Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:17]1[CH:18]=[C:19]([O:23][CH3:24])[C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=1)[CH:8]=[N:7]2
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Clc1cnc2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(-c2cnc3cccc(Br)c3n2)cc(OC)c1OC
Temperature: 105 °C

Procedure:
A microwave tube is charged with 30 mg (0.123 mmol) of 8-Bromo-2-chloro-quinoxaline, 26.4 mg (0.123 mmol) of 3,4,5-trimethoxyphenylboronic acid, 40 mg (0.370 mmol) of Na2CO3 and 4.4 mg (0.0037 mmol) of Pd(PPh3)4. After several cycles of vacuum/purge with argon, 1.5 ml of dry DMF are added. The reaction mixture is then heated tot 105° C. for 15 h. After cooling, the yellow suspension is poured onto de-ionized water and filtered. After drying under H.V. at 50° C., the residue is purified by chromatography (silicagel, hexane:EtOAc=100=>1:1) to afford the title compound as a yellow solid, Rt=1.294 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 375 (M)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([C:24]2[C:29]3[CH:30]=[CH:31][O:32][C:28]=3[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])(O)=O.[Na+]>ClCCCl.CO>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:21]2[CH2:22][CH2:23][N:18]([C:24]3[C:29]4[CH:30]=[CH:31][O:32][C:28]=4[CH:27]=[CH:26][N:25]=3)[CH2:19][CH2:20]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1cc2occc2c(N2CCNCC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Reaction time: 18 h

Procedure:
trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester [CAS-Nr. 215790-29-7] (4.1 g, 17 mmol) was added to a solution under N2 of commercially available 4-piperazine-1-yl-furo[3,2-c]pyridine [CAS-Nr. 81078-84-4] (3.1 g, 15 mmol) in 1,2-dichloroethane (40 ml) and MeOH (0.5 ml). The resulting yellow solution was stirred 8 h at room temperature before addition of Na(AcO)3BH (4.9 g, 23 mmol). Stirring was continued at room temperature for 18 h. The reaction mixture was poured on sat. aq. NaHCO3 sol. (130 ml) and the product was extracted with EtOAc (3×100 ml). The combined organic layers were washed with H2O (130 ml) and brine (100 ml). After drying (MgSO4) the solvent was evaporated and the product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0 to 95:5) to yield trans-{4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-carbamic acid tert-butyl ester as white crystals (3.4 g, 52%), MS (ISP) m/z=429.4 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]2[C:3]=1[C:4](=[O:31])[O:5][CH2:6]2.[C:32]12([C:42](Cl)=[O:43])[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2.O>N1C=CC=CC=1>[C:32]12([C:42]([O:1][C:2]3[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:27])/[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:17])=[C:9]([O:28][CH3:29])[C:8]([CH3:30])=[C:7]4[C:3]=3[C:4](=[O:31])[O:5][CH2:6]4)=[O:43])[CH2:39][CH:38]3[CH2:37][CH:36]([CH2:35][CH:34]([CH2:40]3)[CH2:33]1)[CH2:41]2
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: c1ccncc1
Product: COc1c(C)c2c(c(OC(=O)C34CC5CC(CC(C5)C3)C4)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Morpholinoethyl E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate (10.0 g) was dissolved in pyridine (50.0 ml) followed by the addition of 1-adamantanecarbonyl chloride (10.0 ml). The mixture was stirred at room temperature for 90 minutes, then poured into water and extracted with ethyl acetate. The organic solution was dried and evaporated to give morpholinoethyl E-6-[1,3-dihydro-4-(1-adamantoyloxy)-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl]-4-methyl-4-hexenoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.[C:14]([O:17][C:18](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][O:17][CH3:18]
Reactant: O=C1Cc2cc(Br)ccc2C(=O)N1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: COC(OC)OC
Product: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 125 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-Bromo-4H-isoquinoline-1,3-dione (4.8 g, 20 mmol) in 50 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide, respectively, is added trimethylorthoformate (4.4 mL, 40 mmol). The reaction mixture is shaken in a heating block at 125° C. for 1 hour. Upon cooling to room temperature, the product precipitated out. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 4.8 g of 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC3C=CC=CC=3)[N:18]=2)([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[N:18]=2)([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(Cc2cccc(OCc3ccccc3)n2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CO)(Cc2cccc(O)n2)CC1

Procedure:
A mixture of N-tert-butoxycarbonyl-4-(6-benzyloxypyridin-2-ylmethyl)-4-hydroxymethylpiperidine (0.19 g, 0.5 mmol) and 5% palladium on charcoal (38 mg) in absolute ethanol (10 mL) was stirred under a balloon of hydrogen gas at room temp. for 3 h. The resultant mixture was filtered through a plug of Celite. The filtrate was concentrated under vacuum to provide the title compound as colorless gum.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:35])[CH:22]([C:26]2[C:31]([F:32])=[CH:30][C:29]([OH:33])=[CH:28][C:27]=2[F:34])[O:23][CH2:24][CH3:25])=[CH:15][CH:14]=1)=[NH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:36])[NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][C:21](=[O:35])[CH:22]([C:26]2[C:31]([F:32])=[CH:30][C:29]([O:33][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:28][C:27]=2[F:34])[O:23][CH2:24][CH3:25])=[CH:15][CH:14]=1)=[NH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)cc(O)cc1F
Reactant: OCCN1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)cc(OCCN2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 22.8 %

Procedure:
To a mixture of (RS)-[(4-{[2-(2,6-difluoro-4-hydroxy-phenyl)-2-ethoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid benzyl ester (100 mg), N-(2-hydroxyethyl)morpholine (29 mg) and polymer bound triphenylphosphine (˜3 mmol/g, 167 mg) in CH2Cl2 (2 ml) was added di-tert-butyl azodicarboxylate (93 mg) before shaking 22 h at rt. After filtration of the polymer the solvent was evaporated and the residue was purified by HPLC to obtain 28 mg of (23%) (RS)-{[4-({2-[2,6-difluoro-4-(2-morpholin-4-yl-ethoxy)-phenyl]-2-ethoxy-acetylamino}-methyl)-phenyl]-imino-methyl}-carbamic acid benzyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[N:10]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(OCC)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:10]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)/C=C/CC[C@@H]1CC[C@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCC[C@@H]1CC[C@H](c2ccc(F)c(F)c2)N1C(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
Palladium-carbon (containing 50% water, 0.376 g) was added to a solution of tert-butyl (2R,5R)-2-(3,4-difluorophenyl)-5-{(E)-4-methoxycarbonyl-3-butenyl}pyrrolidine-1-carboxylate (1.3 g) in ethyl acetate (50 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for six hours. Palladium-carbon in the reaction solution was removed by filtration through celite, and the filtrate was concentrated under reduced pressure to obtain 1.3 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[C:5]=2[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2].CC[N:31]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[C:1]([C:3]1[C:4]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:12]=[C:11]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:31])=[O:25])[C:5]=2[C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ncc(C#N)c2c1c(Nc1cccc(C(=O)O)c1)cn2C1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(C#N)c2c1c(Nc1cccc(C(N)=O)c1)cn2C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution of 3-((7-cyano-1-cyclopentyl-4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)benzoic acid (80 mg) and HOBt ammonium salt (52 mg) in DMF (2 mL) was added EDCI hydrochloride (65 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (65 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CCNCC
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: CCN(CC)CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and Diethylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-diethyl-amine, MS: 389 (MH+, 1Cl).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]4[CH:19]([N:7]([C:8]=23)[CH:6]=[C:5]1[C:20]([O:22]CC)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15]4>O>[O:3]=[C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]4[CH:19]([N:7]([C:8]=23)[CH:6]=[C:5]1[C:20]([OH:22])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15]4
Reactant: CCOC(=O)c1cn2c3c(cccc3c1=O)C1CCCCC12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cn2c3c(cccc3c1=O)C1CCCCC12
Yield: 63.1 %

Procedure:
250 ml of a 10% aqueous sodium hydroxide solution was added to 28 g of ethyl 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxylate, followed by heat-refluxing for 2 hours. The reaction system changed from a suspension to a uniform solution as the reaction proceeded. 200 ml of water was added to the reaction mixture which was then filtered, and the filtrate was rendered acidic with concentrated hydrochloric acid to precipitate light yellow crystals. The crystals were separated by filtration, washed successively with water and a small amount of ethanol, dried and recrystallized from chloroform-hexane (1:1 by volume) to obtain 16 g of 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxylic acid as light yellow amorphous crystals having a melting point of 238°-241° C.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[C:11](/[N:13]=[CH:14]/[N:15](C)C)=O)=[N:8][C:4]=2[CH:3]=1.[NH2:28]N>C(O)(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:24])([CH3:23])[CH3:25])[C:7]([C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[C:11]3[N:13]=[CH:14][NH:15][N:28]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN(C)/C=N/C(=O)c1ccccc1-c1nc2cc(Br)ccc2n1C(C)(C)C
Reactant: NN
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1c(-c2ccccc2-c2nc[nH]n2)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-N-[1-dimethylamino-meth-(E)-ylidene]-benzamide (230 mg, 0.538 mmol) in glacial acetic acid (3 mL), followed by the addition of hydrazine (35% wt solution in water) (2 mL). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with EtOAc, washed with sat. NaHCO3 and brine, dried under Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-4% 2M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford 5-bromo-1-tert-butyl-2-[2-(1H-1,2,4-triazol-3-yl)-phenyl]-1H-benzimidazole (180 mg, 84%) as an off-white solid. LCMS (ESMS): m/z 396.68, 398.64 (M++1)
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: Clc1cccc(C2CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4cccc(Cl)c4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 4-(3-chlorophenyl)piperidine hydrochloride (204.2 mg, 0.88 mmol, 2.00 equiv), and DIEA (194.8 mg, 1.51 mmol, 5.00 equiv) in DMF (4 mL) was placed in an 8-mL sealed tube and stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water, then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:100)) yielded 143.5 mg (64%) of methyl 3-(4-(3-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][C:9](=[O:13])[N:10]2[CH3:22])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(-c3ccccc3)cc(=O)[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(-c3ccccc3)cc(=O)n(C)c2c1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
A solution of 7-methoxy-4-phenyl-2-quinolinone from Example 1, Step 2 (1.62 g) in DMF (30 mL) was treated with NaH (60% in mineral oil; 310 mg). After stirring at 50° C. for 45 min., the mixture was cooled to r.t. and methyl iodide (0.6 mL) was added. After 30 min., H2O (100 mL) was added and the resulting solution extracted with EtOAc (3×). The organics were washed with H2O (2×), brine, dried (MgSO4) and the solvents evaporated. Flash chromatography of the residue (silica gel; CHCl3 /EtOAc (4:1)) provided the title compound as a foam.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=1[CH:16]=[O:17].[Cl-].[NH4+]>O1CCCC1>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:15]=1[CH:16]([OH:17])[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: C#CC(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1cc(OC)ccc1OC
Reaction time: 0.17 h

Procedure:
A solution of 8.36 ml (0.1 mol) of methyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 68.8 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 16.6 g (0.1 mol) of 2.5-dimethoxybenzaldehyde in 120 ml of tetrahydrofuran was added within 40 minutes. The reaction mixture was stirred at -78° for a further 20 minutes, then brought to room temperature and treated with 150 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained methyl 4-(2.5-dimethoxyphenyl)-4-hydroxy-2- butynoate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH3:28]>C(#N)C>[CH2:25]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=2[F:1])[CH2:13][CH2:14]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCBr
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)-phenyl]-piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 1-bromobutane (0.009 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 313 (M+, 2), 271 (14), 270 (bp), 147 (7) 133 (7).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[S:26]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH:45]=O)=[CH:37]1)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:45]/[C:38]3[C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:36]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=4)(=[O:28])=[O:27])[CH:37]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.697 g, 2.00 mmol) obtained in Example A16, Step 1 in methanol (10 mL) was added with 1-tosyl-1H-indole-3-carboxaldehyde (0.599 g, 2.00 mmol) synthesized in Step 1 and piperidine (0.0170 g, 0.200 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(1-tosyl-1H-indol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.470 g, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[N:13]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:16]1[CH2:17][CH2:18][CH2:19][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:15]1
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccnc3ccc(Br)cc23)CC1

Procedure:
6-Bromo-4-chloroquinoline (3.5 g, 14.5 mmol) was reacted with tert-butyl 1,4-diazepane-1-carboxylate (3.7 g, 18.8 mmol) and K2CO3 (4 g, 29 mmol) in DMSO at 100° C. overnight. After cooling the mixture was poured into water and extracted with DCM. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by flash chromatography using a gradient of EtOAc:hexane 1:1 to 2:1 giving 2.1 g (36%) of yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (d, J=5.5 Hz, 9H) 2.08-2.16 (m, 2H) 3.35-3.44 (m, 4H) 3.60-3-73 (m, 4H) 6.87 (d, J=5.5 Hz, 1H) 7.69 (dd, J=9.0, 2.0 Hz, 1H) 7.88 (d, J=8.5 Hz, 1H) 8.16 (s, 1H) 8.65 (d, J=5.0 Hz, 1H). MS (ESI+) for C19H24BrN3O2 m/z 406.4 (M+H)+. HRMS (EI) calcd for C19H24BrN3: 405.1052, found 405.1045.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[CH:23]=[C:24]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])[CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:13])=[CH:7][CH:8]=1)(=[O:29])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2cccc(C(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged 45 mL of DMF. To the stirred solvent was added 3-(4-Hydroxy-phenyl)-propanoic acid methyl ester (4.5 g, 16.35 mmol) followed by K2CO3 (6.78 g, 49.074 mmol) and the resulting mixture stirred at room temperature for 30 minutes. (3-bromomethyl-phenyl)-phenyl-methanone (2.94 g, 16.35 mmol) was added to the above mixture and stirring continued at RT for 24 h. After completion of the reaction (reaction monitored by TLC), reaction solvent was removed under reduced pressure. The crude compound was purified by column chromatography on silica gel (100/200 mesh) using petroleum ether (60-80) and ethyl acetate as eluent which yielded the product as yellow color oil (5.1 g, Yield: 83.3%): MS (ESI, 120 eV): m/z=375.1 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.68 (s, 1H), 7.62-7.66 (d, 3H), 7.57-7.59 (d, 1H), 7.53 (m, 1H), 7.45-7.50 (m, 3H), 7.11-7.13 (d, 2H), 6.88-6.90 (d, 2H), 5.10 (s, 2H), 3.66 (s, 3H), 2.85-2.92 (m, 2H), 2.56-2.62 (m, 2H).