Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[N:15]=[C:16](I)[C:3]=12.[C:26]1(B2OC(C)(C)C(C)(C)O2)[CH2:30][CH2:29][CH2:28][CH:27]=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[N:15]=[C:16]([C:26]3[CH2:30][CH2:29][CH2:28][CH:27]=3)[C:3]=12
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: O=C(Cn1nc(I)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1
Product: O=C(Cn1nc(C2=CCCC2)c2c(Cl)c(-c3ccccc3)nnc21)N1CCCC1

Procedure:
Compound In was synthesized according to Example 1 Step 8, except 2-(4-chloro-3-iodo-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)-1-(pyrrolidin-1-yl)ethanone was used instead of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>C(#N)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: COc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(CNCCOc2cccc(-c3noc4ccsc34)c2)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3-methoxybenzylamine and acetonitrile essentially as described above in example 35, except that the column is eluted with a graded solvent mixture of 50% ethyl acetate in heptane to 100% ethyl acetate. Purity by LC/MS (APCI)=99%, [M+H]+=381.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][NH:5][C:6]([C:8]1[CH:28]=[CH:27][C:11]2[N:12]([CH3:26])[C:13]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:14][C:10]=2[CH:9]=1)=[O:7].[OH-].[Li+]>>[Cl:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([NH:15][C:13]3[N:12]([CH3:26])[C:11]4[CH:27]=[CH:28][C:8]([C:6]([NH:5][CH2:4][C:3]([OH:29])=[O:2])=[O:7])=[CH:9][C:10]=4[N:14]=3)[S:17][C:18]=2[CH:24]=1
Reactant: COC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Yield: 62.9 %

Procedure:
{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (300 mg) was prepared by following General Procedure E starting from {[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid methyl ester (493 mg) and lithium hydroxide (192 mg).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][C:5]=1[Cl:14].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[N:28][OH:29])[CH3:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23](/[C:26](=[N:28]/[O:29][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:15])=[C:5]([Cl:14])[CH:6]=2)/[CH3:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(OCCBr)cc1Cl
Reactant: CC(=NO)c1ccc(C(C)(C)C)cc1
Product: C/C(=N\OCCOc1ccc(C(=O)O)c(Cl)c1)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared as white solid (0.334 g, 53%) from 4-(2-bromo-ethoxy)-2-chloro-benzoic acid methyl ester and 1-(4-tert-butyl-phenyl)-ethanone oxime using a procedure similar to that of step 1 of example 6. mp=142.7-143.9° C.; mass spectrum (−ESI, M−H) m/z 388. 1H NMR (400 MHz, DMSO-d6); δ 12.97 (bs, 1H), 7.81 (d, 1H), 7.57 (d, 2H), 7.40 (d, 2H), 7.14 (d, 1H), 7.02 (dd, 1H), 4.42 (t, 2H), 4.38 (t, 2H), 2.13 (s, 3H), 1.28 (s, 9H). Elemental analysis: Calcd. for C21H24ClNO4: C, 64.69; H, 6.20; N, 3.59, Found: C, 64.43; H, 6.20; N, 3.42.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C:5](=[O:8])[N:4]1[CH2:9][C:10]1[S:11][CH:12]=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[N:14]=1.[BH4-].[Na+]>O1CCCC1.C(O)CCC.C(OCC)(=O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C:5](=[O:8])[N:4]1[CH2:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[N:14]=1
Reactant: CCCCOC(=O)/C=C/c1csc(CN2C(=O)CC[C@@H]2CO)n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Solvent: C1CCOC1
Product: CCCCOC(=O)CCc1csc(CN2C(=O)CC[C@@H]2CO)n1
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution of the compound 74 (350 mg) in tetrahydrofuran (4.0 mL) and n-butanol (1.30 mL) was nickel chloride hexahydrate (246 mg) at room temperature and then thereto was added sodium borohydride (156 mg) at 0° C. The solution was stirred for 1 hour. The reaction solution was diluted with ethyl acetate and filtrated through Celite (Brand name). The obtained filtrate was washed an aqueous saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:methanol=1:019:1) to give the title compound (244 mg) having the following physical data.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[O:19]1CCC[CH2:20]1>>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:20]=[O:19])[C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1ccccc1O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cccc(C=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
2-tert-Butylphenol 7.51 g (50 mmol) and THF (tetrahydrofuran) 54 ml were charged in a sufficiently dried 500 ml reactor purged with argon, ethylmagnesium bromide 18.53 ml (an ether solution, 3.0N, 55.6 mmol) was added dropwise to the reactor at 0° C. in 15 minutes and after that, the temperature was gradually raised to a room temperature and the resultant mixture was stirred for 1 hour at a room temperature. Toluene 180 ml was added, the resultant mixture was heated to 100° C., and about 40 ml of the mixed solvents of ether and THF were evaporated off to obtain a slightly opaque slurry. After the slurry was cooled to a room temperature, p-formaldehyde 3.75 g (125 mmol) and triethylamine 10.45 ml (75 mmol) were added and the resultant mixture was stirred at 88° C. for 1 hour. After being cooled to a room temperature, the mixture was quenched with 10% hydrochloric acid and an organic layer was concentrated and purified by a silica gel column to obtain 3-tert-butylsalicylaldehyde 6.22 g (yield 70%).
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][O:7][C:6]=12.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31]C(=O)OC(C)(C)C)[CH:26]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[C:11]1([C:3]2[C:2]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[CH:26]=3)=[C:6]3[O:7][CH2:8][CH2:9][CH2:10][N:5]3[N:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Brc1c(-c2ccccc2)nn2c1OCCC2
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1cc(-c2c(-c3ccccc3)nn3c2OCCC3)ccn1
Temperature: 150 °C

Procedure:
3-bromo-2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (700 mg, 2.25 mmol) and tert-butyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (792 mg, 2.47 mmol, 1.1 eq) are dissolved in 10 mL 1,4-dioxan. To this mixture Bis(tricyclohexylphosphine)palladium(II)-dichloride (166 mg, 0.22 mmol, 0.1 eq) and 5.4 mL sodium carbonate solution (2 molar) are added. The reaction mixture is flushed with argon for 5 mins and then sealed. Next the mixture is heated for 12 mins at 150° C. in the microwave (Biotage). The procedure is repeated 7× using the same scale and all crude reaction mixtures are combined thereafter. After cooling, insoluble components are filtered off over Celite and the residue washed with 1,4-dioxan. The organic phase is evaporated and the crude product purified by column chromatography over silica gel using dichloromethane/methanole as eluent. After evaporation of the solvents 2.10 g (41%) of 4-(2-phenyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)pyridin-2-amine are obtained as a colourless solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[N+:12]([O-:23])[C:13]3[CH:22]=[C:21]4[C:17]([CH2:18][CH2:19][CH2:20]4)=[CH:16][C:14]=3[N:15]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[OH:25].C(Cl)Cl>>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[N+:12]([O-:23])[C:13]3[CH:22]=[C:21]4[C:17]([CH2:18][CH2:19][CH2:20]4)=[CH:16][C:14]=3[N+:15]=2[O-:25])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1nc(CCCN2CCOCC2)nc2cc3c(cc21)CCC3
Reactant: CO
Solvent: ClCCl
Product: [O-][n+]1nc(CCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3

Procedure:
H2O2 (70%, 2.8 mL, ca. 56 mmol) was added dropwise to a stirred solution of TFM (7.9 mL, 56 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. The solution was added to a solution of 1-oxide 76 (1.76 g, 5.6 mmol) and TFA (2.2 mL, 28 mmol) in DCM (40 mL) at 0° C. and the solution was stirred at 20° C. for 6 h. Dilute aqueous NH3 solution (40 mL) was added and the mixture stirred vigorously for 30 min and then extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 76 (173 mg, 10%); and (ii) 1,4-dioxide 77 (868 mg, 47%) as a yellow solid: mp (MeOH/DCM) 109-110° C.; 1H NMR δ 8.30 (s, 1H, H-9), 8.27 (s, 1H, H-5), 3.44 (br t, J=4.4 Hz, 4H, 2×CH2O), 3.24 (br t, J=7.3 Hz, 2H, CH2), 3.13-3.19 (m, 4H, H-6, H-8), 2.50 (t, J=6.5 Hz, 2H, CH2N), 2.38 (br t, J=4.3 Hz, 4H, 2×CH2N), 2.27 (p, J=7.5 Hz, 2H, H-7), 2.06-2.12 (m, 2H, CH2); 13C NMR δ 155.2, 155.1, 150.5, 139.0, 133.7, 115.8, 113.8, 67.0 (2), 58.0, 53.5 (2), 33.3, 32.8, 28.5, 25.5, 21.8. Anal. calcd for C17H22N4O3: C, 61.8; H, 6.7; N, 17.0. Found: C, 62.0; H, 6.8; N, 17.2%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][C:22]=4[N:23]=3)[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:31]([N:33]1[CH2:37][CH2:36][S:35][CH2:34]1)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.C(C1C=CC2OC(C3CCN([C@@H]4CN[C@H](C(N5CCSC5)=O)C4)CC3)=[N:48]C=2C=1)(O)=O.C(Cl)(=O)OCC(C)C.N.CO>O1CCCC1.O.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][C:25]([C:28](=[O:29])[NH2:48])=[CH:24][C:22]=4[N:23]=3)[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:31]([N:33]1[CH2:37][CH2:36][S:35][CH2:34]1)=[O:32])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N2CCC(c3nc4cc(C(=O)O)ccc4o3)CC2)C[C@H]1C(=O)N1CCSC1
Reactant: O=C(O)c1ccc2oc(C3CCN([C@@H]4CN[C@H](C(=O)N5CCSC5)C4)CC3)nc2c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](N2CCC(c3nc4cc(C(N)=O)ccc4o3)CC2)C[C@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(5-carboxy-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of Example 310 (1), 1.06 g] was dissolved in tetrahydrofuran (5 mL), and triethylamine (0.279 mL) and isobutyl chlorocarbonate (0.263 mL) were added thereto under ice-cooling. The mixture was stirred at room temperature for 30 min. A solution of 7 mol/L ammonia-methanol (1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carbamoyl-2-benzoxazolyl)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (345 mg) as a white powder.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[CH3:12].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][C:7]1[C:8]2[C:3](=[C:2]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][N:6]=1
Reactant: C1COCCN1
Reactant: CC1=NCCc2c(I)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1=NCCc2c1cccc2N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.9 %

Procedure:
A flask under Ar was charged with 5-iodo-1-methyl-3,4-dihydroisoquinoline (8.0 g, 29.5 mmol), morpholine (3.1 g, 35.4 mmol) and Cs2CO3 (13.5 g, 41.3 mmol) and a mixture of Pd(OAc)2 (0.33 g, 1.48 mmol) and BINAP (0.92 g, 1.48 mmol) in toluene (150 mL) was added. The reaction was stirred at RT for 5 min and then heated to reflux for 24 h. The reaction was allowed to cool to RT, and then filtered over celite. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1) to provide the title compound (3.05 g). UPLC-MS: MS 231.1 (M+H+); UPLC rt 0.40 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC=O)C.C1COCC1>[CH3:9][NH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC=O
Solvent: C1CCOC1
Product: CNc1cccc(O)c1
Reaction time: 18 h
Yield: 4810.1 %

Procedure:
3-Aminophenol (5.37 g, 49.2 mmol) in ethylformate (30 mL) was treated with p-toluenesulfonic acid (50 mg) and heated at reflux. After 18 hours, the volatiles were evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed with 1N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was dissolved in THF (25 mL) and treated with 1M borane tetrahydofuran complex (27.2 mL, 27.2 mmol) in THF. After 18 hours at ambient temperature, the mixture was carefully quenched by addition of 1N HCl. After stirring for 30 minutes, the solution was basified and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate/hexanes) to provide the title compound as a viscous yellow oil (1.72 g, 28% yield). 1H NMR (300 MHz, CDCl3) δ 7.03 (t, 1H), 6.13-6.24 (m, 2H), 6.11 (t, 1H), 4.54 (bs, 1H), 3.72 (bs, 1H), 2.82 (s, 3H); MS (DCI/NH3) 124 (M+H)+, 141 (M+NH4)+.
Reaction SMILES: [OH-:1].[Na+].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>C(O)C>[CH2:4]([O:1][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [OH-]
Reactant: CCCCCCBr
Agent: [Na+]
Solvent: CCO
Product: CCCCCCOc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 164.4 %

Procedure:
50.0g (0.290mol) of p-bromophenyl was dissolved in 300ml of ethanol and 14.2g (0.340mol) of sodium hydroxide and 49.5g (0.300mol) of 1-bromohexane were added thereto. The resulting solution was stirred at 70° C. for 4 hours to complete the reaction and the solvent was removed by distillation. Then 150ml of water was added and the organic layer was extracted with 200ml of hexane. The hexane was removed by distillation thereafter. The residue was distilled under reduced pressure to yield 63.4g of 4-hexyloxybromobenzene having a b.p. 139° C./7mmHg.
Reaction SMILES: C1C=C[NH+]=CC=1.[Br:7][Br-]Br.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=1)=[CH:17][CH2:16][CH2:15]2>C1COCC1>[Br:7][C:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH3:10])[CH:13]=2)[C:18]=1[C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)CCC=C2c1ccc(OCCN2CCCC2)cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(Br)=C2c1ccc(OCCN2CCCC2)cc1
Reaction time: 60 h
Yield: 82.9 %

Procedure:
Pyridinium bromide perbromide (21.22 g, 60.55 mmol) was added portionwise to a solution of 1-{2-[4-(6-methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine (23 g, 72 mmol) in THF (700 mL). The reaction was stirred for 60 h. The precipitate was filtered through a Celite pad with the aid of THF. The off-white solid was dissolved in CH2Cl2 and MeOH and was filtered away from the Celite. The organic solution was washed with 0.5 N aq HCl followed by satd NaHCO3 (aq). The organic solution was dried (MgSO4), filtered, and concentrated to provide a brown solid (21.5 g, 83%). 1H NMR (250 MHz, CDCl3): d 7.14 (d, J=8.7 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 6.71 (d, J=2.2 Hz, 1H), 6.55 (m, 2H), 4.17 (t, J=6.0 Hz, 2H), 3.77 (s, 3H), 2.96 (m, 4H), 2.66 (m, 4H), 1.85 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7].[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39]Cl>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([CH2:39][CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: CN(C)CCCCl
Reactant: Cc1ccccc1C1=CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1C1=CN(CCCN(C)C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=568.2 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]dec-3-en-1-one and 3-dimethylamino-1-propyl chloride.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:7])[CH:5]=[O:6].CNC.[SH:11][C:12]1[S:13][CH:14]=[C:15]([CH2:17]C(OCC)=O)[N:16]=1>O1CCCC1.C(OCC)(=O)C.O>[CH3:3][N:4]([CH3:7])[C:5](=[O:6])[CH2:17][C:15]1[N:16]=[C:12]([SH:11])[S:13][CH:14]=1
Reactant: CCOC(=O)Cc1csc(S)n1
Reactant: CN(C)C=O
Agent: CNC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1csc(S)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of sodium hydride (24 mg) and N,N-dimethylformamide (4.0 ml) was added a solution of dimethylamine (54 mg) in tetrahydrofuran (320 μl) at -10° C. After stirring at room temperature for 1 hour, ethyl 2-mercapto-4-thiazole acetate (203 mg) was added to the mixture at room temperature. After stirring at room temperature for 3 hours, the mixture was poured into a mixture of water and ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate) to give N,N-dimethyl-2-mercapto-4-thiazole acetamide (72 mg).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:33][NH:34][C:35]([NH2:37])=[O:36].N1C=CC=CC=1.Cl>FC1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=2)[C:8]([NH:37][C:35]([NH:34][CH3:33])=[O:36])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(N)=O
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Fc1ccccc1
Solvent: c1ccncc1
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionic acid (368 mg, 1.0 mmol) in fluorobenzene (1.5 mL) and N,N-dimethylformamide (6 μL) at 25° C. was treated dropwise with oxalyl chloride (107.7 μL, 1.21 mmol) over 2-3 min. The clear solution was stirred for 1 h at 25° C. and then treated with methyl urea (322 mg, 2.0 mmol). The resulting suspension was heated at 70° C. (bath temperature) for 10 min and then treated with pyridine (162 μL, 2.0 mmol). The reaction mixture was then stirred at 70° C. for 20 h. The reaction mixture was then cooled to 25° C. and diluted with ethyl acetate (30 mL) and a 3N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated, in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 to 1/2 hexanes/ethyl acetate) afforded 1-{3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionyl}-3-methyl-urea (338 mg, 80%) as an amorphous white solid: EI-HRMS m/e calcd for C19H23F3N6O2 (M+) 424.1834, found 424.1833.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:16]([N:23]([CH3:37])[C:24]([CH2:26][CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH:35]=O)=[O:29])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:16]([N:23]([CH3:37])[C:24]([CH2:26][CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH:35]1[O:4][CH2:1][CH2:2][O:3]1)=[O:29])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCCO
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C1OCCO1

Procedure:
Ethylene glycol (0.3 ml), p-toluenesulphonic acid (1 mg) were added to a solution of (2S)-1-[3-(N-benzyl-N-methylcarbamoyl) propanoyl]pyrrolidin-2-al (164 mg) in benzene (3 ml). The mixture was refluxed for 1 hr. The reaction solution was poured into a saturated aq. solution of sodium bicarbonate. The mixture was extracted with benzene. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (CH3OH-EtOAc-CH2Cl2) to give the title compound (79 mg) having the following physical data: