Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:20][CH:21]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:22][OH:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][CH:21]([O:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCOCC(CO)OCCCCCCCC
Solvent: c1ccncc1
Product: CCCCCCCCOCC(COS(=O)(=O)c1ccc(C)cc1)OCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
p-Toluenesulfonyl chloride (1.2 g) was added to a stirred solution of 2,3-di-n-octyloxy-1-propanol (930 mg) in dried pyridine (10 ml) at 2° C. over 7 minutes. The reaction mixture was stirred at 0° to 5° C. for 2 hours and at room temperature overnight. The resultant solution was poured into ice water (50 ml) and extracted with ethyl acetate (40 ml). The extract was washed with dil. hydrochloric acid (20 ml) and a saturated aqueous solution of sodium chloride (20 ml) in turn, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give oil (920 mg) of 2,3-di-n-octyloxy-1-propyl p-toluenesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:27][C:28]1([CH3:38])[O:33][CH2:32][C:31]([CH3:37])([C:34](O)=[O:35])[CH2:30][O:29]1>>[CH2:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH2:12][C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][N:9]([C:34]([C:31]3([CH3:37])[CH2:30][O:29][C:28]([CH3:38])([CH3:27])[O:33][CH2:32]3)=[O:35])[CH2:10][CH2:11]2)(=[O:15])=[O:14])=[CH:21][CH:20]=1)[C:24]#[C:25][CH3:26]
Reactant: CC1(C)OCC(C)(C(=O)O)CO1
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1
Yield: 79.1 %

Procedure:
Ethyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-[(2,2,5-trimethyl-1,3-dioxan 5-yl)carbonyl]-4-piperidinecarboxylate was prepared according to the general method as outlined in Example 30 (step 8). Starting from 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylicacid ethyl ester (0.333 g, 0.8 mmol) and 2,2,5-trimethyl-(1,3)dioxane-5-carboxylic acid (0.168 g, 0.96 mmol), 0.339 g (79%) of the desired product was isolated as a white solid. Electrospray Mass Spec: 536.1 (M+H)+
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH2:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7]
Reactant: COCCN
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Product: COCCNCc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1

Procedure:
The title compound was prepared from 2-chloromethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide and 2-methoxy-ethylamine in the same manner as described for N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-morpholin-4-ylmethyl-isonicotinarmide and afforded as yellow solid (60% yield). MS: m/e=457(M+H+), mp 93-95° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[CH2:31]3)=O)[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:14][C:13]([F:16])([F:15])[C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH2:2][O:36][CH:32]1[CH2:33][CH2:34][CH2:35][N:30]([CH2:28][C:24]2([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH2:27][CH2:26][CH2:25]2)[CH2:31]1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: O=C(N1CCCC(O)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(COC2CCCN(CC3(c4ccc(Cl)cc4)CCC3)C2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Following the procedure described in Example 72, 1-Bromomethyl-3,5-bis-trifluoromethyl-benzene was used to alkylate 56 mg (0.19 mmol) of [1-(4-Chloro-phenyl)-cyclobutyl]-(3-hydroxy-piperidin-1-yl)-methanone, forming the ether adduct [3-(3,5-Bis-trifluoromethyl-benzyloxy)-piperidin-1-yl]-[1-(4-chloro-phenyl)-cyclobutyl]-methanone (39 mg, 39%). A portion of this compound (22 mg, 0.043 mmol) was dissolved in 1 mL of THF and excess lithium aluminum hydride (16 mg, ca. 10 equivalents) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 0.5 mL 1M NaOH. Additional THF (10 mL) was added, the suspension was stirred at room temperature for 30 minutes, and then was filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 3-(3,5-Bis-trifluoromethyl-benzyloxy)-1-[1-(4-chloro-phenyl)-cyclobutylmethyl]-piperidine, 189, was obtained (12 mg, 56%). Data for this compound: MS 506 (M++1).
Reaction SMILES: Br[C:2]1[C:6](Br)=[CH:5][S:4][CH:3]=1.[C:8]([Cu])#[N:9].[CH3:11][N:12](C=O)C>Cl>[C:11]([C:2]1[C:6]([C:8]#[N:9])=[CH:5][S:4][CH:3]=1)#[N:12]
Reactant: N#C[Cu]
Reactant: Brc1cscc1Br
Reactant: CN(C)C=O
Agent: Cl
Product: N#Cc1cscc1C#N
Temperature: 180 °C
Yield: 69 %

Procedure:
3,4-Dibromothiophene (12.5 ml, 113 mmol) is combined with CuCN (30.4 g, 339 mmol) in DMF (40 ml) in a dry flask under nitrogen utilizing an over-head stirrer. The reaction is allowed to reflux at 180° C. for 5 h. The dark mixture is then poured into a solution of FeCl3 (113.6 g, 700 mmol) in 1.7M HCl (200 ml) and heated at 65° C. for 0.5 h, again using the over-head stirrer. The reaction is cooled to rt and extracted with CH2Cl2 (7×300 ml). Each extract is washed individually with 200 ml each 6M HCl (2×), water, saturated NaHCO3, and water. The organics are then combined, dried over MgSO4, filtered, and concentrated, affording 10.49 g (69%) of 3,4-dicyanothiophene as a fluffy tan solid. HRMS (EI) calcd for C6H2N2S: 133.9939, found 133.9929 (M+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[CH2:5][CH:6]=[CH2:7].C(=O)(O)[O-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.O>[Cl:14][C:10]1[CH:9]=[C:8]([CH:4]([CH2:5][CH:6]=[CH2:7])[CH2:3][N:2]([CH3:1])[S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH:13]=[CH:12][CH:11]=1
Reactant: C=CCC(CNC)c1cccc(Cl)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC(CN(C)S(=O)(=O)c1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
N-Methyl-(2-(3-chlorophenyl)pent-4-enyl)amine (202 mg, 1.03 mmol) was dissolved in 10 mL of ethyl acetate. A solution of sodium bicarbonate (766 mg, 10.3 mmol) in water (10 mL) was added followed by benzenesulfonyl chloride (363 mg, 4.06 mmol), and the heterogeneous mixture was stirred overnight at room temperature. The mixture was extracted with 5 mL of ethyl acetate followed by an additional 2×15 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate, decanted, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with 10-20% ethyl ether in hexane to give 223 mg the title compound. 1NMR (400 MHz, CDCl3): δ 7.72 (d, 2H, J=8 Hz), 7.58 (tt, 1H, J=8, 1 Hz), 7.50 (t, 2H, J=8 Hz), 7.24 (d, 1H, J=8 Hz), 7.20 (dt, 1H, J=8, 1 Hz), 7.14 (t, 1H, J=1 Hz), 7.10 (dt, 1H, J=8, 1 Hz), 5.63 (ddt, 1H, J=17, 10, 7 Hz), 5.00 (dm, 1H, J=17 Hz),4.97 (dm, 1H, J=10 Hz) 3.42-3.34 (m, 1H), 3.00-2.90 (m, 2H), 2.61 (s, 3H), 2.56 (dtm, 1H, J=14, 6 Hz), 2.36 (dtm, 1H, J=14, 7 Hz). Mass spectrum (NH3 /CI): m/z=350 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:17])[CH3:16])=[O:4].Cl.[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][C:6]=3[NH:14][C:15](=[O:17])[CH3:16])=[O:4])[CH2:23][CH2:24]2)=[N:26]1
Reactant: CC(=O)Nc1cc(C(C)C)ccc1C(=O)CCl
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: CC(=O)Nc1cc(C(C)C)ccc1C(=O)CN1CCN(c2nsc3ccccc23)CC1
Yield: 72.7 %

Procedure:
Starting with N-[2-(2-chloro-acetyl)-5-isopropyl-phenyl]-acetamide (0.30 g, 1.182 mmol), and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.302 g, 1.182 mmol) and following the procedure as outlined in Example 517, N-{2-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-acetyl]-5-isopropyl-phenyl}-acetamide (0.375 g, 0.859 mmol) was obtained as its hydrochloride salt from treatment with dioxane/HCl(gas). Yield=73%. 100% purity at 254 nM. 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 10.36 (bs, 1H), 8.14 (d, J=8.24 Hz, 1H), 8.09 (d, J=8.24 Hz, 1H), 7.78–7.72 (m, 2H), 7.58 (t, J=7.56 Hz, 1H), 7.45 (t, J=7.56 Hz, 1H), 7.18 (d, J=8.24 Hz, 1H), 5.00 (s, 2H), 4.13–4.01 (m, 2H), 3.68–3.44 (m, 6H), 3.40 (s, H2O), 2.93 (heptet, J=6.95 Hz, 1H), 2.08 (s, 3H), 1.19 (d, J=6.95 Hz, 6H).
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2.ICl>CO>[Cl:3][C:4]1[CH:13]=[C:12]([I:1])[C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:15])=[N:9]2
Reactant: Cc1ccc2c(Cl)ccc(O)c2n1
Reactant: II
Agent: ClI
Solvent: CO
Product: Cc1ccc2c(Cl)cc(I)c(O)c2n1
Reaction time: 3 h

Procedure:
Iodine monchloride (19.0 g) is added to a solution of 5-chloro-8-hydroxy-2-methylquinoline (21.5 g) in 250 mL of MeOH, and the resulting mixture is stirred for 3 h. Additional iodine monochloride (4.5 g) is then added, and the mixture is stirred for another 18 h. The reaction mixture is quenched with sated Na2SO3 (aq), then neutralized with sat'd NaHCO, (aq). The solid precipitate is collected by filtration and dried under vacuum to give 31.22 g of the title compound as a pale green solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([N:8]([S:19]([CH3:18])(=[O:21])=[O:20])[C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:21])=[O:20]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.3 %

Procedure:
To a solution of 4-nitroaniline (5.04 g, 36.5 mmol) in CH2Cl2 (100 ml) cooled to 0° C. were added Et3N (6.61 mL, 47.4 mmol) and MsCl (3.39 mL, 43.8 mmol) and the mixture was stirred at room temperature overnight to give dimethanesulfonyl-(4-nitro-phenyl)-amine as a yellow solid (10.46 g, 98%) following work-up.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([CH3:34])=[C:22]([C:24]4[N:29]=[C:28]5[CH:30]=[N:31][N:32]([CH3:33])[C:27]5=[CH:26][CH:25]=4)[CH:23]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:36]([CH3:37])=[CH:35][C:14]2[N:15]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([CH3:34])=[C:22]([C:24]4[N:29]=[C:28]5[CH:30]=[N:31][N:32]([CH3:33])[C:27]5=[CH:26][CH:25]=4)[CH:23]=3)[S:17][C:13]=2[C:12]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc(C)c(-c4ccc5c(cnn5C)n4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3cnc(C)c(-c4ccc5c(cnn5C)n4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 60 °C

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(6-methyl-5-(1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)acetate (26 mg, 0.042 mmol) in THF (0.5 mL) and MeOH (0.5 mL) was added 2N NaOH (410 μL). The reaction mixture was heated at 60° C. for 3 h. The reaction mixture was concentrated down, the residue was dissolved in DMF and MeOH, filtered and purified by reverse phase HPLC, (10-100% ACN/H2O+0.1% TFA) to give the product. 1H NMR (400 MHz, CD3OD) δ 9.11 (d, J=0.8 Hz, 1H), 8.59 (d, J=1.0 Hz, 1H), 8.22-8.18 (m, 2H), 7.81 (s, 1H), 7.69-7.62 (m, 2H), 7.53-7.51 (m, 3H), 5.23 (s, 1H), 4.15 (s, 3H), 2.67 (s, 3H), 2.57 (s, 1H), 0.95 (s, 9H). LCMS-ESI+: calc'd for C33H30ClN5O3S: 612.2 (M+H+); Found: 612.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Cl:22])[CH:15]=1>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Cl:22])[CH:15]=2)[CH:9]=1
Reactant: N#Cc1ccc(CBr)cc1Cl
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: N#Cc1ccc(Cn2cc(Cl)cc(C(N)=O)c2=N)cc1Cl
Temperature: 100 °C
Reaction time: 14 h
Yield: 25.9 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.14 g) in N,N-dimethylformamide (3 ml) was added 4-(bromomethyl)-2-chlorobenzonitrile (0.28 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (85 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32](=[O:49])[CH:33](OS(C(F)(F)F)(=O)=O)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH:33]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:32]([O:31][CH3:30])=[O:49])[CH:23]=[CH:22]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Yield: 87.3 %

Procedure:
In a similar manner as described in step 6 of Example 1, the title compound was prepared from 6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.140 g, 0.373 mmol), prepared in the previous step, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.175 g, 0.560 mmol) and cesium carbonate (0.243 g, 0.746 mmol). Purification on a Biotage FlashElute™ system with a KP-Sil Flash 40+M column (90 g Silica Gel, 60 Å) using 20% to 50% methylene chloride in hexane as the eluent gave methyl 2-{[6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate as a white solid (0.175 g, 88%), mp 57–62° C. Elemental Analysis for C37H31NO3 Calc'd: C, 82.66; H, 5.81; N, 2.61. Found: C, 82.39; H, 5.88; N, 2.46.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.[CH:22]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH:36]=[CH2:37])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[CH:22]1([CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH:36]2[O:1][N:2]=[C:3]([C:4]3[N:5]=[C:6]([CH:9]4[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]4)[S:7][CH:8]=3)[CH2:37]2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C=Cc1ccccc1OCC1CCCCC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OCC4CCCCC4)C3)cs2)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.90 g) and 1-(cyclohexylmethoxy)-2-vinylbenzene (2.40 g) in ethyl acetate (300 ml) were added, at room temperature, potassium hydrogencarbonate (4.60 g) and N-chlorosuccinimide (1.48 g), and then one drop of water. The reaction mixture was stirred at 60° C. for 6 h, then admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-(4-{5-[2-(cyclohexylmethoxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidine-1-carboxylate (3.40 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[N:10]2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.O.NN>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)=[C:4]([C:25]([F:26])([F:28])[F:27])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2ccc(Cl)cc2C(F)(F)F)n1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccn(Cc2ccc(Cl)cc2C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of crude 2-(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-1H-isoindole-1,3(2H)-dione (6.14 g, 15.1 mmol) in THF (50 ml) was added hydrazine hydrate (3.67 ml, 76 mmol, Aldrich). The resulting colourless solution was stirred at 50° C. for 1 h. A white solid precipitated. The reaction was cooled down to ambient temperature and filtered through a sinter funnel. The filtrate was then passed through a hydrophobic frit and concentrated under reduced pressure. The sample was pre-absorbed on florosil (15 ml of DCM:MeOH=1:1) and purified on silica 100 g using 0-50% ethyl acetate-dichloromethane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (1.57 g); LCMS: (System 3) MH+=276, tRET=0.90 min.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[N:18]3[C:14]([O:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH2:29]>C(#N)C>[CH3:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH:29][C:2]1[CH:3]=[C:4]([C:11]2[N:18]3[C:14]([O:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(-c2c(-c3ccc(F)cc3)nc3occn23)cc1F
Reactant: CC(C)(C)CN
Solvent: CC#N
Product: CC(C)(C)CNc1cc(-c2c(-c3ccc(F)cc3)nc3occn23)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 99 %

Procedure:
To a suspension of 5-(3-fluoro-4-nitrophenyl)-6-(4-fluorophenyl)-imidazo[2,1-b]oxazole (0.80 g, 2.2 mmol; Preparation #C.1) in ACN (6.0 mL) was added TEA (0.63 mL, 4.5 mmol) and 2,2-dimethylpropylamine (0.24 g, 2.7 mmol; TCI). The reaction was heated at about 80° C. for about 4 h then cooled to about 4° C. The resulting solid was filtered, washing with cold ACN (ca. 4° C.), and dried in a vacuum oven at about 55-65° C. to give the title compound (0.89 g, 96%): LC/MS (Table 1, Method b) Rt=2.62 min; MS m/z: 409.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:21]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Agent: [Br-]
Product: CCCCCC=CC(C)(C)c1cccc(OCc2ccccc2)c1
Yield: 67.5 %

Procedure:
similarly, 1-benzyloxy-3-(1,1-dimethyloct-2-enyl)benzene (13.5 g., 70%) is prepared from 15.75 g. (0.062 mol.) of 2-(3-benzyloxyphenyl)-2-methylpropionaldehyde and 37.5 g. (0.0899 mol.) of hexyltriphenylphosphonium bromide. The product is an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=C(F)C=3)=NOC=2C)=NC=1.[F:49][C:50]([F:54])([F:53])[CH2:51][NH2:52]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:52][CH2:51][C:50]([F:54])([F:53])[F:49])=[O:21])=[CH:17][N:16]=1
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Agent: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Yield: 14 %

Procedure:
As described for example 92, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (93 mg, 0.3 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) was converted, using 2,2,2-trifluoroethylamine instead of cyclopropylamine, to the title compound (16 mg, 14%) which was obtained as a light brown solid. MS: m/e=393.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:16])[C:10]2[C:5](=[CH:6][C:7]([NH:12][CH3:13])=[C:8]([NH2:11])[CH:9]=2)[C:4]([F:15])([F:14])[O:3]1.O[CH:18]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)S([O-])(=O)=O.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:16][C:2]1([F:1])[C:10]2=[CH:9][C:8]3[N:11]=[C:18]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[N:12]([CH3:13])[C:7]=3[CH:6]=[C:5]2[C:4]([F:14])([F:15])[O:3]1
Reactant: O=S(=O)([O-])C(O)c1ccncc1
Reactant: CNc1cc2c(cc1N)C(F)(F)OC2(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccncc2)nc2cc3c(cc21)C(F)(F)OC3(F)F
Temperature: 120 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A mixture of 0.59 g of 1,1,3,3-tetrafluoro-N-methyl-1,3-dihydroisobenzofuran-5,6-diamine, 0.63 g of sodium hydroxy-pyridin-4-yl-methanesulfonate and 5 ml of DMF was stirred for 1 hour while heating at 120° C. After cooling down to room temperature, a saturated sodium hydrogen carbonate aqueous solution was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.71 g of 5,5,7,7-tetrafluoro-1-methyl-2-(pyridin-4-yl)-5,7-dihydro-1H-furo[3′,4′:4,5]benzo[1,2-d]imidazole (hereinafter, referred to as present active compound 1).