Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C2[NH:23][C:4](=[C:5]([C:35]3[C:40]([CH3:41])=[CH:39][C:38]([CH3:42])=[CH:37][C:36]=3[CH3:43])[C:6]3[CH:7]=[CH:8][C:9]([N:34]=3)=[C:10]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[C:11]3[NH:15][C:14]([CH:16]=[C:17]4[N:24]=[C:20](C=2)[CH2:19][C:18]4([CH3:26])[CH3:25])=[CH:13][CH:12]=3)[CH:3]=1.Cl.[CH2:45](Cl)Cl.[CH2:48]1[CH2:52][O:51][CH2:50][CH2:49]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:50]([C:49]1[C:48]2[NH:23][C:4](=[C:5]([C:35]3[C:40]([CH3:41])=[CH:39][C:38]([CH3:42])=[CH:37][C:36]=3[CH3:43])[C:6]3[CH:7]=[CH:8][C:9]([N:34]=3)=[C:10]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[C:11]3[NH:15][C:14]([CH:16]=[C:17]4[N:24]=[C:20]([CH:52]=2)[CH2:19][C:18]4([CH3:26])[CH3:25])=[CH:13][CH:12]=3)[CH:3]=1)(=[O:51])[CH3:45]
Reactant: ClCCl
Reactant: Cc1ccc(-c2c3nc(c(-c4c(C)cc(C)cc4C)c4cc(Br)c(cc5nc(cc6ccc2[nH]6)C(C)(C)C5)[nH]4)C=C3)cc1
Reactant: C1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(=O)c1cc2[nH]c1cc1nc(cc3ccc([nH]3)c(-c3ccc(C)cc3)c3nc(c2-c2c(C)cc(C)cc2C)C=C3)C(C)(C)C1
Yield: 71 %

Procedure:
Following a procedure for Stille coupling on aromatic compounds (Kosugi, M. et al., Bull. Chem. Soc. Jpn. 1987, 60, 767-768), a mixture of 6 (75 mg, 0.12 mmol), 7 (80 μL, 0.24 mmol) and (PPh3)2PdCl2 (9.0 mg, 0.013 mmol) was refluxed in THF (12 mL) for 20 h in a Schlenk line. The reaction mixture was treated with 10% aqueous HCl (4 mL) at room temperature for 2 h. CH2Cl2 was added and the organic layer was separated. The organic layer was washed with saturated aqueous NaHCO3, water, and brine. The organic layer was dried (Na2SO4), concentrated and chromatographed [silica, CH2Cl2/hexanes (1:1)], affording a purple solid (50 mg, 71%): 1H NMR δ-0.98 (brs, 2H), 1.86 (s, 6H), 2.02 (s, 6H), 2.61 (s, 3H), 2.66 (s, 3H), 3.05 (s, 3H), 4.56 (s, 2H), 7.24 (s, 2H), 7.50 (d, J=7.8 Hz, 2H), 7.96 (d, J=7.8 Hz, 2H), 8.23 (d, J=4.4 Hz, 1H), 8.31 (d, J=4.4 Hz, 1H), 8.68 (d, J=4.4 Hz, 1H), 8.69 (s, 1H), 8.70 (d, J=4.4 Hz, 1H), 8.86 (s, 1H), 9.98 (s, 1H); LD-MS obsd 590.8; FAB-MS obsd 590.3052, calcd 590.3046 (C40H38N4O); λabs 422, 661 (logs ε=4.67) nm, λem 668, 711, 714 nm (Φf=0.23).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.CN[C@@H]1CCCC[C@H]1NC.[CH3:41][OH:42]>[Cu]I>[OH:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([O:42][CH3:41])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: CO
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Product: COc1ccc(Cc2cc3c(=O)n([C@@H]4CCCC[C@H]4O)cnc3c3ccccc23)cn1
Temperature: 25 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.150 g, 0.357 mmol) in 3 mL of MeOH under an atmosphere of nitrogen was added trans-N,N′-dimethylcyclohexane-1,2-diamine (1.7 mg, 0.012 mmol), and copper(I) iodide (2.3 mg, 0.012 mmol). The mixture was irradiated in a microwave reactor at 160° C. for 4 h, cooled to rt and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-100% ethyl acetate in hexanes, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 416.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.03-8.99 (m, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 8.02-7.99 (m, 2H), 7.70-7.65 (m, 2H), 7.37-7.34 (m, 1H), 6.62 (d, J=8.5 Hz, 1H), 4.82 (br s, 1H), 4.39 (s, 2H), 4.01 (br s, 1H), 3.90 (s, 3H), 2.30-2.23 (m, 1H), 2.18-2.12 (m, 1H), 1.99-1.84 (m, 3H), 1.53-1.42 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[Li][CH2:14][CH2:15][CH2:16][CH3:17]>CO>[CH2:14]([C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:15][CH2:16][CH3:17].[CH2:14]([C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[CH:11]=[CH:12][C:4]=1[NH2:1])[CH2:15][CH2:16][CH3:17]
Reactant: [Li]CCCC
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Solvent: CO
Product: CCCCc1c(N)ccc2nc[nH]c12
Product: CCCCc1c([N+](=O)[O-])ccc2nc[nH]c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitrobenzimidazole (0.41 g, 2.5 mmol) was added a solution of n-BuLi (7.5 mmol) and reaction mixture was stirred for 1 h at 0° C. The reaction mixture was quenched by adding a few drops of H2O and concentrated in vacuo yielding an oil which was subjected to silica gel column chromatography (5% MeOH/EtOAC) to provide 0.13 g of 4-n-butyl-5-nitrobenzimidazole and 0.19 g of 4-n-butyl-5-aminobenzimidazole. The nitrobenzimidazole was converted to the amine in hydrogenation (H2/Pd-C) to provide 0.28 g (1.5 mmol, 60%) of the desired product.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O: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.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>C(O)C>[CH:1]([C@H:14]1[CH2:20][C@H:19]([OH:18])[C@@H:17]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Reactant: NCc1ccccc1
Solvent: CCO
Solvent: CO
Product: O[C@H]1C[C@H](C(c2ccccc2)c2ccccc2)OC[C@@H]1NCc1ccccc1

Procedure:
(1R,4R,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28c (0.022 g, 0.082 mmol) was reacted with benzylamine (0.18 g, 1.64 mmol) in ethanol (Procedure E) to yield (2R,4S,5S)-2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol, (+)-29d 0.025 g (81%, [α]D=(+)53.7, c=1, MeOH).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[C:9]([OH:14])(=O)[C:10](O)=O.[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:26])=[CH2:25])[CH:19]=1)([CH3:17])=[CH2:16]>CCCCCCC>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:15]([C:3]2[CH:4]=[CH:10][C:9]([OH:14])=[CH:8][C:1]=2[OH:2])([CH3:17])[CH3:16])[CH:19]=1)([CH3:26])[CH3:25]
Reactant: O=C(O)C(=O)O
Reactant: Oc1cccc(O)c1
Reactant: C=C(C)c1cccc(C(=C)C)c1
Solvent: CCCCCCC
Product: CC(C)(c1cccc(C(C)(C)c2ccc(O)cc2O)c1)c1ccc(O)cc1O
Temperature: 75 °C

Procedure:
Into a 2-liter kettle equipped with stirrer, thermometer, reflux condenser and an addition funnel, 264.0 grams of resorcinol (2.4 moles) 12.0 grams of oxalic acid and 900 ml of heptane were placed. The contents of this flask were heated to about 75° C. While maintaining the temperature of the resorcinolic slurry between about 75°-85° C., 126.4 grams of 1,3-diisopropenyl benzene (0.8 moles) was added dropwise for about 2 hours. After the completion of the above addition, the temperature of the reaction mixture was raised to and maintained at about 95° C. for about an additional 2.0 hours, while the reaction mixture was continuously stirred. The reaction mixture was then cooled and the separated heptane layer was removed by decantation. Finally the solidified mass was treated with excess dichloromethane to separate the reaction product. The white precipitate that separated from the solution was filtered, washed with dichloromethane and then washed with distilled water. After air drying at about room temperature the precipitate weighed 215 grams. Structural characterization by IR/NMR analysis of the reaction product confirmed the structure of 1,3-bis[(2,4-di-hydroxyphenyl)-alpha-methyl ethyl] benzene.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:26]1[CH2:30][CH2:29][N:28]([N:31]=[CH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]1=[O:39])([C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:6]2.[CH3:40][O:41][C:42]1[CH:60]=[CH:59][C:45]([CH2:46][O:47][C:48](SC2N=C(C)C=C(C)N=2)=[O:49])=[CH:44][CH:43]=1.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH:32](=[N:31][N:28]1[CH2:29][CH2:30][N:26]([C@@:5]2([C:10]([O:12][CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:11])[S:4][C@H:3]3[N:7]([C:8](=[O:9])[C@H:2]3[NH:1][C:48]([O:47][CH2:46][C:45]3[CH:59]=[CH:60][C:42]([O:41][CH3:40])=[CH:43][CH:44]=3)=[O:49])[CH2:6]2)[C:27]1=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(COC(=O)Sc2nc(C)cc(C)n2)cc1
Reactant: N[C@@H]1C(=O)N2C[C@@](C(=O)OC(c3ccccc3)c3ccccc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COC(=O)N[C@@H]2C(=O)N3C[C@@](C(=O)OC(c4ccccc4)c4ccccc4)(N4CCN(N=Cc5ccccc5)C4=O)S[C@H]23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
In 80 ml of methylene chloride was dissolved 7.50 g of (3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane. Thereto was added 5 g of S-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine. The mixture was stirred at room temperature for 2 hours. The reaction mixture was mixed with 80 ml of water, and the resulting mixture was adjusted to pH 7.0 with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/acetone=1/0 to 25/1) to obtain 8.36 g (yield: 85.2%) of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-diphenylmethyloxycarbonyl-6-(p-methoxybenzyloxycarbonylamino)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].[CH3:19][O:20][C:21](=[O:35])[CH2:22][O:23][C:24]1[C:32]([CH3:33])=[CH:31][C:30]([SH:34])=[C:29]2[C:25]=1[CH2:26][CH2:27][CH2:28]2>>[CH3:19][O:20][C:21](=[O:35])[CH2:22][O:23][C:24]1[C:32]([CH3:33])=[CH:31][C:30]([S:34][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH3:18])=[C:29]2[C:25]=1[CH2:26][CH2:27][CH2:28]2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: COC(=O)COc1c(C)cc(S)c2c1CCC2
Product: COC(=O)COc1c(C)cc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c2c1CCC2

Procedure:
The title compound was prepared from 5-(chloromethyl)-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole and (7-mercapto-5-methyl-indan-4-yloxy)-acetic acid methyl ester (prepared in a similar manner as described for Example 1D) in a manner analogous to Example 1E. MS m/z 508 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N+:34]([O-])=O)=[C:13]([NH:15][C:16]3[S:17][C:18]([C:31]([NH2:33])=[O:32])=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[N:20]=3)[CH:14]=2)[CH2:4][CH2:3]1.[H][H].[CH:39]([OH:41])=[O:40]>[Pd]>[F:28][C:27]([F:30])([F:29])[C:39]([OH:41])=[O:40].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:34]=[CH:39][N:15]([C:16]4[S:17][C:18]([C:31]([NH2:33])=[O:32])=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=5)[N:20]=4)[C:13]=3[CH:14]=2)[CH2:4][CH2:3]1
Reactant: O=CO
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4ccc(C(F)(F)F)cc4)c(C(N)=O)s3)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5ccc(C(F)(F)F)cc5)c(C(N)=O)s4)c3c2)CC1
Product: O=C(O)C(F)(F)F

Procedure:
A mixture of 0.072 g (0.138 mmole) of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-(4-trifluoromethyl-phenyl)thiazole-5-carboxylic acid amide (VI.47c), 0.0696 g of 10% palladium on carbon catalyst, and 6 mL of 96% formic acid was stirred under one atmosphere of hydrogen for 17 hours. The mixture was filtered through Diatomaceous earth and the filter pad was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water-trifluoroacetic acid (gradient 10:90:0.1-60:40:0.1) to give 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-(4-trifluoromethyl-phenyl)thiazole-5-carboxylic acid amide trifluoroacetic acid salt (I.47a). This salt was partitioned between 10 mL of saturated sodium carbonate solution and 150 mL of ethyl acetate. The organic layer was washed with 15 mL of water, then 15 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.0401 g of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-(4-trifluoromethyl-phenyl)thiazole-5-carboxylic acid amide (I.47) as a white solid. MH+/Z=501.
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[C:12]([O:17][CH:18]([O:20][C:21]([NH:23][CH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]1)=[O:22])[CH3:19])(=[O:16])[CH2:13][CH2:14][CH3:15].C(=O)(O)[O-].[Na+:38].C(#N)C>O>[C:12]([O:17][CH:18]([O:20][C:21]([NH:23][CH2:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([C:31]([O-:33])=[O:32])[CH2:29][CH2:30]1)=[O:22])[CH3:19])(=[O:16])[CH2:13][CH2:14][CH3:15].[Na+:38]
Reactant: CCCC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)[O-])CC1

Procedure:
Following the general procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 946 mg (3.0 mmol) of trans-4-{[1-(butanoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid 10 was reacted with 252 mg (3.0 mmol) of sodium bicarbonate (NaHCO3) in 20 mL of a mixture of acetonitrile and water (1:1) to yield 1.02 g (quant.) of the title compound 11 as a colorless powder. 1H NMR (400 MHz, DMSO-d6): δ=0.73-0.84 (m, 2H), 0.87 (t, J=6.8 hz, 3H) 1.08-1.20 (m, 2H), 1.20-1.32 (m, 1H), 1.38 (d, J=5.2 Hz, 3H), 1.46-1.56 (m, 2H), 1.60-1.74 (br. m, 3H), 1.76-1.83 (br. m, 2H), 2.25 (t, J=7.2 Hz, 2H), 2.78 (t, J=6.0 Hz, 2H), 6.65 (q, J=5.2 Hz, 1H), 7.41 (t, J=5.6 Hz, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.18 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](F)(=[O:35])=[O:34].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([S:33]([C:28]3[C:27]([CH3:26])=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: Cc1ccccc1S(=O)(=O)F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1S(=O)(=O)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (0.55 g; 1.66 mmol) in THF (25 mL) was added drop wise a solution of n-BuLi in hexanes (1.32 ml; 2.50 mol/l; 3.31 mmol), at −78° C. The resulting mixture was stirred at −78° C., for 30 min. and then 2-methyl-benzenesulfonyl fluoride (0.63 g; 3.64 mmol) was added. After complete addition the mixture was allowed to come to room temperature, and treated with EtOAc and a 5% aqueous NaHCO3-solution. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford 4-benzyl-2-[4-(toluene-2-sulfonyl)-phenyl]-morpholine (0.50 g). The required 2-methyl-benzenesulfonyl fluoride was prepared as follows: To a solution of o-toluenesulfonyl chloride (0.70 mL; 4.85 mmol) in CH3CN (15 mL) was added spray-dried KF (1.13 g; 19.4 mmol). The resulting mixture was stirred at RT for 18 hours, treated with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 2-methyl-benzenesulfonyl fluoride (0.68 g).
Reaction SMILES: C([C:3]1([C:18]([F:21])([F:20])[F:19])[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:17])[C:9]=2[F:16])[O:4]1)C.O.[OH-].[Li+].C(O)C>C1COCC1.O>[Cl:17][C:8]1[C:9]([F:16])=[C:10]2[C:5](=[CH:6][CH:7]=1)[O:4][CH:3]([C:18]([F:21])([F:19])[F:20])[C:12]([C:13]([OH:15])=[O:14])=[CH:11]2
Reactant: CCC1(C(F)(F)F)Oc2ccc(Cl)c(F)c2C=C1C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2c(ccc(Cl)c2F)OC1C(F)(F)F
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To the solution of ethyl 6-chloro-5-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid (1.1 g, 3.4 mmol) in 5 mL of THF was added a solution of lithium hydroxide hydrate (0.72 g, 17 mmol) in 5 mL of water. To the resulting mixture was added 5 mL of ethanol. The resulting solution was heated to reflux over three hrs. The reaction turned red. After cooling to room temperature, the volatiles were removed, the residue was diluted with water. The resulting solution was acidified at 0° C. with ice cold dilute hydrochloric acid. The product was then extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified on reverse phase HPLC. It gave a yellow solid (0.3 g). LC-MS(ES+) 297.2(M+1, 100). 1H NMR (CDCl3/CD3OD/400 MHz) 7.85(s, 1H), 7.24(m, 1H), 6.69(d, J=8.8 Hz, 1H), 5.63(q, J=6.4 Hz, 1H). 19F (CDCl3/CCD3OD/400 MHz) −78.94(d, J=6.8 Hz), −111.92(d, J=7.5 Hz). 13C NMR(CDCl3/CD3OD/400 MHz) 165.4, 155.0(d, J=64.4 Hz), 152.3, 133.2, 129.4, 123.3 (q, J=287.3 Hz) 118.5 114.2(d, J=4.3 Hz), 112.6, 110.1 (d, J=4.7 Hz), 70.9(q, J=33.2 Hz). HRSM((EI+) m/z calc. for (C11H5ClF4O3): 295.9863(M+), found 295.9875(M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[N:32]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[N:32]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)n1

Procedure:
Example 68 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.07 (d, 1H, J=8.0 Hz), 7.79 (br s, 1H), 7.66 (t, 1H, J=8.0 Hz), 7.45–7.41 (m, 2H), 7.04–7.00 (m, 2H), 6.89 (d, 1 H, J=7.6 Hz), 6.85 (br s, 1H), 3.30 (dd, 2H, J=6.0, 12.0 Hz), 2.97 (d, 2H, J=11.6 Hz), 2.57–2.50 (m, 2H), 2.37–2.32 (m, 4H), 2.01–1.77 (m, 8H), 1.65–1.60 (m, 8H), 1.27 (d, 6H, J=7.2 Hz); ESMS m/e: 509.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([CH:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])[CH3:23].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:25]([O:24][CH2:22][CH3:23])=[O:26])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCC2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCCc2nc(C(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of Intermediate 58 (99 mg) and triethylmethanetricarboxylate (0.14 mL) in anhydrous Toluene (3 mL) and anhydrous Tetrahydrofuran (THF) (3.00 mL) under a nitrogen atmosphere was added trimethylphosphine, 1M in Toluene (0.650 mL). The reaction was then cooled to −78° C. and diisopropyl azodicarboxylate (0.13 mL) added dropwise via syringe over 1 min. The reaction was stirred at −78° C. under an atmosphere of nitrogen for 90 mins before being allowed to warm to ambient temperature and stirred for a further 1 h. The reaction was concentrated in vacuo. The residue was taken up in dichloromethane (40 mL) and washed with water (40 mL), dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (139 mg). LC/MS MH+ 519, Rt 2.15 min (5 min run).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])O)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>S(Cl)(Cl)=O.CN(C)C=O>[CH2:1]([O:4][C:5]1[C:6]([CH:11]([S:28][C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cccnc1C(O)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOc1cccnc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.7 %

Procedure:
The 3-allyloxy-2-[(2,5-difluorophenyl)-hydroxymethyl]pyridine (370 mg, 1.33 mmol) obtained in Referential Example 10 was dissolved in thionyl chloride (2.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide. The resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. Dioxane was added to the residue, followed by further concentration. The residue thus obtained was dissolved in dimethylformamide (10 ml). To the resulting solution were added 4-chlorobenzenethiol (217 mg, 1.5 mmol) and potassium carbonate (828 mg, 6.0 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=10:1) to give the title compound (256 mg, 68%) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>C(O)C>[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.8 mg, 0.0572 mM), then 3-chloro-benzaldehyde (6.5 μL, 0.057 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to thus give the title compound (9.6 mg, yield: 34%).