Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1N=C2C=C(OCC3SC=C(C(C)C)N=3)C=CN2C(=O)C=1/C=C/C(OC(C)(C)C)=O.[CH:32]1([C:36]2[N:37]=[C:38]([NH:41][C:42]([C:44]3[CH:72]=[CH:71][N:47]4[C:48](=[O:70])[C:49](/[CH:61]=[CH:62]/[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=[C:50]([N:52]5[CH2:57][CH2:56][CH2:55][CH:54]([O:58]C=O)[CH2:53]5)[N:51]=[C:46]4[CH:45]=3)=[O:43])[S:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1>>[CH:32]1([C:36]2[N:37]=[C:38]([NH:41][C:42]([C:44]3[CH:72]=[CH:71][N:47]4[C:48](=[O:70])[C:49](/[CH:61]=[CH:62]/[C:63]([O:65][C:66]([CH3:67])([CH3:68])[CH3:69])=[O:64])=[C:50]([N:52]5[CH2:57][CH2:56][CH2:55][CH:54]([OH:58])[CH2:53]5)[N:51]=[C:46]4[CH:45]=3)=[O:43])[S:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(OC=O)C2)nc2cc(C(=O)Nc3nc(C4CCC4)cs3)ccn2c1=O
Agent: CC(C)c1csc(COc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(O)nc3c2)n1
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(O)C2)nc2cc(C(=O)Nc3nc(C4CCC4)cs3)ccn2c1=O

Procedure:
Reactions were performed in the same manner as in Example 1, (K) by using tert-butyl (E)-3-[8-{[(4-cyclobutyl-1,3-thiazol-2-yl)amino]carbonyl}-2-(3-formyloxy-piperidino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-2-propenoate (35 mg, 0.060 mmol), and the resulting crude crystals were purified by thin layer silica gel chromatography (chloroform:methanol=40:1) to obtain 16 mg (40% for the two steps) of the title compound as yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([CH2:10][CH3:11])[N:3]=1.[CH:12]1([CH2:17][NH:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH2:17][N:18]([CH2:19][CH3:20])[C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([CH2:10][CH3:11])[N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCNCC1CCCC1
Reactant: CCc1ccc(C#N)c(Cl)n1
Product: CCc1ccc(C#N)c(N(CC)CC2CCCC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
2-Chloro-6-ethylpyridine-3-carbonitrile (500 mg, 3.00 mmol) synthesized by the method described in International Patent Publication WO1997/19078 and N-(cyclopentylmethyl)-N-ethylamine (1.50 g, 11.8 mmol) were mixed, and the mixture was stirred at 100° C. for 8 hours in an argon atmosphere. The mixture was further added with N-(cyclopentylmethyl)-N-ethylamine (0.19 g, 1.49 mmol), and stirred at 100° C. for 8 hours, and then the reaction mixture was azeotroped with toluene. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to obtain 2-[(cyclopentylmethyl)(ethyl)amino]-6-ethylpyridine-3-carbonitrile (484 mg, 63%) as pale yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>>[F:26][C:27]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:30]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)c1cccc(F)c1F
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(F)c4F)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2,3-difluorobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12](=O)[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].Cl>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:10]2[N:34]([C:31]3[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:33][CH:32]=3)[N:35]=[C:12]([CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=3)[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=CC(=O)C=Cc2ccc(OC)c(O)c2)cc1O
Reactant: NNc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C=CC2=NN(c3ccc([N+](=O)[O-])cc3)C(c3ccc(OC)c(O)c3)C2)cc1O
Yield: 97.4 %

Procedure:
To a stirred mixture of 1,5-bis(3-hydroxy-4-methoxyphenyl)-1,4-pentadien-3-one (29.6 g, 90.8 mmol), absolute ethanol (220 mL), and 4-nitrophenylhydrazine (16.8 g, 100 mmol for 90 percent purity, 10 percent water) was added conc. HCl (20 mL), and the mixture was stirred and heated at reflux for 24 hours. The mixture was then stirred at room temperature for 16 hours, and the orange crystals that formed were removed by filtration. The product was washed with ethanol and hexane, and dried in a vacuum oven at 90°-100° C. for 12 hours. The product was obtained as orange-red microcrystals (37.2 g, 97.4 percent yield) mp 215°-217° C.; 1H NMR (DMSO-d6) δ9.09 (s, 2H), 8.05 (d, 2H, J=9.5 Hz), 7.06-6.61 (m, 10H), 5.52 (dd, 1H, J1=11.6 Hz, J2= 4.1 Hz,), 3.80 (s, 3H), 3.76 (m, 1H), 3.73 (s, 3H), and 3.07 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](Cl)=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[CH3:28][NH:29][C@H:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH:31]1C.C(N(CC)CC)C.Cl>ClCCl>[C@H:30]1([N:29]([CH3:28])[C:21]([C:19]2[N:20]=[C:16]([CH:13]3[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH2:7][N:6]4[C:2]([CH3:1])=[CH:3][C:4]([C:24]([F:27])([F:26])[F:25])=[N:5]4)[CH2:11][CH2:12]3)[S:17][CH:18]=2)=[O:22])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1
Reactant: CN[C@H]1c2ccccc2CC1C
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
2-[1-[[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (210 mg, 0.5 mmol) (i.e. the product of Example 19, Step D) was treated with a solution of (1R)-2,3-dihydro-N,2-dimethyl-1H-inden-1-amine (147 μL, 1.0 mmol) and triethylamine (139 μL, 1.0 mmol) in 5 mL of dichloromethane. The reaction mixture was stirred at room temperature for 2 h, passed through a Varian 1005 Chem Elut™ column pretreated with 3 mL of 1 N aqueous hydrochloric acid. The column was flushed with three column volumes of dichloromethane. The collected dichloromethane solution was evaporated in vacuo and purified by medium-pressure liquid chromatography on silica gel using 50-100% of ethyl acetate in 1-chlorobutane as eluant to give 214 mg of the title compound, the product of present invention as a white foam.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CCOC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Temperature: 105 °C
Yield: 53 %

Procedure:
Ethyl 4-chlorobutyrate (0.154 ml, 1.1 mmol) was added to a mixture of 4-(4chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (319.5 mg, 1 mmol), (prepared as described for the starting material in Example 2), and anhydrous potassium carbonate (690 mg, 5 mmol) in DMF (10 ml). The mixture was stirred and heated at 105° C. for 4 hours then allowed to cool. The mixture was diluted with methylene chloride and the insolubles were removed by filtration. The solvent was removed from the filtrate by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(3-ethoxycarbonylpropoxy)-6-methoxyquinazoline (230 mg, 53%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[N:23]=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[N:23]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: COc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Reaction time: 4 h
Yield: 80 %

Procedure:
To 3-iodo-4-nitro-1H-indazole (5.01 g, 17.3 mmol) in DMF (40 mL) was added K2CO3 (4.79 g, 34.7 mmol) and 2-(bromomethyl)-6-methoxypyridine (4.20 g, 20.8 mmol). The reaction mixture was stirred for 4 hours. The reaction mixture was concentrated to remove DMF, diluted with EtOAc and washed with H2O and brine. The organic phase was dried (Na2SO4) and concentrated. Silica gel chromatography (EtOAc/Hexane 1:5) gave the desired product (5.68 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:23])[CH3:24]
Reactant: Ic1ccccc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)cc3)ccc2[nH]1
Product: CC(C)Oc1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccccc2)cc1

Procedure:
The title compound was prepared in accordance with Example 10 using 5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester and iodobenzene.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:11]2[C:16]([CH3:17])=[CH:15][S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:11]3[C:16]([CH3:17])=[CH:15][S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c12
Reactant: Cc1ncc[nH]1
Product: Cc1csc2nc(-n3ccnc3C)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16]COC(C)=O.C(=O)(O)[O-].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:16])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Bromopicolinic acid (411 mg, 2.03 mmol) was slurried in anhydrous MeOH (6 ml). Concentrated sulfuric acid (0.3 ml) was added and the resulting solution was stirred at room temperature for approximately 3 h. EtOAc was added, followed by a saturated solution of sodium bicarbonate. The phases were separated, and the organic phase was washed with water, dried over MgSO4, and concentrated to dryness. The crude ester (313 mg) was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:20])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[CH3:21][O:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:21][O:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:10](=[O:20])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1
Reactant: Cc1cccc(C=CC(=O)c2c(O)cc(C)oc2=O)c1
Reactant: COCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cc(C)oc(=O)c1C(=O)C=Cc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.81 g of 4-hydroxy-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one, 10 ml of tetrahydrofuran, 0.25 ml of 2-methoxyethanol, and 0.87 g of triphenylphosphine was added dropwise a solution of 0.57 g of diethyl azodicarboxylate in 6 ml of tetrahydrofuran, and this was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 389 mg of 4-(2-methoxyethoxy)-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (2a-24)] as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18]CN=C=NCCCN(C)C.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:18][O:16][C:15](=[O:17])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
[4-(tert-Butoxycarbonyl)phenyl]acetic acid (2.94 g, 12.4 mmol) and DMAP (152 mg, 1.24 mmol) were dissolved in CH2Cl2 (50 mL) and cooled to 0° C. EDCI (3.10 g, 16.2 mmol) and MeOH (660 μL, 16.2 mmol) were added. After stirring for 30 min at 0° C., the reaction was allowed to warm to room temperature and stirred 2 h. The mixture was then diluted with CH2Cl2, washed (sat. NaHCO3, brine), dried (MgSO4), and concentrated. Flash chromatography on silica gel (0-10% EtOAc/hexanes) afforded tert-butyl 4-(2-methoxy-2-oxoethyl)benzoate as a colorless oil. 1H NMR (CDCl3) δ 7.93 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 3.68 (s, 3H), 3.66 (s, 2H), 1.57 (s, 9H). MS (ESI) calcd [M+Na]+ 273.1, found 273.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3C(=O)[C:11](=[O:14])[C:12]([CH:13]=1)=[C:5]23.[OH-:16].[Na+].OO>O>[Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][NH:6][C:5]2=[C:12]([C:11]([OH:14])=[O:16])[CH:13]=1
Reactant: [OH-]
Reactant: O=C1C(=O)N2CCOc3cc(Cl)cc1c32
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Cl)cc2c1NCCO2
Yield: 80.5 %

Procedure:
To a stirred suspension of 8-chloro-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-5,6-dione (4.47 g) in water (50 ml) was added 2N sodium hydroxide solution (30 ml), and the mixture was stirred to a solution. 30% hydrogen peroxide solution (20 ml) was added and stirred for an hour, insoluble material was filtered off and then acidified with concentrated hydrochloric acid. The yellow precipitate was collected by filtration, washed with water and dried to yield 3.44 g (80.5%) of the title compound. The compound was recrystallized from benzene (75 ml) to give pale yellow prisms, mp 209°-210° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:19]([O:21]C)=[O:20].[OH-].[Li+].Cl>CO.O>[CH3:1][C:2]1[N:10]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1c(C)n(C(C)c2ccccc2)c2cccnc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)c2ncccc2n1C(C)c1ccccc1
Yield: 26.4 %

Procedure:
To a solution of methyl 2-methyl-1-(1-phenylethyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (80 mg, 0.27 mmol) in methanol (3 mL) and water (1 mL) was added lithium hydroxide (57 mg, 1.36 mmol). The reaction mixture was stirred with refluxing for 15 hours. The mixture was adjusted pH 3 with 1N aqueous hydrochloric acid. The aqueous phase was extracted with dichloromethane (50 mL×3). The organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 2-methyl-1-(1-phenylethyl)-1H-pyrrolo-[3,2-b]pyridine-3-carboxylic acid (20 mg, 26%). LRMS (M−H+) m/z: calcd 279.12. found 279.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:43]([NH:51][C:52]1[CH:64]=[C:63](Br)[CH:62]=[CH:61][C:53]=1[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:43]([NH:51][C:52]1[CH:64]=[C:63]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:62]=[CH:61][C:53]=1[C:54]([O:56][C:57]([CH3:59])([CH3:60])[CH3:58])=[O:55])(=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
31 mg of 4-nitrophenol was added to 1.0 mL of toluene suspension containing of 8.9 mg of 60% sodium hydride at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 15 minutes. After the reaction mixture was cooled to room temperature, 0.5 mL of toluene solution containing 3.8 mg of 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl, 1.3 mg of palladium acetate and 56 mg of tert-butyl 2-(benzamido)-4-bromobenzoate were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature, 1.3 mg of tri-tert-butylphosphine tetrafluoroborate and 4.1 mg of tris(dibenzylideneacetone)dipalladium(0) were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 4 hours. After the reaction mixture was cooled to room temperature, 10% citric acid aqueous solution and ethyl acetate were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia chemical Ltd., eluent; hexane:ethyl acetate=10:1] to obtain 18 mg of tert-butyl 2-(benzamido)-4-(4-nitrophenoxy)benzoate as white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH3:12])[CH3:2].[Li+].CC([N-]C(C)C)C.C(=O)=O.CC(C)=O.[CH3:31][Si:32](Cl)([CH3:34])[CH3:33]>C1COCC1>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([Si:32]([CH3:34])([CH3:33])[CH3:31])[CH3:12])[CH3:15]
Reactant: C[Si](C)(C)Cl
Reactant: CCc1ccccc1C(=O)N(CC)CC
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCN(CC)C(=O)c1ccccc1C(C)[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a solution of 5.13 g (25 mmol) of N,N,2-triethylbenzamide in THF (50 mL) at -78° C. was added a solution of LDA (Aldrich 2.0M, 15.63 mL, 31.25 mmol). The solution was warmed to -10° C. with ice water over 1 hr, then cooled to -78° C. with dry ice-acetone. TMSCl (6.34 mL, 50 mmol) was added neat at -78° C. and then reaction brought to room temperature after 1 hr. The reaction was quenched with saturated NH4Cl and extracted with ether (2×100 mL), dried over MgSO4, stripped and the residue distilled in a Kugelrohr (130°-140° C., 0.65 mm) to obtain 6.51 g (94%) of N,N-diethyl-2-[1-(trimethylsilyl)ethyl]benzamide.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].C1([C+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[S:36][CH2:35][CH2:34][S:33]2)=[CH:28][CH:27]=1.C(Cl)Cl.CCOCC>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]2[S:33][CH2:34][CH2:35][SH+:36]2)=[CH:30][CH:31]=1
Reactant: Cc1ccc(C2SCCS2)cc1
Agent: F[B-](F)(F)F
Agent: c1ccc([C+](c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C2SCC[SH+]2)cc1
Yield: 14 %

Procedure:
A 3.30 g (0.01 mole) sample of triphenylcarbenium tetrafluoroborate is added to a solution 3.92 g of 2-(4-methylphenyl)-1,3-dithiolane in 35 ml of acetonitrile under nitrogen at 5° C. Methylene chloride is added then ether. The yellow solid is collected and washed with ether. There is obtained 0.7 g (14% yield) of 2-(4-methylphenyl)-1,3-dithiolanium fluoroborate, m.p. 119°-120° C.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:15][C:16]#[CH:17])[C:5](=[O:18])[C:4]=1[CH2:19][C:20](OC)=[O:21])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1.CCOCC>[CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:6]([CH2:15][C:16]#[CH:17])[C:5](=[O:18])[C:4]=1[CH2:19][CH2:20][OH:21])[CH3:2]
Reactant: C#CCn1c(-c2ccccc2)nc(CC)c(CC(=O)OC)c1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCn1c(-c2ccccc2)nc(CC)c(CCO)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 1.35 g (4.4 mmol) of 6-ethyl-5-methoxycarbonylmethyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 105) in 30 mL of THF was cooled in an ice bath and a slurry of 0.10 g (2.6 mmol) of lithium aluminum hydride in 10 mL of ether was added. The ice bath was allowed to melt and the reaction mixture was stirred at room temperature for 3 h. An additional 0.05 g (1.3 mmol) of lithium aluminum hydride was added. The mixture was stirred for 1 h at room temperature. The mixture was poured into 100 mL of water and 100 mL of ether and allowed to stand for 1 h. The layers were separated and the aqueous layer was extracted with 100 mL of ethyl acetate. the combined organic extracts were washed with 50 mL of 5% aqueous NaOH and dried over MgSO4. Removal of the solvent left 1.36 g of crude product as an amber syrup. Flash chromatography on 30 g of silica gel, eluting sequentially with 20, 40, 60, 80 and 100% ethyl acetate in hexanes afforded 6-ethyl-5-(2-hydroxyethyl)-2-phenyl-3-propargyl-4(3H)-pyrimidinone (Compound 274) as an oil. 1H-NMR (CDCl3) 1.2(3H,t), 2.35(1H,t), 2.65(2H,q), 2.90(2H,t), 3.85(2H,t), 4.55(2H,d), 7.5(3H,m), 7.7(2H,m).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[C:8]2[N:10]=[C:11]([CH2:13][CH3:14])[NH:12][C:7]2=[C:6]([CH3:15])[CH:5]=1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[I-].[Na+]>CN(C=O)C>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:10]2[C:8]3=[N:9][C:4]([CH3:3])=[CH:5][C:6]([CH3:15])=[C:7]3[N:12]=[C:11]2[CH2:13][CH3:14])=[CH:30][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 78.6 %

Procedure:
To a suspension of 0.503 g (12.5 mmol) of a 60% oil dispersion of sodium hydride in 20 mL of DMF was added 2.0 g (11.4 mmol) of the product of Step C and the mixture was stirred at room temperature. After 25 minutes, 2.92 g (12.5 mmol) of 4-benzyloxybenzyl chloride and a catalytic amount of sodium iodide were added and the reaction was stirred for an additional 4 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 3.33 g (79%) of the title compound.