Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:13]([CH3:14])=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21](F)([F:23])[F:22])[CH:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].F[CH:32](F)C1C=CC=CC=1B(O)O.BrC1C(=O)C(C(O)=O)=CN(CC2C=CC(C#N)=CC=2)C=1C.BrC1C(=O)C(C(O)=O)=CN(C(C2C=CC(C#N)=CC=2)C)C=1C>>[C:1]([C:3]1[CH:30]=[CH:29][C:6]([CH:7]([N:8]2[C:13]([CH3:14])=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([F:23])[F:22])[CH:16]=3)[C:11](=[O:25])[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2)[CH3:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Reactant: OB(O)c1ccccc1C(F)F
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)c1ccc(C#N)cc1
Agent: Cc1c(Br)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)O)cn1C(C)c1ccc(C#N)cc1

Procedure:
Preparation 3 is prepared following the procedure described for preparation 1d, substituting 3-(trifluoromethyl)phenylboronic acid with 2-(difluoromethyl)phenylboronic acid and substituting preparation 1c with preparation 2b as starting material. ESI mass spectrum: [M+H]+=409; Retention time HPLC: 1.00 min (Z018_S04).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.COC(OC)[N:23]([CH3:25])C.C(O)(=O)C.[NH2:32]N>O>[NH:19]1[C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:23][CH:25]=[N:32]1
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc2[nH]nc(-c3ccc(O)cc3)c2c1
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1
Temperature: 90 °C
Yield: 9.7 %

Procedure:
A mixture of 3-(4-hydroxyphenyl)-1H-indazole-5-carboxamide (100 mg, 0.425 mmol) and N,N-dimethylformamide dimethyl acetal (10.0 mL, 75.3 mmol, 177 equiv.) was heated at 90° C. for 3 h. The reaction mixture was separated from some dark residue via pipet and concentrated. To the concentrate was added 20 mL of glacial acetic acid (AcOH), and anhydrous hydrazine (357 mg, 11.1 mmol, 26.1 equiv.). The mixture was heated at 90° C. for 2 h. Water (50 mL) was added to the mixture, and the acetic acid was removed on a rotary evaporator. The remaining mixture was extracted with EtOAc. The combined organics were dried (Na2SO4) and purified by prep HPLC to afford the title compound (11.4 mg, 9.7% yield): 1H NMR (DMSO-d6) δ 13.25 (br s, 1H), 9.70 (br, 2H), 8.64 (s, 1H), 8.42 (br s, 1H) 8.05 (d, 1H), 7.83 (d, 2H), 7.65 (d, 1H), 6.95 (d, 2H); ES-MS (m/z) 278 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20]N(C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[CH2:18]([O:17][C:15]([C:14]1[C:12](=[O:13])[C:11]2[CH:10]=[C:9]3[CH:8]=[C:7]([F:24])[C:6]([F:25])=[CH:5][C:4]3=[N:3][C:2]=2[N:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=1)=[O:16])[CH3:19]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc3cc(F)c(F)cc3cc2c1=O
Yield: 69.1 %

Procedure:
3-Ethoxycarbonyl-7,8-difluoro-4-oxo-1-tert-butyl-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Example 10, but starting with 4 g of ethyl 2-(2-chloro-6,7-difluoro-3-quinolylcarbonyl)-3(dimethylamino)acrylate and 0.87 g of tert-butylamine. 2.7 g of 3-ethoxycarbonyl-7,8-difluoro-4-oxo-1-tert-butyl-1,4dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 206° C., which is used without further purification for the subsequent steps.
Reaction SMILES: C([O:8][CH:9]1[CH2:13][O:12][CH:11]2[CH:14]([O:17][CH3:18])[CH2:15][O:16][CH:10]12)C1C=CC=CC=1>CCO.[Pd]>[CH3:18][O:17][CH:14]1[CH:11]2[O:12][CH2:13][CH:9]([OH:8])[CH:10]2[O:16][CH2:15]1
Reactant: COC1COC2C(OCc3ccccc3)COC12
Agent: [Pd]
Solvent: CCO
Product: COC1COC2C(O)COC12
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.4 %

Procedure:
To a solution of 3-(benzyloxy)-6-methoxyhexahydrofuro[3,2-b]furan (7.84 g, 31.3 mmol) in EtOH (80 mL) was added Pd/C (10%, 812 mg). The reaction was stirred at rt for two days under H2 atmosphere and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=1/1) to give the title compound as colorless oil (4.53 g, 90.3%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH:16]3[CH2:17][O:18]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCC1CO1
Reactant: Oc1ccc(C2CCCCC2)cc1
Product: c1cc(C2CCCCC2)ccc1OCC1CO1

Procedure:
The title compound was prepared from 4-cyclohexylphenol and epichlorohydrin employing the procedure in Step 1 of Example 2.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([C:11]([C:13]2[CH:22]=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=2)=[CH2:12])[N:8]=[CH:7]1)(=O)=O.[H][H]>CCO.[Pd]>[O:17]1[C:16]2[CH:21]=[CH:22][C:13]([CH:11]([C:9]3[N:8]=[CH:7][NH:6][CH:10]=3)[CH3:12])=[CH:14][C:15]=2[O:20][CH2:19][CH2:18]1
Reactant: C=C(c1ccc2c(c1)OCCO2)c1cn(S(=O)(=O)N(C)C)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccc2c(c1)OCCO2)c1c[nH]cn1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
4-[1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-imidazole-1-sulfonic acid dimethylamide (Intermediate-J1) (0.25 g, 0.75 mmol) in EtOH (10 mL) was reduced with 10% Pd/C catalyst (25 mg) under 40 psi of hydrogen at rt for 2.5 h. The mixture was filtered through Celite. The solution was concentrated and the residue was dissolved in 1.5 M HCl (10 mL) and heated to reflux for 3 h. The mixture was cooled to rt and basified with sat solution of NaHCO3. The mixture was extracted with ethyl acetate (2×) and the organic solution was dried over Na2SO4, filtered and evaporated to give 4-[1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-1H-imidazole (Intermediate-J2) as a tan solid 0.14 g (87%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:26][CH2:27][CH3:28])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:24])[C:8]=2[N:25]=1)[CH3:2].[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:26][CH2:27][CH3:28])[C:7]2[C:16]3[CH:15]=[C:14]([O:17][CH:18]4[CH2:19][CH2:20][N:21]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:22][CH2:23]4)[CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:24])[C:8]=2[N:25]=1)[CH3:2]
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCNCC4)cc3c21
Reactant: CC(C)C(=O)Cl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCN(C(=O)C(C)C)CC4)cc3c21

Procedure:
A modification of the procedure described in Example 413 was used. 2-(Ethoxymethyl)-8-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 411, 0.650 g, 1.69 mmol) was treated with isobutyryl chloride instead of the methanesulfonic anhydride. After the work up, the crude product was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-25% CMA in chloroform) followed by recrystallization from acetonitrile to yield 0.500 g of 2-(ethoxymethyl)-8-[(1-isobutyrylpiperidin-4-yl)oxy]-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 177-179° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:24][CH:23]=1
Reactant: Nc1ccc(F)cc1
Reactant: COc1cc2c(=O)[nH]c3nccc(Cl)c3c2cc1OC
Product: COc1cc2c(=O)[nH]c3nccc(Nc4ccc(F)cc4)c3c2cc1OC
Yield: 3.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 212 using Compound 211 (50 mg, 0.17 mmol) and 4-fluoroaniline (25 mg, 0.22 mmol) to provide 215 (2 mg, 2% yield) as a white solid. LC-MS (M+H=366, obsd.=366).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:31][CH2:32][NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH2:36]([O:35][C:34](=[O:43])[NH:33][CH2:32][CH2:31][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=C(NCCO)OCc1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCCNC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 84.2 %

Procedure:
In around-bottomed flask equipped with a mechanical stirrer, 4-hydroxyacetophenone (5.00 g, 36.7 mmol) was dissolved in toluene (122 ml), and triphenylphosphine (14.4 g, 55.1 mmol), and benzyl N-(2-hydroxyethyl)carbamate (10.8 g, 55.1 mmol) were added. The reaction mixture was cooled to about 0° C., and 1,1′-(azodicarbonyl)dipiperidine (13.9 g, 55.1 mmol) was added in one portion. The mixture was allowed to warm to room temperature, and after stirring for about ten minutes, an additional 122 ml of toluene and 122 ml of tetrahydrofuran were added to the thick orange solution. The mixture was stirred for an additional twenty-four hours, and the solids were filtered off. The filtrate was concentrated in vacuo and the resulting solid was purified by column chromatography (silica gel; hexanes to 2:1 hexanes/ethyl acetate) to afford 9.68 g (84% yield) of the desired product as a white solid. LRMS ([M−1]−)=312.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[S:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1)(=[O:9])=[O:8]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2)Cc2cccc(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN(Cc2cccc(F)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
Methyl 4-(N-(3-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (500 mg, 1.12 mmol) was dissolved in MeOH/THF (1:1, 40 mL) and treated with a solution of aqueous NaOH (10 N, 8 ml). The mixture was stirred at ambient temperature overnight, then MeOH and THF were removed by rotary evaporation. The resulting aqueous solution was washed with EtOAc (10 mL) and acidified with 6 N aq HCl (˜15 mL) to pH˜4. The aqueous solution was extracted with EtOAc (3×, 40 mL) and the combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by recrystallization from EtOH to afford the title compound 4-(N-(3-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid as a white crystalline solid (150 mg) in 30% yield.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:10]([O:18]COCCOC)[C@@H:11]([OH:17])[CH2:12][N:13]([O:15][CH3:16])[CH3:14])=O)(C)(C)C>Cl.C(O)C>[NH2:8][C@@H:9]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:10]([OH:18])[C@@H:11]([OH:17])[CH2:12][N:13]([O:15][CH3:16])[CH3:14]
Reactant: COCCOCO[C@H]([C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)[C@@H](O)CN(C)OC
Agent: Cl
Solvent: CCO
Product: CON(C)C[C@H](O)[C@H](O)[C@@H](N)CC1CCCCC1

Procedure:
The resultant compound from Example 137 (1.00 mmol) was stirred for 1 h in 4M HCl/ethanol. The mixture was evaporated and the residue was dissolved in water which was made basic with solid K2CO3 and was then saturated with NaCl. The mixture was extracted with chloroform which was dried over Na2SO4 and evaporated to afford the desired product.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Br:12][C:13]1[CH:14]=[C:15]([CH2:19]C(O)=O)[CH:16]=[CH:17][CH:18]=1.C([O-])(=O)C.[Na+]>C(O)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH:19]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:6]1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1OC(=Cc2cccc(Br)c2)c2ccccc21
Temperature: 220 °C
Yield: 81 %

Procedure:
A mixture of phthalic acid anhydride (43 g, 0.291 mol), 3-bromophenyl acetic acid (62.5 g, 0.291 mol) and sodium acetate (2 g, 0.015 mol) was heated at 220° C. for 2 h under an atmosphere of nitrogen. The reaction mixture was cooled to about 80° C. and ethanol (75 ml) was added. The precipitate was filtered off, washed with a mixture of heptane and ethanol (9:1) and dried in vacuo at 50° C. which afforded 71 g (81%) of 3-(3-bromobenzylidene)-3H-isobenzofuran-1-one as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([CH:17]2[NH:26][C:25](=[O:27])[C:24]3[C:19](=[CH:20][C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:23]=3)[NH:18]2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[NH:26][C:25](=[O:27])[C:24]3[C:19](=[CH:20][C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:23]=3)[N:18]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)NC(C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1)NC2=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(=O)[nH]c(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 139.4 %

Procedure:
To a solution of methyl 2-({[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}carbonyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (60 mg, 0.1 mmol) in chloroform (1.5 mL) was added manganese (IV) oxide (81.4 mg, 0.94 mmol). The reaction mixture was heated to 70° C. and stirred for 3 h. The mixture was cooled to rt, the solid filtered and washed with MeOH to afford methyl 2-({[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}carbonyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (60 mg, quant). LC-MS: (FA) ES+ 331.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[CH2:12]([NH2:17])[CH2:13][CH2:14][CH2:15][CH3:16].[Cl-].[NH4+]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CCCCCN
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCNc1nc(Cl)nc2c1CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (410 mg) and pentylamine (1 ml) were stirred at room temperature for 8 hours. The reaction mixture was poured into an aqueous ammonium chloride solution and the solution was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo to give the object compound (296 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.C(OCC)C.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20](=[O:26])[C:21](=[O:25])[NH:22]2)=[CH:18][CH:17]=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:20]([C:19]3[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=3)([OH:26])[C:21](=[O:25])[NH:22]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1Nc2cc(Cl)ccc2C1(O)c1ccc(Cl)cc1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chlorophenyl magnesium bromide in diethyl ether (1.0 M, 25 mL, 25 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (1.82 g, 10 mmol) in tetrahydrofuran (40 mL) under argon with cooling in a −25° C. bath at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 2 hour, 15% aqueous ammonium chloride solution (25 mL) and water (50 mL) were added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-(4-chloro-phenyl)-3-hydroxy-1,3-dihydro-indol-2-one as an off-white powder. This was used in the next step without further purification.
Reaction SMILES: O=C(C)CC[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:22]2[CH2:25][CH2:24][CH2:23]2)([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7]1.[CH2:28]([Li])[CH2:29][CH2:30][CH3:31].[CH3:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH3:31]/[C:30](=[CH:33]/[CH3:34])/[CH2:29][CH2:28][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:22]2[CH2:23][CH2:24][CH2:25]2)([OH:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:7]1.[CH3:28]/[C:35](=[CH:34]\[CH3:33])/[CH2:36][CH2:37][CH2:38][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:26])[C:14]([CH:22]2[CH2:23][CH2:24][CH2:25]2)([OH:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:7]1
Reactant: [Li]CCCC
Reactant: CC(=O)CCCN1CCC(NC(=O)C(O)(c2ccccc2)C2CCC2)CC1
Reactant: CCCCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C/C=C(/C)CCCN1CCC(NC(=O)C(O)(c2ccccc2)C2CCC2)CC1
Product: C/C=C(\C)CCCN1CCC(NC(=O)C(O)(c2ccccc2)C2CCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
62 mg of N-[1-(4-oxopentyl)piperidin-4-yl]-2-cyclobutyl-2-hydroxy-2-phenylacetamide was added at 0° C. to an ylide compound prepared from 124 mg of ethyltriphenylphosphonium bromide and 200 μl of n-butyl lithium (as a 1.62M hexane solution), and this mixture was stirred at 0° C. for 30 minutes and then at room temperature for 4 hours. After the solvent was distilled off under reduced pressure, the resulting residue was mixed with 20 ml of water and then extracted with chloroform (30 ml×3). The organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by preparative thin-layer chromatography [Kieselgel™ 60F254, Art 5744 (manufactured by E. Merck); developing solvent: chloroform to chloroform/methanol=10/1) to obtain 18.0 mg of N-[1-(Z)-(4-methyl-4-hexenyl)piperidin-4-yl]-2-cyclobutyl-2-hydroxy-2-phenylacetamide and 9.0 mg of N-[1-(E)-(4-methyl-4-hexenyl)piperidin-4-yl]-2-cyclobutyl-2-hydroxy-2-phenylacetamide.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.[Cu]I>[CH3:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(N2CCCC2)c2ccc(NS(C)(=O)=O)cc2n1
Temperature: 110 °C
Yield: 19 %

Procedure:
In a dried reaction flask flushed with argon a suspension of 169 mg (0.5 mmol) 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline and 57 mg (0.6 mmol) of methanesulfonamide, 325 mg (1 mmol) of cesium carbonate, 1.9 mg (0.01 mmol) copper (I) iodide in 1,4-dioxane was treated at RT with 5.7 mg (0.05 mmol) of trans-diaminocyclohexane and the mixture was heated at 110° C. (oil bath temperature) for 48 h under an argon atmosphere (for the gerneal method: Buchwald: J. Am. Chem. Soc., p7727, 2001). The reaction mixture was then cooled to RT, diluted with methylene chloride and filtered. The filtrate was concentrated in a vacuo, the residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (9:1:0.5) as eluent. Combination of the purified fractions and concentration in vacuo gave 29 mg (25.5%) of the desired N-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-methanesulfonamide which was re-crystallized from methylene chloride: light brown solid. ISP mass spectrum, m/e: 306.3 (M+1 calculated for C15H19IN3O2S: 306).
Reaction SMILES: BrC1C=C(N[C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[O:14])C=C(Br)C=1OCC.C(Cl)CCl.[CH2:29]([O:31][C:32]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[C:43]([F:46])([F:45])[F:44])[CH3:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:29]([O:31][C:32]1[C:33]([C:43]([F:44])([F:45])[F:46])=[CH:34][C:35]([NH:36][C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[O:14])=[CH:37][C:38]=1[C:39]([F:40])([F:41])[F:42])[CH3:30]
Reactant: CCOc1c(C(F)(F)F)cc(N)cc1C(F)(F)F
Reactant: CCOc1c(Br)cc(NC(=O)c2ccc(C(=O)OC)cc2)cc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOc1c(C(F)(F)F)cc(NC(=O)c2ccc(C(=O)OC)cc2)cc1C(F)(F)F
Yield: 26.1 %

Procedure:
4-(Methoxycarbonyl)benzoic acid (4) (246 mg, 1.37 mmol) was dissolved in DCM (15 mL) and treated with EDC (654 mg, 3.41 mmol) and DMAP (33 mg, 273 μmol). The resultant mixture was stirred at RT for 15 min. 4-Ethoxy-3,5-bis(trifluoromethyl)aniline (3) (360 mg, 1.32 mmol) was added and the resultant mixture was stirred at RT for 20 h. The mixture was diluted with EtOAc and washed three times with 1 M HCl and then three times with NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by silica gel chromatography (10% EtAOc in isohexane) to afford methyl 4-(4-ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoate (5) (150 mg, 28%): m/z 436 [M+H]+ (ES+).
Reaction SMILES: C[O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH:8]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH:8]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OC(C)(C)C2N1CCCCC1
Agent: Br
Solvent: CC(=O)O
Product: CC1(C)Oc2c(O)cccc2C1N1CCCCC1

Procedure:
7-Methoxy-3-piperidino-2,2-dimethylbenzofuran (65.1 g) is added to a stirred mixture of glacial acetic acid (340 ml) and 48% HBr (340 ml) and the solution refluxed for 3 hours. The reaction mixture is poured into crushed ice/H2O and brought to a pH=8-10. The alkaline reaction mixture is extracted with methylene chloride and the organic phase washed with water, dried, filtered and evaporated in vacuo. The residue is chromatographed on silica gel eluting with ethyl acetate/hexane (1:3) affording the desired product as a liquid.