Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][CH2:32][C@@H:27]([NH:26][C:24]([C:20]2[C:16]3=[N:17][CH:18]=[CH:19][C:14]([C:8]4[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:15]3[NH:22][C:21]=2[CH3:23])=[O:25])[C@H:28]([OH:33])[CH2:29]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Agent: Cl
Product: CC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)[C@H](O)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f10) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]=[N:39][N:38]=[N:37]2)=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]=[N:39][N:38]=[N:37]2)=[CH:32][C:28]=1[C:29]([N:13]1[CH2:14][CH2:15][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:16][CH2:17][OH:18])[CH2:12]1)=[O:30]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Reactant: COc1ccc(C2(CCO)CCNC2)cc1OC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C2(CCO)CCN(C(=O)c3cc(-n4cnnn4)ccc3OC)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 3-(3,4-dimethoxyphenyl)--3-(2-hydroxyethyl)pyrrolidine (5.34 g, 21.2 mmol) and sodium carbonate (1.24 g, 11.7 mmol) in ethyl acetate/water (4/1) (120 mL). Cool the reaction mixture to -5° C. with an salt-ice bath. Slowly, add 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (22.3 mmol) as a solution in ethyl acetate (60 mL) at a rate such that the temperature of the reaction mixture does not rise above 0° C. Maintain the reaction temperature at about 0° C. After 18 hours, separate the organic layer. Extract the organic layer twice with 1M aqueous hydrochloric acid solution, saturated solution of sodium bicarbonate, water and a saturated solution of sodium chloride. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Combine the aqueous layers and neutralize with a saturated solution of sodium bicarbonate. Extract the neutralized aqueous layers with dichloromethane. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O>C(O)C.[Pd]>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:4]=[N:3][O:2][CH3:1]
Reactant: CON=Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CON=Cc1ccccc1N

Procedure:
2-(N-methoxyiminomethyl)-nitrobenzene (6.5 g) in 350 ml 99.9% ethanol was reduced catalytically at room temperature, 1 atm. using 0.7 g 10% Pd on carbon. Upon completion of the reduction the solution was filtered throughfilter aid and concentrated in vacuo. The product was redissolved in methylene chloride and filtered through silicagel. Evaporation of the solvent gave the desired product as an oil.
Reaction SMILES: ClCCCl.[NH2:5][C:6]1[C:7]([OH:13])=[N:8][CH:9]=[C:10]([Cl:12])[CH:11]=1.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Cl:12][CH:10]1[CH2:9][NH:8][CH:7]([OH:13])[CH:6]([NH:5][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cc(Cl)cnc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(NC2CC(Cl)CNC2O)CC1
Yield: 62.1 %

Procedure:
To a 1,2-dichloroethane suspension (177 ml) of 3-amino-5-chloropyridin-2-ol (8.85 g) and tert-butyl 4-oxopiperidine-1-carboxylate (24.4 g) was added sodium triacetoxyborohydride (26.0 g), followed by stirring under heating at reflux for 4 hours. Tert-butyl 4-oxopiperidine-1-carboxylate (12.4 g) and sodium triacetoxyborohydride (13.7 g) were further added, and stirred under heating at reflux for 2 hours. After the reaction solution was brought back to room temperature, water and dichloromethane were added, and the solution was separated. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-[(5-chloro-2-hydroxypiperidin-3-yl)amino]piperidine-1-carboxylate (12.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=O)[CH2:7][CH2:6]2.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1C)C(=O)CC2
Reactant: CCOC(=O)CBr
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCc2cc(OC)c(C)cc21
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a mixture of activated Zn dust (1.46 g, 22.3 mmol) in THF (10 mL), a solution of 5-methoxy-6-methylindanone (2.62 g, 14.8 mmol, from Step B) from and ethyl bromoacetate (2.14 mL, 19.3 mmol) in THF (15 mL) were added dropwise via cannula. The reaction was heated to reflux for 45 min and cooled to ambient temperature. The reaction was quenched into 2 N HCl and extracted with EtOAc. The organic layer was washed with H2O, brine, dried over MgSO4, and filtered. Solvents were removed in vacuo, and the residue was purified by flash chromatography (5% EtOAc/hexanes) on SiO2 to afford 2.64 g that was recrystallized from hexanes to afford 2.02 g of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.35 (t, 3H, J=7.2 Hz), 2.24 (s, 3H), 3.04-3.06 (m, 2H), 3.29-3.31 (m, 2H), 3.88 (s, 3H), 4.23, (q, 2H, J=7.1 Hz), 6.16 (t, 1H, J=2.4 Hz), 6.79 (d, 1H, J=8.8 Hz), 7.38 (d, 1H, J=8.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:26]1[C:27]2[CH:34]=[CH:33][NH:32][C:28]=2[N:29]=[CH:30][N:31]=1.C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:22])[CH2:17][CH2:18][N:19]([C:26]4[C:27]5[CH:34]=[CH:33][NH:32][C:28]=5[N:29]=[CH:30][N:31]=4)[CH2:20][CH2:21]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCNCC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 180 °C

Procedure:
To a solution of N-(3-(4-fluorophenoxy)phenyl)-4-methylpiperidine-4-carboxamide from example 1, step B, (20 mg, 0.05 mmol) in isopropanol (1 mL), was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (15 mg, 0.1 mmol) and triethylamine (0.04 mL, 0.3 mmol). The reaction mixture was heated at 180° C. for 30 minutes under microwave conditions, and then concentrated under vacuum. The product was isolated by prep HPLC to give the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:8]([S:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[N:7]([CH:26]([CH3:28])[CH3:27])[N:6]=1)=[N+]=[N-]>C(OCC)(=O)C.[Pd]>[Cl:25][C:20]1[CH:19]=[C:18]([S:17][C:8]2[N:7]([CH:26]([CH3:28])[CH3:27])[N:6]=[C:5]([CH2:4][NH2:1])[C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:23]=[C:22]([Cl:24])[CH:21]=1
Reactant: CC(C)n1nc(CN=[N+]=[N-])c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)n1nc(CN)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 2 h
Yield: 54.1 %

Procedure:
A solution containing 120 mg of 4-[3-Azidomethyl-5-(3,5-dichloro-phenylsulfanyl)-1-isopropyl-1H-pyrazol-4-ylmethyl]-pyridine in 5 ml of ethyl acetate was treated with 20 mg of 10% palladium on charcoal and then hydrogenated at atmospheric pressure for 2.0 h. The mixture was filtered and then the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (1:9) for the elution to give 61 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3-methylamine as a pale yellow oil. Mass spectrum (ESI) m/z 407 [M+H]+. 1H NMR (DMSO) 1.30 (d, 6H), 3.72 (s, 2H), 3.90 (s, 2H), 4.70 (m, 1H), 6.78 (s, 2H), 7.10 (d, 2H), 7.37 (s, 1H), 8.30 (d, 2H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].N1C=CC=CC=1.[Br:19][C:20]([CH3:25])([CH3:24])[C:21](Br)=[O:22]>O1CCCC1.CCCCCC>[Br:19][C:20]([CH3:25])([CH3:24])[C:21]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1])=[O:22]
Reactant: CC(C)(Br)C(=O)Br
Reactant: C=CCCCCCCCCCO
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CCCCCCCCCCOC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 4.257 g (25 mmol) of ω-undecylenyl alcohol in 25 mL of dry tetrahydrofuran was added 2.1 mL of pyridine (26.5 mmol) followed by dropwise addition of 3.10 mL of 2-bromoisobutyryl bromide (25 mmol) over 5 min. The mixture was stirred at room temperature overnight and then diluted with hexane (50 mL) and washed with 2 N HCl and twice with water. The organic phase was dried over sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure, and the colorless oily residue was purified by flash column chromatography (hexane/ethyl acetate 25/1 v/v) to give 7.34 g (92%) of the ester as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[C:6]([CH3:8])[CH:7]=1.S(=O)(=O)(O)[OH:16]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]2[C:3]=1[C:11](=[O:16])[C:10](=[O:14])[NH:9]2
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(C)cc(NC(=O)C=NO)c1
Product: Cc1cc(C)c2c(c1)NC(=O)C2=O
Temperature: 80 °C

Procedure:
N-(3,5-Dimethyl-phenyl)-2-hydroxyimino-acetamide (13.7 g, 71.3 mmol) was added to concentrated sulfuric acid (70 mL) in a 250 mL flask. The reaction mixture was then heated at 80° C. for 30 minutes, then cooled to room temperature, and poured into ice-water (200 mL). The precipitated solid was filtered and washed with water (100 mL) and dried under vacuum to give 4,6-dimethyl-1H-indole-2,3-dione as an orange solid. Yield: 5.53 g (44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:20])[CH:10]([CH3:21])[N:9]=1.[Cu][C:23]#[N:24].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:23]#[N:24])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:20])[CH:10]([CH3:21])[N:9]=1
Reactant: CC1N=C(c2ccccc2F)c2cc(I)ccc2NC1=O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: CC1N=C(c2ccccc2F)c2cc(C#N)ccc2NC1=O

Procedure:
23.2 g (58.8 mmol) of 5-(o-fluorophenyl)-1,3-dihydro-7-iodo-3-methyl-2H-1,4-benzodiazepin-2-one and 10 g (0.11 mol) of copper (I) cyanide in 250 ml of dimethylformamide are heated at 150° for 2 hours under argon. After cooling, 700 ml of water are added to the mixture and the resulting precipitate is filtered off. This is dissolved in 1 l of water/ethylenediamine (1:1) and extracted with 1 l of methylene chloride; the separated aqueous phase is extracted a further twice with methylene chloride. The combined organic extracts are washed with water, dried and evaporated. The residue gives, from cyclohexane, 5-(o-fluorophenyl)-2,3-dihydro-3-methyl-2-oxo-1H-1,4-benzodiazepine-7-carbonitrile of melting point 216°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2.[C:15]([C:22]1[NH:23][CH:24]=[CH:25]N=1)(C1NC=CN=1)=O.N1CCCC1.O>O1CCCC1>[CH3:1][O:2][C:3]1[C:11]([C:12]([N:23]2[CH2:22][CH2:15][CH2:25][CH2:24]2)=[O:14])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH2:7]2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COc1c(C(=O)O)ccc2c1CCC2
Solvent: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(=O)N2CCCC2)ccc2c1CCC2
Temperature: 67.5 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a clear solution of 4-Methoxy-indan-5-carboxylic acid (12.0 gm, 0.0625 mole) in Tetrahydrofuran (60 ml), Carbonyl-diimidazole (13.24 gm, 0.0812 mole) was added at 25-28° C. The reaction mixture was heated to 65-70° C. and stirred for 2 hours to the reaction mixture, a solution of Pyrrolidine (5.74 ml, 0.0687 mole) in Tetrahydrofuran (20 ml) was added at 10-15° C. The reaction mixture was poured into water (200 ml) and extracted with Ethylacetate (2×100 ml). The organic layer was dried over Sodium sulphate, distilled under vacuum and purified by column chromatography using Ethyl acetate:Hexane (20:80) as mobile phase. The fractions were distilled under vacuum to give 6.0 gm of desired product as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([S:19]([OH:22])(=O)=[O:20])[CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl.S(Cl)(Cl)(=O)=O.[NH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([CH2:36][CH3:37])[CH2:31]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([S:19]([NH:29][CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([CH2:36][CH3:37])[CH2:31]4)(=[O:20])=[O:22])[CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1cccc(Nc2ccnc3cc(Cl)ccc23)c1
Reactant: CCN1CCCC(N)C1
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCN1CCCC(NS(=O)(=O)c2cccc(Nc3ccnc4cc(Cl)ccc34)c2)C1

Procedure:
3-(7-Chloro-4-quinolylamino)benzenesulphonic acid was converted to the corresponding sulphonylchloride hydrochloride and reacted with 3-amino-1-ethylpiperidine in a similar manner to that described in Example 1 (b) to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.C(=NO)C1C(=CC=CC=1)O.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:25]1[C:26]([Br:33])=[C:27]([O:31][CH3:32])[CH:28]=[CH:29][CH:30]=1>CN(C)C=O>[Br:33][C:26]1[CH:25]=[CH:30][C:29]([N:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:7]=[N:6]2)=[CH:28][C:27]=1[O:31][CH3:32]
Reactant: COc1cccc(I)c1Br
Reactant: OCc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-n2cc(CO)cn2)ccc1Br
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
A mixture of 4-(hydroxymethyl)pyrazole (500 mg, 5.10 mmol), salicylaldoxime (140 mg, 1.019 mmol), cesium carbonate (4.98 g, 15.29 mmol), cuprous oxide (58.2 mg, 0.306 mmol), iodobromoanisole (1.59 g, 5.10 mmol) and N,N-dimethyl-formamide (10 mL) were combined in a microwave vial fitted with an N2 inlet and magnetic stir bar. The reaction mixture was stirred under a nitrogen atmosphere at 90° C. overnight. The reaction mixture was cooled to RT, then filtered through celite, and the filtrate was concentrated in vacuo. The crude material was purified by column chromotography (10% to 60% EtOAc in heptanes) to give (1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-4-yl)methanol (800 mg, MS: 285.3 [M+H+].)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.CC(C)([O-])C.[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: Cc1cccc(B(O)O)c1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4C)c3O2)cc1
Yield: 69.5 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 3-methylphenylboronic acid (0.266 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium tert-butoxide (0.366 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.358 g (70%) of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 98-100° C.; Anal. calcd. for C23H22O4S: C, 70.03; H, 5.62. Found: C, 69.83; H, 5.61.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:9][C:10]([N:12]3[CH2:17][CH2:16][C:15](=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.[CH3:27][C:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[C:31]([CH3:42])[O:30][N:29]=1.CC(C)([O-])C.[Na+].[Cl-].[NH4+]>C(COC)OC.O.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>[CH3:27][C:28]1[C:32]([C:2]2[CH:26]=[CH:25][C:5]3[N:6]=[C:7]([NH:9][C:10]([N:12]4[CH2:17][CH2:16][C:15](=[CH:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=5)[CH2:14][CH2:13]4)=[O:11])[S:8][C:4]=3[CH:3]=2)=[C:31]([CH3:42])[O:30][N:29]=1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(Nc1nc2ccc(Br)cc2s1)N1CCC(=Cc2ccccn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1ccc2nc(NC(=O)N3CCC(=Cc4ccccn4)CC3)sc2c1
Reaction time: 16 h
Yield: 88.3 %

Procedure:
The compound (300 mg, 699 μmol) obtained in Example 1 and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)isoxazole (458 mg, 2.10 mmol) were dissolved in a mixture of dimethoxyethane (10 mL) and water (1 mL), under a nitrogen atmosphere, sodium tert-butoxide (470 mg, 4.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (323 mg, 280 μmol) were added thereto, followed by stirring for 16 hours while heating under reflux. A saturated ammonium chloride aqueous solution was added to the resulting mixture to stop the reaction, and after extraction with ethyl acetate, the extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the residue obtained by evaporation under reduced pressure was purified using medium pressure flash column chromatography (silica gel; methanol:chloroform=1:100), thereby giving the title compound (275 mg, 88%) as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[N:4][CH:3]=1.[NH3:18]>CO>[Br:1][C:2]1[C:7]([C:8]([NH2:18])=[O:9])=[CH:6][C:5]([NH:12][C:13]([NH:15][CH2:16][CH3:17])=[O:14])=[N:4][CH:3]=1
Reactant: CCNC(=O)Nc1cc(C(=O)OC)c(Br)cn1
Reactant: N
Solvent: CO
Product: CCNC(=O)Nc1cc(C(N)=O)c(Br)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
A solution of methyl 5-bromo-2-(3-ethylureido)isonicotinate (Intermediate 4, 261 g, 865 mmol) and 7N ammonia in methanol (1.7 L) was allowed to stir at room temperature for 3 d. The solid that precipitated was then collected by filtration, rinsed with methanol (2×500 mL), and then dried on a high vacuum pump overnight, yielding 237 g (95%) of 5-bromo-2-(3-ethylureido)isonicotinamide as a smooth white solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]([CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1.[O-]CC.[Na+].[CH3:55][N:56]1[CH:60]=[CH:59][N:58]=[C:57]1[CH2:61][CH2:62][CH:63]=O.O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9](/[CH:16]=[CH:63]/[CH2:62][CH2:61][C:57]1[N:56]([CH3:55])[CH:60]=[CH:59][N:58]=1)[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]2[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][CH3:50])[CH:42]=1
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: Cn1ccnc1CCC=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(/C=C/CCc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
[6,7-Dimethoxy-4-(3,4-dimethoxyphenyl)-3-ethoxycarbonylquinolin-2-yl]methyltriphenylphosphonium chloride (3.0 g) was added at room temperature to a solution of sodium ethoxide in ethanol (prepared from Na (0.13 g) and ethanol (45 ml)). Then 3-(1-methylimidazol-2-yl)propionaldehyde (0.787 g) was added. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with ethyl acetate/methanol (30/1, v/v) gave ethyl (E)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[2-[2-(1-methylimidazol-2-yl)ethyl]vinyl]quinoline-3-carboxylate (0.36 g, 15%) as an oil.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:3][Si:2]([CH3:5])([CH3:4])[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1
Reactant: Brc1cncnc1
Reactant: C[Si](C)(C)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C[Si](C)(C)c1cncnc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 9.9 %

Procedure:
In a 500 ml 4 neck round bottom flask stirring under N2 was charged 1.2 g of Mg (0.050 moles, 1.0 eq) and 5.43 g of chlorotrimethylsilane (0.050 moles, 1.0 eq.) in 50 ml of HMPA (hexamethylphosphoramide) which was heated at 80° C. for 4 hours. To the reaction was added dropwise, 6.4 g of 5-bromopyrimidine (0.040 moles, 0.8 eq.) in 50 ml of HMPA while maintaining the temperature at 80° C. The reaction mixture was stirred for 18 hours at 75° C. after which GLC indicated complete consumption of the 5-bromopyrimidine. The reaction was quenched by adding 100 ml of water, acidified with 10% HCl and extracted with 2×250 ml of ethyl acetate (EtOAc). The acidic aqueous solution was neutralized with 6M NaOH to pH 10 and extracted with 250 ml of EtOAc. The extractions were combined and washed with 4×250 ml aliquots of distilled water. Drying and concentrating afforded 1.2 g of crude product which was purified by flash chromatography with 1:4 ethyl acetate/hexane and afforded 0.6 g of a clear oil (9.8% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:23]=2[CH2:24]Cl)=[CH:18][CH:17]=1>CC(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:23]=2[CH2:24][O:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[CH:20][CH:21]=1
Reactant: Oc1ccc(I)cc1
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2ccc(Cl)cc2)c(COc2ccc(I)cc2)c1
Yield: 98.8 %

Procedure:
4-Iodophenol (5.0 g) was dissolved in acetone (50 ml), and potassium carbonate (4.7 g) and 4′-chloro-2-chloromethyl-4-methoxybiphenyl (6.0 g) obtained in Example 241, Step 4 were added. The mixture was refluxed for 10 hr. The reaction mixture was concentrated and 4N aqueous sodium hydroxide solution (50 ml) was added. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound (10.0 g, yield 98%).