Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A modification of the method described in Part E of Example 367 was used to treat 7-benzyloxy-4-chloro-3-nitroquinoline (87.81 g, 279 mmol, Parts A through D of Example 367) with triethylamine (58.3 mL, 419 mmol) and tert-butyl N-(3-aminopropyl)carbamate (58.0 g, 334 mmol). The reaction was stirred overnight at ambient temperature. After filtration, the solid was washed with water and 1:1 cold 2-propanol:water. After the drying step 120.98 g of tert-butyl 3-[(7-benzyloxy-3-nitroquinolin-4-yl)amino]propylcarbamate were obtained.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Reactant: NCCCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C/C(=O)NCCCCCCc2cccnc2)c2cccc(OC)c2)c1
Yield: 76.4 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (3.0 g) and 3-pyridinehexanamine (1.25 g) in tetrahydrofuran (20 mL) was stirred for 1.5 hours at room temperature and was then worked up in the usual manner. The product was purified by HPLC (ethyl acetate) and triturated with ether to give 2.5 g of (E)-5,5-bis(3-methoxyphenyl)-N-[6-(3-pyridinyl)hexyl]-2,4-pentadienamide mp 66°-70° C. Crystallization of a portion from ethyl acetate-hexane afforded of the pure amide, mp 71°-72° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.Cl[CH2:20][CH:21]1[CH2:23][CH2:22]1.[BrH:24].CCOCC>CN(C)C=O.CCOCC>[BrH:24].[CH:21]1([CH2:20][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[N:11]2)[CH2:23][CH2:22]1
Reactant: ClCC1CC1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CCC(c2nn(CC3CC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a stirred mixture of 1.19 g of sodium hydride (50% oil dispersion) in 65 ml of dimethylformamide was added, dropwise, 4.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 20 ml of hot dimethylformamide. The mixture was stirred for 1 hr at ambient temperature and then 1.40 g of chloromethylcyclopropane in 10 ml of dimethylformamide was added dropwise. The reaction mixture was stirred for 21/2 days at ambient temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was dissolved in ether and saturated hydrogen bromide/ether solution was added dropwise to precipitate a salt. The salt was recrystallized from toluene and ethyl acetate to yield 2.8 g (32%) of product, mp 177°-179° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].Br[CH2:21][C:22]1[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=1.[H-].[Na+].C(O)(=O)C>C1COCC1>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH2:21][C:22]2[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Reactant: CCOC(=O)c1cnc(CBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Temperature: 55 °C
Yield: 33.7 %

Procedure:
To a mixture of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (6.0 g, 0.018 mol) and ethyl 5-(bromomethyl)pyrazine-2-carboxylate (4.9 g, 0.02 mol) in THF (50.0 mL) was added NaH (0.5 g) and heated at 55° C. under argon atmosphere for 3 h. The reaction mixture was cooled added acetic acid (1.2 ml) and concentrated under reduced pressure. The residue was triturated with water and filtered the solid. It was washed with water, followed by ethanol and dried in vacuo to afford the title compound (3.0 g, 78%)as alight brown powder: 1H NMR (CD3OD/400 MHz) δ9.10 (d. 1H, J=1.2 Hz), 8.77 (d, 1H, J=1.2 Hz), 7.61 (m, 1H), 7.01 (m 2H), 6.54 (s, 1H), 5.54 (s, 2H), 5.30 (s, 2H), 4.43 (q, 2H, J=6.8 Hz), 2.52 (s, 3H), and 1.39 (t, 3H, J=6.8 Hz); 19F NMR (CD3OD/400 MHz) δ−111.64 (m), and −116.04 (m); ES-HRMS m/z 494.0482 (M+H C21H19N3O4BrF2 requires 494.0522).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]([C:11]([OH:13])=[O:12])=[C:4]([CH3:14])[N:3]=1.N1C=C(C(O)=O)C=C(C(O)=O)[CH:16]=1>>[CH3:16][O:12][C:11]([C:5]1[C:4]([CH3:14])=[N:3][C:2]([CH3:1])=[C:7]([CH:6]=1)[C:8]([OH:10])=[O:9])=[O:13]
Reactant: Cc1nc(C)c(C(=O)O)cc1C(=O)O
Reactant: O=C(O)c1cncc(C(=O)O)c1
Product: COC(=O)c1cc(C(=O)O)c(C)nc1C

Procedure:
5-(methoxycarbonyl)-2,6-dimethylnicotinic acid was synthesized from 2,6-dimethylpyridine-3,5-dicarboxylic acid following the general procedure as described for the pyridine-3,5-dicarboxylic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.[NH:54]1[C:62]2[C:57](=[CH:58][C:59](O)=[CH:60][CH:61]=2)[CH:56]=[N:55]1>O1CCCC1>[NH:54]1[C:62]2[C:57](=[CH:58][C:59]([O:1][CH:2]3[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]3)=[CH:60][CH:61]=2)[CH:56]=[N:55]1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(Oc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
Ethyl 4-hydroxycyclohexylcarboxylate (1.44 ml, 8.95 mmol), triphenylphosphine (2.15 g, 8.20 mmol) and dibenzyl azodicarboxylate (3.34 g, 11.18 mmol) were added at 0° C. to a solution of the 1H-indazol-5-ol (1.0 g, 7.45 mmol) obtained in Reference Example 4 in tetrahydrofuran (40 ml). After 1 hour, the mixture thus obtained was warmed up to room temperature. After stirring overnight, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate, hexane/ethyl acetate) to obtain ethyl 4-(1H-indazol-5-yloxy)cyclohexanecarboxylate (928 mg, 43%).
Reaction SMILES: Cl[C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:4]=2[N:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:4]=2[N:3]=1
Reactant: CN(C)CCN
Reactant: COc1ccc2c3c(c(Cl)nc2c1)C(=O)c1ccncc1-3
Product: COc1ccc2c3c(c(NCCN(C)C)nc2c1)C(=O)c1ccncc1-3
Temperature: 55 °C
Reaction time: 4 h

Procedure:
6-Chloro-3-methoxy-5,10-diaza-benzo[c]fluoren-7-one (Example 1c-1) (120 mg) was suspended in N,N-dimethylethylenediamine (50 ml) and the mixture was stirred at 55° C. for four hours under Ar. N,N-dimethylethylenediamine was evaporated and the residue was dissolved in dichloromethane. The solution was washed with water and dried over anhydrous sodium sulfate. Dichloromethane was evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol-ammonia water (28%)=400:20:1 and dichloromethane-methanol-ammonia water (25%)=300:20:1. The desired product was obtained as a reddish powder. ESI−MS: m/z 349 (MH+); 1H-NMR (CDCl3): δ2.41 (6H, s), 2.72 (2H, t, J=6 Hz), 3.82 (2H, q-like, J=ca 6 Hz), 3.97 (3H, s), 7.00 (1H, dd, J=9 Hz, 2.5 Hz), 7.07 (1H, d, J=2.5 Hz), 7.34 (1H, brt, J=ca 5 Hz), 7.55 (1H, dd, J=4.5 Hz, 1 Hz), 8.05 (1H, d, J=9 Hz), 8.81 (1H, d, 4.5 Hz), 9.27 (1H, d, J=1 Hz).
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+].[CH3:31][O:32][C:33](=[O:44])[CH2:34][C:35]1([CH2:38]OS(C)(=O)=O)[CH2:37][CH2:36]1>CN(C=O)C>[CH3:31][O:32][C:33](=[O:44])[CH2:34][C:35]1([CH2:38][N:6]2[C:5]([C:12](=[O:13])[C:14]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:16]([C:17]#[N:18])[CH:15]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]2=[O:11])[CH2:37][CH2:36]1
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COC(=O)CC1(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC1(Cn2c(C(=O)c3cc(C)cc(C#N)c3)c(C(C)C)c(=O)[nH]c2=O)CC1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
To a mixture of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (962 mg, 4.16 mmol), anhydrous powdered potassium carbonate (574 mg, 4.16 mmol), and lithium iodide (557 mg, 4.16 mmol), was added DMF (18 mL) at room temperature. After stirring for 30 min, crude (1-methanesulfonyloxymethyl-cyclopropyl)-acetic acid methyl ester (962 mg) in DMF (2 mL) was added. The mixture was then heated in an oil bath (70-80° C.) and stirred for ca. 19 hr. After cooling to room temperature, the mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (5:95) and filtered through a celite pad. The filtrate was evaporated and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to give 230 mg (13%) of {1-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-cyclopropyl}-acetic acid methyl ester (82) as a white syrup. 1H-NMR (200 MHz, CDCl3) δ 0.36-0.65 (4H, m), 1.12 (3H, d, J=7.0 Hz), 1.23 (3H, d, J=7.0 Hz), 2.17-2.32 (2H, m), 2.44-2.52 (4H, m), 3.58 (1H, d, J=15.2 Hz), 3.69 (3H, s), 3.76 (1H, d, J=15.2 Hz), 7.79 (1H, s), 7.95 (1H, s), 8.06 (1H, s), 9.36 (1H, s); m/z (EI) 423 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.C([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([NH2:33])[CH:39]=3)[C:3]=12
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc(-c2nn(Cc3oc4ccccc4c(=O)c3-c3ccccc3)c3ncnc(N)c23)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
To a solution of Example 57a (0.400 g, 0.804 mmoles) in DMF (10 ml), ethanol (5 ml) and water (5 ml), 3-Acetamidophenyl boronic acid (0.187 g, 1.045 mmoles) and sodium carbonate (0.426 g, 4.02 mmoles) were added and the system is degassed for 30 min Palladium tetrakis triphenylphosphine (0.183 g, 0.158 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. To the concentrate ethanol (5 ml) and Con.HCl (0.5 ml) were added and refluxed for 2 h. The reaction mixture was basified with sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as yellow solid (0.140 g, 38% yield). MP: 157-159° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.21(s,1H), 8.06(dd, J=7.8,1.3Hz, 1H),7.77(dt, J=8.6,1.5Hz, 1H),7.49(t, J=7.4Hz, 1H),, 7.37-7.29(m,5H), 7.17(t, J=7.7Hz, 1H), 6.84(s,1H), 6.71(d, J=7.5Hz, 1H),6.65(d, J=7.9Hz, 1H), 5.51(s,2H), 5.34(s, 2H). Mass: 460.84(M+).
Reaction SMILES: FC(O[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:12])=O.[FH:13]>>[CH3:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=1[F:13]
Reactant: F
Reactant: Cc1cccc(C)c1OC(=O)F
Product: Cc1cccc(C)c1F
Temperature: 140 °C
Yield: 75 %

Procedure:
200 ml of anhydrous hydrogen fluoride were placed at 0° C. in a stainless steel laboratory autoclave and 100 g of 2,6-dimethylphenyl fluoroformate were added dropwise. The autoclave was sealed and heated at a maximum temperature of 140° C. for 1.5 hours. The reaction mixture was worked up as described in Example 9. 2,6-Dimethylfluorobenzene was obtained in a yield of 75%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.Cl.[C:25](=[O:41])([O:27][CH2:28][CH:29]([NH2:40])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[C:25](=[O:41])([O:27][CH2:28][CH:29]([NH:40][C:21](=[O:22])[CH2:20][N:10]1[C:11](=[O:19])[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=1)[NH2:26]
Reactant: NC(=O)OCC(N)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)OCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Of the compound from Example 77A, 100 mg (0.29 mmol) were introduced in 3 ml of DMF and admixed with 98.3 mg (0.35 mmol) of the compound from Example 60A, 66.1 mg (0.35 mmol) of EDC, 49 mg (0.35 mmol) of HOBt and 75 μl (0.43 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 30 min and then admixed with 1 ml of 1N hydrochloric acid and purified by preparative HPLC (Method 10). This gave 140 mg (84% of theory) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(Br)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[C:14]([CH3:21])=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CO>[CH3:20][O:19][C:16]1[N:15]=[C:14]([CH3:21])[C:13]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:18][CH:17]=1
Reactant: COc1ccc(Br)c(C)n1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(-c2cccc(C#N)c2)c(C)n1
Yield: 60.7 %

Procedure:
To a nitrogen flushed mixture of 3-cyanophenylboronic acid (5.0 g, 34 mmol), 3-bromo-6-methoxy-2-methylpyridine (4.6 g, 22.7 mmol) and palladium tetrakis(triphenylphosphine) (789 mg, 0.68 mmol) is added toluene (150 mL), methanol (12 mL) and sodium carbonate (22.7 mmol) and the mixture is heated overnight at reflux. The cooled reaction is concentrated and the residue is purified by chromatography eluting with cyclohexane-3.2 to 9% ethyl acetate. Product containing fractions are combined and concentrated to afford 3-(6-methoxy-2-methylpyridin-3-yl)benzonitrile (3.09 g, 61% yield) as a white solid. LC/MS: MS m/e=225 (M+H); RT 3.58 min; 1H NMR (CDCl3, δ ppm) 7.65 (1H, m), 7.60 (1H, m), 7.56 (2H, m), 7.40 (1H, d), 6.63 (1H, d), 3.98 (3H, s), 2.40 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH:12][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[C:5]2[C:4](=[O:13])[N:3]=1
Reactant: NCC1=C2C(=O)N=C(N)N=C2N=C1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CNCC2=C3C(=O)N=C(N)N=C3N=C2)cc1

Procedure:
By the same procedure as Example 5, 162 mg of the above-identified compound is synthesized from 252 mg of 2-amino-5-aminomethylpyrrolo[2,3-d]pyrimidin-4-one (dihydrochloride) and 157 mg of p-methoxybenzyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[NH2:43][O:44][CH2:45][C:46]([OH:48])=[O:47].C([O-])(O)=O.[Na+].Cl>O.C(Cl)(Cl)Cl.C(O)C>[CH2:1]([C:3]1[S:42][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:40][C:39](=[O:41])[O:38][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13](=[N:43][O:44][CH2:45][C:46]([OH:48])=[O:47])[C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Reactant: NOCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCc1cc2c(=O)n(CC(=NOCC(=O)O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), (aminooxy)acetic acid (0.053 g), NaHCO3 (1.0 g) and ethanol (20 mL) was stirred at 80° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.062 g, 27%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)[C:7]1=[O:18]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (45 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (42.5 g), potassium carbonate (27 g) and acetonitrile (1 L) was stirred at 50° C. for 2 hr. The precipitated solid was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give the title compound as a colorless solid (64 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][OH:22])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:23][CH3:24])[CH:3]=1.O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccc2c(c1CO)C(C)=CC(C)(C)N2
Reactant: COC(=O)Cc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(=O)Cc1ccccc1OCc1c(-c2ccc(F)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(4-Fluoro-2-methoxyphenyl)-5-hydroxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-3, 100.1 mg, 0.31 mmol), methyl 2-hydroxyphenylacetate (76.1 mg, 0.46 mmol), tri-n-butylphosphine (114 μL, 0.46 mmol), and 1,1′-(azodicarbonyl)dipiperidine (117 mg, 0.46 mmol) were dissolved in anhydrous benzene (2 mL), and the mixture was stirred under argon atmosphere at room temperature for 1 hour. Hexane (5 mL) was added to the reaction mixture and unsoluble materials were filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (107.1 mg) as a colorless amorphous product (Yield 74%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([NH2:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:16][CH:17]([CH3:25])[C:18](=O)[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(O)(=O)C.O>C1C=CC=CC=1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([NH:14][C:18]([CH:17]([CH3:25])[CH3:16])=[CH:19][C:20]([O:22][CH3:23])=[O:21])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(N)c1ccc(Cl)cc1
Reactant: COC(=O)CC(=O)C(C)C
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)CC(NC(=CC(=O)OC)C(C)C)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
5.70 g (25.0 mmol) of ethyl-3-amino-3-(4-chlorophenyl)propanoate [V. Wehner et al., Synthesis 14, 2023-2036 (2002)], 3.993 ml (27.5 mmol) of methyl 4-methyl-3-oxopentanoate and 2.87 ml (50.1 mmol) of acetic acid were taken up in 70 ml of benzene and reacted at reflux on a water separator overnight. After cooling, the mixture was washed with saturated aqueous sodium bicarbonate solution, the organic phase was dried with magnesium sulfate and the solvent was destilled off under reduced pressure. This gave 8.57 g (68% of theory) of the target compound in a purity of 70%. The fraction was used without further work-up for the subsequent steps.