Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([O:49][CH2:50][CH3:51])(=[O:48])[CH:46]=[CH2:47]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:13]([O:12][C:10]([CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH:47]=[CH:46][C:45]([O:49][CH2:50][CH3:51])=[O:48])=[CH:3][CH:4]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)CSc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C=Cc1ccc(SCC(=O)OC(C)(C)C)cc1
Yield: 73.7 %

Procedure:
3.46 g of t-butyl [(4-bromophenyl)thio]acetate was mixed with 8 ml diisopropylethylamine, 0.6 g of triphenylphosphine, 5.2 ml ethyl acrylate and 35 ml acetonitrile to form a solution. 0.26 g of palladium acetate was further added to the solution and refluxed under a stream of argon for 44 hours. The reaction mixture was extracted with ethyl acetate, washed with water. The aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated and purified via column chromatography on silica gel (ethyl acetate:hexane=1:20) to give ethyl 4-[[(t-butoxycarbonyl)methyl]thio]cinnamate (2.7 g, 73.7%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:15]=[C:14]([C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:33])[CH:12]=2)[CH:7]=1)C.O.[OH-].[Li+]>O1CCCC1.O>[F:33][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH2:5][C:4]([OH:34])=[O:3])[CH:15]=[C:14]2[C:16](=[O:32])[C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCNCC3)cc2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(C(=O)c2ccc(S(=O)(=O)N3CCNCC3)cc2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
To a stirred solution of {6-fluoro-4-[4-(piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid ethyl ester (0.100 g, 0.17 mmol) in tetrahydrofuran (6 mL) was added a solution of lithium hydroxide monohydrate (0.035 g, 0.83 mmol) in water (1.5 mL) and the reaction mixture was stirred for 48 hours at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with water (8 mL) and washed with ethyl acetate (2×5 mL). The aqueous layer was acidified with an aqueous solution of hydrochloric acid (1 N), then extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.050 g (52%) of {6-fluoro-4-[4-(piperazine-1-sulfonyl)-benzoyl]-naphthalen-2-yl}-acetic acid as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.13-8.17 (m, 1 H), 8.12 (s, 1 H), 7.99 (d, J=8.0 Hz, 2 H), 7.93-7.98 (m, 1 H), 7.89 (d, J=8.0 Hz, 2 H), 7.67 (s, 1 H), 7.57 (td, J=8.6, 2.0 Hz, 1 H), 3.76 (s, 2 H), 2.89 (br. s, 4 H), 2.76 (br. s, 4 H). MS cald. for C23H21FN2O5S [M+] 456, obsd. 456.9.
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([N:12]([NH2:18])C(OCC)=O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.CN(C)[CH:23]=[O:24]>>[CH3:20][O:19][C:7]1[CH:6]=[CH:5][C:4]2[NH:3][C:2](=[O:1])[N:11]3[C:23](=[O:24])[NH:18][N:12]=[C:10]3[C:9]=2[CH:8]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)N(N)c1nc(O)nc2ccc(OC)cc12
Product: COc1ccc2[nH]c(=O)n3c(=O)[nH]nc3c2c1
Temperature: 25 °C

Procedure:
3.0 g (0.011 mol) of ethyl 2-hydroxy-6-methoxy-quinazoline-4-yl-carbazate in 70 ml of dimethylformamide were boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off, washed with methanol and dried in a vacuum. There were obtained white crystals which were recrystallized from methanol/acetone. Yield: 1.16 g (46%) of 9-methoxy-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as beige crystals; m.p. >350° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:8]([CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1ccccc1-c1n[nH]c2ncc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(Br)cc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 5-bromo-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine (4.8 g, 15.8 mmol) in DMF (60 ml) at −40° C. under nitrogen, sodium hydride (1.1 g, 47.3 mmol) was added. The mixture was stirred at −40° C. for 1 hour. Then 2,2-dimethyl-propionic acid chloromethyl ester (6.9 ml, 47.3 mmol; chloromethyl pivalate) in DMF (20 ml) was added dropwise and the resulting mixture was allowed to stir at 40° C. for another 2 hours. The reaction was quenched with saturated aqueous NH4Cl (40 ml) and worked up with ethyl acetate, brine, dried with Na2SO4 and evaporated. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2,2-dimethyl-propionic acid 5-bromo-3-(2-methoxy-phenyl)-pyrazolo[3,4,b]pyridine-1-ylmethyl ester (4.1 g, 62% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.11 (s, 9H), 3.85 (s, 3H), 6.46 (s, 2H), 7.09 (m, 1H), 7.24 (d, 1H), 7.51 (m, 1H), 7.60 (d, 1H), 8.43 (s, 1H), 8.74 (s, 1H).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][O:10][C:9]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]3[O:17][C:16]([CH3:26])([CH3:25])[CH2:15][CH2:14][C:13]=3[C:12]2=[O:27])[O:8]1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C.C(Cl)Cl>[N:28]([CH2:6][CH:7]1[CH2:11][O:10][C:9]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]3[O:17][C:16]([CH3:26])([CH3:25])[CH2:15][CH2:14][C:13]=3[C:12]2=[O:27])[O:8]1)=[N+:29]=[N-:30]
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(COS(C)(=O)=O)O1)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CN=[N+]=[N-])O1)C2=O
Temperature: 100 °C
Yield: 14.6 %

Procedure:
To a solution of 4′-(hydroxymethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (316 mg, 1.0 mmol) in dichloromethane (2 mL) is added methanesulfonyl chloride (0.095 mL, 1.3 mmol) and triethylamine (0.163 mL, 1.24 mmol). The mixture is stirred at room temperature for 2 hours. The reaction mixture is washed with water (2×1.0 mL), dried over sodium sulfate and concentrated to provide (2,2-dimethyl-5-oxo-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-4′-yl)methyl methanesulfonate as a white solid (99% by LC/MS, UV 254 nm). The (2,2-dimethyl-5-oxo-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-4′-yl)methyl methanesulfonate (197 mg, 0.5 mmol) is dissolved in DMF (2 mL) followed by the addition of sodium azide (97 mg, 1.5 mmol). The reaction is heated at 80° C. for 24 hour and 100° C. for 12 h. The mixture is diluted with CH2Cl2 (4 mL), washed with water (2 ml) and concentrated. The organic layer is dried with sodium sulfate, concentrated under reduced pressure and purified by flash column chromatography (SiO2, 30% EtOAc in hexane) to provide 4′-(azidomethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (25 mg, 15%) as a white solid. 400 MHz 1H NMR (CDCl3) δ: 7.78-7.56 (m, 1H), 7.60-7.57 (m, 1H), 7.44-7.40 (m, 2H), 4.68-4.62 (m, 1H), 4.46-4.42 (m, 1H), 4.23 (t, J=8 Hz, 1H). 3.96-3.91 (m, 1H), 3.54-3.49 (m, 1H), 2.48-2.42 (m, 2H), 1.79 (t, J=6.8 Hz, 2H), 1.42 (d, J=3.2 Hz, 6H); LCMS: 342 [M+H].
Reaction SMILES: C(O[CH:5]1[S:9][C@@H:8]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)(=O)C.[Cl:29][C:30]1[N:38]=[C:37]2[C:33]([NH:34][CH:35]=[N:36]2)=[C:32]([Cl:39])[N:31]=1>>[Si:12]([O:11][CH2:10][C@@H:8]1[S:9][C@H:5]([N:36]2[CH:35]=[N:34][C:33]3[C:37]2=[N:38][C:30]([Cl:29])=[N:31][C:32]=3[Cl:39])[CH2:6][CH2:7]1)([C:25]([CH3:27])([CH3:26])[CH3:28])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)OC1CC[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Product: CC(C)(C)[Si](OC[C@H]1CC[C@@H](n2cnc3c(Cl)nc(Cl)nc32)S1)(c1ccccc1)c1ccccc1
Yield: 60 %

Procedure:
9-[5-O-(tert-Butyldiphenylsilyl)-2,3-dideoxy-4-thio-beta-L-ribofuranosyl]-2,6-dichloropurine (69) was synthesized from the acetate 57 and 2,6-dichloropurine by the similar methodology as described for the synthesis of compound 62 in an approximate 2:3 alpha/beta anomer ratio in 60% yield. The alpha and beta anomers were separated by silica gel column chromatography. Compound 69 was treated with saturated ammonia/methanol and then deprotected with 1M tetrabutylammonium fluoride in THF to provide 2',3'-dideoxy-4'-thio-2-chloro-beta-L-adenosine (70 R'=R"=H) in 52% yield: MS m/e 286 (m+ +1); 1HNMR (DMSO-d6) delta 8.46 (s, 1H, 2-H), 7.82 (br s, 2H, NH2, D2O exchangeable), 6.10 (m, 1H, 1'-H), 5.10 (m, 1H, 5'-OH, D2O exchangeable), 3.74 (m, 1H, 4'-H), 3.60 (m, 2H, 5'-H), 2.42 (m, 2H, 2'-H), 2.13 (m, 1H, 3'-H), 2.02 (m, 1H, 3'-H).
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:28]([S:31]([NH2:34])(=[O:33])=[O:32])([CH3:30])[CH3:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:34][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)S(N)(=O)=O
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)C(C)C)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and isopropylsulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (13%); 1H NMR (d6-DMSO) δ 11.60 (br s, 1H), 7.46 (d, J=15.7 Hz, 1H), 7.40-7.09 (m, 12H), 6.86 (d, J=8.1 Hz, 2H), 6.48 (d, J=15.7 Hz, 1H), 3.64 (m, 1H), 2.37 (q, J=7.3 Hz, 2H), 1.23 (d, J=7.0 Hz, 6H), 0.83 (t, J=7.3 Hz, 3H); APcI m/z: 460 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(Cl)cc4)cc3c2C1
Yield: 17.1 %

Procedure:
To a mixture of 10.6 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 14.0 mg (0.12 mMol) polyvinylpyridine in 3.0 mL dichloromethane were added 8.8 μL (0.069 mMol) 4-chlorobenzoyl chloride. The reaction mixture was mixed for 1 day at ambient temperature. To this mixture were then added 160 mg (0.128 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was diluted with 1.0 mL methanol, treated with potassium carbonate, and filtered through a short column of sodium sulfate. The filtrate was then evaporated to give 2.9 mg (17%) of the title compound as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C[O-].[Na+].Cl[C:15]1[C:16]2[N:24]=[N:23][N:22]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:17]=2[N:18]=[C:19]([CH3:21])[N:20]=1>C(#N)C>[CH2:26]([CH:25]([N:22]1[C:17]2[N:18]=[C:19]([CH3:21])[N:20]=[C:15]([O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:16]=2[N:24]=[N:23]1)[CH2:28][CH3:29])[CH3:27]
Reactant: CCC(CC)n1nnc2c(Cl)nc(C)nc21
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(CC)n1nnc2c(Oc3c(C)cc(C)cc3C)nc(C)nc21
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
2,4,6-Trimethylphenol (0.114) was added to a solution of sodium methoxide (0.334 g) methanol (10 mL) and the resulting solution was evaporated to dryness under reduced pressure. The salt thus obtained was taken up in 10 mL of acetonitrile and added dropwise by to a cold solution (0-5° C.) of 7-chloro-3-(1-ethylpropyl)-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidine in 35 mL of acetonitrile, such that the temperature did not rise above 5° C. The mixture was stirred at 0-5° C. for 3 hours. The solvent was then removed from the mixture under reduced pressure and the residue treated with water and extracted three times with methylene chloride. The combined extracts were dried over MgSO4 and stripped of the solvent under reduced pressure. The material was purified on silica gel using a solution of 1% methanol in methylene chloride to yield the title compound as a colorless powder, mp 92° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:10]=[C:11](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[C:19]([NH:23][C:24]4[C:29]([N+:30]([O-])=O)=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:20]=[CH:21][CH:22]=3)[CH:12]=[N:13][CH:14]=2)=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(O)C.O.[Fe]>[NH2:30][C:29]1[C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17](/[CH:16]=[CH:15]/[C:11]3[CH:12]=[N:13][CH:14]=[C:9](/[CH:8]=[CH:7]/[C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:10]=3)[CH:18]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cncc(/C=C/c3ccncc3)c2)c1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccnc1Nc1cccc(/C=C/c2cncc(/C=C/c3ccncc3)c2)c1
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
A mixture of 2-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenylamino]-3-nitropyridine (331 mg), iron powder (132 mg) and ammonium formate (297 mg) in ethanol (6 ml) and water (2 ml) was stirred at 90pbC. for 30 minutes. The mixture was filtered while hot. The filtrate was added to aqueous sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic solution was washed with sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was washed with diisopropyl ether to give 3-amino-2-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenylamino]pyridine (270 mg).
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: CCOC(=O)c1ccc(NC)cc1
Reactant: N#Cc1nc(CCl)c(Cl)nc1N
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: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)#[N:29]>>[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:35])=[CH:32][CH:31]=1)#[N:29]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)cc1

Procedure:
The title compound, off-white solid (111 mg, 97%), MS (ISP) m/z=460.5 [(M+H)+], mp 262.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-cyano-benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:37])[O:13][C@@H:14]([CH3:36])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4[CH:27]=[CH:28][C:29]([C:31](=[O:33])[CH3:32])=[CH:30][C:25]=4[N:24]=[C:23]3[CH2:34][CH3:35])=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12](=[O:37])[O:13][C@H:14]([CH3:36])[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[C:26]4[CH:27]=[CH:28][C:29]([C:31](=[O:33])[CH3:32])=[CH:30][C:25]=4[N:24]=[C:23]3[CH2:34][CH3:35])=[CH:20][CH:21]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(C[C@H](C)OC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(C[C@@H](C)OC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.7 %

Procedure:
To a solution of (1R)-1-methyl-2-(4-nitrophenyl)ethyl propanoate (step 1 of Example 248, 1.91 g, 8.05 mmol) in ethanol (20 ml) was added 2N aqueous NaOH (5 ml) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water, extracted with diethyl ether (2×50 ml). The organic layer was washed with brine, dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/diethyl ether (1:1) afforded 1.16 g (80%) of title compound as a colorless solid (79% e.e.). Recrystallization from hexane/diethyl ether afforded 717 mg of a colorless needle (99% e.e.).
Reaction SMILES: CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[C:34]([O:36][CH2:37][CH3:38])=[O:35].[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1>C1COCC1.C(OCC)(=O)C>[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[C:26]2[C:34]([O:36][CH2:37][CH3:38])=[O:35])(=[O:48])=[O:47])=[CH:42][CH:41]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of 0.5 g of potassium t-butoxide and 0.1 g of 18-crown-6 in 3 mL of THF, a mixed solution of 0.7 g of ethyl 1H-indole-2-carboxylate and 3 mL of THF was added, and the resulting mixture was stirred at room temperature for 30 minutes. The solution was cooled with ice, 1.13 g of 4-bromobenzenesulfonyl chloride was added, and the resulting mixture was stirred at room temperature for 5 hours. To the solution was added 60 mL of ethyl acetate, the resulting mixture was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:5) to obtain 1.44 g of ethyl 1-[(4-bromophenyl)sulfonyl]-1H-indole-2-carboxylate as a pale yellow syrup. FAB+: 408, 410
Reaction SMILES: [C:1]1([CH2:7][C:8]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]3[CH2:13][NH:14][CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:25][C:26]1[CH:35]=[CH:34][C:29]([CH2:30][N:31]=[C:32]=[O:33])=[CH:28][CH:27]=1>O1CCCC1>[C:19]1([CH2:18][C:8]2([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]3[CH2:13][N:14]([C:32]([NH:31][CH2:30][C:29]4[CH:34]=[CH:35][C:26]([F:25])=[CH:27][CH:28]=4)=[O:33])[CH2:15][CH2:16][N:11]3[C:10](=[O:17])[O:9]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C=NCc1ccc(F)cc1
Reactant: O=C1OC(Cc2ccccc2)(Cc2ccccc2)C2CNCCN12
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)N1CCN2C(=O)OC(Cc3ccccc3)(Cc3ccccc3)C2C1
Temperature: 50 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
To 1,1-bis(phenylmethyl)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one (0.16 g, 0.50 mmol) were added tetrahydrofuran (10 mL) and 4-fluorobenzyl isocyanate (0.30 g, 2.0 mmol), and the mixture was stirred at 50° C. for 4 hours. The reaction solution was concentrated, and then the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate). The fractions were collected and concentrated. To the residue was added diisopropyl ether, and the obtained solid matter was collected by filtration and washed with diisopropyl ether to obtain the title compound (0.17 g, yield 70%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].[I:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[I:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Reactant: Nc1ccccc1I
Product: NS(=O)(=O)c1ccc(NC(=S)Nc2ccccc2I)cc1

Procedure:
The subject compound was prepared utilizing the procedure described above from 4-isothiocyanatobenzenesulfonamide and 2-iodoaniline. 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.60 (s, 1H), 7.90-7.81 (m, 8H), 7.76 (bs, 2H); (M+H)+ (434).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]([C:21](=[O:22])[CH2:20][Cl:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CN(C(=O)CCl)c1ccccc1
Yield: 69.1 %

Procedure:
To methylene chloride (20 ml) was added N-phenylglycine methyl ester (2.02 g, 10 mmol) and pyridine (1.58 g, 20 mmol) and the mixture was stirred. To the mixture was added dropwise a solution of chloroacetyl chloride (1.13 g, 10 mmol) in methylene chloride (3 ml) at room temperature and the resulting mixture was stirred for 15 hours, washed with water, dried and evaporated. The resultant residue was crystallized from isopropyl ether to give N-chloroacetyl-N-phenylglycine methyl ester (1.67 g, 70%) as a colorless powder.