Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:43][C@@H:44]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([CH:71]2[S:75](=[O:77])(=[O:76])[NH:74][C:73](=[O:78])[CH2:72]2)=[CH:67][CH:66]=1)[C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[C:54]=1[C:55]([O:57][CH3:58])=[O:56])=[O:46]>CN(C=O)C>[O:76]=[S:75]1(=[O:77])[CH:71]([C:68]2[CH:67]=[CH:66][C:65]([CH2:64][C@H:44]([NH:43][C:7]([C@@H:5]3[CH2:4][CH2:3][C:2](=[O:1])[NH:6]3)=[O:9])[C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[C:54]=3[C:55]([O:57][CH3:58])=[O:56])=[O:46])=[CH:70][CH:69]=2)[CH2:72][C:73](=[O:78])[NH:74]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
To a solution of (2S)-5-oxopyrrolidine-2-carboxylic acid (2.0 mg, 0.015 mmol) in DMF (0.5 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (5.8 mg, 0.015 mmol) and N,N-diisopropylethylamine (0.008 mL, 0.045 mmol) and premixed for 5 minutes. To the solution was added methyl 2-[4-({(2S)-2-amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoyl}amino)-butoxy]-6-hydroxybenzoate (8.0 mg, 0.015 mmol) and stirred overnight at room temperature. The product was purified by preparative LCMS to afford the desired product (1.4 mg). LCMS found for C29H35N4O10S (M+H)+: m/z=631.0
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:7]=2)[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[CH:5][N:6]([CH2:11][CH2:12][N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[N:7]=4)[CH:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc2nn(CCN3CCCC3)cc2c1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4nn(CCN5CCCC5)cc4c3)nc2)cc1

Procedure:
Prepared according to general working method I from 5-iodo-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole (170 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (106 mg, 0.50 mmol).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.S([O-])([O-])(=O)=O.[Mg+2].[N+]([O-])([O-])=O.[Na+].P([O-])(O)(O)=O.[K+].CCC1(C2C=CC(N)=CC=2)C(=O)NC(=O)CC1.[CH2:47]([OH:69])[C@H:48]1[O:53][C@H:52]([O:54][C@:55]2([CH2:64][OH:65])[O:59][C@H:58]([CH2:60][OH:61])[C@@H:57]([OH:62])[C@@H:56]2[OH:63])[C@H:51]([OH:66])[C@@H:50]([OH:67])[C@@H:49]1[OH:68].C1[C@H](N[C@H]2[C@H](O)[C@@H](O)[C@H](O)C(CO)=C2)[C@H](O)[C@@H](O)[C@H](O[C@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2O)[C@H]1CO>S([O-])([O-])(=O)=O.[Fe+2].O>[CH2:47]([OH:69])[C@H:48]1[O:53][C@H:52]([O:54][C@H:55]2[O:59][C@H:58]([CH2:60][OH:61])[C@@H:57]([OH:62])[C@H:56]([OH:63])[C@H:64]2[OH:65])[C@H:51]([OH:66])[C@@H:50]([OH:67])[C@@H:49]1[OH:68]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: [Fe+2]
Agent: CCC1(c2ccc(N)cc2)CCC(=O)NC1=O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: OC[C@H]1O[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 0.25 h

Procedure:
100 ml of a modified Czapek's liquid culture medium (consisting of glucose 30 g, magnesium sulfate 0.5 g, sodium nitrate 2 g, potassium dihydrogenphosphate 1 g, iron sulfate 0.01 g and deionized water 1000 ml) was put into a 200 ml.-capacity flask, which was sterilized at 115°C. for 15 minutes. The resultant culture medium was inoculated with a pieceof the growth (punched out with a cork borer, diameter 1 cm) of Rhizoctoniasolani AG-1 (accession number IFO-30465) cultured on a potato sucrose agar (PSA) culture medium at 28° C. for two days, which was subjected toshake-culture at 28° C. for four days. Then the same experiment was carried out with the exception that validamycin A was added to the culturemedium before the cultivating the medium, the amount of validamycin A being0.005% relative to the whole culture medium. In each of the two experiments, the culture cells obtained thus above were respectively separated and purified, followed by subjecting to quantitative determination. As shown in Table 1, from the culture cells by culturing inthe medium to which validamycin A was supplemented, a remarkably increased amount of trehalose was obtained as compared with those by culturing in the medium to which no validamycin A was supplemented.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](Cl)(=[O:10])=[O:9])=[N:6][CH:7]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)(=[O:10])=[O:9])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Reactant: CC(C)CNc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of 5-bromo-pyridine-2-sulfonyl chloride (330 mg, 1.29 mmol) in DCM (10 mL) was added pyridine (208 μL, 2.57 mmol) followed by a solution of (4-fluoro-phenyl)-isobutyl-amine (215 mg, 1.29 mmol) in DCM (10 mL) and the reaction was stirred at room temperature for 16 hours. Water and saturated aqueous NaHCO3 were added and then extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (0-20% EtOAc in cyclohexane) to give 5-bromo-pyridine-2-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (414 mg, 78%). LCMS (m/z, Method A) ES+ 387/389 [M+1]+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.O1CCOCC1>[Cl:25][C:24]1[CH:23]=[N:22][C:21]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]([N:9]=3)[CH2:10][CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]=1[N:20]=2)[CH:15]=[CH:16][CH:17]=3
Reactant: Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1cnc2nc1Nc1cccc(c1)CCc1cccc(n1)N2
Yield: 36 %

Procedure:
To a mixture of N-{3-[2-(6-aminopyridin-2-yl)ethyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride (50 mg, 0.12 mmol) and triethylamine (0.048 mL, 0.35 mmol) in a mixed solvent of 1,4-dioxane (0.80 mL) and N,N-dimethylformamide (0.80 mL) were added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (8.0 mg, 0.014 mmol), palladium acetate (3.1 mg, 0.014 mmol) and cesium carbonate (75.2 mg, 0.23 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 160° C. for 30 min. The reaction mixture was diluted with THF/MeOH, filtered and concentrated to give the residue, which was purified by silica gel column chromatography to provide the desired product as a white powder (14 mg, 37%). LCMS for C17H15ClN5 (M+H)+: m/z=324.0. 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 8.02 (s, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.07 (m, 2H), 6.90 (dd, J=8.0, 1.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 3.22 (s, 4H).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([CH2:12]O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:34]>O1CCCC1.CC#N>[Br:34][CH2:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:11][CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1csc(-c2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: BrCc1csc(-c2ccccc2)c1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
Prepare a solution of (5-phenylthiophene-3-yl)methanol (394 mg, 2.07 mmol) in tetrahydrofuran (30 mL). Cool to 0° C. under nitrogen. Add PPh3 (723 mg, 2.75 mmol). Add dropwise a solution of carbon tetrabromide (912 mg, 2.75 mmol) in CH3CN (15 mL). Stir the reaction at 0° C. for 2 hours, then warm to room temperature overnight. Concentrate the mixture and flash-chromatograph on silica gel eluting with 7:3 ethyl acetate/hexane to afford 515 mg of 4-bromomethyl-2-phenylthiophene as a white solid. MS: m/e=254 [MH+].
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[CH3:4].[N:15]#[C:16][NH2:17].[O-]Cl.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>C(#N)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:5]([CH:3]([S:2]([CH3:1])=[N:17][C:16]#[N:15])[CH3:4])=[CH:10][CH:9]=1
Reactant: CSC(C)c1ccc(C(F)(F)F)nc1
Reactant: N#CN
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)=NC#N
Temperature: -5 °C
Reaction time: 0.75 h

Procedure:
A solution of 22.1 g (0.1 mol) of 3-[1-(methylthio)ethyl]-6-(trifluoromethyl)pyridine and 5.04 g (0.12 mol) of cyanamide in 150 mL of acetonitrile was cooled to −5° C. To this solution was added 150 g (0.115 mol, Clorox™ 5.7% wt) of aqueous NaOCl dropwise over 15 min. The reaction mixture was allowed to stir at −5° C. for 45 min, and then allowed to warm to 5° C. To the mixture was added 5 mL of 25% aq sodium metabisulfite and the two phase mixture was allowed to settle. To the organic phase was added 5.7 mL (0.1 mol) of glacial acetic acid, and the solution concentrated in vacuo to an oil. This oil was dissolved in 70 mL of CH2Cl2 and washed with 50 mL of water. The aqueous layer was re-extracted with 30 mL of CH2Cl2. The organics were combined and dried over MgSO4. After filtration, the dichloromethane solution was analyzed by LC and contained 42:52 (area) ratio of isomers A and B above.
Reaction SMILES: [NH:1]([CH2:5][C:6]1[CH2:12][C:11]2[CH:13]=[C:14]3[O:19][CH2:18][O:17][C:15]3=[CH:16][C:10]=2[C:9]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[N:8][N:7]=1)[C:2]([CH3:4])=O.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[CH3:4][C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[C:10]3[CH:16]=[C:15]4[O:17][CH2:18][O:19][C:14]4=[CH:13][C:11]=3[CH2:12][C:6]2=[CH:5][N:1]=1
Reactant: CC(=O)NCC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ncc2n1N=C(c1ccc([N+](=O)[O-])cc1)c1cc3c(cc1C2)OCO3
Reaction time: 3 h
Yield: 84.1 %

Procedure:
0.40 g (1.05 mmol) of the acetamido compound of step C is suspended in 20 ml of methylene chloride and mixed with 0.48 ml (5.3 mmol) of phosphorus oxychloride. Then, the mixture is heated to boiling for 3 hours. After concentration by evaporation, the residue is taken up in methylene chloride (30 ml) and washed with sodium bicarbonate solution and water, dried, filtered and concentrated by evaporation. 0.38 g of solid substance, which is purified by column chromatography, is obtained (silica gel, eluant chloroform:methanol=95:5). 0.32 g (84%) of pure title compound with a melting point of 305-310° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)[CH:11]=1)(=[O:9])=[O:8].[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[CH:39]2[CH2:40][CH2:41][O:36][CH2:37][CH2:38]2)[CH:11]=1)(=[O:9])=[O:8]
Reactant: O=C1CCOCC1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4)cccc3c2)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(C4CCCN4C4CCOCC4)cccc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(2,4-dimethoxybenzyl)-5-(pyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (Intermediate NN, 0.033 g, 0.065 mmol) and tetrahydro-4h-pyran-4-one (8.97 μl, 0.097 mmol) were dissolved in DCM (0.648 ml). Sodium triacetoxyborohydride (0.041 g, 0.194 mmol) and acetic acid (5.56 μl, 0.097 mmol) were added and the reaction was stirred for three hours at room temperature. 1M sodium hydroxide solution was added followed by ethyl acetate, and the reaction was stirred for one hour. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford crude N-(2,4-dimethoxybenzyl)-5-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide as an off-white solid. m/z (ESI) 594.3 (M+H)+.
Reaction SMILES: [OH-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([C:15](=[O:25])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CS(C)=O>[CH2:9]([C:15]([CH:16]1[CH2:4][CH:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C[S+](C)(C)=O
Reactant: CCCCCCC(=O)C=Cc1cccc(O)c1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCC(=O)C1CC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a 300 ml round bottom flask equipped with magnetic stirrer, nitrogen inlet, thermometer and addition funnel was charged 0.3 g (0.0069 moles) of powdered sodium hydroxide, 1.5 g (0.0069 moles) of trimethyl sulfoxonium iodide, and 50 mls of anhydrous DMSO. The mixture was then stirred at ambient temperature for 1 hour. The mixture was then cooled to 15° C., and a solution of 1-n-hexyl-3-(3-hydroxyphenyl)-2-propene-1-one (0.8 g, 0.0069 moles) was added dropwise in 5 mls of DMSO. The reaction was stirred for 1 hour at 10-15° C., then allowed to warm to ambient temperature, and stirred for an additional 16 hours. The reaction mixture was the quenched with 200 mls of 0.1 N HCl, and extracted with 3×100 mls of ethyl ether. The combined ether extracts were washed successively with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. to afford 0.64 g of the title compound, 2-(3-hydroxyphenyl)cyclopropyl n-hexyl ketone, as a thick yellow oil in a 76% isolated yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:28][CH2:27]5)[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C.O>O1CCCC1.C(OCC)(=O)C>[C:32]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:27][CH2:28]5)[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:34])[CH3:33]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)sc5c4)c3)c2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.47 mmol) produced in Example A15(iii) in tetrahydrofuran (20 mL) were added acetyl chloride (0.3 mL, 4.22 mmol) and triethylamine (1.0 mL, 7.18 mmol), and the mixture was stirred at room temperature for 10 min. To the reaction mixture were added water (200 mL) and ethyl acetate (200 mL) and the mixture was stirred for 30 min. The organic layer was separated, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=20/80→0/100), and triturated with ethyl acetate/hexane to give the title compound (151 mg, 69%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=2[N:13]=1>C(Cl)Cl>[CH3:18][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])[S:10][C:11]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc2sc(N)nc12
Reactant: COC(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)NC(=O)Nc1nc2c(C)cccc2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37 %

Procedure:
Two and one half parts by weight of methoxycarbonyl isocyanate was added gradually with stirring to a solution of 4 parts by weight of 2-amino-4-methylbenzothiazole dissolved in 250 parts by weight of methylene chloride. The reaction mixture was stirred at room temperature for 12 hours. The solution was concentrated to one fifth the original volume and the solid isolated by filtration to give a 37% yield of methyl 4-(4-methylbenzothiazol-2-yl)allophanate having a melting point of 272°-280° with decomposition.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl>[Pd].C(O)C>[CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)Oc1ccc(Cc2ccc(N)cc2)cc1
Reaction time: 16 h
Yield: 87.8 %

Procedure:
A mixture of 4-(4-isopropoxybenzoyl)-nitrobenzene (14.0 g, 49.09 mmol) and 10% palladium on carbon (2.0 g) in a solution of ethanol (250 mL) and concentrated hydrochloric acid (30 mL) was hydrogenated at 50 psi in a Parr apparatus for 16 hours. The catalyst was removed by filtration through a Celite pad, and filtrate was concentrated in vacuo. The residue was diluted with ice cold water, basified with concentrated ammonium hydroxide solution, and extracted into ethyl acetate. The organic extracts were washed with water and brine, and dried (MgSO4). Removal of the solvent gave a thick oil which on crystallization from ethyl acetate/hexanes gave 4-(4-isopropoxybenzyl)-phenylamine (10.4 g, 87%) as a white solid, m.p. 92-93° C.; Analysis for C16H19NO: Calc.: C, 79.63; H, 7.94; N, 5.80; Found: C, 79.51; H,7.92; N, 5.96. MS m/e (%): 241 (M+, 83).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Br)[C:4]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[H-].[Na+].[CH:27]1([SH:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[CH:27]1([S:32][C:5]2[C:4]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:3]([CH:2]([F:24])[F:1])[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: SC1CCCC1
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1SC1CCCC1
Yield: 100.2 %

Procedure:
This compound was prepared as described in Example 108: 8.4 g (0.02 mol) of product of Example 106, 0.88 g (0.022 mol) of 60% NaH, and 2.45 g (0.024 mol) of cyclopentylmercaptan in 100 ml of dry THF were reacted affording 8.85 g of a light brown oil. The crude product mixture was kugelrohr distilled at 110°-130° C./67 Pa affording 8.44 g (96%) of product as a light yellow oil, nD25 1.4808.
Reaction SMILES: BrC1C=CC(O[C@H]2CCC[C@H]2N[S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=CC=1.[Br:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]2[NH2:33])=[CH:24][C:23]=1[F:36].BrC1C=CC(O[C@@H]2CCCC[C@@H]2N)=CC=1.BrC1C=CC(O)=CC=1F>>[Br:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]2[NH2:33])=[CH:24][C:23]=1[F:36].[Br:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@@H:28]2[NH:33][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:24][C:23]=1[F:36]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Agent: N[C@H]1CCCC[C@H]1Oc1ccc(Br)c(F)c1
Agent: N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Agent: Oc1ccc(Br)c(F)c1
Product: CC(C)S(=O)(=O)N[C@H]1CCCC[C@H]1Oc1ccc(Br)c(F)c1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of cis-N-[2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide in Example 5, except that (1S,2R)-2-(4-bromo-3-fluorophenoxy)cyclohexanamine was used in place of cis-2-(4-bromophenoxy)cyclopentanamine, and the chromatographic purification employed 0% to 1% methanol in dichloromethane as gradient. (1S,2R)-2-(4-Bromo-3-fluorophenoxy)cyclohexanamine was synthesized according to the general procedures described for synthesis of (1S,2R)-2-(4-bromophenoxy)cyclohexanamine in Example 7, except for the use of 4-bromo-3-fluorophenol in place of 4-bromophenol. The title compound was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.33-1.53 (m, 4H), 1.35-1.38 (m, 6H), 1.78-1.89 (m, 3H), 2.04-2.10 (m, 1H), 3.12 (septet, J=6.8 Hz, 1H), 3.54 (m, 1H), 4.44 (d, J=9.6 Hz, 1H), 4.55 (m, 1H), 6.67 (br dd, J=8.9, 2.8 Hz, 1H), 6.75 (dd, J=10.2, 2.7 Hz, 1H), 7.43 (dd, J=8.5, 8.5 Hz, 1H). The absolute configuration of the title compound was established via X-ray crystallography.
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13]>>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: BrCC1CC1
Reactant: Oc1ccccc1Br
Product: Brc1ccccc1OCC1CC1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
Prepared from cyclopropylmethyl bromide and 2-bromophenol by the method of Example 42 (b) except that the reaction mixture was stirred at 75° C. for 4 h. This gave the product as a colourless oil.