Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH:6]=[C:5]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)[C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]1=2.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[O:47]=[C:48]1[NH:57][C:56]2[N:55]=[CH:54][C:53](/[CH:58]=[CH:59]/[C:60](O)=[O:61])=[CH:52][C:51]=2[CH2:50][CH2:49]1>CN(C)C=O.O.C(OCC)(=O)C>[S:2]1[CH:6]=[C:5]([O:7][CH:8]2[CH2:11][N:10]([C:60](=[O:61])/[CH:59]=[CH:58]/[C:53]3[CH:52]=[C:51]4[C:56](=[N:55][CH:54]=3)[NH:57][C:48](=[O:47])[CH2:49][CH2:50]4)[CH2:9]2)[C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]1=2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1ccc2c(OC3CNC3)csc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(Oc4csc5ccccc45)C3)cnc2N1
Reaction time: 8 h

Procedure:
3-(benzo[b]thiophen-3-yloxy)azetidine hydrochloride (140 mg, 0.58 mmol), EDCI (111 mg, 0.48 mmol), HOBt (78 mg, 0.58 mmol) and diisopropylethylamine (420 μL, 2.41 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (123 mg, 0.48 mmol) in dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred overnight and then diluted by addition of ethyl acetate (40 mL) and water (40 mL). The aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (98:2 to 95:5) as eluent. The title product was obtained as a white solid (52 mg, 26%).
Reaction SMILES: CO.[NH3:3].[Si:4]([O:21][CH2:22][C@@H:23]1[CH2:27][C@H:26]([N:28]2[C:32]3[N:33]=[CH:34][N:35]=[C:36](Cl)[C:31]=3[C:30]([I:38])=[CH:29]2)[CH2:25][N:24]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1>[NH2:3][C:36]1[C:31]2[C:30]([I:38])=[CH:29][N:28]([C@@H:26]3[CH2:25][N:24]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:23]([CH2:22][O:21][Si:4]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:27]3)[C:32]=2[N:33]=[CH:34][N:35]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](n2cc(I)c3c(N)ncnc32)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
THF (10 ml) and an 8N ammonia methanol solution (5 ml) were added to the (2S,4S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (400 mg) obtained in Step 1. The mixture was stirred at 120° C. for 2 hours under microwave irradiation, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/ethanol) to obtain the title compound as a light-yellow solid (293 mg). Physical properties: m/z [M+H]+ 698.5
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2Br)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:30])[F:31])=[CH:26][CH:25]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccn(Cc3ccccc3)c12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2cccc3ccn(Cc4ccccc4)c23)cc1
Yield: 49.6 %

Procedure:
1-Benzyl-7-bromo-1H-indole (0.677 g, 2.37 mmol) was coupled to 4-trifluoromethoxyphenylboronic acid (0.585 g, 2.84 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.0585 g, 0.0716 mmol), and potassium carbonate (0.492 g, 3.56 mmol), in dioxane (18 mL) and water (1.8 mL), according to the procedure described in Step 1 of Example 11. Purification by HPLC using hexane as the mobile phase yielded the title compound as a sage green solid (0.432 g, 50%). 1HNMR (300 MHz, DMSO-d6): δ 7.65 (d, 1H, J=7.5 Hz), 7.5 (d, 1H, J=3.8 Hz), 7.15-7.35 (m, 4H), 7.0-7.15 (m, 4H), 6.8 (d, 1H, J=7.5 Hz), 6.65 (d, 1H, J=3.8 Hz), 6.25 (d, 2H, J=7.5 Hz), and 5.05 ppm (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:16]3[N:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][C:17]=3B3OC(C)(C)C(C)(C)O3)[CH:12]=[CH:13][C:14]=2[Cl:15])=[CH:5][CH:4]=1.Br[C:38]1[C:43]([Cl:44])=[CH:42][C:41]([Cl:45])=[CH:40][N:39]=1.COCCOC.O.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=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>[CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:16]3[C:17]([C:38]4[C:43]([Cl:44])=[CH:42][C:41]([Cl:45])=[CH:40][N:39]=4)=[CH:18][CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:21]=3)[CH:12]=[CH:13][C:14]=2[Cl:15])=[CH:5][CH:4]=1
Reactant: Clc1cnc(Br)c(Cl)c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
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: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ncc(Cl)cc2Cl)c(-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)n1
Temperature: 80 °C
Yield: 38.5 %

Procedure:
To a suspension of 1 g (1.96 mmol) of methyl 6-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate and 0.58 g (2.55 mmol) of 2-bromo-3,5-dichloropyridine in 10 mL of a 2/1 DME/water mixture, argon is sparged through for 10 minutes, followed by successive addition of 0.81 g (5.88 mmol) of K2CO3 and 0.159 g (0.14 mmol) of Pd(PPh3)4. The reaction mixture is heated for 4 hours at 80° C. and then cooled and diluted in 50 mL of EtOAc. The organic phase is washed with 2×20 mL of water, dried over Na2SO4 and then concentrated under reduced pressure. The residue is then purified on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of from 0 to 40% EtOAc, to give 0.4 g of methyl 2′-[3-[(4-methoxybenzyl)oxy]-4-chlorophenyl]-3,5-dichloro-2,3′-bipyridine-6′-carboxylate in the form of an oil.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.[C:19]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:31])[CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].N1C=CC=CC=1.S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[C:20]([C:19]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=CCCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C(=CCCCCCN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
A solution of 2.95 ml of titanium tetrachloride in 8 ml of carbon tetrachloride was added dropwise while stirring under a nitrogen atmosphere to 50 ml of dry tetrahydrofuran at 0°. The resulting yellow suspension was treated with a solution of 2.45 g of 6-phthalimidohexan-1-al and 3.55 g of dibenzyl malonate in 40 ml of tetrahydrofuran and the mixture was stirred at 0° for 2 hours. A solution of 4.5 g of dry pyridine in 12 ml of dry tetrahydrofuran was added dropwise to give a blood-red suspension. The mixture was left to come to room temperature and was stirred for 18 hours while maintaining the nitrogen atmosphere. 200 ml of 2M sulfuric acid were added and the mixture was extracted four times with dichloromethane. The combined extracts were washed with sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel using ethyl acetate/n-hexane (1:2) for the elution to give 3.6 g of dibenzyl 2-(6-phthalimidohexylidene)malonate as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: CCCCCCCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(CCC(=O)OCC)cc1-c1cc(CCC(=O)OCC)ccc1O
Yield: 74.7 %

Procedure:
To 4 ml of a DMF solution containing 94 mg (0.2435 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 394.4 μl (2.435 mmol) of heptyl bromide, there were added 40.3 mg (0.3109 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through elite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 10 g of WAKO-gel C-200, eluent: benzene and benzene/ethyl acetate of 300/1, 150/1 and 50/1) to obtain 88.1 mg (0.182 mmol, 75%) of 2-heptyloxy-2'-hydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 0.85 (3H, t, CH3), 1.23 (6H, t, 2CH3), 1.1-1.5 (8H, m, 4CH2), 1.6-1.9 (2H, m, CH2), 2.5-2.8 (4H, m, 2CH2), 2.8-3.1 (4H, m, 2CH2), 4.01 (2H, t, CH2), 4.13 (4H, q, 2CH2), 6.58 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 483 (M-H)-
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:18][CH:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([O-:22])=[O:21])([CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][P:4]([CH2:18][CH:19]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:20]([OH:22])=[O:21])([CH2:6][N:7]1[C:8](=[O:17])[C:9]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:10]2[C:11]1=[O:12])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)[O-])CN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)c2ccccc2C1=O

Procedure:
4.5 g of benzyl (R or S)-2-[[(ethoxy)(phthalimidomethyl)phosphinyl]methyl]-4-methylvalerate were dissolved in 120 ml of ethanol and the solution was hydrogenated over 1.6 g of 10% palladium-on-charcoal for 5.5 hours. After filtration and evaporation of the filtrate, there were obtained 3.0 g of (R or S)-2-[[(ethoxy)(phthalimidomethyl)phosphinyl]methyl]-4-methylvaleric acid in the form of a white foam.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:4]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:3]=1.CN1CCOCC1.Cl[C:33]([O:35][CH3:36])=[O:34].CO>C(Cl)Cl.O1CCCC1.O>[C:21]1([CH3:24])[CH:22]=[CH:23][C:18]([S:15]([O:14][C:4]2[N:3]=[C:2]([NH:1][C:33]([O:35][CH3:36])=[O:34])[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)[n+]1[O-]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(NC(=O)OC)[n+]1[O-]
Reaction time: 1 h

Procedure:
3.5 g of crude methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate-3-oxide are dissolved in 100 ml of methylene chloride and 50 ml of tetrahydrofuran. At 0° there are added thereto 2.2 g of N-methylmorpholine and subsequently 1.45 ml of methyl chloroformate in 20 ml of methylene chloride. The mixture is stirred at 0° for 1 hour and then at room temperature for 2 hours and thereupon treated with a small amount of methanol and water. The organic phase is separated, dried and evaporated. The residue is recrystallized from methylene chloride and ether, there being obtained pure dimethyl 6-[(p-tolylsulfonyl)oxy]-2,4-pyrimidinedicarbamate-3-oxide of melting point 178°-179°.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(F)cc1
Product: O=C(Cc1ccc(F)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-fluorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.3 Hz, 1H), 8.02-8.05 (m, 1H), 7.97-8.01 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 7.40-7.43 (m, 2H), 7.16-7.20 (m, 2H), 3.78-3.83 (m, 4H), 3.70 (s, 2H), 3.04-3.13 (m, 4H); MS (ESI−) M/Z 381 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH:25]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:31]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:32])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: O=C(O)C1CCCCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3C(=O)C3CCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate (Example 89b) and cyclohexanecarboxylic acid as brown solid (46%). MS 440 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17](=[O:19])[N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1
Reactant: O=C(O)CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O
Reactant: C1CCNC1
Product: O=C(CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O)N1CCCC1

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(8-((3,4-difluorobenzyl)oxy)-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl)acetic acid and pyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:25][CH2:26][CH2:27]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]2[O:10][CH2:27][CH2:26][CH2:25][N:11]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)(=[O:13])=[O:14])[C:5]=12)=[O:23]
Reactant: BrCCCBr
Reactant: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cccc2c1N(S(=O)(=O)c1ccc(OC)cc1)CCCO2
Yield: 46.4 %

Procedure:
In the same manner as described in Example 159, 0.300 g (0.890 mmol) of the product of Example 31 and 0.127 mL (1.246 mmol) of 1,3-dibromopropane provided 0.156 g (46%) of the desired product as a colorless oil. Electrospray Mass Spec: 378 (M+H).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].CO.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:28]([O:30][CH3:31])=[O:29]>O1CCOCC1>[C:1]([CH2:2][CH2:3][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:28]([O:30][CH3:31])=[O:29])#[N:4]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc2ccccc2n1CCC#N
Temperature: 55 °C
Yield: 99.7 %

Procedure:
After 3.63 g (68.4 mmol) of acrylonitrile and 2.2 ml of 40% methanol solution of N-benzyltrimethylammonium hydroxide was added to a solution of 10.0 g (57.1 mmol) of methyl 2-indolecarboxylate in 150 ml of 1,4-dioxane, the mixture was stirred at 55° C. for an hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was added to a mixture of 5 ml of acetic acid and 500 ml of water. The aqueous layer was extracted twice with methylene chloride and the combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 13.0 g of methyl 1-(2-cyano-ethyl)-2-indolecarboxylate.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH:4]=[CH2:5].C([Li])CCC.[C:18](=O)=[O:19].CC(C)=O.CN(C)C=O>O1CCCC1.CCCCCC.O>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:18]=[O:19])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCc1ccc(Br)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C=CCCCc1ccc(C=O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 1.13 g of 4-(4-pentenyl)-bromobenzene in 20 ml of tetrahydrofuran wa added dropwise 4 ml of 1.5 M n-butyl lithium in n-hexane with dry-ice - acetone cooling, and the mixture was stirred for 15 minutes. To the reaction mixture was added 0.58 ml of dimethylformamide and stirred for an hour. Then the reaction mixture, after addition of 50 ml of water, was extracted with ether. The organic layer was washed with water and dried. Evaporation of the solvent under reduced pressure gave 850 mg of 4-(4-pentenyl)benzaldehyde.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([Cl:18])[C:7]([CH3:17])=[C:8]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=2)[C:4](=[O:19])[C:3]21[CH2:23][CH2:22][CH2:21][CH2:20]2.[OH-].[K+].CO.Cl>O>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([Cl:18])[C:7]([CH3:17])=[C:8]([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=2)[C:4](=[O:19])[C:3]21[CH2:23][CH2:22][CH2:21][CH2:20]2
Reactant: COC(=O)COc1cc2c(c(Cl)c1C)C(=O)C1(CCCC1)C2=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(OCC(=O)O)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O

Procedure:
A mixture of methyl [1',3'-dioxo-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-yloxy]acetate (3.5 g., 0.0104 mole) potassium hydroxide (0.67 g., 0.012 mole) and methanol (200 ml.) is refluxed for 1/2 hour, diluted with water (800 ml.) and acidified with hydrochloric acid affording 3.1 g. of [1',3'-dioxo-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-ylox]acetic acid which melts at 204°-4°C. after recrystallization from acetic acid-water.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([CH3:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:15])[C:4]=1[NH:16][C:17](=O)[CH3:18])=O.[NH3:20]>>[CH3:18][C:17]1[N:20]=[CH:1][C:3]2[C:4](=[C:5]([CH3:15])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH3:14])[CH:13]=2)[N:16]=1
Reactant: CCOC(=O)c1c(C)cc(C=O)c(NC(C)=O)c1C
Reactant: N
Product: CCOC(=O)c1c(C)cc2cnc(C)nc2c1C
Yield: 40 %

Procedure:
Instead of the compound of formula (II) used in Example 1, ethyl 4-formyl-2,6-dimethyl-3-acetylaminobenzoate was used and reacted with ammonia in the same way as in Example 1. The reaction product was chromatographed on a silica gel column in the same way as in Example 1. The solvent was evaporated, and the residue was recrystallized from ethanol/water to give 2-methyl-7-ethoxycarbonyl-6,8-dimethylquinazoline having a melting point of 84° to 86° C. in a yield of 40%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19](=[O:28])[NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19](=[O:28])[NH:20][CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76.4 %

Procedure:
Dissolve oxalyl chloride (18.4 mL, 211 mmol) in CH2Cl2 (1000 mL), cool below −70° C., and add DMSO (18.0 mL, 253 mmol) via syringe pump over 30 min. Stir for 45 min, and then add portionwise a suspension of trans-(4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (35.00 g, 140 mmol) in CH2Cl2 (1000 mL), while maintaining the temperature below −70° C. Add the suspension by removing a stopper from the reaction flask and quickly pouring in as much of the suspension as possible while keeping the temperature below −70° C., resulting in a slightly turbid solution upon complete addition. Stir the reaction for 90 min, then add triethylamine (97.8 mL, 702 mmol) slowly via syringe. Stir for another hour, and allow the reaction to slowly warm to room temperature overnight. Wash sequentially with water (1500 mL), brine (2×1500 mL), and saturated aqueous NaHCO3 (2×1500 mL). Separate the organic portion and dry (MgSO4), filter, and concentrate under reduced pressure. Triturate the crude residue twice with 4:1 Hexane/EtOAc (500 mL, then 250 mL). (Alternatively, triturate with 15% EtOAc/Hexane. Then only one trituration is required.) Filter and collect the solids and dry at 35° C. in a vacuum oven to obtain 26.44 g of the product. Combine the filtrates of the triturations and concentrate under reduced pressure, followed by trituration of the residue in 9:1 hexane/EtOAc (100 mL) to afford a second crop of 5.70 g, for a combined yield of 32.14 g (93%). ESI MS: m/z 248 [C14H17NO3+H]+; 1H NMR (300 MHz, CDCl3): δ 1.63-1.78 (m, 2H), 2.22-2.27 (m, 2H), 2.32-2.49 (m, 4H), 3.95-4.04 (m, 1H), 4.75 (br s, 1H), 5.11 (s, 2H), 7.29-7.42 (m, 5H)