Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[NH:13][C:14]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[C:25]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:24]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1>C(O)(=O)C.C(OCC)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[NH:13][C:14]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:24]=2)=[C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1
Reactant: O=[N+]([O-])c1ccc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccccc2)cc1NCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccccc2)cc1NCc1ccccc1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 55.2 %

Procedure:
Add tin(II) chloride (0.11 g, 0.6 mmol) to a solution of 2-(2,6-difluorophenyl)-4-phenyl-5-(3-(benzyl)amino-4-nitrophenyl)imidazole (0.09 g, 0.2 mmol) in 10 mL acetic acid. Bubble nitrogen through the solution for 15 minutes and then heat at 90° C. for 1 hour under a nitrogen atmosphere. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and then wash sequentially with 3:1 ammonium hydroxide:saturated aqueous ammonium chloride, saturated aqueous sodium chloride, and water. Dry the organic phase over magnesium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 5:1 dichloromethane:acetonitrile to provide the title compound (0.05 g, 59%).
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[O:16]=[C:12]1[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:15][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Reaction time: 1 h

Procedure:
Sodium hydride (88 mg, 60% wt.) was added portionwise to a solution of 4-BOC-piperazinone (400 mg) in DMF (10 ml). The reaction mixture was stirred for 1 h, and then benzyl bromide (262 μl) was added dropwise and the mixture stirred at room temp for 16 h. The reaction was quenched with methanol and diluted with water, and then extracted with EtOAC. The organic extracts were concentrated in vacuo and the residue was purified by chromatography (silica, 20% ether/hexane as eluent) to give the sub-title compound (429 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[O:32])[CH:25]=3)=[CH:22][C:15]=2[N:14]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>O1CCOCC1>[C:39]([N:36]1[CH2:37][CH2:38][CH:33]([C:31]([NH:30][C:26]2[CH:25]=[C:24]([O:23][C:21]3[CH:20]=[CH:19][C:16]4[N:17]([CH3:18])[C:13]([NH:12][C:3]5[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=5[F:1])=[N:14][C:15]=4[CH:22]=3)[CH:29]=[CH:28][N:27]=2)=[O:32])[CH2:34][CH2:35]1)(=[O:41])[CH3:40]
Reactant: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(NC(=O)C4CCNCC4)c3)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(c3)nc(Nc3cc(C(F)(F)F)ccc3F)n4C)ccn2)CC1
Reaction time: 1 h

Procedure:
To N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide (1 eq) in dioxane and N,N-disopropylethylamine (2 eq) was added acetic anhydride (1 eq) and the resulting mixture was stirred for 1 h. 1-acetyl-N-{4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-1-methyl-1H-benzimidazol-5-yl)oxy]pyridin-2-yl}piperidine-4-carboxamide thus formed was purified by preparative chromatography. MS: MH+=571.5.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O.[OH-].[Na+].CN(C)[CH:35]=[O:36]>C(O)(=O)C>[CH:35]([C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=2)[NH:18][C:17]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:36]
Reactant: CCCCCCCCCCCc1cc2cc(C(=O)OC)ccc2[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCc1[nH]c2ccc(C(=O)OC)cc2c1C=O
Reaction time: 2 h

Procedure:
A solution of phosphorus oxychloride (21.5 ml) in dimethylformamide (80 ml) was added to a solution of methyl 2-(n-undecyl)indole-5-carboxylate (36.9 g) in dimethylformamide (320 ml) and the mixture was stirred at a temperature of 60°-70° C. for 2 hours. After cooling the mixture was poured into water (500 ml). An aqueous solution of sodium hydroxide (50% w/v) was added to the mixture to adjust the pH to 12. Glacial acetic acid was then added to the stirred mixture to readjust the pH to 5. The resultant solid was collected and on recrystallisation from ethanol gave methyl 3-formyl-2-(n-undecyl)indole-5-carboxylate (34.8 g), m.p. 162°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([Cl:31])[CH:33]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(Cl)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 78.1 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.34 g, 0.0008 mol) in DMF (10 mL), was added 3-chlorobenzyl bromide (0.25 g, 0.0012 mol) and powdered potassium carbonate (0.77 g, 0.0056 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (8:2 Hexanes/EtOAc) to give the desired product as oil 0.33 g in 77% yield. 1H NMR (CDCl3) δ 7.23 (d, 2H), 7.18 (m, 4H), 7.14 (m, 6H), 6.91 (d, 2H), 6.83 (d, 1H), 6.82 (d, 1H), 6.65 (s, 1H), 6.63 (d, 1H), 4.16 (t, 1H), 3.67 (s, 3H), 3.63 (t, 2H), 3.57 (s, 2H), 3.55 (s, 2H), 3.05 (d, 2H), 2.63 (t, 2H), 1.80 (t, 2H); 13C NMR (CDCl3) δ 173.3, 160.5, 144.7, 143.3, 136.6, 135.3, 130.8, 130.7, 130.3, 129.7, 129.6, 128.4, 128.3, 127.7, 122.7, 116.9, 114.5, 66.9, 61.1, 60.1, 53.5, 51.8, 51.1, 42.7, 28.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.O[C@H:13]([CH3:23])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(P(CCCC)CCCC)CCC.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[C:3]([O:11][C@@H:13]([CH3:23])[CH2:14][NH:15][C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: COC(=O)c1scc(Br)c1O
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)c1scc(Br)c1O[C@@H](C)CNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (237 mg), tert-butyl [(2R)-2-hydroxypropyl]carbamate (175 mg), tri-n-butylphosphine (0.75 mL) and THF (10 mL) was added dropwise diethyl azodicarboxylate (40% toluene solution, 1.4 mL) at room temperature, and the mixture was stirred for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent gradient; 0→15% ethyl acetate/hexane) to give the title compound (239 mg, 65%) as a colorless oil.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(C[CH2:14][CH:15]1[CH:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:19][C:18](=[O:28])[NH:17][CH2:16]1)(O)=O.C[OH:30]>O1CCCC1.C1(C)C=CC=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]2[CH2:19][C:18](=[O:28])[NH:17][CH2:16][CH:15]2[CH2:14][OH:30])=[CH:22][CH:23]=1
Reactant: O=C(O)CCC1CNC(=O)CC1c1ccc(F)cc1
Reactant: CO
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1CC(c2ccc(F)cc2)C(CO)CN1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
DIBAL-H (15.1 ml, 0.0225 mol) was added at a rate of 50 ml/hour, by means of a syringe pump, to a solution of 3-carboxyethyl-4-(4-fluorophenyl)-piperidine-6-one (1.99 g, 0.0075 mol) in tetrahydrofuran (15 ml) at −70° C. under an argon atmosphere keeping the temperature below 0° C. The mixture was allowed to warm to 23° C. and stirred for 45 minutes, then a solution of methanol (0.9 ml) in toluene (7.5 ml) was added to destroy the excess DIBAL-H, followed by 30% potassium carbonate solution (8.5 ml), all below 30° C. The organic phase was separated, dried with anhydrous sodium sulphate, filtered, and evaporated to afford the title compound (1.54 g) as a slightly colored oil, which was crystallized by trituration with ether. Yield 67%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([F:34])=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39]>>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[S:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[N:7]=2)[C:17]=1[F:34])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.100 g, 0.190 mmol) and 2-aminoethyl-methyl-sulfone (0.100 g, 0.812 mmol), the title compound was obtained as an off-white solid (53 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.09 (d, J=5.1 Hz, 1H), 7.62-7.74 (m, 1H), 7.39-7.49 (m, 2H), 7.33-7.39 (m, 1H), 7.20-7.32 (m, 3H), 5.89-6.05 (m, 1H), 3.63 (br. s., 2H), 3.34-3.39 (m, 2H), 3.25-3.31 (m, 1H), 2.99-3.04 (m, 3H), 1.35 (d, J=6.9 Hz, 6H). MS (ESI): 613.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]2[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1.Cl.[NH+]1C=CC=CC=1>O>[CH:12]1[C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[S:15][C:14]=2[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1cccc2c1sc1ccccc12
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: Oc1ccccc1-c1cccc2c1sc1ccccc12
Temperature: 60 °C
Yield: 62.9 %

Procedure:
4-(2-Methoxyphenyl)dibenzo[b,d]thiophene (6.6 g, 23 mmol) and pyridinium hydrochloride (27 g, 230 mmol) were mixed together, placed in the 100 ml round bottom flask and heated to reflux for 45 min. Reaction mixture was cooled to 60° C., diluted with 100 ml water and extracted with ethyl acetate. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica (eluent hexane/ethyl acetate 5/1), providing 4.00 g of 2-(dibenzo[b,d]thiophen-4-yl)phenol as clear solidified oil.
Reaction SMILES: CC1C=C(C)C=CC=1N1CCN(C(C2C=NC(F)=CC=2C)=O)CC1.COC1C=CC(CN)=CC=1.[Cl:35]CCCS(Cl)(=O)=O.NC1N=CC(C(N2CCN(C3C=CC(C)=CC=3C)CC2)=O)=C(C)C=1.[CH3:67][C:68]1[CH:73]=[C:72]([CH3:74])[CH:71]=[CH:70][C:69]=1[N:75]1[CH2:80][CH2:79][N:78]([C:81]([C:83]2[CH:84]=[N:85][C:86]([N:90]3[CH2:94][CH2:93][CH2:92][S:91]3(=[O:96])=[O:95])=[CH:87][C:88]=2[CH3:89])=[O:82])[CH2:77][CH2:76]1>>[ClH:35].[CH3:67][C:68]1[CH:73]=[C:72]([CH3:74])[CH:71]=[CH:70][C:69]=1[N:75]1[CH2:76][CH2:77][N:78]([C:81]([C:83]2[CH:84]=[N:85][C:86]([N:90]3[CH2:94][CH2:93][CH2:92][S:91]3(=[O:96])=[O:95])=[CH:87][C:88]=2[CH3:89])=[O:82])[CH2:79][CH2:80]1
Reactant: O=S(=O)(Cl)CCCCl
Agent: COc1ccc(CN)cc1
Agent: Cc1ccc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Agent: Cc1ccc(N2CCN(C(=O)c3cnc(N)cc3C)CC2)c(C)c1
Product: Cl

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (470 mg) described in Preparation Example 175, 4-methoxybenzylamine (1 mL) and 3-chloropropane-1-sulfonyl chloride (0.20 mL) and by the reaction and treatment in the same manner as in Example 223, the title compound (485 mg) was obtained via (6-amino-4-methylpyridin-3-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone and [4-(2,4-dimethylphenyl)piperazin-1-yl][6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-methylpyridin-3-yl]methanone.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].[Cl:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:18][CH:17]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:15][C:16]1[C:21]([C:22]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[N:7]=[CH:6][N:5]=[C:4]3[O:3][CH2:1][CH3:2])=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:18][CH:17]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CCOc1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 17.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-ethoxyquinazolin-8-amine (Intermediate-38, 140 mg, 0.80 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 323 mg, 1.12 mmol), oxalyl chloride (141 mg, 1.12 mmol), DMF (1 drop) and DIPEA (310 mg, 2.40 mmol) in CH2Cl2 (4 mL) to afford 65 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.79 (m, 2H), 8.13 (t, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.69 (t, 1H), 7.36-7.31 (m, 2H), 4.62 (m, 2H), 4.29 (d, J=6.0 Hz, 2H), 1.44 (t, J=7.5 Hz, 3H), 1.12 (s, 9H); MS (m/z): 459.20 (M+H)+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].O>C1COCC1.CN(C=O)C>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COC(=O)CBr
Reactant: COc1cc(C=O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C=O)cc1OC

Procedure:
(4-Formyl-2-methoxy-phenoxy)-acetic acid methyl ester was prepared by dissolving vanillin (4.1 mmol) (Aldrich) in dry THF (10 mL) and dry DMF (1 mL). Sodium hydride (109 mg, 4.5 mmol) was then added to the solution slowly and the resulting mixture was stirred at room temperature for 1 h at which time methyl bromoacetate (5 mmol) (Aldrich) was added dropwise. The reaction was stirred at room temperature for 14 h at which time water (10 mL) was added and the THF was evaporated in vacuo. The aqueous layer was then extracted with ethyl acetate (3×15 mL), and the combined organic layers were dried over magnesium sulfate and concentrated. The resulting (4-formyl-2-methoxy-phenoxy)-acetic acid methyl ester was purified via flash column chromatography (SiO2, 230-400 mesh) with ethyl acetate/hexane.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11]Cl)=[N:9][CH:10]=1)=[O:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:9][CH:10]=1)=[O:5]
Reactant: C1COCCN1
Reactant: COC(=O)c1cnc(CCl)n1C
Agent: Cl
Product: COC(=O)c1cnc(CN2CCOCC2)n1C

Procedure:
Using 2-chloromethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester hydrochloride and morpholine, the title compound was obtained as light brown solid (>98% yield). MS: m/e=240(M+H+).
Reaction SMILES: [CH:1](NC(C)C)(C)C.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([Li])CCC.[CH3:27][O:28][C:29](=[O:53])[CH:30]([O:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.CI>O1CCCC1.CCCCCC.O.CN(C)P(N(C)C)(N(C)C)=O>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([O:45][C:30]([C:31]2[CH:32]=[CH:33][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)=[CH:35][CH:36]=2)([CH3:1])[C:29]([O:28][CH3:27])=[O:53])=[CH:47][CH:48]=1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Li]CCCC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCCCCC
Solvent: CI
Solvent: O
Product: COC(=O)C(C)(Oc1ccc(Cl)cc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.02 g of N,N-diisopropylamine and 5 mg of 1,10-phenanthroline in 15 ml of dry tetrahydrofuran is cooled to 0° C. under argon and a solution of 0.017 mole of n-butyllithium in hexane is added dropwise while keeping the temperature of 0°-5° C. After 15 minutes, the solution is cooled to -70° C. and a solution of 6.05 g of methyl(p-chlorophenoxy)[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of tetrahydrofuran is added over 15 minutes while keeping the temperature at -70° C. to -65° C. After 15 minutes 3.58 g of hexamethylphosphoramide is added. After 1/2 hour, 4.26 g of methyl iodide is added in one portion. The color lightens slowly over one hour. The mixture is allowed to warm to room temperature and the reaction mixture is stirred overnight. The mixture is poured into 100 ml of water and extracted with two 75 ml portions of ether. The extracts are washed with four 50 ml portions of 10% HCl, water, saturated NaHCO3, saturated brine and dried (MgSO4). Evaporation of the solvent yields a brown oil, which is filtered through 30 g of silica gel (benzene eluent) to yield the product as a light yellow oil, which solidifies on standing.
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1.[CH:8]1(Br)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH:8]1([C:4]2([CH:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:3]=[CH:7][CH:6]=[CH:5]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: BrC1CCCCC1
Reactant: C1=CCC=C1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C1=CC(C2CCCCC2)(C2CCCCC2)C=C1
Temperature: 8 °C
Reaction time: 6 h

Procedure:
A double-walled reactor having a volume of 1 L, provided with baffles, condenser, top stirrer, thermometer and dropping funnel, was charged with 600 g of clear 50% strength NaOH (7.5 mol), followed by cooling to 8° C. Then 20 g of Aliquat 336 (49 mmol) and 33 g (0.5 mol) of freshly cracked cyclopentadiene were added. The reaction mixture was stirred vigorously for a few minutes, then 172 g of cyclohexyl bromide (1.05 mol) were added. The reaction mixture was then cooled with circulating water at 10° C. After two hours of stirring at room temperature, the reaction mixture was heated to 70° C., followed by a further 6 hours of stirring. GC was used to show that 79% of the mixture of mono-, di- and tri-(cyclohexyl)cyclopentadiene was disubstituted cyclopentadiene. The product was distilled at 0.04 mbar and 110-120° C. After distillation, 73.6 g of di(cyclohexyl)cyclopentadiene were obtained, which was characterized with GC, GC-MS, 13C- and 1H-NMR.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:11]3=[N:12][C:13]=2[N:14]([CH2:16][CH3:17])[CH:15]=1)=[O:5])C>Cl.C(O)(=O)C>[CH2:16]([N:14]1[C:13]2[N:12]=[C:11]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:10]3=[CH:9][C:8]=2[C:7](=[O:24])[C:6]([C:4]([OH:5])=[O:3])=[CH:15]1)[CH3:17]
Reactant: CCOC(=O)c1cn(CC)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Temperature: 20 °C
Yield: 86 %

Procedure:
A suspension of 8 g of 3-ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 80 cm3 of 17.5% hydrochloric acid and 80 cm3 of acetic acid is heated, with stirring, at a temperature close to 100 hour and 30 minutes. After cooling to about 20° C., the insoluble matter is drained, washed with 3 times 20 cm3 of water and recrystallized from 50 cm3 of dimethylformamide. 6.3 g of 1-ethyl-7,8-difluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 330° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.[CH:22]([Mg]Br)=[CH2:23].C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]([OH:18])[CH:22]=[CH2:23])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: C=C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a degassed suspension of 3-(2-(7-chloro-2-quinolinyl)ethenyl)benzaldehyde (U.S. Pat. No. 4,851,409, Example 24, Step 1) (100 g, 0.34 mol) in toluene (700 mL) at 0° C. was slowly added 1.0M vinylmagnesium bromide in toluene/THF (370 mL, 0.37 mol). After stirring for 1 hour at 0° C., the reaction was quenched by the slow addition of saturated NH4Cl solution (150 ml), followed by H2O (500 mL) and HOAc (50 mL). The product was extracted with EtOAc and the two-phase system was filtered through celite to remove an insoluble precipitate. The aqueous phase was then re-extracted with EtOAc (100 mL) and the combined organic layer was washed with H2O, followed by brine. The solution was dried (MgSO4), and evaporated to give a dark yellow residue which was purified by flash chromatography (EtOAc:hexane 1:5, then 1:3). The product was filtered from the column fractions to give a beige solid (67.6 g, mp=110°-112° C.). The filtrate was concentrated and the resulting residue was recrystallized from EtOAc/hexane 1:4 to give a second crop of 15.1 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[CH:6]=[CH:7]\[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CCC)c1=O
Solvent: CO
Product: CCCn1c(=O)c2c(nc(/C=C\c3ccc(OC)c(OC)c3)n2C)n(CCC)c1=O
Yield: 56.6 %

Procedure:
Compound 1 (1.00 g, 2.42 mmol) obtained in Reference Example 1 was dissolved in 1.6 L of methanol, and the solution was irradiated with sunlight for 5 hours. After evaporation under reduced pressure, the residue was purified by high performance liquid chromatography (column: YMC Pack ODS-A, SH-365-10, S-10; 30 mmφ×500 mm, flow rate: 90 ml/min, detection: UV 246 nm) to give 565 mg (yield 57%) of Compound 186 as white needles.