Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][C:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH3:24])[CH:6]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:13][C:14]2[C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[N:16]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[C:15]=2[CH3:24])[CH:6]=1)[CH3:2]
Reactant: Cn1cc(Br)cn1
Reactant: CCOC(=O)c1ccc(OC)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1ccc(OC)c(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 40, Step 6, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methoxy-benzoic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[CH2:14]([C:16]1[S:20][C:19]([CH:21]=[O:22])=[CH:18][CH:17]=1)[CH3:15].[Cl-].[NH4+]>O1CCCC1>[Br:8][C:4]1[CH:3]=[C:2]([CH:21]([C:19]2[S:20][C:16]([CH2:14][CH3:15])=[CH:17][CH:18]=2)[OH:22])[CH:7]=[CH:6][CH:5]=1
Reactant: CCc1ccc(C=O)s1
Reactant: Brc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cccc(Br)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
A solution of 1,3-dibromobenzene (3.7 g) in tetrahydrofuran (25 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 5.55 ml). The reaction mixture was stirred at the same temperature for 10 minutes, and thereto was added dropwise a solution of 5-ethyl-2-thiophenecarboxaldehyde (2.0 g) in tetrahydrofuran (10 ml). The mixture was stirred at the same temperature for 30 minutes, and thereto was added a saturated ammonium chloride solution, and the reaction mixture was warmed to room temperature. The mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3-85:15) to give 3-bromophenyl-5-ethyl-2-thienylmethanol (2.97 g) as a pale yellow syrup. APCI-Mass m/Z 279/281 (M+H—H2O). (2) The above 3-bromophenyl-5-ethyl-2-thienylmethanol (2.90 g) was dissolved in dichloromethane (38 ml), and the mixture was cooled to −78° C. under argon atmosphere. To the mixture were added triethylsilane (6.18 ml) and boron trifluoride•diethyl ether complex (2.45 ml), and the mixture was gradually warmed to room temperature over a period of one hour. The mixture was basified with a saturated aqueous sodium hydrogen carbonate solution, and the dichloromethane layer was collected, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give the desired 3-bromo-(5-ethyl-2-thienylmethyl)benzene (2.57 g) as a colorless syrup. APCI-Mass m/Z 281/283 (M+H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1([O:18][CH2:17][CH2:16][O:15]1)[CH2:13][Br:14])[C:7]([O:9]CC)=[O:8].S(=O)(=O)(O)O>O.CO>[CH3:3][O:4][N:5]=[C:6]([C:12]1([O:15][CH2:16][CH2:17][O:18]1)[CH2:13][Br:14])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)C1(CBr)OCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CON=C(C(=O)O)C1(CBr)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
A solution of sodium hydroxide (8.64 g) in water (20 ml) was added to a solution of ethyl 2-methoxyimino-3,3-ethylenedioxy-4-bromobutyrate (syn isomer, 26.6 g) in methanol (60 ml) under ice-cooling, stirred at ambient temperature for 2 hours. Water (100 ml) was added to the resultant solution and adjusted to pH 7.0 with 20% sulfuric acid under ice-cooling. After removing methanol therefrom in vacuo, the solution was washed with diethyl ether (100 ml). Diethyl ether (100 ml) was added to the aqueous layer and adjusted to pH 2.0 with 20% sulfuric acid below 10° C. The organic layer was separated, and then the aqueous layer was extracted with diethyl ether (100 ml) twice. The organic layer was washed with water and a sodium chloride saturated aqueous solution in turn, and dried over magnesium sulfate. The solution was concentrated in vacuo and the residue was allowed to stand in refrigerator overnight to give 2-methoxyimino-3,3-ethylenedioxy-4-bromobutyric acid (syn isomer, 18.0 g). (Yield: 74.7%).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([N:24]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][C:30]=5[Cl:33])[C:25]4=[O:34])[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:43])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([N:24]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][C:30]=5[Cl:33])[C:25]4=[O:34])[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:10][CH2:11]2)[CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(N3Cc4c(Cl)cccc4C3=O)cnc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(N4Cc5c(Cl)cccc5C4=O)nc23)C2CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
To a solution of 2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (40 mg, 0.065 mmol) in dichloromethane (1 mL) at r.t. was added trifluoroacetic acid (0.30 mL, 3.87 mmol). The solution was stirred for 3 h at room temperature then concentrated under vacuum. The residue was dissolved in dichloromethane (1 mL) and ethylenediamine (0.43 mL, 6.45 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated under vacuum. The crude residue was suspended in water:EtOAc (2 mL: 5 mL) and the resultant solid was collected by filtration, washing with EtOAc, to afford 23 mg (73%) of 2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a white solid. MS: (M+Na)+=512.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(CO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C=O)CC1
Reaction time: 16 h
Yield: 82.3 %

Procedure:
The above alcohol (7.5 g, 40.0 mmol, 1.0 equiv) was dissolved in 500 mL of CH2Cl2. Pyridinium chlorochromate (12.96 g, 60.1 mmol, 1.5 equiv) was added and resulting mixture was stirred for 16 h. The dark liquid was decanted and the solvent was removed in vacuo. The residue was triturated with 500 mL of diethyl ether and the mixture was filtered. The filtrate was washed with 150 mL of 1 N HCl and dried over Na2SO4. The liquid was decanted and concentrated by rotary evaporation to yield 4-formyl-piperidine-1-carboxylic acid ethyl ester as a light brown oil (6.1 g).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]4=[O:32])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:39][NH2:40]>CCO>[NH2:5][C:4]1[C:3]2[C:2](=[N:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][N:17]4[CH2:22][CH2:21][CH:20]([N:23]5[C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[NH:25][C:24]5=[O:32])[CH2:19][CH2:18]4)=[CH:14][CH:15]=3)=[C:7]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:6]=2)[NH:40][N:39]=1
Reactant: NN
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Solvent: CCO
Product: Nc1n[nH]c2nc(-c3ccc(CN4CCC(n5c(=O)[nH]c6ccccc65)CC4)cc3)c(-c3ccccc3)cc12

Procedure:
The solution of 2-chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl]-5-phenylnicotinonitrile (1-6; 0.040 g, 0.077 mmol) and hydrazine (0.2 mL) in EtOH (2 mL) was heated to 130° C. in microwave for 10 min. The mixture was concentrated, treated with aqueous Na2CO3 solution (5 mL, 2 M) and extracted with CH2Cl2 (3×10 mL). The combined organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (3-5% MeOH in CH2Cl2) to give 1-{1-[4-(3-amino-5-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (1-7). 1H-NMR (500 MHz, CDCl3) δ 9.89 (s, 1H), 8.71 (s, 1H), 7.95 (s, 1H), 7.35 (d, J=8.1, 2H), 7.18-7.27 (m, 8H), 6.98-7.05 (m, 2H), 6.85 (d, J=7.5, 1H), 4.33-4.36 (m, 1H), 4.21 (s, 2H), 3.55 (s, 2H), 3.00-3.02 (m, 2H), 2.41-2.47 (m, 2H), 2.13-2.17 (m, 2H), 1.77-1.79 (m, 2H). LRMS m/z (M+H) Calcd: 516.5, found: 516.2.
Reaction SMILES: [N:1]([CH:4]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:5]1=[O:21])=[N+]=[N-]>C(O)C.[Pd]>[C:8]([CH:7]1[N:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:5](=[O:21])[CH:4]1[NH2:1])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1C(N=[N+]=[N-])C(=O)N1c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(N)C(=O)N1c1ccc(OC)cc1

Procedure:
A solution of 2.16 g of 3-azido-4-carboethoxy-1-(p-methoxyphenyl)-azetidine-2-one in ethanol was hydrogenated with palladium to yield 4-carboethoxy-1-(p-methoxyphenyl)-3-aminoazetidin-2-one. This amine was acylated with 1.1 ml of trifluoro acetic anhydride in 10 ml CH2Cl2 containing 1.5 ml pyridine, followed by methylation using 1 ml dimethyl sulfate in 30 ml acetone containing 3 g potassium carbonate. After isolation, the crude product was crystallized to give 2.2 g of 4-carboethoxy-1-(p-methoxyphenyl)-3-(N-methyltrifluoroacetamido)azetidine-2-one, m.p. 102°-104°.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCCC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCN1CCCC1
Yield: 84.5 %

Procedure:
A solution of the product from step c (4.32 g, 15.9 mmol) and hydrazine hydrate (3.85 ml, 79.4 mmol) in ethanol (75 ml) was heated at reflux for 1.5 h. The resultant white suspension was diluted with further ethanol (50 ml) and the solid removed by filtration. The filtrate was evaporated at reduced pressure and the residue was suspended in chloroform (50 ml). The solid was removed by filtration and the filtrate evaporated at reduced pressure to afford the title compound (1.91 g, 85%). 1H NMR 2.74-2.69 (2H, m), 2.52-2.42 (6H, m), 1.83-1.75 (4H, m), 1.64-1.46 (6H, m).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:6]=[CH:5][N:4]=1.[SH:23][C:24]1[NH:32][C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N:25]=1>>[CH3:9][C:8]1[C:3]([CH2:2][S:23][C:24]2[NH:32][C:31]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[N:25]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1
Reactant: Sc1nc2cnccc2[nH]1
Reactant: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CO
Product: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CSc1nc2cnccc2[nH]1

Procedure:
The same reaction as in Example 1 was carried out using 2-hydroxymethyl-3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)pyridine in place of 2-hydroxymethyl-3-methyl-4-(2-morpholinoethylthio)pyridine and 2-mercaptoimidazo[5,4-c]pyridine in place of 2-mercaptobenzimidazole to give 2-((3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)-2-pyridyl)methylthio)imidazo[5,4-c]pyridine as crystals, melting point 215° C. (dec.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)(=[O:3])[CH3:2].ClN1C(=[O:19])CCC1=O>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:19])[CH2:9]2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1cccc2cc[nH]c12
Solvent: ClCCl
Product: CC(=O)c1cccc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 12.57 g. (79 mmoles) of 7-acetylindole in 187 ml. of methylene chloride was added 11.07 g. (82.9 mmoles) of N-chlorosuccinimide and the reaction allowed to stir at room temperature for 2 hours. The solvent was removed in vacuo and the residue treated with 155 ml. of acetic acid and heated to 80° C. Phosphoric acid (80 ml.) was added and the reaction mixture heated to reflux for 9 hours. The mixture was cooled, the acetic acid removed under vacuum and the residue poured into 500 ml. of ice and water. The product was extracted with methylene chloride, 11.91 g. (65% yield), 174°-175° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].C(N(CC)CC)C.[CH:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)(Cl)Cl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(Cl)C1CCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCC1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A solution of 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) in chloroform (100 mL) was cooled with an acetone/ice bath. Cyclopentanecarbonyl chloride (0.47 mL, 3.9 mmol) was slowly added. The reaction was complete within 10 minutes. The reaction mixture was washed with water (1×100 mL) and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was slurried with acetonitrile. The resulting solid was isolated by filtration and dried in an oven overnight to provide 1.01 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclopentanecarboxamide as a light brown solid, m.p. 178.6-179.5° C. Analysis: Calculated for C22H29N5O.0.25 H2O: % C, 68.81; % H, 7.74; % N, 18.24. Found: % C, 68.77; % H, 7.87; % N, 18.19.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[O:14][N:13]=[CH:12][CH:11]=1.[Na]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([CH2:11][C:12]#[N:13])=[O:14]
Reactant: Fc1cc(-c2ccno2)c(Cl)cc1Cl
Agent: [Na]
Solvent: CCO
Product: N#CCC(=O)c1cc(F)c(Cl)cc1Cl
Yield: 93.5 %

Procedure:
23.2 g (0.1 mole) of 5-(2,4-dichloro-5-fluoro- phenyl)-isoxazole are added in portions to a solution of 2.3 g (0.1 g atom) of sodium in 100 ml of absolute ethanol in the course of about 30 minutes while cooling with ice and stirring. The mixture is then stirred at room temperature for 1 hour, the alcohol is distilled off in vacuo, the residue is dissolved in about 1 liter of warm water, the solution is extracted twice with methylene chloride, the aqueous phase is acidified to pH=4 with 10 per cent strength hydrochloric acid (~38 ml) and the precipitate is filtered off cold with suction and dried in vacuo at 50° C. 21.7 g (93%) of 2,4-dichloro5-fluoro-benzoylacetonitrile of melting point 98°-99° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:27][CH2:28][CH3:29])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl[CH2:31][O:32][CH2:33][CH3:34].C1C=CC=CC=1>CCCCCC>[CH2:33]([O:32][CH2:31][N:3]1[C:4]([CH2:27][CH2:28][CH3:29])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]1[CH3:1])[CH3:34]
Reactant: CCOCCl
Reactant: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(C)N1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCC1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(C)N1COCC

Procedure:
By following the same procedure as in Example 25 except that 0.5 g. of diethyl 2-methyl-6-propyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.5 g. of chloromethoxyethane were used as the starting materials, benzene was used as the eluant, and hexane was used as the solvent for recrystallization, 0.35 g. of colorless acicular crystals of diethyl 1-ethoxymethyl-2-methyl-4-(3-nitrophenyl)-6-propyl-1,4-dihydropyridine-3,5-dicarboxylate melting at 97° C. were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=1
Reactant: CCOC(=O)COc1cccc(CCCn2cc(-c3ccccc3Br)ccc2=O)c1
Reactant: COc1ccccc1B(O)O
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+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1cccc(CCCn2cc(-c3ccccc3-c3ccccc3OC)ccc2=O)c1
Temperature: 98 °C
Reaction time: 30 h
Yield: 30.2 %

Procedure:
A mixture of ethyl (3-{3-[5-(2-bromophenyl)-2-oxopyridin-1(2H)-yl]propyl}phenoxy)acetate (235 mg), (2-methoxyphenyl)boronic acid (114 mg), Na2CO3(159 mg), Pd(PPh3)4 (29 mg) in toluene (8 mL) and water (4 mL) was stirred under N2 gas atmosphere at 98° C. for 30 hours and cooled to ambient temperature. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The aqueous layer of the reaction mixture was acidified with 1M HCl aqueous solution and extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The filtrate and the residue of the first extract was combined and evaporated in vacuo. The residue was dissolved in EtOH (20 mL). To the solution was added concentrated H2SO4 (1.5 mL) at ambient temperature and refluxed for 1 hour. The reaction mixture was cooled to ambient temperature, neutralized with saturated NaHCO3 aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=60:40) to afford ethyl (3-{3-[5-(2′-methoxybiphenyl-2-yl)-2-oxopyridin-1(2H)-yl]propyl}phenoxy)acetate (75 mg) as a colorless oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].[Cl:19][C:20]1[C:25](Cl)=[N:24][CH:23]=[CH:22][N:21]=1.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:25]2[C:20]([Cl:19])=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2s1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2s1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
In 250 mL round bottom flask were charged benzo[d]thiazol-2-yl(4-hydroxyphenyl)methanone (6.0 g, 23.5 mmol), 2,3-dichloro-pyrazine (3.48 g, 23.5 mmol), DMSO (60 mL), and cesium carbonate (15 g, 47 mmol). The reaction mixture was stirred at 90° C. for 6 h. The reaction mixture was diluted with cold water and the precipitate was collected by filtration. The crude product was purified by silica gel column chromatography with hexane and ethyl acetate to give the title compound. [M+H]=368.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCCCC)CCC.[Cu]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([NH:1][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: CC(=O)c1ccc(Cl)cc1N
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOCCCC
Product: CC(=O)c1ccc(Cl)cc1Nc1ccccc1
Temperature: 142.5 °C
Yield: 67.5 %

Procedure:
A 3-necked round-bottomed flask equipped with a mechanic stirrer, a thermocouple probe, a reflux condenser and a nitrogen bubbler was charged with 1-(2-amino-4-chlorophenyl)ethanone (81 g, 478 mmol) in di-n-butyl ether (1 L). The reaction was then treated with pulverized potassium carbonate (200 g, 1.45 mol) and copper powder (5 g, 78 mmol). The reaction mixture was refluxed at 140-145° C. for 3 h. At this time, additional potassium carbonate (100 g, 0.72 mol), iodobenzene (100 g, 0.49 mol) and copper powder (2 g, 31 mmol) was added. The resulting mixture was refluxed overnight. At this time, the reaction was cooled to 25° C., filtered and washed with methyl tert-butyl ether. The filtrate was concentrated in vacuo. Flash chromatography (4″×16″ silica gel column; 0-2% ethyl acetate/hexanes) followed by concentration of the appropriate fractions, slurrying with hexanes, filtration and drying afforded 1-(4-chloro-2-phenylamino-phenyl)-ethanone (79.3 g, 67.6%) as a yellow solid. This material was used without further purification.
Reaction SMILES: C([O:8][N:9]1[C:18]2[C:13](=[CH:14][C:15]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=2)[N:12]=[C:11]([NH:35][NH:36][C:37](=[O:47])[CH2:38][P:39]([O:44][CH2:45][CH3:46])([O:41][CH2:42][CH3:43])=[O:40])[C:10]1=[O:48])C1C=CC=CC=1>[Pd].C(O)C>[CH2:45]([O:44][P:39]([CH2:38][C:37]([NH:36][NH:35][C:11]1[C:10](=[O:48])[N:9]([OH:8])[C:18]2[C:13]([N:12]=1)=[CH:14][C:15]([N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=2)=[O:47])([O:41][CH2:42][CH3:43])=[O:40])[CH3:46]
Reactant: CCOP(=O)(CC(=O)NNc1nc2cc(-n3cc(C)nc3-c3ccccc3)c(C(F)(F)F)cc2n(OCc2ccccc2)c1=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(CC(=O)NNc1nc2cc(-n3cc(C)nc3-c3ccccc3)c(C(F)(F)F)cc2n(O)c1=O)OCC
Reaction time: 9 h
Yield: 97.7 %

Procedure:
A suspension of 1-benzyloxy-3-[2-[(diethoxyphosphoryl)acetyl]hydrazino]-6-(4-methyl-2-phenyl-1H-imidazol-1-yl)-7-trifluoromethylquinoxalin-2(1H)-one (1.8 g, 2.6 mmol) and 50 mg of 5% palladium on carbon in 50 ml of ethanol was hydrogenated at room temperature and atmospheric pressure for 9 h. The catalyst was removed by filtration, the filtrate evaporated to dryness in vacuo and the residue finally triturated with ether to give 1.51 g (97%) of the title compound. M.p.>177° C. decomp. 1H-NMR (DMSO-d6): δ 1.10-1.22 (m, 6H), 2.23 (s, 3H), 2.98 (d, 2H), 4.00 (quint., 4H), 7.12 (s, 1H), 7.18-7.30 (m, 5H), 7.31 (s, 1H), 7.92 (s, 1H), 10.24 (s, 2H), 12.52 (br. s, 1H).