Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5]OC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1>C(Cl)Cl.CO>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[CH:38][CH:39]=1
Reactant: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCCOc1ccc(Nc2ncc(-c3ccsc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12). Title compound: ES-MS: 360.0 [M+H]+; single peak at tR=6.16 min (System 1); Rf=0.12 (CH2Cl2/MeOH, 85/15).
Reaction SMILES: F[C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:9]1[C:2]2[S:16][C:15]([C:14]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cccc(C(F)(F)F)c2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
A mixture of 1.10 g of 2-fluoro-3-(trifluoromethyl)benzaldehyde, 663 mg of methyl thioglycolate, 1.03 g of potassium carbonate and 15 ml of DMF was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature. To the reaction mixture was added water, and then extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with water, followed by saturated aqueous sodium chloride solution. The mixture was dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 1.34 g of methyl 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate.
Reaction SMILES: [C:1]([O:20][C:21](=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=O)[CH2:2]CCCCCCCCCCCCCCCC.C(O)C[OH:42].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:21]([O:20][CH2:1][CH2:2][OH:42])(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCC
Reactant: OCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)OCCO
Reaction time: 1.5 h
Yield: 39.2 %

Procedure:
A solution of stearic anhydride (1.14 g, 2.06 mmol) in dichloromethane (30 mL) was cannulated into a stirred solution of ethylene glycol (1.10 mL, 19.7 mmol), DMAP (22 mg, 0.18 mmol) and triethylamine (0.300 mL, 2.16 mmol) in dichloromethane (20 mL). After stirring for 90 min. the reaction was quenched with the addition of H2O (100 mL). After separation of the phases the aqueous fraction was re-extracted with dichloromethane (2×50 mL) and the combined organic extract was washed with brine (70 mL). After drying (MgSO4) and filtration the solvent was removed at reduced pressure to give the crude product that was purified by chromatography on silica gel. Gradient elution with ethyl acetate/petroleum ether (10:90→30:70) afforded the title compound 48 (265 mg, 0.807 mmol, 39%) as an oil; 1H NMR (300 MHz, CDCl3) δ 4.25-4.20 (m, 2H), 3.83-3.78 (m, 2H), 2.38 (t, 2H, J 7.5 Hz), 2.00-1.97 (m, 1H), 1.62-1.55 (m, 2H), 1.35-1.20 (m, 28H), 0.87-0.81 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 174.6, 66.3, 61.7, 34.6, 32.3, 30.1, 29.8, 29.7, 29.6, 29.5, 25.3, 23.1, 14.5; HRMS-ESI (+ve) (Found: m/z 346.3323 (MNH4+). C20H44NO3 requires m/z 346.3316).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[I:13][C:14]1[CH:15]=[C:16](O)[CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([I:13])[CH:19]=2)[CH:9]=1)=[O:4]
Reactant: Oc1cccc(I)c1
Reactant: COC(=O)c1cc(CO)c(C)o1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2cccc(I)c2)c(C)o1
Temperature: 0 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
A mixture of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (1.85 g, 10.9 mmoles), 3-iodophenol (3.6 g, 16.35 mmoles), triphenylphosphine (4.3 g, 16.35 mmoles) in tetrahydrofuran (15 mL) was cooled to 0° C. Diisopropylazodicarboxylate (3.3 g, 16.35 mmoles) was added and the mixture was allowed to warm to room temperature, then stirred for 72 h. The tetrahydrofuran was evaporated and the residue purified by flash chromatography using hexane/ethyl acetate 7:3 v/v as eluent to give compound 106 (2.8 g). This was used directly in step (b).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>CO>[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH2:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1ccccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
In this reference example, 9.76 g of salicylaldehyde, 15.12 g of 1-benzyl-4-amino-piperidine and 100 ml of methanol are mixed and stirred at room temperature for one hour. While the resultant mixture is cooled with ice, 3.2 g of sodium borohydride is added thereto over a period of one hour and 30 minutes. Then, the mixture is stirred at room temperature for 2 hours. The resultant reaction mixture is poured into 1 l of ice water. The light yellow crystals deposited are separated by filtration and then dissolved in 200 ml of ethyl acetate. The ethyl acetate solution is washed with a saturated aqueous sodium chloride, dried and subsequently concentrated under reduced pressure to obtain 19.0 g of light yellow crystals. The crystals are recrystallized from ethanol to obtain 12.0 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:17]([OH:18])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:17]([O:18][CH3:27])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc2cc(S(C)(=O)=O)ccc2c1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
A mixture of 5-(4-fluorobenzoyl)-6-hydroxy-2-methylsulfonylnaphthalene (1.0 g, 2.9 mmol), [prepared as described in step 3 above], methyl iodide (0.65 ml, 10.45 mmol), and potassium carbonate (0.64 g, 4.65 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature. After 16 h, the reaction mixture was diluted with water and extracted into ethyl acetate. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by flash chromatography (gradient elution 40-100% ethyl acetate/hexanes) to give 1.0 g of 5-(4-fluorobenzoyl)-6-methoxy-2-methylsulfonylnaphthalene as a solid (96% yield).
Reaction SMILES: ICI.[CH3:4][Si:5]([CH3:14])([CH3:13])[O:6][C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1.[CH2:15]([Zn]CC)C.[NH4+].[Cl-]>CCCCCC>[CH3:4][Si:5]([CH3:14])([CH3:13])[O:6][C:7]12[CH2:15][CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: C[Si](C)(C)OC1=CCCCC1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: ICI
Product: C[Si](C)(C)OC12CCCCC1C2
Temperature: 0 °C
Reaction time: 10 h
Yield: 63 %

Procedure:
Diiodomethane(120 μl, 1.5 mmol) was added slowly to perfluorohexanes (FC-72, 3 mL) in a test tube (14 mm×105 mm) and then trimethylsiloxycyclohexene (180 mg, 1.05 mmol) in hexane (3.5 mL) was slowly poured into the test tube. A hexane solution of diethylzinc (1.0 M, 1.5 mmol, 1.5 mmol) was added to the hexane layer, and the diiodomethane layer on the bottom was stirred gently so as not to mix the three phases. After 10 h at room temperature, additional diidomethane (40 μl, 0.5 mmol) was added to the bottom layer of the test tube by using a syringe. After 14 h, the reaction mixture was cooled to 0° C., and saturated NH4Cl (10 mL) was added. The hexane layer was decanted, washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by short column chromatography (17 mm×20 mm of florisil layer over 50 mm of silica gel layer) with benzene/hexane: ¼ to give 1-trimethylsiloxybicyclo[4.1.0]heptane in 63% yield (123 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24](OCC)=[O:25])[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][CH2:24][OH:25])[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4ccccc4)c3[nH]2)S1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 12 %

Procedure:
Ethyl (2-{7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (470 mg) was dissolved in tetrahydrofuran (8 mL), lithium borohydride (100 mg) was added, and the mixture was stirred at room temperature for 13 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=30:70 to 100:0, volume ratio), and the obtained yellow oil was crystallized from ethanol. The obtained crystals were recrystallized from ethanol to give the title compound (52 mg, yield 12%) as colorless crystals. melting point 97-98° C. MS 523 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C:37]([F:44])([F:43])[C:38](OCC)=[O:39])=[C:32]([C:45]([F:48])([F:47])[F:46])[CH:31]=3)=[O:28])=[C:22]([F:49])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CC(=O)OCC>C1COCC1>[F:44][C:37]([F:43])([CH2:38][OH:39])[CH2:36][C:33]1[CH:34]=[CH:35][C:30]([NH:29][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:6]3[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:21][C:22]=2[F:49])=[CH:31][C:32]=1[C:45]([F:46])([F:47])[F:48]
Reactant: CCOC(=O)C(F)(F)Cc1ccc(NC(=O)Cc2ccc(-c3cnc(OCc4ccc(OC)cc4)c(OCC)c3)cc2F)cc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(F)(F)CO)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a mixture of ethyl 3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate (100 mg, 0.145 mmol) in THF (5 mL) was added LAH (5.50 mg, 0.145 mmol) at 0° C. The mixture was stirred for 1 h. LCMS and TLC (PE/EA=1:1, Rf=0.2) showed the reaction was finished. The reaction was quenched by water (0.3 mL). The mixture was filtered, and the filtrate was concentrated to give N-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (80 mg, 0.104 mmol, 71.6% yield): 1H NMR (400 MHz, CD3OD-d4) δ 8.01 (s, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.47-7.27 (m, 6H), 6.90 (d, J=8.8 Hz, 2H), 5.35 (s, 2H), 4.22-4.11 (m, 2H), 3.82-3.75 (m, 3H), 3.67 (t, J=13.0 Hz, 2H), 3.47-3.37 (m, 2H), 3.37-3.34 (m, 2H), 1.41 (t, J=7.1 Hz, 3H). ES-LCMS m/z 649 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38](O)=[O:39])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:64][C:65]1([OH:71])[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>C(#N)C.C(N(CC)CC)C>[C:27]([C:24]1[N:23]=[C:22]([NH:31][CH2:32][C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@@H:12]2[CH2:11][C@H:10]([C:38]([N:68]3[CH2:69][CH2:70][C:65]([OH:71])([CH3:64])[CH2:66][CH2:67]3)=[O:39])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:13]2)=[O:20])=[CH:26][N:25]=1)([CH3:28])([CH3:29])[CH3:30]
Reactant: CC1(O)CCNCC1
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H]1C[C@H](C(=O)N2CCC(C)(O)CC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.3 %

Procedure:
(3R*,5S*)-1-(tert-Butoxycarbonyl)-5-[({2-tert-butyl-4-[(2-furylmethyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (100 mg), HOBt (41 mg) and WSC.HCl (52 mg) were dissolved in acetonitrile (3 ml), 4-methylpiperidin-4-ol monohydrochloride (27 mg) and triethylamine (75 μl) were added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:5-3:1) was concentrated under reduced pressure to give the object compound (110 mg).
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[Cl:9][C:10]1[CH:21]=[C:20]([C:22]2[CH:23]([CH3:29])[NH:24][C:25](=[O:28])[NH:26][N:27]=2)[CH:19]=[CH:18][C:11]=1[O:12][CH2:13][C:14]([NH:16][NH2:17])=[O:15]>C(O)(=O)C>[Cl:9][C:10]1[CH:21]=[C:20]([C:22]2[CH:23]([CH3:29])[NH:24][C:25](=[O:28])[NH:26][N:27]=2)[CH:19]=[CH:18][C:11]=1[O:12][CH2:13][C:14]([NH:16][N:17]1[C:6]([CH3:7])=[CH:5][CH:1]=[C:2]1[CH3:4])=[O:15]
Reactant: CC1NC(=O)NN=C1c1ccc(OCC(=O)NN)c(Cl)c1
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(C)n1NC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Temperature: 70 °C
Yield: 64 %

Procedure:
0.27 g of acetonylacetone was added to a solution of 0.5 g of α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetohydrazide (prepared as described in Example 13) dissolved in 5 ml of acetic acid, and the mixture was heated at 70° C. for 4 hours. The acetic acid used as the solvent was removed by evaporation under reduced pressure, and the residue was mixed with water to precipitate crystals. These crystals were collected by filtration, washed with water and dried. The product was purified by column chromatography through silica gel (eluent: a 98:2 by volume mixture of methylene chloride and ethanol), followed by recrystallization from ethanol to give 0.4 g of the title compound melting at 189°-190° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[I:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[I:34][C:35]1[CH:43]=[CH:42][C:38]([CH2:39][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[CH3:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]3[OH:13])[CH:5]=2)=[CH:37][CH:36]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(I)cc1
Product: Cc1cccc2c1c(Cc1ccc(I)cc1)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
4-Methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 23-(1) and 4-iodobenzoyl chloride were treated in a manner similar to Example 27 to give the titled compound as a colorless powder. APCI-Mass m/Z 510 (M+H). 1H-NMR (DMSO-d6) δ 2.38 (s, 3H), 3.24 (m, 1H), 3.30-3.47 (m, 4H), 3.68 (m, 1H), 4.16 (s, 2H), 4.52 (t, J=5.6 Hz, 1H), 5.08 (d, J=5.3 Hz, 1H), 5.14 (d, J=5.0 Hz, 1H), 5.16 (d, J=5.9 Hz, 1H), 5.34 (d, J=9.0 Hz, 1H), 6.71 (d, J=7.1 Hz, 1H), 6.98 (dd, J=8.3, 6.9 Hz, 1H), 6.99 (d, J=8.2 Hz, 2H), 7.15 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[Cl:17][C:18]([Cl:22])([Cl:21])[CH2:19]O.Cl.CN(C)CCCC(N=C=N)C.C(Cl)Cl>O.CCOC(C)=O>[CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:19][C:18]([Cl:22])([Cl:21])[Cl:17])=[O:9]
Reactant: Cc1cc(C)c(C)c(OCCCC(=O)O)c1
Reactant: OCC(Cl)(Cl)Cl
Agent: CC(CCCN(C)C)N=C=N
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C)c(OCCCC(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2,3,5-trimethylphenoxy)butyric acid (4.82 mg) dimethylaminopyridine (DMAP, 0.26 g), 2,2,2-trichloroethanol (2.50 ml), 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (4.57 g) and CH2Cl2 was stirred at room temperature overnight. The reaction mixture was poured into a mixture of AcOEt and water. The separated AcOEt was washed with dil. HCl, sat. NaHCO3, water, and brine, and dried over MgSO4, and then evaporated to give 2,2,2-trichloroethyl 4-(2,3,5-trimethylphenoxy)butyrate (8.11 g) as an oil compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([O:14][C:15]([N:17]1[CH:22](C)[CH2:21][C:20](=O)[CH2:19][CH:18]1C)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:27].[Na+].[OH-].[Na+]>C(O)(=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:21]([CH2:26][CH3:27])[CH2:22]1)=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC1CC(=O)CC(C)N1C(=O)OC(C)(C)C
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCC1CN(C(=O)OC(C)(C)C)CCC1n1ccc2ccccc21
Temperature: 70 °C

Procedure:
Dissolve 1H-Indole (10 g, 50.2 mmol) and 2,6-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (8.62 g, 55.2 mmol) in glacial acetic acid (100 mL), add sodium triacetoxyborohydride (15.96 g, 75.3 mmol) and heat the mixture to 70° C. for 20 h. Cool the reaction mixture in an ice bath and made basic with 5N sodium hydroxide solution. Extract the mixture with methylene chloride, wash with water, brine and dry over sodium sulphate to yield the title compound. Flash chromatography using a gradient of ethyl acetate in hexanes yields the pure product. ESMS m/z (relative intensity) ES(M++H): 329.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)=[N:18][N:17]=[C:16]1[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35].O.NN>C(O)C>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][C:16]1[N:15]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:21][CH2:20][C:19]2=[N:18][N:17]=1
Reactant: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccccc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)CCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1C, 2'-chloro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is refluxed with hydrazine hydrate to give 1-[2-(dimethylamino)ethyl]-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine. Its methanesulfamate is obtained by treatment with methanesulfamic acid in ether.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:8])[CH:3]([CH2:4]2)[CH2:2]1.O.O1CC[CH2:12][CH2:11]1>>[C:11]([C:7]1([OH:8])[CH2:6][CH:5]2[CH2:4][CH:3]1[CH2:2][CH2:1]2)#[CH:12]
Reactant: C1CCOC1
Reactant: O=C1CC2CCC1C2
Solvent: O
Product: C#CC1(O)CC2CCC1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
500 mg of norcamphor was dissolved in 6 ml of tetrahydrofuran and the solution was added dropwise in a suspension of 543 mg of lithium acetylide-ethylenediamine complex in tetrahydrofuran at room temperature, and the resulting reaction mixture was stirred for 18 hours. After water was added to the resulting reaction mixture, it was evaporated while maintaining the temperature of the water bath at 25° C. The residue was extracted with ethyl acetate twice. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 523 mg of the title compound.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:12][C:13]1[C:14]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1>ClCCl>[Br:12][C:13]1[C:14]([O:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[CH:15][C:16]([NH:19][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])=[N:17][CH:18]=1
Reactant: Nc1cc(Oc2c(F)cccc2F)c(Br)cn1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: O=C(NC(=S)Nc1cc(Oc2c(F)cccc2F)c(Br)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoyl isothiocyanate (1.63 g, 10.0 mmol) is added to a solution of 5-bromo-4-(2,6-difluorophenoxy)pyridin-2-amine (3.01 g, 10 mmol) in dichloromethane (20 mL) at 0° C. The reaction mixture is warmed to room temperature and stirred for one hour. The reaction mixture is diluted with hexanes and filtered to afford N-(5-bromo-4-(2,6-difluorophenoxy)pyridin-2-ylcarbamothioyl)benzamide.
Reaction SMILES: FC1C=CC=C(F)C=1N[N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH2:19].C(#N)CC#N.O.[NH2:31][NH2:32]>>[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH:19][N:10]=[C:11]1[C:12]([NH2:13])=[N:32][N:31]=[C:14]1[NH2:15]
Reactant: N#CC(C#N)=NNc1c(F)cccc1F
Reactant: Nc1c(F)cccc1F
Reactant: NN
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1c(F)cccc1F

Procedure:
4-[(2,6-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 103 mg (0.5 mmol) of 2-[(2,6-difluorophenyl)hydrazono]malononitrile, which was derived from 2,6-difluoroaniline (108 μL, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 minutes after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 44 mg (37%) of the compound as an orange solid.