Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:20]([NH:22][C:23]2([C:27](OCC)=[O:28])[CH2:26][CH2:25][CH2:24]2)=[O:21])[CH:11]=3)=[O:5])[CH2:3][CH2:2]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[CH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:20]([NH:22][C:23]2([CH2:27][OH:28])[CH2:26][CH2:25][CH2:24]2)=[O:21])[CH:11]=3)=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1(NC(=O)c2ccc(C)c(-c3ccc4cc(NC(=O)C5CC5)ncc4c3)c2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2(CO)CCC2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 10.5 %

Procedure:
To a solution of ethyl 1-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylbenzamido)cyclobutanecarboxylate (153.8 mg; 0.3261 mmol) in tetrahydrofuran (5.0 mL; 62 mmol) at 0° C. was dropwise added lithium aluminum hydride (1.0 M in THF) (0.50 mL; 0.50 mmol). The reaction mixture was stirred at 0° C. for 1.5 hours, followed by the addition of lithium aluminum hydride (1.0 M in THF) (0.20 mL; 0.2 mmol). After an additional 3 hours, the reaction was quenched by the sequential addition of 27 μL water, 27 μL 15% aqueous NaOH, and 80 μL water. The reaction mixture was diluted with dichloromethane, dried over MgSO4, filtered through celite, and evaporated in vacuo to yield 109.2 mg crude product. 36.8 mg of the crude product was purified via preparatory reverse-phase HPLC and lyophilized to yield 14.7 mg of the title compound. LCMS (ESI): RT=3.55, M+H=430.3, method=H; 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 9.19 (s, 1H), 8.51 (s, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.86 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 4.78 (t, J=5.8 Hz, 1H), 3.64 (d, J=5.8 Hz, 2H), 2.32 (s, 3H), 2.24 (m, 2H), 2.17-2.01 (m, 3H), 1.91-1.63 (m, 2H), 0.85 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2(/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:9]2(/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)/C=C/C1(c2ccc(F)c(F)c2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C1(c2ccc(F)c(F)c2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-ethyl 3-(1-(3,4-difluorophenyl)cyclohexyl)acrylate (Preparation Int. 3-C, 53 mg, 0.180 mmol) in MeOH (1 mL) was added 1M NaOH (0.216 mL, 0.216 mmol), and the mixture was stirred at room temperature overnight. The mixture was acidified by the addition of 0.3 mL of 1N HCl, and the product was extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and evaporated to give the (E)-3-(1-(3,4-difluorophenyl)cyclohexyl)acrylic acid as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 11.94 (1 H, br. s.), 7.11 (2 H, m), 7.02 (1H, d, J=15.82 Hz), 6.98-7.06 (1H, m), 5.62 (1 H, d, J=15.82 Hz), 1.83-2.06 (4 H, m), 1.37-1.65 (6 H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([C:21](O)=[O:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[C:24]1([CH:30]=[CH:31][CH2:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([N:41](CC)CC)C.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F>CN(C)C=O.C(OCC)(=O)C>[C:24]1([CH:30]=[CH:31][CH2:32][N:33]2[CH2:34][CH2:35][N:36]([NH:41][C:21]([C:19]3[CH:18]=[CH:17][C:14]4[N:15]([CH3:16])[C:11]([CH2:10][CH2:9][C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)=[N:12][C:13]=4[CH:20]=3)=[O:22])[CH2:37][CH2:38]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C(=Cc1ccccc1)CN1CCNCC1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)O)ccc21
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)NN3CCN(CC=Cc4ccccc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.4 g of 2-[2-(4-Cyanophenyl)-ethyl]-1-methyl-benzimidazole-5-yl-carboxylic acid (1.3 mmol), 4-(3-phenyl-allyl)-piperazine (0.26 g, 1.3 mmol) and 0.4 ml of triethylamine are dissolved in 8 ml of dimethylformamide. 0.54 g of O-(Benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (═TBTU; 1.7 mmol) are added and stirred for 24 h at room temperature. After diluting with 20 ml of ethyl acetate, it is washed with saturated, aqueous sodium bicarbonate solution and with water, and dried over sodium sulphate. The solvent is boiled down and the product purified chromatographically (silica gel; gradient; acetic ester/methanol 100% in 60% acetic ester). Yield: 0.52 g (80%); yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1F)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[C:24]1([C@H:34]([N:36]([CH2:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH:46]2[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH3:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[C:39]([O:38][C:37]([N:36]([CH2:44][CH:45]1[CH2:50][CH2:49][N:48]([C:11]2[C:10]([F:13])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[F:1])[CH2:47][CH:46]1[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C@@H:34]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:35])=[O:43])([CH3:40])([CH3:41])[CH3:42]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(F)c(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 116 mg of methyl 3,4,5-trifluorobenzoate, 113 mg of potassium carbonate, and 2.0 mL of DMSO was added 181 mg of a solution of tert-butyl [(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate in 3.0 mL of THF at room temperature. It was stirred at 100° C. overnight, and then cooled. To the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic layer was then washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 248 mg of methyl 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-3,5-difluorobenzoate as a crude product. FAB+: 615
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)=[CH:7][C:4]=1[CH:5]=O.[Br-].[F:26][C:27]1[CH:28]=[C:29]([CH:50]=[CH:51][C:52]=1[O:53][CH3:54])[CH2:30][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:5][C:4]2[CH:7]=[C:8]([CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[O:11][C:12]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[C:17]3[C:13]=2[CH2:14][CH2:15][CH2:16]3)[CH:50]=[CH:51][C:52]=1[O:53][CH3:54]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C=O
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Agent: [Br-]
Product: COc1ccc(C=Cc2cc(Oc3c(C)cc([N+](=O)[O-])c4c3CCC4)ccc2OC)cc1F

Procedure:
4-{3-[2-(3-Fluoro-4-methoxyphenyl)vinyl]-4-methoxyphenoxy}-5-methyl-7-nitroindane was prepared in a similar manner to those described in Reference Example 15 using 2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy) benzaldehyde instead of 2-benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy) benzaldehyde and using (3-fluoro-4-methoxybenzyl)triphenylphosphonium bromide instead of furfuryltriphenylphosphonium bromide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:16]([O:18][Si](OCC)(OCC)OCC)[CH3:17].C(=O)([O-])[O-].[K+].[K+].[CH2:35](O)[CH3:36]>O.C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([O:18][CH2:16][CH3:17])([O:14][CH2:35][CH3:36])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: CCO
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC1(OCC)CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of 1-benzylpiperidin-4-one (240 ml, 1.3 mol) in ethanol (500 ml) was saturated with gaseous hydrogen chloride under cooling on an ice bath. The mixture was treated with tetraethoxysilane (300 ml), kept overnight at RT, then poured with stirring into a mixture of diethyl ether (500 ml), potassium carbonate (500 g) and water (1000 ml). The organic layer was separated, the diethyl ether was evaporated and the residue was distilled under vacuum to give the title compound (369 g, 77%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].C[C:24]1[C:28]2[CH:29]=[C:30]3[C:35]4([C:43]5[C:38](=[CH:39][CH:40]=[CH:41]C=5)NC4=O)[CH2:34][O:33][C:31]3=[CH:32][C:27]=2ON=1.C(OC1C=CC(CCl)=CC=1)C1C=CC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH2:34]([O:33][C:31]1[CH:32]=[CH:27][C:28]([CH2:24][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[CH:29][CH:30]=1)[C:35]1[CH:43]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: ClCc1ccc(OCc2ccccc2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(OCc3ccccc3)cc2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure described in EXAMPLE 9 and making non-critical variations using (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 4-benzyloxybenzyl chloride to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, (8S)-1′-[4-(benzyloxy)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 151-153° C.; 1H NMR (300 MHz, DMSO-d6) δ7.45-7.23 (m, 8H), 7.18-7.14 (m, 1H), 7.05-6.97 (m, 4H), 6.53 (s, 1H), 6.06 (s, 1H), 5.07 (s, 2H), 4.86 (ABq, J=27.9, 15.6 Hz, 2H), 4.73 (ABq, J=39.9, 9.3 Hz, 2H), 4.22-4.07 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.6, 157.7, 154.6, 144.1, 142.1, 137.8, 136.9, 131.7, 128.7, 128.6, 128.4, 128.3, 127.8, 127.6, 123.5, 122.9, 121.2, 114.9, 110.8, 109.4, 98.8, 79.4, 69.1, 64.1, 63.5, 57.2, 42.4; MS (ES+) m/z 491.8 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][C:18]2([OH:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=1.CN(C(ON1N=N[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[N:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([N:21]2[CH2:20][CH2:19][C:18]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([F:12])=[CH:26][CH:25]=3)([OH:24])[CH2:23][CH2:22]2)=[O:6])[C:2]=1[C:38]1[CH:37]=[CH:36][N:41]=[CH:40][CH:39]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1cccnc1-c1ccncc1)N1CCC(O)(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
A suspension of 2-chloronicotinic acid (0.15 g), 4-(4-fluorobenzyl)-4-hydroxypiperidine hydrochloride (0.26 g), HATU (0.43 g) and triethylamine (0.66 mL) in DMF (5 mL) was stirred at room temperature for 4 hr. The reaction mixture 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. The residue was dissolved in DME (5.0 mL), and pyridine-4-boronic acid (0.13 g), sodium carbonate (0.20 g), tetrakis(triphenylphosphine)palladium(0) (0.055 g) and water (1.0 mL) were added thereto, and the mixture was stirred at 140° C. for 1 hr under microwave irradiation. The reaction mixture 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. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then purified by preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), and the obtained fraction was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.21 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11]([O:13]CC)=[O:12])=[CH:8][C:7](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)[N:3]=1.[OH-].[K+].C1COCC1>CC(O)C.O>[CH3:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][C:5]=2[N:4]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(/C=C/c2ccccc2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1nn(Cc2ccc(Oc3ccccc3)cc2)c2nc(/C=C/c3ccccc3)cc(C(=O)O)c12
Yield: 88.6 %

Procedure:
A solution of ester 52 (56 mg, 0.11 mmol) and KOH (19 mg, 0.34 mmol) in iPrOH:THF (2 mL/1 mL) was refluxed at 87° C. for 2 h. Reaction mixture was diluted with water (10 mL) and washed with EtOAc (10 mL×2). Aqueous layer was acidified with 1N HCl and extracted with EtOAc (10 mL×2). Combined organic extracts were washed with brine, dried (Na2SO4) and filtered. The solvent was removed under reduced pressure to give the title compound (45 mg, 94%) as a yellow solid. 88% pure by HPLC. 1H NMR (500 MHz, DMSO-d6) δ 13.86 (s, 1H), 7.87 (d, J=16.2 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=7.8 Hz, 2H), 7.52 (d, J=16.2 Hz, 1H), 7.42 (t, J=7.5 Hz, 2H), 7.37-7.29 (m, 5H), 7.09 (t, J=7.4 Hz, 1H), 6.98-6.92 (m, 4H), 5.64 (s, 2H), 2.58 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 167.16, 156.97, 156.47, 155.22, 152.20, 140.74, 136.47, 135.39, 134.92, 133.00, 130.46, 129.90, 129.30, 128.04, 127.87, 123.90, 119.11, 119.02, 116.60, 110.13, 49.41, 16.02. ESI MS: m/z 462.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].CO>[CH2:1]([C@@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([C@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C(Cc2ccccc2)CCC1
Agent: [Ni]
Solvent: CO
Product: O[C@H]1CCC[C@@H](Cc2ccccc2)C1
Product: O[C@H]1CCC[C@H](Cc2ccccc2)C1
Yield: 92 %

Procedure:
Then, 9.6 g of 3-benzylcyclohexenone were hydrogenated at room temperature using 1 g of Raney nickel in methanol under hydrogen pressure (3 kg/cm2) until the absorption of hydrogen was stopped. After an organic layer was collected by decantation and concentrated, the residue was purified by column chromatography, thereby obtaining 4.5 g of cis-3-benzylcyclohexanol and 4.5 g of trans-3-benzylcyclohexanol (yield: 92% in total).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:30]3[CH:31]=[N:32][N:33]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:45])[F:43])[CH:37]=4)[CH:34]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(C(F)(F)F)c3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)c3cc(Br)cnc32)cc1
Yield: 46.2 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (300 mg, 0.629 mmol) was coupled with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrazole (Intermediate 4) (310 mg, 0.88 mmol) in sodium carbonate (200 mg, 1.88 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (22 mg, 0.0314 mmol) and toluene/ethanol/water (30/10/2.5 ml) to afford 167 mg (46.2% yield) of the pure product after column purification using 30% ethyl acetate in hexane as eluent. MS: m/z=577.00 (M+2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[C:15]=1[NH2:16])[CH3:13]>>[CH2:12]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH3:22])[C:15]=1[NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])[CH3:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCc1cccc(CC)c1N
Product: CCc1cccc(CC)c1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,6-diethylaniline to yield 2-[(2,6-diethylphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](Cl)=[O:8].CNCC1C=C2C(=CC=1)C=C(O)C=C2.[CH2:28]([NH:35][CH2:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([OH:47])[CH:41]=[CH:40]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)(=O)C>C(Cl)Cl>[CH2:28]([N:35]([CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([OH:47])[CH:43]=2)[CH:38]=1)[C:7]([C:6]1[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3][C:2]=1[CH3:1])=[O:8])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1oc2ccccc2c1C(=O)Cl
Reactant: Oc1ccc2cc(CNCc3ccccc3)ccc2c1
Agent: CNCc1ccc2cc(O)ccc2c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc2cc(O)ccc2c1
Yield: 30 %

Procedure:
Prepared in the same manner as described in step 2 of Example 32, and replacing 2-ethyl-benzofuran-3-carbonyl chloride with 2-methyl-benzofuran-3-carbonyl chloride, prepared in step 2 of Example 20 and 6-methylaminomethyl-naphthalen-2-ol with 6-(benzylamino-methyl)-naphthalen-2-ol, prepared in step 3 of Example 48. Chromatography of the crude oil on 400 g silica gel (230-400 mesh) using 2-3% ethyl acetate in methylene chloride as the eluent gave 2-methyl-benzofuran-3-carboxylic acid benzyl-(6-hydroxy-naphthalen-2ylmethyl)-amide (0.71 g, 30%) as a yellow solid, mp 190-193° C.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.Cl[C:19]1C=CC=C(C(OO)=O)C=1.[S:29]([O-:32])([O-])=[O:30].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:19][S:29]([C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)(=[O:32])=[O:30]
Reactant: CSc1nccc(-c2cnc3ccccn23)n1
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1nccc(-c2cnc3ccccn23)n1
Reaction time: 0.5 h

Procedure:
150 mg of 3-[2-methylthio-4-pyrimidinyl]imidazo[1,2-a]pyridine [1-3] was dissolved in 3 mL of chloroform and 169 mg of m-chloroperbenzoic acid was added under an ice-cold condition, and stirred for 30 minutes at the same temperature. The resultant solution was added with a saturated aqueous solution of sodium sulfite and a saturated aqueous solution of sodium hydrogen carbonate, and then was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then the insolubles were filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography, and 160 mg of 3-[2-methylsulfonyl-4-pyrimidinyl]imidazo[1,2-a]pyridine [1-4] was obtained as a colorless amorphous substance.
Reaction SMILES: [NH:1]([C:8]1[CH:12]([N:13]2[CH:17]=[C:16]([NH2:18])[C:15]([CH3:19])=[N:14]2)[C:11](=[O:20])[N:10]([C:21]2[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=2[Cl:29])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](Cl)(=[O:44])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C(OCC)(=O)C>C(#N)C>[NH:1]([C:8]1[CH:12]([N:13]2[CH:17]=[C:16]([NH:18][C:30](=[O:44])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:15]([CH3:19])=[N:14]2)[C:11](=[O:20])[N:10]([C:21]2[C:22]([Cl:29])=[CH:23][C:24]([Cl:28])=[CH:25][C:26]=2[Cl:27])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(C2C(=O)N(c3c(Cl)cc(Cl)cc3Cl)N=C2Nc2ccccc2)cc1N
Reactant: CCCCCCCCCCCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCCCCCCCCCC(=O)Nc1cn(C2C(=O)N(c3c(Cl)cc(Cl)cc3Cl)N=C2Nc2ccccc2)nc1C

Procedure:
The 4-(4-amino-3-methyl-1-pyrazolyl)-3-anilino-1-(2,4,6-trichlorophenyl)-5-oxo-2-pyrazoline obtained in Step 2 was suspended in 100 ml of acetonitrile and stirred with heating. To the solution, 9 g of tetradecanoylchloride was added and the mixture was refluxed for 2 hours. To the reaction mixture, 500 ml of ethyl acetate was added and the mixture was washed several times with water. The oil layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from a solvent mixture of acetonitrile and benzene, 8 g of Coupler (23) was obtained. The melting point of the coupler was 123° to 131° C.
Reaction SMILES: [Na].[C:2]1(C)[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[C:18]([CH2:24]Br)[CH:17]=1.[CH3:27]O>>[CH3:13][O:14][C:15]([C:16]1[CH:17]=[C:18]2[C:19](=[CH:20][CH:21]=1)[CH2:22][N:11]([S:8]([C:3]1[CH:2]=[CH:7][C:6]([CH3:27])=[CH:5][CH:4]=1)(=[O:9])=[O:10])[CH2:24]2)=[O:26]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: CO
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Agent: [Na]
Product: COC(=O)c1ccc2c(c1)CN(S(=O)(=O)c1ccc(C)cc1)C2
Reaction time: 8 h

Procedure:
Sodium (0.60 g) is dissolved in methanol (100 mL) and toluene sulfonamide (4.25 g) is added portion wise. After 30 min at ambient temperature 3,4-bis-bromomethyl-benzoic acid methyl ester are added (4.00 g). After stirring overnight, the resulting solid is collected, washed with methanol and dried. 2.80 g of the title compound are obtained with MP=164-166° C.