Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]2([CH3:12])[O:10][C:7]([CH3:11])([C:8]=1Cl)[CH:6]=[CH:5]2.[CH3:14][OH:15].C[O-].[Na+]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3](=[O:13])[C:4]2([CH3:12])[O:10][C:7]([CH3:11])([C:8]=1[O:15][CH3:14])[CH:6]=[CH:5]2
Reactant: CC12C=CC(C)(O1)C(Cl)=C(Cl)C2=O
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC1=C(Cl)C(=O)C2(C)C=CC1(C)O2
Temperature: 25 °C
Yield: 52.9 %

Procedure:
6.0 g (27.39 mmol) of 3,4-dichloro-1,5-dimethyl-8-oxa-bicyclo[3.2.1]octa-3,6-dien-2-one is introduced into 39 ml of anhydrous methanol. At a temperature of 0° C., the reaction mixture is further diluted dropwise with a solution of 15.2 ml of 5.4M sodium methanolate (82.17 mmol) and treated with 10 ml of absolute methanol. The reaction mixture is then heated to ambient temperature with 35 minutes' stirring. Using thin-layer chromatography (hexane/ethyl acetate 8:2) it can be established that reaction of the starting material is complete. The reaction solution is then concentrated under reduced pressure. The residue is then extracted by means of carbon tetrachloride against water. The aqueous phase is extracted a further three times using fresh carbon tetrachloride. The combined organic extracts are dried over sodium sulfate and concentrated by evaporation under reduced pressure; with ice-cooling, the oily product that remains behind crystallises out in the form of a ˜1:1 mixture. The mixture is separated by means of column chromatography on silica gel (eluant: gradient from 1-5% ethyl acetate/hexane). 3.1 g (52.9%) of pure 3-chloro-1,5-dimethyl-4-methoxy-8-oxa-bicyclo[3.2.1]octa-3,6-dien-2-one are isolated.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1F)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:7]1[CH:8]=[C:4]([CH2:3][Cl:2])[N:5]=[CH:6]1)([O-:11])=[O:10]
Reactant: ClCc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2cnc(CCl)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Chloromethyl)imidazole hydrochloride (790 mg) was dissolved in 20 ml of acetonitrile. To this solution was added 713 μL of 2,4-dinitrofluorobenzene and 2.14 g of potassium carbonate. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated. The crude reaction product was purified by flash silica gel chromatography (8:2 ethyl acetate-hexane elution) to give 745 mg of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:30])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][CH2:4][OH:3])[N:7]=2)=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc(CCO)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared as in Example 3(B)(d), 120 mg, 0.26 mmol) in diethyl ether (500 μL) was cooled to 0° C. and then slowly treated with lithium aluminum hydride (15 mg, 0.39 mmol). The reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. After 1 h at 25° C., thin layer chromatography still indicated the presence of the starting material. An additional amount of lithium aluminum hydride (10 mg, 0.26 mmol) was added to the reaction mixture, and the reaction mixture was allowed to stir at 25° C. for 1 h. The reaction mixture was then slowly quenched by the dropwise addition of water (10 mL). The resulting mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide (20 mg, 18%) as a yellow foam: mp 84–87° C.; EI-HRMS m/e calcd for C20H26N2O4S2 (M+) 422.1334, found 422.1335.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=1.O.[N+:14]([CH:17]([CH:20]=O)[CH:18]=O)([O-:16])=[O:15].[Na]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]2[C:10](=[N:12][CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:20]=2)[NH:9][N:8]=1
Reactant: Nc1cc(-c2ccccn2)n[nH]1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na]
Solvent: O
Product: O=[N+]([O-])c1cnc2[nH]nc(-c3ccccn3)c2c1
Temperature: 100 °C
Yield: 88.2 %

Procedure:
A 50 mL reaction vessel was charged with 3-(pyridin-2-yl)-1H-pyrazol-5-amine (1.5 g, 9.4 mmol), sodium nitromalonaldehyde monohydrate (1.54 g, 9.8 mmol) and water (9 mL). The flask was heated to 100° C. overnight, and the cooled reaction mixture was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried (MgSO4), to provide crude 3-(pyridin-2-yl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (2.0 g, 88% yield) as a solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:23]=[C:22](F)[C:21]([F:25])=[CH:20][C:9]=1[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:11].[Cl:26][C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[N:31][C:32]=1[F:33]>CS(C)=O.CCOC(C)=O>[Cl:26][C:27]1[CH:28]=[C:29]([O:34][C:22]2[C:21]([F:25])=[CH:20][C:9]([C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[O:11])=[C:8]([F:7])[CH:23]=2)[CH:30]=[N:31][C:32]=1[F:33]
Reactant: Oc1cnc(F)c(Cl)c1
Reactant: Cc1ccc(OC(=O)c2cc(F)c(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(=O)c2cc(F)c(Oc3cnc(F)c(Cl)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
Potassium carbonate (1.40 g, 10.14 mmol) was added to a solution of 4-Methylphenyl 2,4,5-trifluorobenzoate (Preparation 12, 1.80 g, 6.76 mmol), 5-chloro-6-fluoropyridin-3-ol (1.05 g, 7.10 mmol) in DMSO and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted in EtOAc (50 mL), washed with water (2×25 mL) and the organic layer dried over sodium sulfate, filtered, and concentrated in vacuo. The remaining crude was then purified by silica gel chromatography eluting with 10 to 50% EtOAc in heptane to afford the title compound (1.48 g, 56%):
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1.P(Cl)(Cl)([Cl:20])=O.[OH-].[Na+]>CN(C)C=O>[Cl:20][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:3]=1
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(O)c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(Cl)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
40.5 g (174.1 mmole) of 2-(4-fluorophenylamino)-4-hydroxy-5,6-dimethylpyrimidine produced in Example 1 was suspended in 80 ml of N,N-dimethylformamide and the resulting suspension was heated to 80° C. 31.9 g (19.4 ml, 210.1 mmole) of phosphorus oxychloride was added thereto over one hour at constant temperature of 85° C. The reaction solution was stirred for 30 minutes and then 400 g of ice-water was added thereto with stirring. The mixture was adjusted to pH 11 by adding sodium hydroxide and then the resulting solid product was filtered. The separated solid product was washed with 150 ml of 50% aqueous methanol solution and then dried to obtain 42.3 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[P:14](Cl)([Cl:17])([Cl:16])=[O:15]>[Cl-].[Mg+2].[Cl-]>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][P:14]([Cl:17])([Cl:16])=[O:15]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Mg+2]
Product: O=P(Cl)(Cl)Oc1ccccc1-c1ccccc1
Temperature: 105 °C
Yield: 101.3 %

Procedure:
A four-necked 1-liter flask, equipped with a stirrer, a thermometer, and a reflux condenser, was filled with 170.2 g (1 mol) of 2-hydroxybiphenyl, 337.3 g (2.2 mol) of phosphorus oxychloride and 0.95 g (0.01 mol) of anhydrous magnesium chloride. This mixed liquid was heated to the temperature of 105° C. over three hours while being stirred under a nitrogen atmosphere, and it was stirred for 1 hour at the same temperature (105° C.) to allow a reaction to proceed. After the reaction, the pressure was reduced to 6.7 kPa at a liquid temperature of 105° C. The same pressure was maintained for 1 hour and excess (unreacted) phosphorus oxychloride was recovered. Thus, 290.8 g of 2-biphenylylphosphorodichloridate (chlorine content: 24.7%) was obtained.
Reaction SMILES: [OH:1][C:2]1([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:2]2([OH:1])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]2)[CH:19]=1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2)CC1
Agent: [Pd]
Solvent: CCO
Product: OC1(c2cccnc2)CCNCC1
Reaction time: 8 h
Yield: 79.9 %

Procedure:
Benzyl 4-hydroxy-4-(pyridin-3-yl)piperidine-1-carboxylate (32.7 g, 104.69 mmol) was dissolved in ethanol (350 mL) and hydrogenated over 10% palladium on carbon (3.2 g) at 2 bar pressure at 30° C. After hydrogen uptake was complete, the mixture was filtered through a pad of diatomaceous earth to remove the catalyst and the pad was washed with ethanol. The filtrate was concentrated to dryness under vacuum to give an oil which crystallised on standing overnight. The solid was triturated with MTBE (100 mL), collected by filtration, washed with MTBE (2×50 ml) and dried in a vacuum oven at 40° C. to afford 4-(pyridin-3-yl)piperidin-4-ol (14.9 g, 80%) as a solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13].CSC.B.O>C1COCC1>[SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: O=C(O)CCCCCCCCCCS
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: OCCCCCCCCCCCS
Temperature: 25 °C
Reaction time: 4 h

Procedure:
11-Mercaptoundecanoic acid (G) (1.0 g, 4.6 mmol) was dissolved in dry THF (20 mL) and borane dimethyl sulphide (3 mL, 1.1 equiv.) was slowly added under N2 atmosphere. The mixture was stirred at room temperature for 4 hr. Water was added to the solution was extracted using ethyl acetate. The organic extract was washed with 1N HCl, water and saturated sodium bicarbonate solution successively. After drying (MgSO4), the solvent was evaporated to give a clear oil. The crude oil was purified by column chromatography [eluant: hexane/ethyl acetate (8:2)]. Yield: 0.45 g (48%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5](=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[OH:6].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:25]([C:16]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=1[O:6][C:5]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=1[C:3]([O:2][CH3:1])=[O:13])([O-:27])=[O:26]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Methyl-4-methoxysalicylate (12.0 g, 0.066 mol), 4-chloro-3-nitrobenzotrifluoride (9.75 mL, 0.066 mol) and potassium carbonate (18.16 g, 0.131 mol) were mixed in dimethylformamide, under argon, at 150° C. for 16 h. The reaction mixture was filtered and the solvents evaporated. The residue was flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, CDCl3) δ8.25 (d, 1H), 8.04 (d, 1H), 7.65 (dd, 1H), 6.91 (dd, 1H), 6.81 (d, 1H), 6.70 (d, 1H), 3.88 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>COC>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][NH2:24])[CH:19]=4)[CH2:14][CH2:13][N:12]=3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Agent: COC
Agent: Cl
Product: NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CC1)=NCC2
Temperature: 25 °C

Procedure:
A solution of tert-butyl [2-({1-[1-(4-chlorophenyl)cyclopropyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethyl]carbamate (440 mg, 1 mmol) methylenehloride (10 ml) was treated with 5N HCl in dimethylether (0.5 ml) and stirred over night at room temperature. The solvent was removed, the residue triturated with diisopropyl ether and the insoluble slid collected. Yield: 370 mg (0.98 mmol, 98%)
Reaction SMILES: S(C)C.[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]=[C:8]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO>C1COCC1>[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([OH:14])[CH:9]=[C:8]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc2c(c1)C(c1ccccc1)=CC2=O
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c(c1)C(c1ccccc1)=C[C@@H]2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
(R)-MeCBS catalyst (0.22 ml, 1 M, 0.22 mmol) was mixed in 5 ml of dry THF, and stirred for 1 h at room temperature. After cooling to 0° C., 2.5 ml of 2 M BH3:Me2S (4.99 mmol) in THF were added. 5-Methyl-3-phenyl-inden-1-one (1.00 g, 4.54 mmol) was added as a solution in toulene (2 ml) over 2 h via a syringe pump. The reaction was followed by TLC. After completeness, methanol (0.6 ml, 17 mmol) was added at 0° C. and the mixture was evaporated to dryness. Flash chromatography eluting with ethyl acetate:pentane 10:90 gave 0.96 g (95%) of the title compound. Rf 0.35 (ethyl acetate:pentane 20:80) (ChiralCel OD-H) 0.5 ml/min of hexane/isopropanol: 95/5 (S)-isomer 24.53 min, (R)-isomer 27.22 min, 93% ee. IR (neat cm−1): 3300, 1605, 1446, 949, 813. 1H NMR δ: 1.40 (s, 1H), 2.40 (s, 3H), 5.27 (d, J=8 Hz, 1H), 6.43 (d J=2 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.27 (s, 1H), 7.47 (m, 4H), 7.59 (m, 2H). 13C NMR δ: 21.6, 76.2, 121.6, 123.6, 126.9, 127.6, 128.2, 128.6, 134.1, 134.9, 138.2, 142.1, 143.7, 145.6. MS (EI 70 eV) m/z (rel. intensity): 220 (100) [M+], 207 (71), 178 (66), 144 (42), 116 (23).
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=O.[NH2:24][C@@H:25]1[C@@H:30]([OH:31])[CH2:29][CH2:28][O:27][CH2:26]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:10]2[CH:9]=[C:4]3[C:3]([CH2:1][N:24]([C@@H:25]4[C@@H:30]([OH:31])[CH2:29][CH2:28][O:27][CH2:26]4)[C:5]3=[O:6])=[C:12]([CH3:13])[C:11]=2[CH3:14])=[CH:21][CH:20]=1
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(OC)cc2)c(C)c(C)c1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc3c(c(C)c2C)CN([C@H]2COCC[C@@H]2O)C3=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.8 %

Procedure:
To a solution of methyl 2-formyl-5-(4-methoxybenzyl)-3,4-dimethylbenzoate (0.10 g) in THF (1.90 mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.04 g) and anhydrous magnesium sulfate (0.07 g), and the mixture was stirred at room temperature for 5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was diluted with methanol (1.90 mL)-THF (1.90 mL), sodium triacetoxyborohydride (0.13 g) was added thereto, and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1Cl.[CH3:11][O-:12].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[O:12][CH3:11]
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(CO)cc1Cl

Procedure:
(5,6-Dichloro-pyridin-3-yl)-methanol was dissolved in a saturated solution of NaOMe in MeOH and heated to reflux overnight. Evaporation of MeOH, work-up (EtOAc) and evaporation gave the title compound. 1H-NMR (CDCl3) δ 8.03 (d, 1H), 7.72 (d, 1H), 4.65 (s, 2H), 4.04 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc2ccc(F)cc2c(O)c1C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (3.4 g, 10.0 mmol) in methanol (50 mL) was added 10% palladium on carbon (0.5 g). The resulting mixture was vigorously stirred under a hydrogen (balloon) atmosphere overnight. The filtrate was concentrated in vacuo to give (6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (2.44 g, 98%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.69-7.74 (m, 2H), 7.34 (s, 1H), 7.21 (td, J=2.4, 8.4 Hz, 1H), 5.16 (s, 1H), 3.82 (s, 2H), 3.74 (s, 3H), 2.35 (s, 3H); MS cald. for C14H13FO3 248, obsd. (ESI+) [(M+H)+] 249.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]2[C:13](O[C:16](=[O:17])[C:6]=2[CH:5]=1)=[O:14]>C(O)(=O)C>[O:17]=[C:16]1[C:6]2[C:7](=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:4][CH:5]=2)[C:13](=[O:14])[NH:3][NH:2]1
Reactant: NN
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2c(=O)[nH][nH]c(=O)c2c1
Temperature: 120 °C
Yield: 84.9 %

Procedure:
Hydrazine hydrate (26 g, 0.52 mol) was added in one portion to a stirred mixture of 1,2,4-benzenetricarboxylic anhydride (10 g, 0.52 mol), in acetic acid (1.0 L) at room temperature. The mixture was heated to 120° C. for 2 hours and then allowed to cool to room temperature. The solid was filtered, washed with water (250 ml) and dried in the vacuum oven at 50° C. for 20 hours to give the title compound (91 g, 85% yield).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[N:6]1([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)(Cl)Cl>[CH2:1]([NH:3][C:4]([NH:14][CH2:13][CH2:12][CH2:11][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NCCCN1CCCC1
Reactant: CCN=C=O
Solvent: ClC(Cl)Cl
Product: CCNC(=O)NCCCN1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
To a solution of 27.7 g (0.39 mol) ethyl isocyanate in 250 mL chloroform was added 50 g (0.39 mol) 3-(1-pyrrolidinyl)propylamine dropwise with cooling. Once the addition was complete, the cooling bath was removed and the reaction mixture stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to give 74.5 g (96.4%) of the desired urea as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9]Cl)=[C:6]([Cl:8])[N:7]=1.[CH3:13][NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1>>[NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][N:14]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH3:13])=[C:6]([Cl:8])[N:7]=1
Reactant: N#Cc1nc(CCl)c(Cl)nc1N
Reactant: CCOC(=O)c1ccc(NC)cc1
Product: CCOC(=O)c1ccc(N(C)Cc2nc(C#N)c(N)nc2Cl)cc1

Procedure:
The method of synthesizing 7-NR1R2 -MTX wherein either R1 or R2 is hydrogen, and the other is C1 -C5 alkyl, is also outlined in FIGS. 1A and 1B. This method comprises (a) reacting phosphorus oxychloride with 3-amino-6-(chloromethyl)-2-pyrazinecarbonitrile 4-oxide (1) to yield 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile (2); (b) reacting 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile with thionyl chloride to form 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile (4); (c) reacting 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile with ethyl 4-methylaminobenzoate (3) to form ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate (5); (d) reacting ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate with guanidine to form 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate (6); (e) reacting 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate with methylamine to form 4-[N-(2,4-diamino-7-methylamino-y-pteridinylmethyl)-N-methylamino]benzoic acid (7b); and (f) coupling 4-[N-(2,4-diamino-7-methylamino-y-pteridinylmethyl)-N-methylamino]benzoic acid and diethyl L-glutamate to form the diethyl ester of 7-methylamino-MTX.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][S:17]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)(=[O:19])=[O:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]([C:38]2[C:39]([CH3:46])=[C:40]([CH:44]=O)[NH:41][C:42]=2[CH3:43])=[O:37])[CH2:32]1>N1CCCCC1.C(O)C>[OH:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]([C:38]2[C:39]([CH3:46])=[C:40](/[CH:44]=[C:23]3\[C:24](=[O:29])[NH:25][C:26]4[C:22]\3=[CH:21][C:20]([S:17]([CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)(=[O:19])=[O:18])=[CH:28][CH:27]=4)[NH:41][C:42]=2[CH3:43])=[O:37])[CH2:32]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3OCCN3CCOCC3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CC[C@@H](O)C1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4OCCN4CCOCC4)cc32)c(C)c1C(=O)N1CC[C@@H](O)C1
Yield: 69.3 %

Procedure:
5-[2-(2-Morpholin-4-yl-ethoxy)-phenylmethanesulfonyl]-1,3-dihydro-indol-2-one (42 mg, 0.1 mmol) was condensed with 4-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (24 mg, 0.1 mmol) and piperidine (1 drop) in ethanol (1.5 mL) at rt for 48 hours. The solvent was removed and the residue was purified on a silica gel column to give 44 mg (69%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[NH:15][C:16]([CH3:24])=[CH:17][C:18]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:14]1[NH:15][C:16]([CH3:24])=[CH:17][C:18]=1[CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: Cc1cc(CCC(=O)O)c(C=O)[nH]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1cc(CCC(=O)O)c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]1

Procedure:
5-Chloro-1,3-dihydroindol-2-one (61 mg, 0.36 mmol) was condensed with 3-(2-formyl-5-methyl-1H-pyrrol-3-yl)-propionic acid (66 mg) to give the title compound.