwise. After 1 hr, the mixture was treated with water and extracted 3× with ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes, to provide tert-butyl 4-ethenyl-4-hydroxypiperidine-1-carboxylate that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.N1C=CC=CC=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(#N)C.O>[C:1]1([NH:11][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nccc2ccccc12
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1nccc2ccccc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
Isoquinolin-1-amine (300 mg, 2.08 mmol) was dissolved in acetonitrile. The reaction mixture was added pyridine (0.02 mL, 2.50 mmol) and phenyl chloroformate (0.27 mL, 2.18 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl isoquinolin-1-ylcarbamate (285 mg, 52%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.[CH2:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C=O)C.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>[C:28]1([CH:27]=[CH:26][C:2]2[CH:7]=[CH:6][C:5]3[CH2:8][C:9]4[C:21]5[NH:20][C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[C:13]=5[C:12]5[C:22](=[O:25])[NH:23][CH2:24][C:11]=5[C:10]=4[C:4]=3[CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Reactant: C=Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(C=Cc2ccccc2)cc1-3
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (100 mg, 0.26 mmol), styrene (30 mg, 0.29 mmol) and triethylamine (0.5 mL) in DMF (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (25 mg). The solution was heated in a sealed reaction tube at 100°-110° C. for 48 hours. The mixture was cooled to ambient temperature, filtered through a pad of Celite®, then the solvent was concentrated at reduced pressure. The product was triturated with MeOH to give 85 mg (80%) of a brown solid. Recrystallization from DMF-Et2O gave the product, Compound I-24, as a tan solid. The melting point was greater than 300° C. The following NMR data were obtained: 1H NMR (DMSO-d6, 300 MHz): δ 4.2 (s, 2H), 5.02 (s, 2H), 7.25-7.5 (m, 7H), 7.6-7.75 (m,4H), 7.8 (d, 1H, J=8Hz), 8.2 (s, 1H), 8.6 (s, 1H), 9.4 (d, 1H, J=9 Hz), 12.8 (s, 1H). MS(FAB): m/e 413 (m+1)+.
Reaction SMILES: [Na].C[Si](N[Si](C)(C)C)(C)C.C1COCC1.[C:16]([CH:19]=[CH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:31][C:32]3[CH:37]=[CH:36][C:35](Cl)=[CH:34][C:33]=3F)=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41])([OH:18])=[O:17].OC1C=C2C(=CC=1)[NH:48][C:47]([CH3:52])=[CH:46]2>CS(C)=O>[C:16]([CH:19]=[CH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:31][C:32]3[CH:37]=[C:36]4[C:35](=[CH:34][CH:33]=3)[NH:48][C:47]([CH3:52])=[CH:46]4)=[N:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41])([OH:18])=[O:17]
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1C=CC(=O)O
Reactant: Cc1cc2cc(O)ccc2[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
1M Sodium HMDS in THF (0.84 ml, 8.4 mmol) was added to a suspension of 7-(2-carboxyvinyl)-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (105 mg, 0.28 mmol) and 5-hydroxy-2-methylindole (82 mg, 0.56 mmol), (prepared as described for the starting material in Example 48), in DMSO (1.5 ml). After stirring for 2 hours at ambient temperature, the mixture was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH3 with 2M hydrochloric acid. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 90/10 and 70/30) to give 7-(2-carboxyvinyl)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (75 mg, 71%).
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].[Cl:12][C:13]1[N:14]=[C:15]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:16]2[CH:21]=[C:20]([CH:22]=O)[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:16]2[CH:21]=[C:20]([CH2:22][N:9]3[CH2:10][CH2:11][N:6]([S:3]([CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]3)[S:19][C:17]=2[N:18]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: Cl
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 1-methanesulfonyl-piperazine HCL salt and 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde 33 using General Procedure C yielded 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5].ClCCl.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>O>[CH3:7][O:6][C:4](=[O:5])[CH:3]([NH:2][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([Br:15])=[CH:17][CH:18]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(N)C(=O)OC
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(NC(=O)c1ccc(Br)cc1)C(=O)OC
Reaction time: 8 h

Procedure:
To a stirred solution of dimethyl aminomalonate hydrochloride (1.83 g, 10 mmol) in dichloromethane (30 mL) triethylamine (3 mL, 22 mmol) will be added at 0° C. 4-bromobenzoyl chloride (2.19 g, 10 mmol) will be slowly added the resulting solution will be allowed to stand at room temperature overnight. Water will be added and the organic layer will be separated and dried over anhydrous MgSO4. The evaporation of solvent will result in Int P.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10](/[CH:12]=[CH:22]/[CH:23]=[O:24])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-c2ccccn2)s1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2ccccn2)s1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 5-(2-pyridinyl)-2-thiophenecarboxaldehyde (prepared as described in J. Chem Soc., Perkin Trans. 2 1998, 437) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 216 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH2:3][CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[CH3:1][C:2]([C:7]1[S:11][C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])=[N:9][N:8]=1)([CH3:6])[CH2:3][CH:4]1[CH2:5][O:39]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(C)(C)c1nnc(NC(=O)C(CCC)NC(=O)Cc2cc(F)cc(F)c2)s1
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CC2CO2)s1
Reaction time: 4 h

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide (196 mg, 0.45 mmol) and ˜60% pure m-chloroperbenzoic acid (109 mg, 0.45 mmol) in methylene chloride was stirred for 4 hr. The mixture was quenched with water, saturated Na2S2O3 and extracted with methylene chloride. The organic layer was washed with brine, separated, dried, and concentrated to give 114 mg of crude material with a mixture of desired title compound and undesired N-oxide and recovered starting material. The crude material was purified by HPLC and the title compound was isolated, LC-MS, RT=2.3 min, M=1=453.5.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][CH2:30][CH2:31][NH2:32])=[N:21]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][CH2:30][CH2:31][NH:32][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=2)=[O:13])=[N:21]1
Reactant: NCCNc1nsc2ccccc12
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NCCNc2nsc3ccccc23)nc1
Reaction time: 4 h
Yield: 44.7 %

Procedure:
5-(Methoxycarbonyl)picolinic acid (390 mg, 2.2 mmol), was dissolved in anhydrous dichloromethane. Several drops of dimethylformamide were added, followed by oxalyl chloride (0.23 mL, 1.2 mmol). After 1.5 h at room temperature the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and added to a solution of N1-(benzo[d]isothiazol-3-yl)ethane-1,2-diamine (300 mg, 1.6 mmol) in anhydrous dichloromethane with triethylamine (420 μL, 3.0 mmol). After 4 h, the reaction was diluted with dichloromethane and washed with saturated sodium bicarbonate solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography, on silica gel, eluting with a mixture of 2% methanol in dichloromethane and selected fractions were combined and concentrated under reduced pressure. Trituration with boiling dichloromethane and methanol removed impurities and gave methyl 6-(2-(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)nicotinate (255 mg) as a pale yellow solid. 1H NMR (300 MHz, CDCl3): 9.11 (m, 1H), 8.55 (broad s, 1H), 8.40 (m, 1H), 8.24 (d, 1H), 7.68-7.76 (m, 2H), 7.42 (t, 1H), 7.32 (t, 1H), 3.98 (s, 3H), 3.88 ppm (m, 4H). MW=356 confirmed by LC-MS, tr=12.06 min (Method Y) MH+=357.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:31]1C[CH:32]1[CH2:34][N:35]1[C:43]2[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=2[C:37]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)=[N:36]1>ClCCl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[NH:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][CH:32]([OH:31])[CH2:34][N:35]2[C:43]3[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=3[C:37]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)=[N:36]2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3s2)CC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(Nc3nc4ccccc4s3)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A solution of 220 mg (0.66 mmol) of 4-(benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in MeOH and stirred over 100 mg of sodium bicarbonate for 1 h. The solid was filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 220 mg (0.60 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 240 mg (66%) of a white solid. MS (electrospray): exact mass calculated for C30H33F3N6O2S: 598.23; m/z found, 599.3 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.78 (d, J=8.22 Hz, 1H), 7.72 and 7.68 (A and B of AB quartet, J=8.41 Hz, 2H), 7.64 (d, J=8.22 Hz, 1H), 7.56 (bd, J=8.02 Hz, 1H), 7.51 (bd, J=8.02 Hz, 1H), 7.29 (bd, J=7.63 Hz, 1H), 7.08 (bt, J=7.63 Hz, 1H), 5.29 (br s, 1H), 4.88 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.23-4.16 (m, 1H), 4.16-4.08 (m, 1H), 4.06-3.98 (m, 2H), 3.92-3.65 (m, 3H), 3.03-2.70 (m, 4H), 2.52-2.41 (m, 3H), 2.26-2.18 (m, 1H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 2.16-2.08 (m, 2H), 1.66-1.44 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>O1CCCC1>[CH3:20][N:21]([CH3:25])[C:22]([N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9]1)=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: c1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(-c2ccncc2)nc1-c1ccncc1

Procedure:
To 2.13 g. (0.01 mole) of 3,5-di(4-pyridyl)-1,2,4-triazole in 200 ml. of tetrahydrofuran is added 57% sodium hydride in mineral oil (0.42 g., 0.01 moles). The reaction mixture is heated at reflux for 1 hour, cooled and a solution of dimethylcarbamoyl chloride (1 g., 0.01 mole) in 10 ml. of tetrahydrofuran is added dropwise. The reaction mixture is heated at reflux for 4 hours, cooled, filtered and concentrated to an oil which solidifies. After recrystallization from benzene 1.2 g. of 1-dimethylcarbamoyl-3,5-di(4-pyridyl)-1,2,4-triazole melting at 140°-141.5°C. is obtained.
Reaction SMILES: O[CH2:2][C:3]1[C:7]([CH3:8])=[N:6][O:5][N:4]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13]>Br>[CH3:8][C:7]1[C:3]([CH2:2][S:13][CH2:12][CH2:11][NH2:10])=[N:4][O:5][N:6]=1
Reactant: NCCS
Reactant: Cc1nonc1CO
Agent: Br
Agent: Cl
Product: Cc1nonc1CSCCN
Reaction time: 40 h

Procedure:
A solution of 3-hydroxymethyl-4-methylfurazan (2.49 g; 21.8 mmoles) [prepared in Step A] and 2-aminoethanethiol hydrochloride (2.48 g; 21.8 mmoles) in 60 ml of 48% aqueous hydrobromic acid was stirred and heated at reflux temperature for 23 hours and then at ambient temperature for 40 hours. The excess hydrobromic acid was removed under reduced pressure, and the oil residue was dissolved in isopropyl alcohol, filtered through Celite and the product was crystallized from the filtrate. Recrystallization from isopropyl alcohol yielded the title compound as the hydrobromide salt, mp 142°-143°.