Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[CH3:15][N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.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>[CH3:15][N:16]1[CH:20]=[C:19]([C:2]2[C:7]([NH2:8])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=2)[CH:18]=[N:17]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
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: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ncc(C(F)(F)F)cc2N)cn1
Temperature: 90 °C
Yield: 4.8 %

Procedure:
2-Chloro-3-nitro-5-(trifluoromethyl)pyridine (406 mg, 1.79 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (559 mg, 2.69 mmol), cesium carbonate (1752 mg, 5.38 mmol) and palladium tetrakis (207 mg, 0.179 mmol) were combined in DMF (3 mL) and water (1 mL). The headspace was evacuated and back-filled with nitrogen (4×). The mixture was heated to 90° C. overnight. The mixture was poured into EtOAc (40 mL) and washed with water (3×20 mL) and satd brine (3×20 mL). The organics were concentrated in vacuo and purified by silica gel chromatography to provide 2-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyridin-3-amine (21 mg, 5% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1 H), 8.13 (br s, 1 H), 7.98 (s, 1 H), 7.40 (d, J=2.0 Hz, 1 H) 5.55 (s, 2 H), 3.91 (s, 3 H); MS (ESI): m/z 473.0 (M+H+).
Reaction SMILES: F.C([Si](C)(C)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[N:16]=[C:15]([CH3:35])[N:14]=1)(C)(C)C>C(#N)C.ClCCl>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH:25]2[CH2:26][CH2:27][N:22]([C:17]3[N:16]=[C:15]([CH3:35])[N:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:7])[C:18]=3[N+:19]([O-:21])=[O:20])[CH2:23][CH2:24]2)=[CH:29][CH:30]=1
Reactant: Cc1nc(OCCCCO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])c(N2CCC(c3ccc(F)cc3)CC2)n1
Agent: F
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nc(OCCCCO)c([N+](=O)[O-])c(N2CCC(c3ccc(F)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
0.590 g (14.5 mmol) of hydrofluoric acid (47-51% in water) were slowly added to a solution of 0.375 g (0.723 mmol) of the 4-[4-(tert-butyl-dimethyl-silanyloxy)-butoxy]-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-pyrimidine in 10.0 ml of acetonitrile and 5.0 ml of dichloromethane. The reaction mixture was then stirred at room temperature for 1 hour. It was then poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 to 1:1 v/v gradient of hexane and ethylacetate as the eluent giving 0.181 g (0.448 mmol, 61.9% of theory) of the 4-{6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-pyrimidin-4-yloxy}-butan-1-ol as a light yellowish oil; MS: [M+H]+=405.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>>[C:15]([NH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)(=[O:16])[CH2:14][C:13]([CH3:12])=[O:17]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)NC1CC(C)(C)NC(C)(C)C1

Procedure:
The procedure of Example (1a) was repeated using 4- amino-2,2,6,6-tetramethylpiperidine, without introducing catalyst and performing the addition of diketene at a temperature of 0° C. to 10° C.; 4-acetoacetamido-2,2,6,6-tetramethyl-piperidine was obtained in the form of a white solid which had a melting point of 115° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[CH3:14]I>O1CCCC1>[CH3:14][O:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1
Reactant: CI
Reactant: OCCSCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCSCc1ccncc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (170 mg., 7.1 mmoles, from 340 mg. of 50% dispersion in oil washed, under nitrogen, with hexane) was slurried in 5 ml. of dry tetrahydrofuran. A solution of 4-(2-hydroxyethylthiomethyl)pyridine (1.0 g., 5.9 mmoles) in 10 ml. ws added dropwise over 5 minutes and the mixture stirred for 5 minutes. Finally, methyl iodide (260 mg., 0.1 ml., 5.9 mmoles) in 2 ml. of tetrahydrofuran was added and the mixture stirred overnight. The reaction mixture was clarified by filtration and evaporated to an oil (approximately 1.3 g.) which was chromatographed on silica gel with chloroform as eluent. Pure fractions of product were combined and concentrated to yield 4-(2-methoxyethylthiomethyl)pyridine [210 mg. of oil; m/e 183; pnmr/CDCl3 /TMS/τ: 7.4 (t, 2H), 6.7 (s, 3H), 6.5 (t, 2H), 6.3 (s, 2H), 2.7 (d, 2H), 1.4 (d, 2H)].
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC1c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, white solid, m.p. 114° C. and MS: m/e=373 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:16][CH2:17][C:18]([O:20]C)=O)=[C:4](C(OC)=O)[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.C[O-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[C:3]2[CH2:16][CH2:17][C:18](=[O:20])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: COC(=O)CCc1c(F)cc2nn(C)cc2c1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc2c3c(c(F)cc2n1)CCC3=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of methyl 6-fluoro-5-(3-methoxy-3-oxopropyl)-2-methyl-2H-indazole-4-carboxylate (407 mg, 1.38 mmol) in tetrahydrofuran (14 mL) was added a solution of sodium methoxide (28%, 533 mg, 2.76 mmol) in methanol, and the mixture was stirred at 60° C. for 1 hr. The reaction solution was concentrated to dryness, 10% aqueous sulfuric acid solution (14 mL) was added, and the mixture was heated under reflux for 3 hr. The reaction solution was diluted with ethyl acetate, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (269 mg, yield 95%).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=2)=[N:11][CH:12]=1.[C:22](=[O:25])([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][C@@H:2]([CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:25][CH2:22][CH2:12][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:20]=[CH2:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1
Reactant: CC[C@H](C)CCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCCCCCCCOc1ccc(-c2ncc(CCCC[C@@H](C)CC)cn2)cc1
Temperature: 0 °C
Yield: 242.2 %

Procedure:
A mixture of 0.66 g of 9-decen-1-yl-p-tosylate, 0.5 g of (S)-4-(5-[5-methylheptyl]-2-pyrimidinyl)phenol and 0.97 g of potassium carbonate and 50 ml of absolute butanone was heated under reflux overnight. The cooled reaction mixture was subsequently poured into ice-water and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed with 500 ml of water, dried over magnesium sulphate and concentrated. Chromatography of the residue on silica gel with toluene and subsequent bulb-tube distillation gave 0.9 g of (S)-5-(5-methylheptyl)-2-(4-[9 -decenyloxy]phenyl)pyrimidine; m.p. (C-SC *) 19° C., phase transition (SC *-Ch) 32.5° C., cl.p. (Ch-I) 43° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Li]CCCC.CCCCCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C>C1COCC1>[CH3:10][C:9]1([CH3:11])[C:4]2[CH:3]=[C:2]([B:26]([OH:31])[OH:27])[CH:14]=[CH:13][C:5]=2[NH:6][C:7](=[O:12])[O:8]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (2 g, 7.8 mmol) in anhydrous THF (60 mL) was added a solution of n-BuLi in hexane (10 M, 2.4 mL, 24 mmol) at −78° C. under nitrogen. After stirring at −78° C. for 30 minutes, a slurry was obtained and treated with triisopropyl borate (6.5 mL, 28 mmol). The reaction medium was slowly warmed to ambient temperature and quenched with 1N aqueous hydrochloric acid solution (60 mL). Ethyl acetate (100 mL) was added and organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×60 mL). The combined organic layer was washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (ethyl acetate:hexane/2:1) to afford (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid as a white solid (1.4 g, 81%): mp 249-250° C.; 1H-NMR (DMSO-d6) δ 10.21 (s, 1H, D2O exchangeable), 7.90-7.95 (br s, 2H, D2O exchangeable), 7.67 (m, 2H), 6.79 (d, 1H, J=7.8 Hz), 1.61 (s, 6H); MS (ESI) m/z 222 ([M+H]+, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=2[O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=3[O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:28][CH:29]=2)=[CH:9][CH:8]=1)[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCCCOc1ccc(C)cc1-c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc(C)cc1-c1ccc(COc2ccc(C(CC(=O)OCC)c3ccc(F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 45.2 (48 mg, 0.166 mmol), 4′-Bromomethyl-2-butoxy-5-methyl-biphenyl (67 mg, 0.2 mmol) and cesium carbonate (81 mg, 0.25 mmol) in DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water, acidified with dilute HCl, extracted into ethyl acetate, washed with water and dried over magnesium sulfate. The residue obtained after concentration was flash chromatographed on silica gel to obtain 45.3 (71 mg).
Reaction SMILES: C([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:47]2[N:48]=[C:49]([NH:52]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:50][CH:51]=2)\[C:15]([NH:17][CH:18]2[C:45](=[O:46])[N:20]3[C:21]([C:29]([O:31]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:30])=[C:22]([CH:25]=[CH:26][CH2:27]I)[CH2:23][S:24][C@H:19]23)=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.[NH2:72][C:73]1[S:74][C:75]2[CH:80]=[CH:79][N:78]=[CH:77][C:76]=2[N:81]=1>CS(C)=O.C(OCC)(=O)C>[NH2:52][C:49]1[S:50][CH:51]=[C:47](/[C:14](=[N:13]/[O:12][C:8]2([C:6]([OH:7])=[O:5])[CH2:11][CH2:10][CH2:9]2)/[C:15]([NH:17][CH:18]2[C:45](=[O:46])[N:20]3[C:21]([C:29]([O-:31])=[O:30])=[C:22](/[CH:25]=[CH:26]/[CH2:27][N+:78]4[CH:79]=[CH:80][C:75]5[S:74][C:73]([NH2:72])=[N:81][C:76]=5[CH:77]=4)[CH2:23][S:24][C@H:19]23)=[O:16])[N:48]=1
Reactant: Nc1nc2cnccc2s1
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(C=CCI)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1nc(/C(=N/OC2(C(=O)O)CCC2)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(/C=C/C[n+]4ccc5sc(N)nc5c4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(1-t-butoxycarbonylcyclobut-1-oxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (X-5', 641 mg, 0.58 mmole) and 2-aminothiazolo[4,5-c]pyridine (97 mg, 0.64 mmole) in dimethylsulfoxide (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (150 ml), washed with water (2×150 ml), dried over sodium sulfate and concentrated under reduced pressure. The oily residue was triturated with diisopropyl ether and the resulting precipitate (558 mg) was treated with a mixture of 90% trifluoroacetic acid (10 ml) and anisole (2 ml) at room temperature for 1 hour. Concentration of the mixture followed by trituration of the residue with ether gave 313 mg of crude I-5C, which was purified by column chromatography [HP-20, eluted with 30% and 50% CH3OH: the packing in the PrepPAK-500/C18 (Waters), eluted with 10% CH3OH] to give 40 mg (11%) of I-5C. M.p. >150° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17])=[C:9]([O:21][CH3:22])[CH:8]=2)=[N:4][N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[NH:24][N:25]=3)=[C:9]([O:21][CH3:22])[CH:8]=2)=[N:4][N:3]=1
Reactant: NN
Reactant: COc1cc(-c2nnc(C)o2)ccc1C(=O)C(C)CC(=O)O
Solvent: CCO
Solvent: O
Product: COc1cc(-c2nnc(C)o2)ccc1C1=NNC(=O)CC1C

Procedure:
10.1 g (0.033 mole) of 4-(4-(5-methyl-1,3,4-oxadiazol-2-yl)-methoxy-phenyl)-4-oxo-3-methyl-butyric acid and 2.1 ml (0.043 mole) of hydrazine hydrate are stirred in 100 ml of ethanol at 50° C. for 1 hour. After addition of a mixture of diethyl ether/ligroin until cloudiness results, the product crystallises out. After filtering off with suction, the product is recrystallised from 500 ml of isopropanol.
Reaction SMILES: [C:1]1([C:7]2[N:8]([NH2:18])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20](=O)[C:21](=[O:23])[CH3:22].CN(C=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:12]1([C:9]2[N:8]([N:18]=[C:20]([CH3:19])[C:21](=[O:23])[CH3:22])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nn1c(-c2ccccc2)ccc1-c1ccccc1
Reactant: CC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2,5-Diphenyl-pyrrol-1-ylamine (1.91 g, 8.15 mmol) in toluene (5.45 mL) was treated with 2,3-butanedione (7.15 mL, 81.5 mmol), DMF (10.9 mL) and p-toluene sulfonic acid (10.9 mg). The resulting suspension was stirred under Ar at rt for 30 min, then heated to 70° C. in an oil bath. After 2.5 h, the solutions cooled to rt and concentrated in vacuo. The oily solid was dissolved in toluene and concentrated in vacuo to remove excess 2,3-butanedione. The residue was purified by flash chromatography (SiO2, 10% EtOAc/heptane) to afford 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one: 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.44 (s, 3H), 2.56 (s, 3H), 6.47 (s, 2H), 7.20-7.26 (m, 2H), 7.34 (t, 4H, J=8.0 Hz), 7.47 (d, 4H, J=8.0 Hz).
Reaction SMILES: [CH:1]([C:3]12[CH2:10][C:7]([NH:11][C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[O:13])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)=O.[C:20]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:1]([C:3]12[CH2:10][C:7]([NH:11][C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[O:13])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)#[CH:20]
Reactant: O=C([O-])[O-]
Reactant: O=CC12CCCC(NC(=O)c3cnccn3)(CC1)C2
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC12CCCC(NC(=O)c3cnccn3)(CC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
To a stirred mixture of N-(5-formylbicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide (350 mg, 1.35 mmol) and K2CO3 (370 mg, 2.7 mmol) in methanol (25 mL) under N2 was added dimethyl (1-diazo-2-oxopropyl)phosphonate (310 mg, 1.62 mmol). After stirring at room temperature for three hours, the clear reaction solution was partitioned between ethyl acetate (20 mL) and 5% NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 210 mg (61%) of crude title compound, N-(5-ethynylbicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide, as an off-white solid. ESI-MS m/z: 256 (M+H)+. It was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:19]([NH:21]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[S:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>CO>[C:1]([O:5][C:6](=[O:46])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:19]([NH2:21])=[S:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=S)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: CO
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a solution of 2-{[4-(2-{3-[(9H-fluorene-9-ylmethoxy)carbonyl]-1-heptylthioureido}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.1 g) synthesized in Example 629-1 in methanol (40 mL) was added piperidine (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and subjected to silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (2.0 g) as a colorless oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=O)[CH3:17])[C:11]=3[OH:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:20]([C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]1)=[S:23])[NH2:21].Cl.C(OCC)(=O)C>CN(C)C=O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=[N:21][NH:20][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]4)=[S:23])[CH3:17])[C:11]=3[OH:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)C1CCN(C(=S)NN)CC1
Reactant: CC(=O)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(C(=S)NN=C(C)c2nn(C)c(-c3ccc4c(c3)CCC4)c2O)CC1
Yield: 76.5 %

Procedure:
1-[5-(2,3-dihydro-1H-inden-5-yl)-4-hydroxyl-1-methyl-1H-pyrazol-3-yl]ethanone (50 mg, 0.195 mmol) and methyl 1-(hydrazinecarbonothioyl)piperidine-4-carboxylate (51 mg, 0.234 mmol, synthesized in accordance with WO2006062240) in N,N-dimethylformamide was stirred with concentrated hydrochloric acid (24 μL, 0.293 mmol) at room temperature for 1 day. After the reaction, ethyl acetate was added, and the reaction solution was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. The resulting organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by medium pressure silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)→ethyl acetate) to obtain the desired product (68 mg, 77% yield).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[SH3+].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:17][O:16]1>CC(O)(C)C.CS(C)=O>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:17][CH2:1][O:16]1
Reactant: Brc1cnccc1C1CO1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Agent: [SH3+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: Brc1cnccc1C1CCO1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 44.9 %

Procedure:
potassium tert-butoxide (561 mg, 5 mmol) was added to a solution of sulfonium salt (1100 mg, 5 mmol) in t-BuOH (20 mL) at room temperature. After 15 min, a solution of 3-Bromo-4-oxiranyl-pyridine (200 mg, obtained above) in DMSO (10 mL) was added dropwise at 50° C. The resulting mixture was stirred at 50° C. for 15 h. The reaction mixture was quenched with brine, and the resulting mixture was extracted with ethyl acetate twice. The combined extracts were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column and afforded the title compound (96 mg). ESI-MS m/z: 216.1 [M+1]+, Retention time 1.01 min; 1HNMR (CDCl3, 400.342 MHz) δ ppm 2.50-2.59 (m, 1H), 3.31-3.39 (m, 1H), 4.65-4.70 (m, 1H), 4.87-4.92 (m, 1H), 5.91 (t, J=8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 8.68 (d, J=8 Hz, 1H), 8.73 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:11]1[CH:10]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:24][CH:23]=2)[N:14]=[CH:13][N:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl 6-(4-nitrophenoxy)pyrimidin-4-ylcarbamate (1.22 g, 85% purity, 3.12 mmol) in DCM (12.0 mL) was added TFA (1.4 mL, 18.4 mmol) and the reaction mixture stirred at RT for 1 hr. An additional aliquot of TFA (0.70 mL) was added and the mixture was kept at RT for 15 hr and was then evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and saturated aq NaHCO3 solution (50 mL) and the organic layer was separated and washed with brine (25 mL) and then dried (MgSO4). Evaporation of the volatiles in vacuo the title compound as a yellow solid (0.66 g, 89%); Rt 1.38 min (Method 2); m/z 233 (M−H)+ (ES+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[C:26]1([C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:26]1([C:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C
Reaction time: 15 h
Yield: 37.3 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.8 g), triethylamine (1.4 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (1.6 g) in toluene (30 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling isopropanol (2 cc), 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (1.5 g) is obtained, m.p. 88° C.