Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>CN(C=O)C>[Br:36][CH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC/C=C\CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCC/C=C\CCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of cis-oct-3-en-1-ol (1.00 g, 7.81 mmol) in DMF (18 mL) was added triphenylphosphine (2.28 g, 8.69 mmol). The solution was cooled to 0° C. and NBS (1.50 g, 8.43 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford cis-1-bromo-oct-3-ene (1.36 g, 91%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.53 (1H, m), 5.35 (1H, m), 3.36 (2H, t, J=7.2 Hz), 2.60 (2H, m), 2.04 (2H, m), 1.33 (4H, m), 0.89 (3H, t, J=7.2 Hz); 3C NMR (75 MHz, CDCl3) δ 133.27, 125.84, 32.93, 31.97, 31.12, 27.43, 22.64, 14.30.
Reaction SMILES: [CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:43]([C:45]1[C:46](=[C:53]([C:56]#[N:57])[C:54]#[N:55])[O:47][C:48]([CH3:52])([CH3:51])[C:49]=1[CH3:50])#[N:44].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:39]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:50][C:49]3[C:48]([CH3:51])([CH3:52])[O:47][C:46](=[C:53]([C:54]#[N:55])[C:56]#[N:57])[C:45]=3[C:43]#[N:44])=[CH:16][CH:15]=2)=[C:8]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 47 h
Yield: 56.5 %

Procedure:
In 12 ml of ethanol and 4 ml of tetrahydrofuran were dissolved 500 mg (0.84 mmol) of 5-[2-[4-dibutylamino-2-(tert-butyldiphenylsiloxy)phenyl]vinyl]thiophene-2-carboaldehyde and 185 mg (0.93 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 65 mg of ammonium acetate, and the mixture was stirred at room temperature for 47 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 369 mg of a dark greenish brown crystal (yield: 56.6%; mp: 218-219° C.).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[C:17]([OH:19])[C:16]([CH2:20][CH2:21][CH2:22][NH:23]C(=O)C(F)(F)F)=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:5]>[OH-].[NH4+]>[NH2:23][CH2:22][CH2:21][CH2:20][C:16]1[C:17]([OH:19])=[CH:18][C:2]([OH:1])=[C:3]([CH:15]=1)[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C(O)c1ccccc1C(=O)c1cc(CCCNC(=O)C(F)(F)F)c(O)cc1O
Agent: [NH4+]
Agent: [OH-]
Product: NCCCc1cc(C(=O)c2ccccc2C(=O)O)c(O)cc1O
Yield: 74 %

Procedure:
Compound 5 (167 mg, 0.38 mmol) was incubated in concentrated ammonium hydroxide (4.0 ml) for 1.0 hr at 50 degrees C. The resulting solution was evaporated to dryness and the residue was precipitated from methanol-diethyl ether: 96-mg (74% yield). TLC (50/48/2, ethyl acetate/methanol/acetic acid), Rf=0.50; 1H NMR (DMSO-d6) δ 7.78 (1H, m, aromatic-H), 7.43 (2H, m, aromatic-Hs), 7.18 (1H, m, aromatic-H), 6.95 and 6.26 (2H, 2×s, aromatic-Hs), 2.37 (2H, t, J=6.6 Hz, methylene-Hs), 1.68 (2H, m, methylene-Hs). Note—An additional methylene peak (2Hs) is expected to be hidden under the large water peak covering the range 3.8-3.1 ppm.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:15][C:16]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].S(OC)(O[CH3:29])(=O)=O>C1COCC1>[C:11]([O:15][C:16]([N:18]([C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1)[CH3:29])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(NC(=O)OC(C)(C)C)no1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C(=O)OC(C)(C)C)no1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
Under an atmosphere of argon, a 1M solution of lithium hexamethyldisilazane in THF (1.1 ml) was added dropwise to a stirred solution of 3-tert-butoxycarbonylamino-5-methylisoxazole (Tet. Lett., 1996, 37, 3339-3342; 0.2 g) in THF (9 ml) that had been cooled to −5° C. After 10 minutes, a solution of dimethyl sulphate (0.1 ml) in THF (1 ml) was added dropwise and the resultant mixture was stirred at −5° C. for 2 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was dried over magnesium sulphate and evaporated to give 3-(N-tert-butoxycarbonyl-N-methylamino)-5-methylisoxazole (0.19 g); 1H NMR: (CDCl3) 1.54 (s, 9H), 2.36 (s, 3H), 3.34 (s, 3H), 6.5 (br s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][OH:12].[OH-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:20]([O:19][C:17](=[O:18])[CH2:16][O:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OC/C=C\COC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)COC/C=C\COC1CCCCO1
Reaction time: 0.17 h

Procedure:
6.00 g of (Z)-4-(2-tetrahydropyranyloxy)-2-buten-1-ol was dissolved in 10 ml of benzene and 1.18 g of tetra-n-butylammonium hydrogen sulfate and 10 ml of an aqueous 50% sodium hydroxide solution were added and 6.75 ml of tert-butyl bromoacetate was added dropwise while stirring under ice cooling. After 10 minutes, the temperature was returned to room temperature and the reaction solution was stirred for one hour. The solution was extracted with diethyl ether after adding ice water. The extract was washed with saturated brine and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.00 g of the desired compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([NH:17][CH:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.C([O-])(O)=O.[Na+].[F:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][NH:50]2)=[C:46]([NH:53][CH:54]([C:56]2[N:57]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:58](=[O:67])[C:59]3[C:64]([CH:65]=2)=[CH:63][CH:62]=[CH:61][C:60]=3[CH3:66])[CH3:55])[N:45]=1>Cl.CCO>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:17][C@H:18]([C:20]2[N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22](=[O:31])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:30])[CH3:19])[N:3]=1.[F:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][NH:50]2)=[C:46]([NH:53][CH:54]([C:56]2[N:57]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:58](=[O:67])[C:59]3[C:64]([CH:65]=2)=[CH:63][CH:62]=[CH:61][C:60]=3[CH3:66])[CH3:55])[N:45]=1
Reactant: Cc1cccc2cc(C(C)Nc3nc(F)nc4c3ncn4C3CCCCO3)n(-c3ccccc3)c(=O)c12
Agent: Cc1cccc2cc(C(C)Nc3nc(F)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Cc1cccc2cc([C@H](C)Nc3nc(F)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(1-(2-Fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5203) (160 mg, 0.32 mmol) was dissolved in HCl/EtOH (3 M, 5 mL) and the resulting mixture was stirred at room temperature for 1 h. The mixture was neutralized with saturated NaHCO3 aqueous solution to pH=7-8, and extracted with CH2Cl2 (50 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was recrystallized from ethyl acetate and hexanes. The solid was collected by filtration and dried in vacuo to afford the desired product, 3-(1-(2-fluoro-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5204) (125 mg, 94% yield) as a white solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]4([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:12]=1.[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:39])=[O:4])[CH:8]=[N:9][CH:10]=2)=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2([OH:35])[CH2:31][CH2:32][CH2:33][CH2:34]2)=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(CCC2(O)CCCC2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)O)c2)cc1)c1ccc(CCC2(O)CCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.08 mL, 0.157 mmol) was added to a solution of {5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example 150-(1); 13.1 mg, 0.026 mmol) in methanol (0.26 mL), and the mixture was stirred at room temperature for two hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (dichloromethane:methanol=9:1) to give the title compound (7.6 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][NH:35][NH2:36]>>[CH3:34][NH:35][NH:36][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([CH2:17][S:14]([CH:13]=[C:11]2[CH2:12][N:9]([CH:8]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:10]2)(=[O:16])=[O:15])[CH:19]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: CNN
Product: CNNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0141 cm3 of methylhydrazine. 42 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid N′methylhydrazide are thus obtained in the form of a pale yellow foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 2.96 (s, 3H), 3.18 (broad s, 3H), 3.83 (mt, 2H), 4.22 (mt, 2H), 4.80 (broad s, 2H), from 7.35 to 7.65 (mt, 12H)].
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:27][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Oc2ccc(F)cc2)c1
Product: Fc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
3-(4-Fluorophenoxy)benzaldehyde, prepared as described in Tanaka, et al., J. Med. Chem., 41 (1998) 4408-4420, and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:25]=[CH:24][C:12]3[NH:13][C:14](=[O:23])[O:15][C:16]([CH:20]4[CH2:22][CH2:21]4)([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH4+].[Cl-].[CH3:28][N:29](C=O)C>[C-]#N.[C-]#N.[Zn+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:20]1([C:16]2([CH:17]3[CH2:18][CH2:19]3)[O:15][C:14](=[O:23])[NH:13][C:12]3[CH:24]=[CH:25][C:9]([C:4]4[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=4)[C:28]#[N:29])=[CH:10][C:11]2=3)[CH2:22][CH2:21]1
Reactant: CN(C)C=O
Reactant: O=C1Nc2ccc(-c3cc(F)cc(Br)c3)cc2C(C2CC2)(C2CC2)O1
Agent: [Pd]
Agent: [C-]#N
Agent: [Cl-]
Product: N#Cc1cc(F)cc(-c2ccc3c(c2)C(C2CC2)(C2CC2)OC(=O)N3)c1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 4.6 %

Procedure:
A mixture of 6-(3-bromo-5-fluoro-phenyl)-4,4-dicyclopropyl-1,4-dihydro-benzo-[d][1,3]oxazin-2-one (0.4 g, 1.0 mmol), Zn(CN)2 (0.71 g, 0.61 mmol), and tetrakis(triphenylphosphine)-palladium (0) (0.07 g, 0.06 mmol) in DMF (20 mL) was subject to a blanket of nitrogen for 15 minutes at 50° C. and then was heated at 85° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into NH4Cl (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were washed with brine, dried over MgSO4, and concentrated. The clear oil obtained was triturated with ether (30 ml) to give a white solid. Recrystallization of the solid from ethyl acetate gave 3-(4,4-dicylopropyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile (0.016 g, 4.6%): mp 250-252° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 8.12 (s, 1H), 7.97 (d, 1H, J=10.54 Hz), 7.81-7.79 (m, 2H), 7.73 (dd, 1H, J=8.3, 1.59 Hz), 6.94 (d, 1H, J=8.34 Hz), 1.59 (m, 2H), 0.58-0.42 (m, 6H), 0.30-0.28 (m, 2H); MS (ESI) m/z 347 ([M−H]−, 100%); Anal. Calc. For C21H17FN2O2: C, 72.4, H, 4.92, N, 8.04 Found: C, 72.4, H, 4.74, N, 7.61
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N+:6]([O-:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH2:10][C:11]2[C:12]([Cl:18])=[CH:13][CH:14]=[CH:15][C:16]=2[Cl:17])=[O:27])=[N+:6]([O-:8])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [O-][n+]1cc(Br)ccc1SCc1c(Cl)cccc1Cl
Solvent: ClC(Cl)Cl
Product: O=S(Cc1c(Cl)cccc1Cl)c1ccc(Br)c[n+]1[O-]
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
2.3 g of 5-bromo-2-(2,6-dichlorobenzylthio)pyridine-N-oxide was dissolved in 50 ml of chloroform, and a solution of 1.6 g of metachloroperbenzoic acid (content: 70%) dissolved in 30 ml of chloroform was added dropwise thereto at 5° to 10° C. over 10 minutes. The mixture was stirred at 5° to 10° C. for an additional 2 hours. The resulting mixture was washed twice with potassium carbonate solution and dried over magnesium sulfate. The chloroform was evaporated, and the residue was recrystallized from benzene to obtain 2.0 g of 5-bromo-2-(2,6-dichlorobenzylsulfinyl)pyridine-N-oxide (Compound (2)). Yield, 83%. M.P., 187.5°-188.5° C.
Reaction SMILES: C1(S([C:10]2([CH3:17])[CH:12]([C:13]([F:16])([F:15])[F:14])O2)(=O)=O)C=CC=CC=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31](=[S:33])[NH2:32])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].N1(C(OC(C)(C)C)=O)CCNCC1.C(N1C=CN=C1)(N1C=CN=C1)=S.N>CN(C)C=O>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH2:27][N:28]([C:31]2[S:33][C:12]([C:13]([F:14])([F:15])[F:16])=[C:10]([CH3:17])[N:32]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Reactant: CC1(S(=O)(=O)c2ccccc2)OC1C(F)(F)F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: N
Agent: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C(F)(F)F
Yield: 30 %

Procedure:
A mixture of 4.92 mmol rac-2-benzenesulfonyl-2-methyl-3-trifluoromethyl-oxirane and 5.41 mmol 4-thiocarbamoyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from tert-butyl 1-piperazinecarboxylate, 1,1′-thiocarbonyldiimidazole and ammonia according to the procedure of J. Med. Chem. 1998, 41, 5037–5054) in 15 ml N,N-dimethylformamide was heated at 100° C. for 4.5 h. The reaction mixture was then concentrated in vacuo and the residue purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a yellow crystalline solid (yield 30%). MS (m/e): 352.3 (M+H+, 100%).
Reaction SMILES: [CH2:1]([CH:4]1[O:8][C:7](=[O:9])[CH:6]=[C:5]1[N:10]([CH2:19][CH:20]=[CH2:21])[CH2:11][C:12]1[CH:13]=[N:14][C:15]([Cl:18])=[CH:16][CH:17]=1)C=C>ClCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([CH2:11][N:10]2[CH2:19][CH:20]=[CH:21][CH2:1][CH:4]3[O:8][C:7](=[O:9])[CH:6]=[C:5]23)=[CH:17][CH:16]=1
Reactant: C=CCC1OC(=O)C=C1N(CC=C)Cc1ccc(Cl)nc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: O=C1C=C2C(CC=CCN2Cc2ccc(Cl)nc2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
40 mg (0.13 mmol) of 5-allyl-4-{allyl[(6-chloropyridin-3-yl)methyl]amino}furan-2(5H)-one (VI-1) are dissolved in 4 ml of dichloromethane, 11 mg (0.013 mmol) of the second generation Grubbs catalyst are added and the mixture is stirred at room temperature for 2 hours. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate gives 29 mg (80% of theory) of 4-[(6-chloropyridin-3-yl)methyl]-4,5,8,8a-tetrahydro-2H-furo[3,2-b]azepin-2-one.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].B(F)(F)F.CCOCC.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[NH:23][C:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[CH:25][CH:26]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([C:25]1[CH:26]=[C:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)[NH:23][C:24]=1[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: c1csc(-c2ccc(-c3cccs3)[nH]2)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(=O)c1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 22.7 %

Procedure:
Acetic anhydride (75 μL, 1.75 mmol) was dissolved in 2 mL of anhydrous methylene chloride and stirred for 2 minutes at 0° C. under nitrogen. To this stirred mixture was added boron trifluoride etherate (185 μL, 1.5 mmol), followed by the addition of 1.5 mmol 2,5-dithienylpyrrole in 1 mL of anhydrous methylene chloride. The resultant dark green solution was stirred at 0° C. for 15 minutes and room temperature for 1 hour. The solution was diluted with chloroform (50 mL) and washed four times with water (10 mL), twice with saturated sodium bicarbonate (10 mL), and finally twice with water (10 mL). The organic phase was evaporated and the residue was chromatographed on a silica gel column (50 g). Elution with 30% ethyl acetane in hexane gave 93 mg (68%) of 3-acetyl-2,5-dithienylpyrrole.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O.N1C=CC=CC=1>[C:1]([O:11][CH3:12])(=[O:10])[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC#CCC(=O)OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccncc1
Product: CCCCCC=CCC(=O)OC

Procedure:
A mixture of 5 g. of 1-bromo-2-octyne, 7 g. of potassium cyanide and 35 ml. of dimethylsulfoxide is stirred and heated under nitrogen for about 2.5 hrs. at reflux temperature. The mixture is then poured into water and extracted with ether. The ether extract is washed with water, than with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure leaving a residue comprising 3-nonynenitrile. The thus obtained residue is mixed with 45 ml. of 25% hydrogen chloride in methanol containing 0.5 ml. of water while cooling in an ice bath. The ice is allowed to melt and the mixture is stirred for about 18 hrs., then is poured into water and extracted with ether. The ether extract is washed with water, aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over sulfate, and evaporated under reduced pressure leaving a residue comprising methyl 3-nonynoate. A mixture of the thus obtained methyl 3-nonynoate, 500 mg. of 5% palladium-barium sulfate catalyst and 40 ml. of pyridine is shaken under hydrogen for about 2 hrs., until the uptake of hydrogen practically ceases. The mixture is then filtered, diluted with water, and extracted with ether. The ether extract is washed with water, dilute hydrochloric acid, and aqueous sodium bicarbonate, then is dried over sodium sulfate and evaporated to leave a residue comprising methyl 3-nonenoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:6]([CH:8]=1)[NH2:7].[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[C:6]([N:7]=[C:15]=[S:16])[CH:8]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(F)ccc1N1CCOCC1
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(N2CCOCC2)c(N=C=S)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 5-fluoro-2-morpholino aniline (6 g) and thiophosgene (5.2 g) in dioxan (20 ml) and water (40 ml) was stirred at 0° C. for 15 minutes and at room temperature for one hour to yield a residue which was extracted with dichloromethane to give an oil which was purified by chromatography on a silica gel column (mesh 100-200) using a 1:9 mixture of ethylacetate and hexane as eluant to give 5-fluoro-2-morpholinophenyl isothiocyanate as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH3:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:15])[CH3:14])(=[O:3])[CH3:2].CO[CH:18]([N:21]([CH3:23])[CH3:22])OC>C1(C)C=CC=CC=1>[Br:10][C:8]1[C:7]([CH3:11])=[CH:6][C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([C:1](=[O:3])/[CH:2]=[CH:18]/[N:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1cc(C)c(Br)cc1C(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(C)c(Br)cc1C(=O)/C=C/N(C)C
Temperature: 120 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
Under a nitrogen atmosphere, 6.33 g of N-(2-acetyl-4-bromo-5-methylphenyl)acetamide was added to a mixture of 3.3 g of (dimethoxymethyl)dimethylamine and 19 mL of toluene, followed by stirring at 120° C. for 16 hours. The mixture was cooled to room temperature, concentrated, and diisopropyl ether was added thereto and triturated. The powder was collected by filtration, washed with diisopropyl ether, and then dried under reduced pressure to obtain 6.92 g of N-{4-bromo-2-[(2E)-3-(dimethylamino)prop-2-enoyl]-5-methylphenyl}acetamide.