Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3]P(=O)(OC)OC.[H-].[Na+].[CH3:17][O:18][C:19](=[O:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[C:30](=[O:31])[CH2:29][CH:28]([O:32][C:33](=[O:35])[CH3:34])[CH:27]1[CH:36]=O>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[C:30](=[O:31])[CH2:29][CH:28]([O:32][C:33](=[O:35])[CH3:34])[CH:27]1[CH:36]=[CH:3][C:2](=[O:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCCC1C(=O)CC(OC(C)=O)C1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)C=CC1C(OC(C)=O)CC(=O)C1CCCCCCC(=O)OC

Procedure:
70 Mg. of dimethyl 2-oxoheptylphosphonate in 2 ml. of tetrahydrofuran is added to 12 mg. of 48% sodium hydride in 1 ml. of tetrahydrofuran, and the mixture stirred at 0°C. under nitrogen for 30 minutes. 70 Mg. of 3-acetoxy-2-formyl-5-oxocyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene ketal in 2 ml. of tetrahydrofuran is then added dropwise and the mixture allowed to warm to 20°-25°C. After 3 hours the mixture is chilled, added to cold saturated aqueous NaH2PO4, extracted with ethyl acetate, and the latter extract dried over Na2SO4 and concentrated to dryness. The residue is purified by silica gel chromatography (7.8 g. silica gel), eluting with 7% acetone in chloroform to give 3-acetoxy-2-(3-oxo-1-octenyl)-5-oxocyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal: ir (CHCl3) 5.78, 5.9, 6.0, 6.17, 8.00, 10.55 μ; U.V. λmaxCH3OH 228 mμ (Em 10,050).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[CH3:27][C:28]1[N:33]=[C:32]2[NH:34][CH:35]=[C:36]([CH:37]=O)[C:31]2=[CH:30][CH:29]=1>CO.N1CCCCC1>[Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9]/[C:8](=[CH:37]\[C:36]3[C:31]4[C:32](=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=4)[NH:34][CH:35]=3)/[C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: Cc1ccc2c(C=O)c[nH]c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1ccc2c(/C=C3\Oc4c(cc(Cl)c(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.012 g, 0.031 mmol) obtained in Example A12, Step 2 in methanol (2.0 mL) was added with 6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.005 g, 0.028 mmol) obtained in Example A48, Step 4. Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 50° C. for 3 hours. The solvent was evaporated under reduced pressure, and then the residue was suspended in diethyl ether and thereby washed to obtain tert-butyl (Z)-4-({5-chloro-6-hydroxy-2-[(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.010 g, 68%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: Oc1ccc(F)cc1
Solvent: Cc1ccccc1C
Product: Fc1ccc(Oc2ccnc3cc(Cl)ccc23)cc1
Yield: 615.9 %

Procedure:
To a 50 mL flask equipped with a condenser, drying tube and thermometer, was added 1.98 g (0.01 moles) of 4,7-dichloroquinoline, 1.07 g (0.0015 moles) of polyDMAP™and 20 mL of xylene. The mixture was stirred to reswell the polymer and 1.57 g (0.0014 moles) of 4-fluorophenol were added. The reaction mixure was heated to reflux and maintained at that temperature for 18 hr. The reaction mixture was filtered hot to remove the polymer. After cooling, the filtrate was washed with 50 mL of 5N NaOH. The caustic layer was extracted with 2×25 mL of diethyl ether. The xylene and the ether layers were combined and dried over Na2SO4. Removal of the solvent provided 2.36 g (86 percent yield) of product, mp=89°-91° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)cc(N)c1C
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-methylbenzoate (1 g, 5.02 mmol) and tetrahydropyran-4-one (2.5 g, 25 mmol) in methanol (10 mL), acetic acid (0.3 g, 5.02 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.63 g, 10.05 mmol) was added and reaction stirred overnight. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (0.5 g, 35.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].CN(CCN(CCN(C)C)C)C.[Li]CCCC.[Br:28][C:29]1[N:30]=[C:31]([CH:53]=[O:54])[N:32]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=1>C1COCC1>[Br:28][C:29]1[N:30]=[C:31]([CH:53]([C:4]2[CH:5]=[C:6]([CH2:8][CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=2[F:10])[OH:54])[N:32]([C:34]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:33]=1
Reactant: CCc1ccc(F)c(Cl)c1
Reactant: O=Cc1nc(Br)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(Cl)c(F)c(C(O)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: -40 °C
Yield: 85857.7 %

Procedure:
To a solution of Intermediate 221.1 (100 mg, 0.631 mmol) and PMDTA (0.15 mL) in 5 mL THF at −70° C., was added BuLi (1.4 M in hexanes, 0.473 mL, 0.662 mmol). The mixture was stirred with warming to −40° C. over 30 min, recooled to −70° C., then a solution of Intermediate 175.1 (263 mg, 0.631 mmol) in 2 mL THF was added. The mixture was slowly warmed to −20° C. over 1 h. The reaction was quenched with sat. NH4Cl, then was diluted with EtOAc. The organic phase was washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 312 g of Intermediate 221.2 as a colorless solid. LCMS (50 to 100% B, 4 min gradient, A=95% H2O/5% CH3CN/0.1% TFA, B=5% H2O/95% CH3CN/0.1% TFA) RT=5.45 min, 575.28 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1.[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].CCN(CC)CC>CC(N(C)C)=O>[C:29]([O:28][C:27]([NH:26][C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1)=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COC(=O)c1c(C)nc(Cl)nc1-c1cnn(C)c1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Temperature: 90 °C
Yield: 44.9 %

Procedure:
To a mixture of methyl 2-chloro-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (0.227 g, 0.851 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (0.182 g, 0.851 mmol) in DMA (3 mL) was added Et3N (0.356 mL, 2.55 mmol). The reaction mixture was heated at 90° C. for 4 h. The reaction mixture was cooled to RT and poured onto ice. The solid was filtered and dried under high vacuum to yield the title compound as an off-white foam (170 mg). [M+H] calc'd for C22H32N6O4, 445; found, 445.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:4]=1)#[N:2].[CH2:19]([NH2:22])[CH2:20][CH3:21]>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:22][CH2:19][CH2:20][CH3:21])=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: Cc1ccc(-c2nc(C#N)c(C#N)nc2Cl)cc1
Reactant: CCCN
Product: CCCNc1nc(C#N)c(C#N)nc1-c1ccc(C)cc1
Yield: 74 %

Procedure:
2,3-Dicyano-5-chloro-6-p-tolylpyrazine (1.00 g; 0.0039 mole) and 0.46 g (0.0078 mole) of n-propylamine were worked up in the same way as in Example 13, and then recrystallized from toluene to afford 0.80 g (yield 74%) of 2,3-dicyano-5-n-propylamino-6-p-tolylpyrazine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][N:21]=[CH:20]3)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1CN(Cc2ccccc2)CCC1Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.6 %

Procedure:
1-Benzyl-3-methyl-4-piperidone (152.7 mg), 5-aminoindazole (100 mg), and acetic acid (0.02 ml) were dissolved in methanol (10 ml). Acetic acid (five drops) was added to the solution, and a borane-pyridine complex (0.06 ml) was then added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. After the completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution (1 ml) was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine and was dried over sodium sulfate. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography [silica gel, chloroform/methanol] to give the title compound (95.3 mg, yield 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[CH2:11]([Li])[CH2:12][CH2:13]C.CC(C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:12]([CH3:13])[CH3:11]
Reactant: [Li]CCCC
Reactant: COc1cccc(OC)c1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1cccc(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 1,3-dimethoxybenzene (33 ml) was dissolved in THF (1l). The solution was cooled in an ice bath then n-butyl lithium (200 ml) was added in a dropwise fashion in over a 45 minute period. The resultant mixture was stirred for 2 hours at a temperature of 10° C. The solution was then cooled to 0° C. and acetone (21 ml) was added in a dropwise fashion. Solution was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate and the solvent removed. The residue was dissolved in a mixture of ethyl acetate (50 ml) and sulfuric acid (1 ml). The acidic mixture was subjected to a positive hydrogen pressure (30 psi) over a catalytic amount of 5% palladium-on-carbon in a Parr shaker at room temperature for 30 minutes. The solution was filtered and water added. The organic layer was purified by HPLC (eluted with a gradient of 0 to 5% hexane in ethyl acetate) to yield 6.3 g of 1,3-dimethoxy-2-(iso-propyl)benzene. This latter substituted benzene product was refluxed for 3 days in a mixture of 48% hydrobromic acid in water and acetic acid (300 ml to 500 ml). Ether and brine were added to the reaction mixture. The ether layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was chromatographed by HPLC (column eluted with a gradient of 5 to 15% ethyl acetate in hexane). The chromatography yielded 1.82 g of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:20]([F:28])[CH:21]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Brc1cccc2[nH]ncc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Fc1cc(-n2ncc3c(Br)cccc32)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 60.3 %

Procedure:
To a solution of 4-bromo-1H-indazole (4.32 g, 21.9 mmol) in dichloromethane (100 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (10.8 g, 43.9 mmol), pyridine (3.5 mL, 43.3 mmol), copper acetate (5.9 g, 32.6 mmol) and powdered 4A molecular sieves (5 g). The reaction mixture was stirred at room temperature in the presence of air for 5 days. Celite was added to the reaction mixture and the mixture stirred for 5 minutes. The mixture was then filtered through a pad of celite and washed with dichloromethane and then the filtrate concentrated in vacuo. The residue was diluted in dichloromethane and water. After separation of the layers, the aqueous phase was extracted with dichloromethane (×4). The combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The product was purified by silica gel chromatography eluting with 10-80% dichloromethane in hexane to yield the title compound (D38) (5.25 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:10]([O-:19])(=[O:18])C1C(=CC=CC=1)O.[Ag+:20]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O-:19])=[O:18])[C:4]=2[N:3]=[N:2]1.[Ag+:20]
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C([O-])c1ccccc1O
Agent: [Ag+]
Product: O=C([O-])c1cccc2[nH]nnc12

Procedure:
45 mL of a 20% aqueous solution of benzotriazole with a pH of about 6.5 were added with stirring to the aqueous dispersion of silver salicylate. A fine dispersion of silver benzotriazolate was obtained. The size of the silver benzotriazolate particles was ascertained by optical microscopy to be 1 to 2 μm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:27][C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCN(c2ccccc2F)CC1
Product: CN(C)C(=O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].O>C(O)(=O)C>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(-c2ccc(O)cc2)cc1)c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=C(Oc1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To an argon-flushed flask containing a suspension 0.486 g (1.68 mmol) of 4'-hydroxy-4-biphenylyl benzoate in 10 ml of acetic acid at 10°-15° C., 0.345 ml of HNO3 (d: 1.41) was added dropwise (about a drop per min). Then the reaction mixture was vigorously stirred at the same temperature for 30 min. Water (40 ml ) was added and the mixture was again stirred for 30 min. The yellow precipitate was filtered, washed several times with water, dried and purified by flash chromatography on silica gel using dichloromethane/hexanes [65/35] as eluent to give 4'-hydroxy-3'-nitro-4-biphenylyl benzoate (compound 15, Scheme II) as a yellow solid (0:539 g, 96%). This material was recrystallized from ethanol to give product of mp. 163° C.; Rf [hexanes/dichloromethane 40/60]: 0.42; 1H NMR (300 MHz, CDCl3): δ7.25(d, 1H, J=8.7 Hz), 7.33(d, 2H, J=8.7 Hz), 7.50-7.70(m, 5H), 7.84(dd, 1H, J=2.7 Hz, J=8.7 Hz), 8.23 (d, 2H, J=7.2 Hz), 8.32(d, 1H, J=2.7 Hz), 10.60(s, 1H); 13C NMR (300 MHz, CDCl3): δ120.54, 122.45, 122.81, 127.85, 128.65, 129.33, 130.23, 133.04, 133.78 136.04, 136.22, 150.91, 154.44, 165.15; IR (CHCL3): 3250(broad), 3020, 1740, 1620, 1540, 1510, 1490, 1325, 1270, 1225, 1220, 1170, 1080, 1065, 1025, 1000, 850 cm-1 ; Mass spectrum, m/z(rel.intensity): 335(M+ 7), 105(100), 77(16).
Reaction SMILES: Cl[C:2]1[C:3]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.[S].N1C2SC3CCCCC=3C=2C=NC=1.P(Cl)(Cl)(Cl)=O.CNC.[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH2:51][NH2:52]>CN1CCCC1=O>[Cl:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH2:51][NH:52][C:2]1[C:3]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)[N:7]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(n2)sc2ccccc23)cc1
Agent: CNC
Agent: [S]
Agent: c1ncc2c3c(sc2n1)CCCC3
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(Cl)c3)c3c(n2)sc2ccccc23)cc1
Yield: 125.5 %

Procedure:
A mixture of 1.5 g of methyl 4-(4-chlorobenzothieno[2, 3-d]pyrimidin-2-yl)phenylcarboxylate (“B”), prepared by dehydrogenation of the corresponding 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine compound with sulfur and subsequent chlorination with phosphorus oxychloride/dimethylamine, and 1.5 g of 3-chloro-4-methoxybenzylamine in 20 ml of N-methylpyrrolidone is heated at 110° for 4 hours. After cooling, the mixture is worked up in the customary manner. 2.6 g of methyl 4-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl]-benzoate, m.p. 203-204°, are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH3:17][O:18][C:19]([CH3:27])([CH3:26])[C:20]#[C:21]/[CH:22]=[CH:23]/[CH2:24]Br.C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[CH2:24]/[CH:23]=[CH:22]/[C:21]#[C:20][C:19]([O:18][CH3:17])([CH3:27])[CH3:26])[CH3:2]
Reactant: COC(C)(C)C#C/C=C/CBr
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C/C=C/C#CC(C)(C)OC)P(=O)(OCC)OCC
Reaction time: 5 h
Yield: 55.8 %

Procedure:
3.36 g of diethylphosphonoacetic acid ethyl ester is dissolved in 40 ml of ethanol, 0.60 g of 60% oily sodium hydride is added under ice cooling and stirring, 1.09 g of (E)-6-methoxy-6-methyl-2-hepten-4-ynyl bromide is added dropwise, and the mixture is stirred under ice cooling for 1 hour and then at room temperature for 5 hours. 15 ml of acetic acid is added to the reaction solution, the solvent is distilled off under reduced pressure, and the residue is extracted with a system of water and ethyl acetate. The organic layer is post-treated in a conventional manner, and the product is purified by silica gel column chromatography [Wako gel C-200, 100 g; hexane/ethyl acetate=1/2] and medium pressure liquid chromatography [Lobar column, size B, Lichroprep Si 60F (produced by Merck Co.); hexane/ethyl acetate=1/1→1/2] to obtain 1.01 g of (E)-diethylphosphono(6-methoxy-6-methyl-2-hepten-4-ynyl)acetic acid ethyl ester as colorless oil.
Reaction SMILES: I([O-])(=O)=O.[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=1.[I:17]I.S(=O)(=O)(O)O>O>[I:17][C:11]1[CH:12]=[C:7]([Cl:6])[CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[C:10]=1[CH3:13]
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+2]([O-])[O-]
Solvent: O
Product: Cc1c(I)cc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Sodium iodate (158 g, 0.800 mol, 0.4 eq.) was added portionwise, under nitrogen atmosphere, to an ice-cooled mixture of 4-chloro-2-nitrotoluene (343 g, 2.00 mol), iodine (204 g, 0.800 mol, 0.4 eq.) and conc. sulfuric acid (1960 g, 20.0 mol, 10 eq.) and the resulting mixture was stirred at a temperature of 5° C. to 10° C. for 6 hours. Water (2 L) was added dropwise thereto with stirring in an ice-water bath, and the mixture was extracted with toluene (2.5 L). The combined organic layer was treated with aqueous 10% sodium thiosulfate solution, washed with water (1 L×2) and aqueous sat. sodium hydrogencarbonate solution (1 L×2) successively, dried over sodium sulfate and concentrated to give crude A-1 (548 g, purity 62%) as a yellow oil. This product was used in the following reaction without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[C:15]([CH3:35])[N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:39][Mg]Br>O1CCCC1>[OH:3][C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[C:15]([CH3:35])[N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)([CH3:39])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Solvent: C1CCOC1
Product: Cc1nc(C(N)=O)c2[nH]c3cc(C(C)(C)O)ccc3c2c1-c1cccc(-n2cnc3ccccc3c2=O)c1C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 7-acetyl-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (51 mg, 0.102 mmol) in tetrahydrofuran (10.0 mL) at 0° C. was added methylmagnesium bromide (3 M in diethyl ether, 0.169 mL, 0.508 mmol). The mixture was stirred for 30 min. HPLC analysis indicated that there was still a significant amount of starting material remaining. Additional methylmagnesium bromide (0.10 mL) was added, and the reaction mixture was stirred for an additional 30 min. at 0° C. The reaction was slowly quenched with water and extracted with ethyl acetate (3×). The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a mixture ethyl acetate and hexane (50%-62%-75%-88%-100%) and reverse phase preparative HPLC afforded 7-(2-hydroxypropan-2-yl)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (24% yield) as an off-white solid and as a mixture of atropisomers. LC/MS M+1=518.2. 1H NMR (500 MHz, MeOD) δ 8.42-8.38 (m, 1H), 8.33 (dt, J=8.0, 1.7 Hz, 1H), 7.93-7.87 (m, 1H), 7.83-7.77 (m, 2H), 7.70-7.59 (m, 3H), 7.53-7.44 (m, 1H), 7.25-7.15 (m, 1H), 7.06 (d, J=8.6 Hz, 0.6H), 6.81 (d, J=8.3 Hz, 0.4H), 2.51-2.46 (m, 3H), 1.81-1.78 (m, 3H), and 1.62-1.56 (m, 6H).