Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12]2)=[O:9])=[CH:6][CH:5]=1)[CH3:2].C1COCC1.CO>O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[O:9])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(OCC)cc2)CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOc1ccc(C(=O)NC2(C(=O)O)CC2)cc1
Temperature: 20 °C
Reaction time: 19 h
Yield: 98 %

Procedure:
Charge an 800 L reactor with ethyl 1-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylate (12.19 kg), THF (45.5 kg) and MeOH (20.2 kg). Add a solution of LiOH monohydrate (2.49 kg) in water (25.6 kg) to the reactor maintaining the temperature of less than 23° C. during the transfer. Stir the resulting solution at 20±3° C. for overnight (19 h). Remove THF and MeOH by vacuum distillation and then add water (67 kg) to reactor. Adjust the pH of the reaction to pH about 2.0 with 5N HCl (about 12 L) at 17±2° C. Stir the resulting product slurry at 17±2° C. for 50 minutes. Collect the solids by filtration and wash with water (3×40 Kg). Dry the wet cake at 47° C. under vacuum to afford 1-[(4-ethoxybenzoyl)amino]cyclopropanecarboxylic acid (10.74 kg, 98% yield, >99% purity by HPLC, 0.03% KF) as a white powder solid. LC-MS (M+1=250).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[O:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[C:30](O)=[O:31].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C@H:26]4[CH2:27][CH2:28][CH2:29][O:25]4)=[O:31])[CH:3]=[CH:4][C:5]=2[CH3:24])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)[C@H]2CCCO2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a mixture of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (62.4 mg, 0.167 mmol), (R)-(+)-tetrahydro-2-furoic acid (21.0 uL, 0.217 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (118.4 mg, 0.2284 mmol), and 4-dimethylaminopyridine (4.083 mg, 0.03342 mmol) was added N,N-dimethylformamide (2.0 mL, 26 mmol) and N,N-diisopropylethylamine (88 uL, 0.50 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with ethyl acetate and washed twice with water and once with brine. The organic layer was dried over MgSO4, and filtered through a plug of silica gel, rinsing with ethyl acetate. The filtrate was concentrated and then purified via reverse phase HPLC and lyophilized to yield 45.0 mg (65%) of (R)-N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)tetrahydrofuran-2-carboxamide. LCMS (ESI): RT (min)=4.594, M+H=416.2, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.64 (s, 1H), 9.18 (s, 1H), 8.49 (s, 1H), 7.99 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.68 (dd, J=11.6, 1.9 Hz, 2H), 7.64 (dd, J=8.3, 2.1 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 4.38 (dd, J=8.1, 5.6 Hz, 1H), 3.98 (dd, J=14.5, 6.8 Hz, 1H), 3.82 (dd, J=14.5, 6.9 Hz, 1H), 2.23 (s, 3H), 2.22-2.14 (m, 1H), 2.13-2.03 (m, 1H), 1.98 (td, J=12.6, 6.6 Hz, 1H), 1.86 (p, J=6.9 Hz, 2H), 0.95-0.77 (m, 4H).
Reaction SMILES: [C:1]1([C:11]2C3C([C:18]([C:28]4[C:37]5C(=CC=CC=5)C=CC=4)=[C:19]4[C:24]=2[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20]4)=CC=CC=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N+:45]([O-:47])=[O:46].C([O-])([O-])=O.[K+].[K+].O1[CH2:59][CH2:58]OCC1>C1COCC1.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>[N+:45]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:11]1[CH:1]=[CH:2][C:3]2[C:23](=[C:22]([C:59]3[CH:58]=[CH:9][C:10]4[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=4)[CH:11]=3)[C:21]3[C:20]([C:4]=2[C:5]2[CH:10]=[CH:9][C:8]4[C:7](=[CH:28][CH:18]=[CH:19][CH:20]=4)[CH:6]=2)=[CH:19][CH:18]=[CH:28][CH:37]=3)[CH:24]=1)([O-:47])=[O:46]
Reactant: C1COCCO1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: OB(O)c1ccc2c(-c3cccc4ccccc34)c3ccccc3c(-c3cccc4ccccc34)c2c1
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: C1CCOC1
Product: O=[N+]([O-])c1ccccc1-c1ccc2c(-c3ccc4ccccc4c3)c3ccccc3c(-c3ccc4ccccc4c3)c2c1
Reaction time: 12 h

Procedure:
10 g (21.1 mmol) of 9,10-dinaphthylanthracene-2-boronic acid, 10.64 g (52.7 mmol) of bromonitrobenzene, 1.21 g (0.05 mmol) of Pd(PPh3)4, and 11.65 g (84.3 mmol) of K2CO3 were diluted with 100 ml of dioxane, 100 ml of THF, and 30 ml of H2O, and then, the mixture was refluxed while heating. After 12 hours, a solvent was removed and the resultant mixture was extracted using MC and washed with a saturated NaCl solution. Then, an organic layer was dried and condensed over MgSO4, and the obtained product was purified by column chromatography (MC/Hex=1/5), thereby producing 2-(2-nitrophenyl)-9,10-di(2-naphthyl)anthracene that was yellow solid (8.4 g, 73%).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:5][CH:4]1[C@H:6](O)C)[CH3:2].CN([CH:12]=[O:13])C.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:15].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O>[CH2:1]([C@@H:3]1[CH2:5][C@@H:4]1[CH2:6][C:12]([OH:13])=[O:15])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CN(C)C=O
Reactant: CC[C@@H]1CC1[C@@H](C)O
Agent: c1cc[nH+]cc1
Solvent: O
Product: CC[C@@H]1C[C@@H]1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250-mL, one-necked, round bottomed flask equipped with a magnetic stirrer, and under nitrogen, was charged with 1.7 g (14.9 mmol) of alcohol 23 and 40 ml of dry DMF. Pyridinium dichromate 19.6 g (3.5 eq.; 52.1 mmol) was added in one portion. The reaction mixture was stirred overnight at 25° C. and then poured into 200 ml of water and extracted with ether (4×80 ml). The organic layers were concentrated under reduced pressure, and the residue was then dissolved in chloroform (50 ml) and extracted with a 10% aqueous NaOH (2×25 ml). The combined aqueous layers were washed twice with 25 ml of chloroform, followed by acidification with 10% aqueous HCl. Extraction with ether (4×50 ml), drying over MgSO4, filtration and concentration under reduced pressure afforded the desired compound (1R,2R)-2-ethylcyclopropylacetic acid (24) as a colorless oil (1.05 g).
Reaction SMILES: Br[CH2:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:4]1=[O:17].[CH2:18]([SH:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:18]([S:20][CH2:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:4]1=[O:17])[CH3:19]
Reactant: CCS
Reactant: COC(=O)c1cc2cccnc2n(CBr)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCn1c(=O)c(C(=O)OC)cc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
3.00 g (10.1 mmol) of methyl 1-(bromomethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in N,N-dimethylformamide (40 mL), and 0.94 g (15.1 mmol) of ethanethiol and 2.09 g (15.1 mmol) of potassium carbonate were added to the solution. The resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried, and concentrated. Thus, 2.85 g (yield: quantitative) of the title compound was obtained as pale yellow crystals.
Reaction SMILES: C[N:2](C)C=O.[S:6](Cl)(Cl)(=[O:8])=[O:7].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([S:6]([NH2:2])(=[O:8])=[O:7])=[CH:19][C:14]=2[CH2:13][CH2:12]1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=S(=O)(Cl)Cl
Reactant: CN(C)C=O
Product: NS(=O)(=O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
This compound was prepared essentially according to the teachings of J. A. Aikins, et al., European Patent Publication 254,577, published Jan. 27, 1988. N,N-dimethylformamide (23.0 ml, 297 mmol) was cooled in an ice-salt bath and treated dropwise with sulfuryl chloride (20.0 g, 148 mmol) at such a rate that the reaction temperature was maintained below 15° C. To this was added 2,3-dihydrobenzofuran (17.0 g, 142 mmol), and after warming to room temperature, the reaction mixture was rapidly heated to 130° C. over ten minutes, and then allowed to cool to room temperature. The reaction mixture was poured into water/ice/dichloromethane, 1/5/1 (700 ml), and the organic layer collected. The aqueous layer was diluted with water (100 ml) and extracted with dichloromethane. The combined organic phase was dripped into an ammonium hydroxide solution (3N, 250 ml), and allowed to stir overnight. Residual dichloromethane was removed by distillation and the resulting solid collected on a filter, washed with a small amount of water, followed by ether and then dried by aspiration to provide 12.8 g (45%) of the product.
Reaction SMILES: OO.[C:3]1([O:13][CH3:14])[C:4](=[CH:6][CH:7]=[C:8]([CH:12]=1)[CH:9]=[CH:10][CH3:11])[OH:5].S(=O)(=O)(O)[OH:16].C1(C)C=CC=CC=1>C(O)=O>[CH3:11][C:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:4]([OH:5])=[C:3]([O:13][CH3:14])[CH:12]=1)=[O:16]
Reactant: CC=Cc1ccc(O)c(OC)c1
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: Cc1ccccc1
Solvent: O=CO
Product: COc1cc(CC(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of 30% aqueous hydrogen peroxide (9 ml, 85.5 mm) and formic acid (16 ml, 88%) is added to a solution of isoeugenol (8.1 gm, 50 mm) in formic acid (4 ml). The reaction mixture is stirred at 35° C.-40° C. under nitrogen atmosphere for 3 hours. The resulting 1-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol-monoformate is treated with 10% aqueous sulfuric acid (125 ml.) and toluene (125 ml.). After refluxing with mixing for 6 hours, the reaction mixture is cooled to room temperature, and the toluene layer separated. The aqueous layer is extracted with fresh toluene and the toluene layers are combined, washed with saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate and concentrated to give methylvanillyl ketone in 48% yield.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I:13][CH2:14][CH2:15][OH:16]>C(Cl)(Cl)Cl>[I-:13].[OH:16][CH2:15][CH2:14][N+:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH3:12])([CH3:11])[C:2]=1[CH3:1]
Reactant: OCCI
Reactant: CC1=Nc2ccccc2C1(C)C
Solvent: ClC(Cl)Cl
Product: CC1=[N+](CCO)c2ccccc2C1(C)C
Product: [I-]
Reaction time: 24 h

Procedure:
In a particular example for the preparation, about 16 g of 2,3,3-trimethyl-3H-indole was dissolved in about 100 ml of chloroform. After addition of about 19 g of 2-Iodoethanol, the solution was refluxed while stirring for about 1 day. After cooling, the solvent was removed and the resultant solid was filtered and washed with acetone to yield 1-(2-hydroxyethyl)-2,3,3-trimethyl-3H-indolium iodide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N[C:32]1[CH:33]=[CH:34][C:35](=[O:38])[NH:36][CH:37]=1.[CH:39]([NH:42]C(C)C)(C)C.O>CC(N(C)C)=O>[NH3:14].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[N:20]3)=[C:15]([NH:42][CH2:39][C:32]3[CH:33]=[CH:34][C:35](=[O:38])[NH:36][CH:37]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2cc3ncccc3c(OS(=O)(=O)C(F)(F)F)n2)cc(OC)c1OC
Reactant: CC(C)NC(C)C
Reactant: Nc1ccc(=O)[nH]c1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(-c2cc3ncccc3c(NCc3ccc(=O)[nH]c3)n2)cc(OC)c1OC
Product: N
Temperature: 70 °C
Reaction time: 8 h

Procedure:
100 mg Trifluoro-methanesulfonic acid 7-(3,4,5-trimethoxy-phenyl)-[1,6]naphthyridine-5-yl ester (6.1) was placed in 3 mL dimethylacetamide at ambient temperature before 111 mg 5-amino-1H-pyridine-2-one (2.31) was added. The reaction was heated to 70° C. overnight and then cooled to ambient temperature. 1.3 mL N,N-Diisopropylamine was added and the reaction was heated to 100° C. overnight. After this time, the reaction was heated to 120° C. and stirred overnight. The mixture was then cooled to ambient temperature and water was added. The mixture was extracted into ethyl acetate (×3) and the combined organic fractions were washed with water, separated and the solvent was removed under reduced pressure. Purification by preparative HPLC and then by silica gel chromatography (ethyl acetate containing 1-10% of 7M ammonia in methanol) gave the title compound.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].CCN=C=NCCCN(C)C.Cl.[CH3:57][O:58][CH2:59][CH2:60][NH:61][C:62](=[O:67])[CH2:63][CH2:64][NH:65][CH3:66]>ClCCl.CN(C)C1C=CN=CC=1>[F:44][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29](=[O:30])[C:31]2[CH:39]=[CH:38][CH:37]=[C:33]([C:34]([N:65]([CH2:64][CH2:63][C:62]([NH:61][CH2:60][CH2:59][O:58][CH3:57])=[O:67])[CH3:66])=[O:35])[CH:32]=2)[CH:11]=1)=[O:9]
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CNCCC(=O)NCCOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCNC(=O)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Into a 10-mL vial, was placed a solution of 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid 4.1e (80 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (5 mL), EDC.HCl (51.1 mg, 0.27 mmol), 4-dimethylaminopyridine (32.4 mg, 0.27 mmol, 2.00 equiv), and N-(2-methoxyethyl)-3-(methylamino)propanamide (31.2 mg, 0.20 mmol, 1.47 equiv). The resulting solution was stirred for 6 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 50 mL of dichloromethane. The resulting mixture was washed with 3×70 mL of NH4Cl. The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. This yielded 50.4 mg (44%) of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-(3-(2-methoxyethylamino)-3-oxopropyl)-N3-methylisophthalamide as a yellow solid. 1H-NMR (300 MHz, DMSO-d6+D2O, ppm) δ 8.89 (d, J=5.1 Hz, 1H), 8.43 (t, 1H), 8.31 (s, 1H), 7.94 (t, J=9.3 Hz, 4H), 7.83 (m, 7H), 4.58 (s, 2H), 3.32-3.65 (m, 7H), 3.07-3.17 (m, 6H), 2.85-2.95 (m, 3H), 2.31 (s, 2H), 1.63-1.85 (m, 6H). MS (ES, m/z): 745 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:38])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O>CCCCCC.C(OCC)(=O)C>[O:10]=[C:6]1[C:5]2[CH:11]=[CH:12][C:2]([O:1][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C:18]([OH:38])=[O:17])=[C:3]([CH2:13][CH2:14][CH3:15])[C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: COC(=O)CCc1ccccc1CCCCCCOS(C)(=O)=O
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCCc2ccccc2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 11 and starting with 0.2 g (1 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.32 g (1 mmol) of 2-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester (from example 36), 2-[6-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]hexyl]benzenepropanoic acid was obtained in 45.6% overall yield, as a colorless solid, mp 98°-99° C. (recrystallized from hexane-ethyl acetate).
Reaction SMILES: [N:1]([CH:4]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([O:7]CC)=[O:6])=[C:2]=[O:3].[CH3:15][N:16]([CH3:18])[NH2:17].C(Cl)Cl>C(O)(=O)C>[CH3:15][N:16]([CH3:18])[NH:17][C:2]([NH:1][CH:4]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]([OH:7])=[O:6])=[O:3]
Reactant: CCOC(=O)C(N=C=O)c1cccs1
Reactant: CN(C)N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)NC(=O)NC(C(=O)O)c1cccs1
Reaction time: 0.5 h

Procedure:
A solution of 4.2 g. (0.02 mole) of DL-α-isocyanato-2-thiopheneacetic acid, ethyl ester and 1.2 g. (0.02 mole) of N,N-dimethylhydrazine in 80 ml. of methylene chloride is stirred overnight. The solution is concentrated and to the syrupy residue are added 10 ml. of 2N sodium hydroxide solution. After stirring for 30 minutes, a clear yellow solution results. By the addition of acetic acid, 3.9 g. of α-dimethylhydrazinocarbonylamino-2-thiopheneacetic acid are obtained, m.p. 208°-210°.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([S:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[O:4].B.CSC.CO.[H][H]>C1COCC1>[CH3:1][N:2]([CH3:14])[C:3]([S:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1)=[O:4]
Reactant: CN(C)C(=O)Sc1ccc(C#N)cc1
Reactant: [H][H]
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: CN(C)C(=O)Sc1ccc(CN)cc1

Procedure:
Dissolve 4-dimethylcarbamoylthio-benzonitrile (3.07 g, 14.9 mmol) in anhydrous THF (30 mL). Add borane-dimethylsulfide complex (4.24 mL, 44.7 mmol, 1M solution in diethyl ether) and stir the mixture at room temperature for 3 h. Add methanol dropwise until hydrogen evolution ceases. Concentrate the mixture in vacuo and purify the crude mixture by SCX chromatography eluting with methanol and 2M ammonia in methanol to obtain the title compound as a slightly impure oil (2.9 g). Dissolve the oil (2.9 g) in DCM and add 2M hydrogen chloride in ether. Stir the mixture for 1 h and concentrate in vacuo to obtain a solid. Suspend the solid in DCM and add diethyl ether to precipitate the salt. Filter and dry the solid in vacuo to obtain the hydrochloride salt of the title compound as a white solid (2.33 g, 64%). Elute the compound through a SCX column to obtain the desired intermediate as an oil. MS (ES+) m/z: 211 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH3:11][S:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.[H-].[Na+].C(O)(=O)C>CN(C)C=O>[CH3:11][S:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])=[CH:15][CH:14]=1
Reactant: CSc1ccc(N)cc1
Reactant: O=C(O)c1ccnc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CSc1ccc(Nc2cc(C(=O)O)ccn2)cc1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
To a solution of 2-fluoroisonicotinic acid (620 mg, 4.95 mmol) and 4-(methylthio)aniline (0.984 mL, 8.42 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (792 mg, 19.8 mmol), and the resulting mixture was stirred under an argon atmosphere at 85° C. for 5 hr. After cooling, acetic acid (1.2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, the mixture was stirred for 20 min, and the precipitate was collected by filtration to give crude 2-[[4-(methylthio)phenyl]amino]isonicotinic acid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][CH2:33][NH2:34])=[O:6])[CH:2]=[CH2:3].[Cl-:35].[N+]([C:39]1[CH:44]=[C:43]([N+]([O-])=O)C=[CH:41][C:40]=1[N+]1C=CC=CC=1)([O-])=O>C(O)CCC>[Cl-:35].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][CH2:33][N+:34]1[CH:43]=[CH:44][CH:39]=[CH:40][CH:41]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CCN
Reactant: O=[N+]([O-])c1ccc(-[n+]2ccccc2)c([N+](=O)[O-])c1
Agent: [Cl-]
Solvent: CCCCO
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC[n+]1ccccc1
Yield: 84.2 %

Procedure:
A solution of (2R,4S)-1-allyloxycarbonyl-2-(2aminoethyl)4-(triphenylmethylthio) pyrrolidine (5.78 g) and 1-(2,4-dinitrophenyl)pyridinium chloride (4.19 g) in n-butanol (60 ml) was stirred under reflux condition for 4 hours, and then evaporated under reduced pressure. The residue was column chromatographed on silica gel (chloroform:methanol=5:1 to 4:1) to give (2R,4S)-1-allyloxycarbonyl-2-{2-(1-pyridinio)ethyl}-4(triphenylmethylthio)pyrrolidine chloride (5.88 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.[CH2:19]([NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1)[CH3:20].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:19]([NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:33][CH2:34]2)=[C:25]([CH3:35])[CH:24]=1)[CH3:20]
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(C)c1
Temperature: 90 °C
Yield: 35.4 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride (133 mg, 0.469 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143 mmol) were suspended in Propiononitrile (Volume: 1287 μl) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature and purified using HPLC (NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was slurried with hot MeCN (5 mL), cooled to ambient temperature, filtered off, washed with water (2 mL) and dried in vacuum to afford (S)—N-ethyl-3-methyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (70.3 mg, 0.152 mmol, 35.4% yield) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3H) 1.33-1.57 (m, 3H) 1.64 (d, J=12.13 Hz, 1H) 1.85 (d, J=11.37 Hz, 1H) 2.04 (d, J=12.13 Hz, 1H) 2.26 (s, 3H) 2.52-2.70 (m, 5H) 2.87 (br. s., 4H) 3.19-3.29 (m, 2H) 3.37-3.43 (m, 2H) 3.84 (dd, J=11.49, 2.65 Hz, 1H) 4.50 (d, J=12.88 Hz, 1H) 6.98 (d, J=1.52 Hz, 1H) 7.01 (d, J=8.34 Hz, 1H) 7.62 (d, J=8.59 Hz, 1H) 7.65 (dd, J=9.35, 1.26 Hz, 2H) 8.26 (t, J=5.43 Hz, 1H) 10.49 (s, 1H); [M+H] calc'd for C26H34N6O2, 463. found, 463.