Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[N:36][CH:35]=[C:34]([NH2:38])[N:33]=2)[CH2:28][CH2:27]1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:34]3[N:33]=[C:32]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)[CH:37]=[N:36][CH:35]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1CCN(c2cncc(N)n2)CC1
Product: CN1CCN(c2cncc(Nc3nc4c(NCc5ccccc5N(C)S(C)(=O)=O)cccn4n3)n2)CC1

Procedure:
N-Methyl-N-(2-{[2-(4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-phenyl)-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (130 mg, 0.36 mmol) and 4-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-ylamine (92.159 mg, 0.47689 mmol in a manner analogous to Example 2d. Product was isolated as an off-white foam (28.64 mg, 1.8%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.71 (s, 1H), 8.80 (s, 1H), 7.98 (d, J=6.7 Hz, 1H), 7.81 (s, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.40-7.28 (m, 3H), 6.79-6.66 (m, 2H), 6.22 (d, J=8.6 Hz, 1H), 4.63 (s, 2H), 3.55 (s, 4H), 3.26 (s, 3H), 3.12 (s, 3H), 2.41 (s, 4H), 2.22 (s, 3H). MS=523 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:6]1[C:5]2[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
A solution of Compound 58 (4.9 g, 25 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.2 g, 30 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat benzyl bromide (3.78 mL, 30 mmol) was added and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 6.5 g (90%) of white solids. 1H NMR (DMSO-d6): δ 5.45 (s, 2H), 7.17 (d, J=8.7 Hz, 1H), 7.26–7.39 (m, 5H), 7.65 (dd, J=1.5, 8.7 Hz, 1H), 8.02 (d, J=1.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[S:12]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:37](Cl)(=[O:41])[CH:38]([CH3:40])[CH3:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:15]([C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[S:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1N=C(c2cccc(F)c2)SC1(CCCNC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of {3-[5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-propyl}-carbamic acid tert-butyl ester (400 mg, 0.96 mmol) in DCM (4 mL) was added triethylamine (130 mg, 1.3 mmol), followed by isobutyryl chloride (130 mg, 1.3 mmol). After stirring for 1 hour, the reaction was quenched by the addition of methanol (0.1 mL). The reaction mixture was concentrated and purified by flash column chromatography (15:1 Hexanes/EtOAc) to provide the product (350 mg, 75%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][NH2:13].N1([O:25][S:26]([CH:29]([CH3:31])[CH3:30])(=O)=[O:27])C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[F:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([OH:15])([CH3:14])[CH2:12][NH:13][S:26]([CH:29]([CH3:31])[CH3:30])(=[O:27])=[O:25]
Reactant: CC(C)S(=O)(=O)On1nnc2ccccc21
Reactant: COc1ccc(C(C)(O)CN)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)(O)CNS(=O)(=O)C(C)C)c(F)c1
Temperature: 120 °C

Procedure:
2-(2-Fluoro-4-methoxy-phenyl)-2-hydroxy-propylamine hydrochloride was converted to the free base by partitioning between ethyl acetate and 1 M NaOH. The amine (1.0 g, 5.02 mmol) was combined with propane-2-sulfonic acid benzotriazol-1-yl ester (1.3 g, 5.52 mmol) in DMF (25 mL) and heated at 120° C. for 2 hr. then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and extracted with 1 M HCl. The organic layer was separated and washed with water and saturated NaCl, dried (MgSO4), filtered, and concentrated to a yellow oil which was used in the next step without purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(C(=O)O)C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)C1CCC(=O)C1
Temperature: 0 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-oxocyclopentane-1-carboxylic acid (1.0 g, 7.80 mmol, 1.00 equiv), potassium carbonate (1.62 g, 11.72 mmol, 1.50 equiv), Acetone (20 mL). This was followed by the addition of iodomethane (11.1 g, 78.20 mmol, 10.02 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 60° C. in an oil bath. The reaction progress was monitored by GCMS. The solids were collected by filtration. The filtrate was concentrate. The resulting mixture was diluted with 10 mL of H2O. The resulting solution was extracted with 3×10 mL of ether and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. This resulted in 1.0 g (crude) of methyl 3-oxocyclopentane-1-carboxylate as yellow oil. The crude could be used for the next step directly.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[N:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][CH:17]=1)=O.C(=O)([O-])O.[Na+]>C(O)C>[CH3:26][O:25][CH2:24][CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:11]=[C:8]3[CH:7]=[CH:6][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:10][N:9]3[CH:13]=2)=[CH:21][CH:20]=1
Reactant: CCCSc1ccc(N)nn1
Reactant: COCCOc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCSc1ccc2nc(-c3ccc(OCCOC)cc3)cn2n1

Procedure:
A solution of 6-propylsulfanylpyridazin-3-amine (169 mg, 1 mmol) and 2-bromo-1-[4-(2-methoxyethoxy)phenyl]ethanone (273 mg, 1 mmol) in ethanol (10 mL) was refluxed for 3 h. Sodium hydrogen carbonate (84 mg, 1 mmol) was then added and the mixture was refluxed for a further 3 h. The solvent was evaporated and the organic residue was extracted with chloroform. The chloroform extract was washed with water, dried (sodium sulfate) and evaporated. The residue was purified by radial chromatography on silica gel. Elution with 2-3% methanol in dichloromethane afforded Compound 65 (57 mg). 1H n.m.r. (CDCl3) δ 1.12, t, J=6 Hz, 3H; 1.75-1.95, m, 2H; 3.16-3.22, m, 2H; 3.27, s, 3H; 3.75-3.82, m, 2H; 4.15-4.22, m, 2H; 6.88-7.08, m, 3H; 7.80-7.995, m, 3H; 8.06, s, 1H.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([CH3:7])[C@@H:4]([C:8]([OH:10])=O)[O:3]1.[N+]([O-])(O)=O.[N+:15]([O:18][CH2:19][CH2:20][NH2:21])([O-:17])=[O:16].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[N+:15]([O:18][CH2:19][CH2:20][NH:21][C:8]([C@H:4]1[O:3][C:2](=[O:1])[NH:6][C@@H:5]1[CH3:7])=[O:10])([O-:17])=[O:16]
Reactant: C[C@H]1NC(=O)O[C@@H]1C(=O)O
Reactant: NCCO[N+](=O)[O-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O=[N+]([O-])O
Product: C[C@H]1NC(=O)O[C@@H]1C(=O)NCCO[N+](=O)[O-]
Yield: 14.9 %

Procedure:
Following a procedure similar to that described in Example 1, but using 167 mg of (4R,5S)-2-oxo-4-methyloxazolidine-5-carboxylic acid, 234 mg of N-(2-nitrooxyethyl)amine nitrate and 0.30 ml of diphenylphosphoryl azide, 40 mg of the title compound were obtained as a colorless oil.
Reaction SMILES: Cl([O-])(=O)(=O)=O.Cl[C:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9](=[N+:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=1.[CH2:20]([N:22]1[C:26](=[O:27])[CH2:25][S:24][C:23]1=[S:28])[CH3:21].C(N(CC)CC)C>C(O)C>[CH2:20]([N:22]1[C:26](=[O:27])[C:25](=[C:7]2[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:8]2)[S:24][C:23]1=[S:28])[CH3:21]
Reactant: CCN1C(=O)CSC1=S
Reactant: CC1(C)CC(Cl)=CC(=[N+]2CCCC2)C1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1C(=O)C(=C2C=C(N3CCCC3)CC(C)(C)C2)SC1=S

Procedure:
N-(3-Chloro-5,5-dimethylcyclohex-2-en-1-ylidene)-pyrrolidinium perchlorate (3.1 g., 0.01 mol.), 3-ethylrhodanine (1.6 g., 0.011 mol.) and triethylamine (3.1 ml.) are dissolved in ethanol (20 ml.) and heated at reflux for 10 minutes. After chilling, the solid is collected on a filter, rinsed with ethanol and dried. After one recrystallization from pyridine/methanol, the yield of purified dye is 2.2 g. (65%), m.p. 234°-235°C. with decomposition. This dye is an excellent spectral sensitizer for photographic silver halide emulsions in the minus blue region of the spectrum as set forth in Table 2 hereinafter.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].ClC1C=C(C=CC=1)C(OO)=[O:34]>C(Cl)Cl.CCOC(C)=O>[CH3:27][C:26]1([CH3:28])[O:34][CH:25]1[C:14]1[CH:15]=[C:16]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=2)[C:11]([NH:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:12][CH:13]=1
Reactant: COc1ncc(Nc2ncc(C=C(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ncc(Nc2ncc(C3OC3(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methylprop-1-enyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (380 mg, 0.996 mmol) in DCM (9.9 mL) was cooled to 0° C., and 3-chlorobenzoperoxoic acid (268 mg, 1.196 mmol) was then added. The resulting mixture was stirred at 0° C. for 1.5 h and then allowed to warm to ambient temperature and stir for 2 h. The reaction mixture was then diluted with 200 mL of EtOAc, added to a separatory funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 1 time with 150 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. m/z (ESI, +ve ion) 398.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:10]([O:12]C)=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Li+].Cl>C1COCC1.O>[CH:1]1([C:4]2[C:5]([C:10]([OH:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ncccc1C1CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ncccc1C1CC1

Procedure:
To a solution of methyl 3-cyclopropylpyridine-2-carboxylate (80 mg, 0.45 mmol) in THF (2 ml) and water (2 ml) was added lithium hydroxide (55 mg, 1.36 mmol) and the reaction mixture was refluxed for 2 hours. The reaction was then acidified to pH 2 using 1M HCl (aq) and extracted with DCM (3×50 ml). The combined organics were washed with water (30 ml), brine (30 ml), dried over sodium sulfate and concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[SH:20][C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:20][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: Sc1ncccn1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1oc(Sc2ncccn2)nc1-c1ccc(Cl)cc1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (2.00 g), 2-mercaptopyrimidine (819 mg), anhydrous potassium carbonate (1.10 g) and N,N-dimethylformamide (10 ml) was heated to 100-110° C. and stirred for 4 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was dried over anhydrous magnesium sulfate and then concentrated, the residue was subjected to silica gel column chromatography, and methyl 4-(4-chlorophenyl)-2-(2-pyrimidinylsulfanyl)-5-oxazolepropionate was obtained as a yellow oil (1.42 g, 57%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[C:5]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:4]=2[C:3]=1[F:23].[CH2:24]([C:27]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28]1)[CH:25]=[CH2:26]>CN(C1C=CN=CC=1)C>[CH2:24]([C:27]1([S:30]([N:11]2[C:5]3[C:6]4[O:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]([F:23])[C:4]=3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:32])=[O:31])[CH2:29][CH2:28]1)[CH:25]=[CH2:26]
Reactant: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(I)cc1F
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Product: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c(F)c4ncoc4c32)CC1
Yield: 55.8 %

Procedure:
Intermediate I-21a was prepared from 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-15a: 250 mg, 0.561 mmol), 1-allyl-cyclopropanesulfonyl chloride (202 mg, 1.12 mmol), TEA (228 mL, 1.68 mmol) and DMAP (25 mg) using procedures analogous to those described above for Intermediate I-19a to afford 180 mg of the product (55.3% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[C:18](#[N:21])[CH:19]=[CH2:20].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.C(OCC)C>CO>[C:18]([CH2:19][CH2:20][N:13]1[CH2:12][CH2:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:1])([F:16])[F:17])[CH:5]=2)[CH2:15][CH2:14]1)#[N:21]
Reactant: FC(F)(F)Sc1cccc(N2CCNCC2)c1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: N#CCCN1CCN(c2cccc(SC(F)(F)F)c2)CC1
Reaction time: 48 h
Yield: 84.7 %

Procedure:
N-(m-trifluoromethylthiophenyl)-piperazine (10.8 g, 0.047 g mol.) and acrylonitrile (4.9 g, 0.094 g. mol.) are introduced into a 50 ml round bottomed flask provided with a stirrer and a reflux condenser. 0.1 ml of a 40% solution of benzyltrimethylammonium hydroxide in methyl alcohol is added with cooling and stirring. The mixture is allowed to stand at ambient temperature for 2 days and then heated for 2 hours to 80°C. After cooling, anhydrous diethyl ether (100 ml) is added to the reaction mixture, insoluble materials are filtered off, and the solution obtained evaporated on a water-bath in vacuo. The residue is fractionally distilled and N-(β-cyano-ethyl)-N'-(m-trifluoromethylthiophenyl)-piperazine (11 g, 88% yield) is thus obtained as a clear yellow viscous liquid, b.p. 198°-200°/3 mm Hg, nD23 = 1.5378.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].C([O-])([O-])=O.[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[C:1]([O:7][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCC(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 4-pentynoic acid (5.25 g, 53.5 mmol) in DMF (107 mL) was treated with K2CO3 (11.09 g, 80.3 mmol) and benzyl bromide (6.37 mL, 53.5 mmol), stirred for 24 hours, diluted with water (200 mL), and extracted with diethyl ether (3×150 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography to provide the desired product (10.07 g, 100%). MS (ESI(+)) m/e 206 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 7.37 (m, 5H), 5.12 (s, 2H), 2.61 (t, 1H), 2.57 (m, 2H), 2.42 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[O:8][C@@H:7]1[C:9]([OH:11])=O)=[O:5])[CH3:2].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:35][C@@H:36]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>C(OCC)(=O)C>[OH:38][C@@H:37]([C@@H:36]([NH:35][C:9]([C@H:7]1[O:8][C@@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH2:45][CH:46]([CH3:47])[CH3:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Reactant: CC(C)C[C@H](N)[C@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)[C@H](O)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3S)-3-ethoxycarbonyloxirane-2-carboxylic acid (696 mg, 4.78 mmol.) in ethyl acetate (15 mL) was added N-hydroxysuccinimide (550 my, 4.78 mmol.) and then added N,N′-dicyclohexylcarbodiimide (986 mg, 4.78 mmol.) under chilling with ice. The resulting mixture was stirred at 5° C. for one hour, and to the mixture was added (1R,2S)-2-amino-4-methyl-1-phenyl-1-pentanol (1.01 g, 5.23 mmol.). The mixture was stirred overnight at room temperature for one hour. The resulting insoluble material was removed by filtration, and the filtrate was washed successively with 2N hydrochloric acid, water, an aqueous saturated sodium hydrogen carbonate solution, and an aqueous saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by middle pressure silica gel column chromatography (n-hex e/ethyl acetate=1/1), to give the desired compound as a white crystalline product (1.29 g, yield: 89%).
Reaction SMILES: F[C:2](F)(F)[C:3](OC(=O)C(F)(F)F)=[O:4].[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)(=[O:16])[CH3:15].O>C(O)(=O)C>[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[O:24][C:25]([C:3](=[O:4])[CH3:2])=[CH:26][CH:27]=1)(=[O:16])[CH3:15]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(=O)OCCCCCc1ccco1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCCCCCc1ccc(C(C)=O)o1
Reaction time: 16 h

Procedure:
To a mixture of 100 ml of trifluoroacetic anhydride and 100 ml of glacial acetic acid was added 89 g of 5-(2-furanyl)pentanol acetate in 100 ml of acetic acid. The reaction mixture was allowed to stand at room temperature for about 16 hours, then poured into water and extracted with methylene dichloride. The extracts were concentrated and the residue distilled to give 60.6 g of 5-(5-acetyl-2-furanyl)pentanol acetate, b.p. 120°-123° C. (0.05 mm).
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:13][Mg]Br>CCOCC>[OH:5][C:4]1([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:12][CH2:1][CH2:2][CH2:3]1
Reactant: C[Mg]Br
Reactant: O=C1CCCCc2ccccc21
Solvent: CCOCC
Product: CC1(O)CCCCc2ccccc21
Yield: 93.3 %

Procedure:
Following the procedure of Example 1, step 1, 26.02 g (0.162 mol) of 1-benzosuberone in 250 ml of anhydrous ether was reacted with 68.0 ml (0.204 mol) of 3.0M methyl magnesium bromide in ether to afford 26.65 g (93%) of the title product as a yellow oil. NMR δ(CDCl3) 1.59 (3H, s), 1.77-1.97 (6H, m), 2.83-2.96 (2H, m), 7.06-7.24 (3H, m), 7.67 (1H, d of d, J=7.6 and 1.5 Hz).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>CC#N.O>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:28][C:25]2[CH:26]=[N:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: COc1ccc(N)cn1
Solvent: CC#N
Solvent: O
Product: CCCCN1C(=O)C(Nc2ccc(OC)nc2)=C(c2ccccc2)S1(=O)=O
Temperature: 150 °C
Yield: 4.4 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (58 mg, 0.20 mmol) and 6-methoxypyridin-3-amine (49 mg, 0.40 mmol) was dissolved in MeCN (11.0 mL) and the reaction mixture was heated in a microwave reactor at 150° C. for 5 mins. The reaction mixture was diluted with MeCN and water and purified by preparative HPLC using MeCN/0.1M NH4OAc as eluant giving the title compound (3.4 mg, 4.3%). 1H NMR (500 MHz, CDCl3): δ 7.75 (d, 1H), 7.25-7.1 (m, 4H), 7.0 (bs, 1H), 6.85 (dd, 1H), 6.3 (d, 1H), 3.78 (t, 2H), 1.9-1.8 (m, 2H), 1.5-1.4 (m, 2H), 1.0 (t, 3H); Mass Spectrum: M−H+ 386.
Reaction SMILES: [S:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:20][C:21]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[C:23]([C:30]2[C:34]([C:35]([F:38])([F:37])[F:36])=[N:33][N:32]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]=2[NH2:45])[CH:22]=1>ClCCl.N>[Cl:20][C:21]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[C:23]([C:30]2[C:34]([C:35]([F:38])([F:36])[F:37])=[N:33][N:32]([C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]=2[N:45]=[S:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:22]=1
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Reactant: O=S1CCCC1
Agent: N
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: FC(F)(F)c1nn(-c2ncccn2)c(N=S2CCCC2)c1-c1cc(Cl)c2c(c1)OCO2
Reaction time: 0.33 h

Procedure:
To a solution of 2.2 equivalents of tetrahydro-thiophene 1-oxide (0.23 g, 2.2 mmo) in dichloromethane at −60° C. under argon was added dropwise trifluoroacetic anhydride (0.46 g, 2.2 mmol). The solution was stirred for 20 min at this temperature. Then the 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.383 g, 1.00 mmol) was added and the solution stirred at −60° C. for 1 h. The reaction was diluted with aqueous ammonia; the organic layer separated and further washed with water and then dried and concentrated.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH2:13].[C:14](=S)=[S:15].O>C(O)C>[F:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C@H:2]1[NH:1][C:14](=[S:15])[NH:13][C@@H:3]1[CH2:4][CH2:5]2
Reactant: S=C=S
Reactant: N[C@@H]1CCc2cc(F)ccc2[C@H]1N
Solvent: O
Solvent: CCO
Product: Fc1ccc2c(c1)CC[C@H]1NC(=S)N[C@H]21
Yield: 82 %

Procedure:
Trans-1,2-diamino-6-fluoro-1,2,3,4-tetrahydronaphthalene (3.84 g, 21.3 m mol) was dissolved in ethanol (40 ml) and carbon disulfide (1.4 ml, 23.4 m mol) was added to the solution. After the resulting white suspension was stirred for a while, water (20 ml) was added to the suspension and they were heated under reflux for 30 minutes. The reaction mixture was cooled with ice and the precipitate was filtered. The solid was washed in turn with water (three portions of 20 ml, totaling 60 ml), ethyl ether (20 ml) and n-hexane (50 ml) and dried under vacuum to give trans-7-fluoro-3a,4,5,9b-tetrahydronaphth[1,2-d]imidazoline-2-thione as a yellowish grey solid (3.88 g, 17.4 m mol) in 82% yield. The product was recrystallized from acetone-acetonitrile to give light-yellow needles melting at 256.5° to 257.5° C. (decomposition). The data on spectroscopy were as follows: