Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[NH2:57][C@@H:58]1[C:84](=[O:85])[N:60]2[C:61]([C:72]([O:74][CH2:75][C:76]3[CH:81]=[CH:80][C:79]([O:82][CH3:83])=[CH:78][CH:77]=3)=[O:73])=[C:62]([S:65]/[CH:66]=[CH:67]\[C:68]([O:70][CH3:71])=[O:69])[CH2:63][S:64][C@H:59]12>CN(C)C=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[O:41][CH3:42])/[C:27]([NH:57][C@@H:58]2[C:84](=[O:85])[N:60]3[C:61]([C:72]([O:74][CH2:75][C:76]4[CH:77]=[CH:78][C:79]([O:82][CH3:83])=[CH:80][CH:81]=4)=[O:73])=[C:62]([S:65]/[CH:66]=[CH:67]\[C:68]([O:70][CH3:71])=[O:69])[CH2:63][S:64][C@H:59]23)=[O:28])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(CO/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c(OC)c1
Reactant: COC(=O)/C=C\SC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)/C=C\SC1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](NC(=O)/C(=N\OCc3ccc(OC)cc3OC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a solution of 531 mg (0.92 mM) of 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2,4-dimethoxybenzyloxyimino]acetic acid in 10 ml of N,N-dimethylformamide was added 124 mg (0.96 mM) of diisopropylethylamine. To the cooled (-50° C.) mixture was added 105 mg (0.92 mm) of methanesulfonyl chloride, and the mixture was stirred for 30 minutes. Then, 200 mg (0.46 mM) of 4-methoxybenzyl 7β-amino-3-[(Z)-2-methoxycarbonylvinylthio]-3-cephem-4-carboxylate and 60 mg (0.46 mM) of diisopropylethylamine were added at the same temperature, and the mixture was stirred for 30 minutes. After the reaction, 30 ml of water was added, the mixture was extracted with 50 ml of ethyl acetate, and the extract was washed with 30 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel column (eluent; ethyl acetate:benzene=1:4) to give 270 mg of 4-methoxybenzyl 7β-{2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2,4-dimethoxybenzyloxyimino]acetamido}-3-[(Z)-2-methoxycarbonylvinylthio]-3-cephem-4-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([C:13]1[N:14]=[C:15]([CH3:25])[S:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:12].[OH-].[Na+]>CO.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[S:16][C:15]([CH3:25])=[N:14][C:13]=2[C:11]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[CH2:4][C:3]([OH:26])=[O:2])=[O:12])=[CH:19][CH:20]=1
Reactant: COC(=O)CC1CCCCN1C(=O)c1nc(C)sc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(C(=O)N2CCCCC2CC(=O)O)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A stirring solution of (1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-yl)-acetic acid methyl ester, D16 (4.00 g, 10.6 mmol) in methanol/water (75 ml/25 ml) was treated with sodium hydroxide (0.85 g, 21.3 mmol). The mixture was stirred for 16 h at room temperature. The methanol was removed in vacuo and the residue was diluted with water and extracted with diethyl ether (2×). The aqueous phase was acidified with 5N HCl and the product was extracted with ethyl acetate. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with pentane to afford the title compound as a white solid (3.10 g, 82%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[N:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])=[CH:13][CH:12]=1.[CH:27]1([CH2:30][NH2:31])[CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[N:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([NH:31][CH2:30][CH:27]2[CH2:29][CH2:28]2)=[O:19])=[CH:13][CH:12]=1
Reactant: NCC1CC1
Reactant: O=C(O)c1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC1CC1)c1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Reaction time: 0.08 h

Procedure:
To a 100 mL round bottomed flask was added 2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)nicotinic acid (0.3031 g, 0.834 mmol), cyclopropylmethanamine (0.0869 g, 1.22 mmol), and triethylamine (0.347 mL, 2.50 mmol) in N,N-dimethylformamide (3 mL) to stir for 5 min. HATU (0.3955 g, 0.917 mmol) was then added and allowed to stir overnight. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (1×10 mL), saturated sodium chloride (1×10 mL), saturated sodium bicarbonate (1×10 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini™ column, 5 micron, 150×30 mm, 0.1% trifluoroacetic acid in acetonitrile/water, gradient 10% to 100% over 15 min. The product was taken up in DCM and extracted with saturated sodium bicarbonate to remove TFA salts to provide 2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)-N-(cyclopropylmethyl)nicotinamide as a white powder. MS (ESI, pos. ion) m/z: 417 (M+1). IC50 (uM) +++.
Reaction SMILES: CO[C:3](=O)[C@H:4]([CH3:6])O.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N:23]1[C:28](C)=C[CH:26]=[CH:25][C:24]=1C.C([N:33](CC)CC)C>C(Cl)Cl>[CH3:3][C:4]1([CH3:6])[CH2:28][NH:23][CH2:24][C@@H:25]([CH3:26])[NH:33]1
Reactant: COC(=O)[C@H](C)O
Reactant: CCN(CC)CC
Reactant: Cc1cccc(C)n1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CNCC(C)(C)N1

Procedure:
A mixture of methyl-(S)-(-)-lactate (XXVIII, 2.53 ml) in methylene chloride (130 ml) is cooled to 0°. Triflic anhydride (4.9 ml) is added and the reaction is stirred for 10 minutes at which time 2,6-lutidine (3.55 ml) is added. After an additional ten minutes of stirring at 0°, a mixture of 1-N-(triphenylmethyl)-1,2-diamino-2-methylpropane (XXVII, Step I, 7 g) and triethylamine (4.2 ml) in methylene chloride (50 ml) is added. The reaction is allowed to stir for 1 hr at 0° and 4 hr at 20-25°. After a standard basic workup (methylene chloride, sodium bicarbonate, saline and magnesium sulfate) the residue is chromatographed (silica gel; hexane/ethyl acetate, 4/1), to provide the desired compound, mp 78-80°; IR (mineral oil) 2954, 2924, 2853, 1734, 1457, 1451, 1197 and 709 cm-1 ; NMR (CDCl3) 7.50, 7.24-7.29, 7.17, 3.60, 1.71-2.93, 1.92-2.05, 1.13, 1.08 and, 1.00 δ; MS (m/e) 243, 165, 144 and 84.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:17][C:16]([C:23](OCC)=[O:24])([C:18](OCC)=[O:19])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[NH3:14].[CH2:7]([N:14]1[CH2:17][C:16]([CH2:18][OH:19])([CH2:23][OH:24])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N
Product: OCC1(CO)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.6 %

Procedure:
LiAlH4 (1.0 M in THF, 65 mL, 65 mmol) was added dropwise to a solution of diethyl 1-benzylazetidine-3,3-dicarboxylate (1.0 g, 3.43 mmol) in THF (20 mL). The resulting suspension was stirred overnight at room temperature, quenched with water (0.25 mL), 15% aq. NaOH (0.25 mL), and water (0.75 mL), filtered through celite, and concentrated in vacuo. Chromatography (7N NH3 in MeOH/CH2Cl2=5:95→10:90) of the resulting residue afforded 4 (450 mg, 63%) as an oil. 1H NMR (CDCl3): δ 7.33-7.20 (m, 5H), 3.74 (s, 4H), 3.65 (s, 2H), 3.12 (s, 4H). 13C NMR (CDCl3): δ 137.4, 129.02, 128.8, 127.7, 66.8, 63.3, 58.7, 41.0. HRMS for C12H17NO2 [M+] calcd, 207.1259; found, 207.1259.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][C:12](O)=[O:13])=[CH:4][C:3]=2[O:2]1.B.O1CCCC1>CCOCC>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)CCc1ccc2c(c1)OCO2
Agent: B
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCCc1ccc2c(c1)OCO2

Procedure:
To a solution of 3-(3,4-methylenedioxyphenyl)propionic acid (1.0 g, 5.2 mmoles) in ether (100 ml) at 0° C. was added borane-tetrahydrofuran (1.0M, 6.2 ml, 6.2 mmoles). The cooling bath was removed and 15 minutes later methanol (5 ml) was slowly added. One hour later the reaction was washed with H2O (200 ml), and then the organic layer was dried (MgSO4), filtered and concentrated to collect 0.91 g (98%) of the title compound as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Clc1nc(NCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Product: c1ncn(-c2nc(NCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)n1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxybenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[NH:28][N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:39](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[N:28]([CH3:39])[N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1nc2n(c1=O)-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a solution of tert-butyl(1-(4-(1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (26 mg, 0.05 mmol) in dry DMF (1 ml) was added potassium carbonate (21 mg, 0.15 mmol) and methyliodide (10 μl, 0.15 mmol) under nitrogen. The resulting mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with EtOAc (3×5 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 40% EtOAc in cyclohexane) to give the title compound (22 mg, 82%). 1H NMR (500 MHz, CDCl3): 8.50 (1H, s), 7.25 (2H, d), 7.20-7.19 (5H, m), 7.15-7.12 (2H, m), 5.21 (2H, s), 5.00 (1H, br s), 3.46 (3H, s), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH2:17][CH3:18])([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+]>CO>[CH3:7][C:4]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH2:17][CH3:18])([C:13]([OH:15])=[O:14])[CH:10]=[CH:9]2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CC[C@]1(C(=O)OC)C=C[C@@H](n2c(C)ccc2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@]1(C(=O)O)C=C[C@@H](n2c(C)ccc2C)C1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of methyl (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-ethylcyclopent-2-ene-1-carboxylate (12.94 g, 52.3 mmol) in methanol (100 ml) was treated with 2.5 N NaOH (30 ml, 75.0 mmol) and stirred at room temperature. After 15 hours more 2.5 N NaOH (10 ml, 25.0 mmol) was added and the reaction was stirred for an additional four days. The methanol was removed under reduced pressure and the residue partitioned between diethyl ether and water. The layers were separated and the aqueous was acidified with 4 N HCl, extracted twice with ethyl acetate, washed with brine, dried over MgSO4, and concentrated under reduced pressure to give (1R,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-ethylcyclopent-2-ene-1 carboxylic acid as a brown oil (11.83 g, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 5.98-5.96 (2H), 5.73 (2H), 5.30-5.26 (1H), 2.47-2.35 (2H), 2.20 (6H), 1.82-1.77 (2H), 0.96-0.92 (3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][CH:8]=1.[N:11](=[C:13]([C:19](=O)[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[OH:12].[ClH:22].COC1C=CC(C2OC(C)=C(C)[N+]=2[O-])=CC=1>>[ClH:22].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:19]([CH3:20])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N+:11]=2[O-:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: COc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Agent: Cl
Product: CCOC(=O)c1c(C)oc(-c2ccc(OC)cc2)[n+]1[O-]
Yield: 67 %

Procedure:
2-(4-Methoxyphenyl)-4-carbethoxy-5-methyloxazole N-oxide hydrochloride was prepared in 67% yield from anisaldehyde and ethyl 2-oximino-3-oxobutanoate according to the procedure of Example 89, part (a). The crude product was used directly in the next reaction.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34](O)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:34]([C:29]2[C:30]3[C:25](=[C:24]([F:23])[CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:27][CH:28]=2)=[O:35])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cccc2c(F)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1ccc(CC(NC(=O)c2cccc3c(F)cccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol (300 mg, 0.94 mmol) in acetonitrile (20 ml) were added 5-fluoronaphthalenecarboxylic acid (180 mg, 0.94 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg, 1.13 mmol) and 1-hydroxybenzotriazole hydrate (145 mg, 0.94 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the objective substance (0.24 g, 53%).
Reaction SMILES: [Cl:1][O-].[Ca+2].Cl[O-].[C:6]([C:8]1[CH:17]=[CH:16][C:11]([NH:12][C:13](=[O:15])[CH3:14])=[CH:10][CH:9]=1)#[N:7].O>C(O)C.C(O)(=O)C>[Cl:1][C:10]1[CH:9]=[C:8]([C:6]#[N:7])[CH:17]=[CH:16][C:11]=1[NH:12][C:13](=[O:15])[CH3:14]
Reactant: [O-]Cl
Reactant: CC(=O)Nc1ccc(C#N)cc1
Agent: [Ca+2]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C#N)cc1Cl
Reaction time: 96 h
Yield: 82.3 %

Procedure:
An aqueous solution (200 ml) of calcium hypochlorite (21 g) was added to a solution of p-cyanoacetanilide (12.5 g) in ethanol (27 ml), acetic acid (27 ml), and water (27 ml). The mixture was stirred for 4 days and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated to give a powder of 2'-chloro-4'-cyanoacetanilide (12.5 g).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[C:37]([OH:39])=O.C(N(CC)CC)C.Cl.[NH2:48][C:49]1([C:55]#[C:56][C:57]2[CH:66]=[CH:65][C:60]([C:61]([O:63][CH3:64])=[O:62])=[CH:59][CH:58]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>CN(C=O)C.C(OCC)(=O)C>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]1[C:37]([NH:48][C:49]1([C:55]#[C:56][C:57]2[CH:58]=[CH:59][C:60]([C:61]([O:63][CH3:64])=[O:62])=[CH:65][CH:66]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:39]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: COC(=O)c1ccc(C#CC2(N)CCCCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC2(NC(=O)c3cc4ccccc4[nH]3)CCCCC2)cc1
Reaction time: 0.33 h

Procedure:
A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 249 mg, 0.51 mmol) and indole-2-carboxylic acid (83 mg, 0.51 mmol) in DMF (5 ml) was treated with triethylamine (0.21 ml, 1.5 mmol). After 20 min, methyl 4-(1-amino-cyclohex-1-yl-ethynyl)-benzoate hydrochloride (150 mg, 0.51 mmol) was added and the reaction mixture was stirred for additional 16 h. The reaction mixture was diluted with ethyl acetate (50 ml) and the organic layer was washed with water (25 ml), 1M aqueous HCl (25 ml), saturated sodium bicarbonate (25 ml), and brine, dried over sodium sulfate, and concentrated in vacuo to provide crude methyl 4-[1-(1H-indol-2-yl-carbonylamino)-cyclohex-1-yl-ethynyl]-benzoate which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-:10][C:11]#[N:12].[NH4+].[NH2:14][N:15]1[CH2:23][C:22]2[C:17](=[C:18]([CH3:25])[CH:19]=[CH:20][C:21]=2[CH3:24])[CH2:16]1.[Cl-].[NH4+]>C(COC)OC>[C:1]([NH:12][C:11]([NH:14][N:15]1[CH2:16][C:17]2[C:22](=[C:21]([CH3:24])[CH:20]=[CH:19][C:18]=2[CH3:25])[CH2:23]1)=[S:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Reactant: Cc1ccc(C)c2c1CN(N)C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Product: Cc1ccc(C)c2c1CN(NC(=S)NC(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
4.4 g (0.031M) of benzoyl chloride in 10 ml of dimethoxyethane is dripped into a suspension of 2.5 g (0.033M) of ammonium thiocyanate in 50 ml of 1,2-dimethoxyethane. The mixture is stirred at room temperature for 1 hour. 4.5 g (0.028M) of 2-amino-4,7-dimethylisoindoline in 30 ml of dimethoxyethane are dripped in. The mixture is stirred at room temperature for 1 hour. The precipitated ammonium chloride is suctioned off. Evaporation yields 5.3 g of 1-benzoyl-3-(4,7-dimethylisoindolin-2-yl)-thiourea (Mp. 163°-164° C.) from the filtrate, which is converted by saponification with 50 ml of 10% sodium hydroxide into the (4,7-dimethylisoindolin-2-yl)-thiourea.
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[OH-].[Na+].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>O.C(OCC)C>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]2[CH:18]=[CH:19][C:8]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)=[CH:9][CH:10]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: NCCCCOc1ccc(-n2ccnc2)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)NCCCCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
A solution of 3.0 g of 4-[4-(1H-imidazol-1-yl)phenoxy]butaneamine dihydrochloride (Example 2) is dissolved in 100 ml H2O and while stirring 3.5 ml of 10N NaOH, and then 2.6 g of 4-(t-butyl)benzenesulfonyl chloride in 100 ml of diethyl ether are added. The mixture is stirred at room temperature for 4 hours. The precipitate is collected, washed with 50 ml of water and 50 ml of diethyl ether, and air dried. Recrystallization from 50% aqueous ethanol gives 2.6 g of the title compound, m.p. 138°-140° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([NH2:11])=[O:10])=[CH:5][CH:4]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:16][CH2:17][C:18]1[N:11]=[C:9](/[CH:8]=[CH:7]/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:13][CH:12]=2)[O:10][CH:20]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=Cc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
4-(Trifluoromethyl)cinnamamide (1 g, 4.65 mmol) and 1,3-dichloroacetone (1.1 g, 8.66 mmol) were added to toluene (5 ml) and the mixture was refluxed under heating for 8 hours. Ethyl acetate (20 ml) was added, and the mixture was washed with water (20 ml) twice and concentrated under reduced pressure. To the residue was added methanol (4 ml) and the mixture was stirred at room temperature. The crystals were filtrated and dried under reduced pressure to give 4-(chloromethyl)-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (733 mg, yield 55%).
Reaction SMILES: [Cl:1]Cl.[CH3:3][O:4][C:5]1([O:13][CH3:14])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[N:11][OH:12].Cl>C(Cl)Cl>[Cl:1][CH:10]1[CH2:9][CH2:8][CH2:7][C:6](=[N:11][OH:12])[C:5]1([O:4][CH3:3])[O:13][CH3:14]
Reactant: ClCl
Reactant: COC1(OC)CCCCC1=NO
Agent: Cl
Solvent: ClCCl
Product: COC1(OC)C(=NO)CCCC1Cl
Reaction time: 0.5 h

Procedure:
Following the general procedure of Example 1, about 7.5 parts of elemental chlorine were added over a 21/2 hour period to a solution of 17.3 parts of 2,2-dimethoxycyclohexanone oxime and a catalytic amount of anhydrous hydrogen chloride dissolved in about 85 parts dry methylene chloride. The reaction contents were maintained at a temperature of about 25° to 35° C. under a dry nitrogen atmosphere. After the addition was completed, the contents were allowed to stir for an additional half hour and were then treated by the procedure as described in Example 1. There was obtained 19.9 parts (90% of theory) of product 3-chloro-2,2-dimethoxycyclohexanone oxime as determined by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1[C:10]([C:19]([NH2:21])=[O:20])=[CH:11][C:12]2[C:17](C=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.N1C=CC=CC=1>>[C:5]([O:4][C:1]1[C:10]([C:19]([NH2:21])=[O:20])=[CH:11][C:12]2[C:17]([CH:2]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1cc2ccccc2cc1O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2ccccc2cc1C(N)=O
Temperature: 25 °C

Procedure:
Acetic anhydride (19.2 ml, 200 mmol) was added to a solution of 18 (29.95 g, 160 mmol) in pyridine (32 ml, 400 mmol) and the mixture was maintained at room temperature for 30 minutes. The solid was filtered off, washed with acetone and dried (MgSO4), generating 27.06 g (74%) of 19 as pale yellow crystals, mp 201°-202° C. (lit. 203°-205° C.).