Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][N:5]=[C:4]([C:9]([NH:11][C@@H:12]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[C:22]([F:31])[CH:21]=2)[C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:10])[CH:3]=1.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl.CCOC(C)=O>C1COCC1.CCCCCC>[F:31][C:22]1[CH:21]=[C:20]([C@@H:12]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[NH:11][C:9]([C:4]2[N:5]=[CH:6][C:7]3[O:8][C:33](=[O:35])[NH:1][C:2]=3[CH:3]=2)=[O:10])[CH:25]=[CH:24][C:23]=1[O:26][C:27]([F:28])([F:29])[F:30]
Reactant: Nc1cc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ncc1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1cc2[nH]c(=O)oc2cn1
Temperature: -78 °C

Procedure:
To a cooled (−78° C.) stirred mixture of (S)-4-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxypicolinamide (200 mg, 0.00045 mol) in THF (5 mL) were added TEA (0.31 mL, 0.002 mol, Spectrochem, India) and triphosgene (270 mg, 0.0009 mol, Spectrochem, India) in one lot and the reaction mixture was stirred for 2 h at the same temperature, warmed to rt and stirred for 12 h. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), the reaction mixture was quenched with sat'd NaHCO3 (5 mL), extracted with EtOAc (10 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated. The product thus obtained was purified by column chromatography, silica gel (60-120 mesh) using 50-60% EtOAc in petroleum ether as the eluent, and further purified using Prep TLC plates, mobile phase 50% EtOAc in hexanes to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (d, J=7.6 Hz, 1H), 8.60 (s, 1H), 8.58 (d, J=4.8 Hz, 1H), 7.82 (t, J=8.8 Hz, 1H), 7.70 (s, 1H), 7.56-7.50 (m, 3H), 7.34 (d, J=8.4 Hz, 1H), 6.53 (d, J=6.8 Hz, 1H). MS (ESI, positive ion) m/z: 468.0 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].Cl[CH2:16][C:17]([CH2:19]Cl)=[CH2:18].O>CN(C=O)C>[CH3:12][CH:2]1[CH2:3][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])[CH2:19][C:17](=[CH2:16])[CH2:18][O:1]1
Reactant: CC(O)CNC(=O)OC(C)(C)C
Reactant: C=C(CCl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C1COC(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a mixture of tert-butyl N-(2-hydroxypropyl)carbamate (5.00 g, 28.54 mmol, 1.00 eq) in DMF (100.00 mL), was added NaH (2.51 g, 62.79 mmol, 2.20 eq) in one portion at 0° C. under N2. The mixture was stirred at 0° C. for 1 hr, then 3-chloro-2-(chloromethyl)prop-1-ene (3.57 g, 28.54 mmol, 1.00 eq) was added to the mixture, the mixture was stirred at 0° C. for 4 hr. TLC showed the reaction was completed. The mixture was poured into water (100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL*2). The combined organic phase was washed with saturated brine (100 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=10/1) to afford tert-butyl 2-methyl-6-methylene-1,4-oxazepane-4-carboxylate (2.20 g, 9.68 mmol, 33.91% yield) as yellow oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([Cl:14])[CH:6]=1)=[N+:2]=[N-:3].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][N:16]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:22])=[O:10])=[C:7]([Cl:14])[CH:6]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1ccc(C(=O)O)c(Cl)c1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc(C(=O)ON2C(=O)CCC2=O)c(Cl)c1
Yield: 97 %

Procedure:
A solution of 4-(azidomethyl)-2-chlorobenzoic acid (6.82 g, 32.2 mmol), N-hydroxysuccinimide (5.19 g, 45.1 mmol) and dicyclohexylcarbodiimide (9.31 g, 45.1 mmol) in tetrahydrofuran (250 Ml) was stirred overnight at room temperature. The dicyclohexylurea (7.70 g, 76%) was filtered off and discarded. Silica gel was added, the solvent was evaporated and the residue was chromatographed (40–60% ethyl acetate/hexanes) to give 1-[[4-(azidomethyl)-2-chlorobenzoyl]oxy]-2,5-pyrrolidinedione (9.64 g, 97%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].C(O[CH:19](OCC)[CH2:20][Cl:21])C>>[Cl:21][CH2:20][CH:19]1[O:10][CH2:9][C:6]([O:5][CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[Cl:1])([CH3:11])[CH2:7][O:8]1
Reactant: CCOC(CCl)OCC
Reactant: CC(CO)(CO)OCc1ccccc1Cl
Product: CC1(OCc2ccccc2Cl)COC(CCl)OC1

Procedure:
By the method of Example 39, 2-(2-chlorobenzyloxy)-2-methyl-1,3-propanediol was reacted with chloroacetaldehyde diethyl acetal to yield a mixture of isomers which were separated by column chromatography. The cis-isomer was a solid, m.p. 53°-54° C. The trans-isomer was a liquid, b.p. 104°-107° C/0.02 mm Hg; nD25 1.5280.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[I-].[CH3:11][S+](C)C.[OH-].[K+]>CC#N.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[CH2:11][O:9]2)[N:7]=1
Reactant: C[S+](C)C
Reactant: O=Cc1cccc(F)n1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Fc1cccc(C2CO2)n1
Temperature: 67.5 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
A mixture of 6-fluoro-pyridine-2-carbaldehyde (1.88 g, 15 mmol), trimethylsulfonium iodide (3.3 g, 16.2 mmol) and KOH (crashed, 3.46 g, 61.9 mmol) in CH3CN (190 mL, containing 0.2 mL of water) was stirred at 65-70° C. under N2 for overnight. The mixture was cooled to rt and diluted with EtOAc (100 mL). After filtration, the filtrate was concentrated. The residue was portioned between H2O (100 mL) and EtOAc (80 mL), the aqueous layer was further extracted with EtOAc (4×80 mL). the combined EtOAc was dried (Na2SO4) and concentrated. The residue was subjected to ISCO (40 g column, hexane 3 min. then 0-60% EtOAc in hexane over 60 min.) to give the desired product (530 mg).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH:19]=[O:20])[C:6]3[C:11]([C:12]=2[CH:16]=[O:17])=[CH:10][C:9]([OH:18])=[CH:8][CH:7]=3)[CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[C:28](O)(=[O:30])[CH3:29]>>[C:21]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([CH:19]=[O:20])[C:6]3[C:11]([C:12]=2[CH:16]=[O:17])=[CH:10][C:9]([O:18][C:28](=[O:30])[CH3:29])=[CH:8][CH:7]=3)[CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: O=Cc1c2ccc(O)cc2c(C=O)c2ccc(O)cc12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc2c(C=O)c3cc(OC(C)=O)ccc3c(C=O)c2c1

Procedure:
A solution of 2.66 g. (0.01 mole) of 2,6-dihydroxy-9,10-anthracenedicarboxaldehyde in 100 ml. of hot glacial acetic acid is treated with 2.5 g. (0.025 mole) of acetic anhydride. The mixture is stirred, heated on a steam for one hour, then allowed to cool yielding crystals of 2,6-diacetoxy-9,10-anthracenedicarboxaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[CH2:22]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a mechanically stirred solution of 4-fluoro-3-nitro-benzoic acid (113.0 g, 0.61 mol, 1.0 equiv) in DMF (770 ml) was added portionwise potassium carbonate (168.7 g, 1.22 mol, 2.0 equiv). Allyl bromide (110.8 g, 0.92 mol, 1.5 equiv) was added to the reaction mixture and stirring continued at rt overnight. The reaction mixture was filtered, the filtrate poured into water (4 L), kept for 2 h and then extracted with ethyl acetate (3×1 L). The organic layer was washed with water, dried over Na2SO4 and concentrated by evaporation under reduced pressure. The residue was purified with silica column chromatography eluting with a gradient of hexane/ethyl acetate (100:0→98:2) to obtain 114.1 g (83%) of the title compound. 1H NMR (400 MHz, DMSO): δ 4.86 (d, J=5.4 Hz, 2H), 5.30 (d, J=10.6 Hz, 1H), 5.43 (d, J=17.2, 1H), 6.01-6.10 (m, 1H), 7.73-7.78 (m, 1H), 8.34-8.37 (m, 1H), 8.60 (d, J=7.2 Hz, 1H).
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]#[CH:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:17])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCOC(C)=O.O.[Si]([N:29]=[N+:30]=[N-:31])(C)(C)C>>[CH:1]1([C:5]2[C:14]([C:15]3[CH:16]=[N:31][NH:30][N:29]=3)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:17])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1cc(C(=O)OC)c(C)cc1C1CCC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cn[nH]n2)c(C2CCC2)cc1C
Temperature: 170 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Methyl 4-cyclobutyl-5-ethynyl-2-methylbenzoate (compound 446.2, 180 mg, 0.69 mmol) was dissolved in TMSN3 (1 ml) in sealed tube. The reaction was heated to 170° C. for 24 hours behind a blast shield then cooled down to 0° C. EtOAc (10 ml) and water (20 ml) were added. The resulting mixture was stirred at RT for 1 hr. The organic phase was then washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (SiO2; 0-30% EtOAc in Hexane) to give 92 mg (49%) of the title compound as a liquid. m/z (ES+) (272) (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.83 (s, 1H), 7.35 (s, 1H), 3.90 (s, 4H), 2.69 (s, 3H), 2.27-2.15 (m, 2H), 2.13-2.03 (m, 2H), 1.99-1.90 (m, 1H), 1.86-1.76 (m, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[O:15]1[C:19]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[O:15]1[C:19]2([CH2:24][CH2:23][N:22]([C:2]3[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=3)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)CCC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Yield: 47 %

Procedure:
A mixture of 19.6 g of 4-fluoro-γ-oxobenzenebutanoic acid [prepared by following the procedure of W. Adcock and M. J. S. Dewar, J. Amer. Chem. Soc., 89, 2(1967)], 14.3 g of 1,4-dioxa-8-azaspiro[4,5]decane and 13.9 g of anhydrous K2CO3 in 75 ml of DMSO is heated at 100° C. for 18 hours and cooled. The reaction mixture is filtered and the residue is washed with DMSO. The filtrate and the washings are diluted with 300 ml of water and the pH of the solution is adjusted to 6. The solid is filtered, washed with water, and air-dried to yield 15.0 g of 4-(1,4-dioxa-8-azaspiro [4,5]-dec-8-yl)-γ-oxobenzenebutanoic acid as off-white powder, mp 130°-131° C.
Reaction SMILES: [S:1]([CH3:13])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].Cl[Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.ClCCCl.ClCCl>[Si:15]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([S:1][CH3:13])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]1[OH:8])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A mixture of methyl 1-thio-β-D-galactopyranoside (25) 5 g, 28 mmol), chloro t-butyldiphenylsilane (5.85 g, 21 mmol) and DMAP (2.63 g, 21 mmol) in dry 1,2-dichloroethane (130 mL) was left to stir at reflux for 2.5 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (200 mL) and washed with saturated sodium chloride solution (2×250 mL). The organic phase was dried over MgSO4 and subsequently evaporated to dryness to give methyl 6-O-(t-butyldiphenylsilyl)-1-thio-β-D-galactopyranoside (26) (7.5 g, 81%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:13][C:14](=[O:29])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[CH:3]1.[CH2:31]=[O:32]>O>[OH:32][CH2:31][N:13]1[C:14](=[O:29])[C:15]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[C:12]1=[O:30]
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Reactant: C=O
Solvent: O
Product: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(CO)C2=O)c2ccccc21
Reaction time: 14 h

Procedure:
A suspension consisting of 0.5 g (1.25 mmole) of 3-(1-methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dione (See Davis U.S. Pat. No. 5,057,614), 4.0 ml of formaldehyde solution (37% w/w), and 2.0 ml of water was heated to 125° C. with stirring and with a reflux condensed attached for 14 hours. The reaction mixture was cooled and diluted with water. The red solid was filtered, washed with water and dried. The solid was purified by chromatography using silica gel and a mixture of EtOAc/Hexane as elutant to afford 1-hydroxymethyl-3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (mp=209-211° C.).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([OH:19])=O.C(N(CC)CC)C.[NH2:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][C:17]([NH:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:19]
Reactant: O=C(O)C=Cc1ccco1
Reactant: CCOC(=O)c1ccccc1N
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1NC(=O)C=Cc1ccco1
Yield: 30.2 %

Procedure:
Under nitrogen stream, 2-chloro-1-methylpyridinium iodide (1.272 g, 4.34 mmol) was suspended in dry methylene chloride (5 ml). To the suspension a solution of 3-(2-furyl)acrylic acid (500 mg, 3.62 mmol), triethylamine (1.2 ml, 8.69 mmol), and ethyl 2-aminobenzoate (0.53 ml, 3.62 mmol) in dry methylene chloride (5 ml) was added. The mixture was heated under reflux for 40 hours. Then, the reaction mixture was diluted with methylene chloride, and washed with 10% aqueous HCl, saturated aqueous sodium chloride, 1N-aqueous NaOH, and saturated aqueous sodium chloride successively, and dried. Removal of solvent gave a viscous oil, which, on washing with n-hexane gave white solids of the title compound (312 mg, yield: 30.2%), which was recrystallized from methanol. m.p., 85°-86° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=[O:13])[CH:7]=1.[Cl:19][C:20]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=S)=[CH:30][C:21]=1[O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH3:29]>CC#N.CN(C=O)C>[Cl:19][C:20]1[CH:33]=[CH:32][C:31]([NH:34][C:35]2[O:18][C:17]3[CH:16]=[CH:15][C:4]([O:5][C:6]4[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=[O:13])[CH:7]=4)=[CH:3][C:2]=3[N:1]=2)=[CH:30][C:21]=1[O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH3:29]
Reactant: NC(=O)c1cc(Oc2ccc(O)c(N)c2)ccn1
Reactant: CN1CCC[C@H]1COc1cc(N=C=S)ccc1Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1COc1cc(Nc2nc3cc(Oc4ccnc(C(N)=O)c4)ccc3o2)ccc1Cl

Procedure:
To a stirring RT solution of 4-(3-amino-4-hydroxy-phenoxy)-pyridine-2-carboxylic acid amide (Step d, 217 mg, 0.884 mmol) in CH3CN (30 ml) and DMF (3 mL) was added (2S)-2-(2-chloro-5-isothiocyanato-phenoxymethyl)-1-methyl-pyrrolidine (208 mg, 0.737 mmol). The following day, the CH3CN was evaporated off, and the crude mix was diluted into 1N NaOH and EtOAc. The layers were separated. The aqueous layer was extracted 3× with EtOAc, and the combined organic layers were washed once with 1N NaOH and once with brine. The organic layer was then dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield the title compound. (MH+)=494.2; Calc'd 493.15 for C25H24ClN5O4.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][SH:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(Cl)Cl>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][S:31][C:2]2[N:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Reactant: Fc1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(-n2cnc(SCc3ccc(F)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A mixture of 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one Part A of procedure 11 (20 mg, 0.06 mmol), (4-fluorophenyl)methanethiol (26 mg, 0.18 mmol), and potassium carbonate (25.5 mg, 0.185 mmol) in THF (0.5 mL) was stirred at 70° C. overnight. The reaction was diluted with CH2Cl2, filtered, and concentrated. The crude product was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product 6-(4-fluorobenzylthio)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one H-3 (17.25 mg, 0.038 mmol, 61.8% yield) as off-white solid. LC/MS 431 (M+H)+, tR 0.91 min (method 5). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.14 (1H, s), 7.35-7.45 (2H, m), 6.95-7.09 (3H, m), 6.80-6.90 (2H, m), 6.49 (1H, s), 4.28 (2H, s), 3.88 (5H, s), 1.39 (6H, s)
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]([F:46])([F:45])[C:33]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:34]=1[CH2:35]Br.Cl>CC(N(C)C)=O>[F:31][C:32]([F:45])([F:46])[C:33]1[CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=[CH:37][C:34]=1[CH2:35][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:24]
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1=O
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2,4-bis(trifluoromethyl)benzyl bromide (375 uL, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from acetic acid-water gave the title compound (180 mg, 34%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 8.06 (s, 1 H), 7.98 (d, J=8.59 Hz, 1 H), 7.53 (d, J=8.34 Hz, 1 H), 5.23 (s, 2 H), 4.64 (t, J=12.00 Hz, 1 H), 4.13 (d, J=5.56 Hz, 2 H), 2.24 (q, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.52-1.73 (m, 3 H), 1.28 (q, J=13.05 Hz, 2 H), 1.10 (q, 1 H).
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9](I)=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:25]=2)O1>COCCOC.O>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][CH:26]([N:24]2[CH:25]=[C:21]([C:9]3[CH:8]=[N:7][C:6]([NH2:11])=[C:5]4[O:12][C:2]([Cl:1])=[CH:3][C:4]=34)[CH:22]=[N:23]2)[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: Nc1ncc(I)c2cc(Cl)oc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Yield: 91.3 %

Procedure:
A mixture of 2-chloro-4-iodofuro[2,3-c]pyridin-7-amine (7.7 g, 26.2 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (10.52 g, 27.7 mmol) in 1,2-dimethoxyethane (300 mL) and water (100 mL) was sparged with N2 for 15 min, then treated with K2CO3 and Pd(PPh3)4. After sparging again with N2 for 5 min, the mixture was heated at reflux 4-6 h. The 1,2-dimethoxyethane was removed in vacuo, water was added and the mixture extracted with DCM. The combined DCM extracts were dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography using triethylamine-coated silica (2% MeOH:DCM) to afford 10 g (80%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.44-1.55 (m, 9H) 1.90-2.12 (m, 2H) 2.21 (d, J=10.61 Hz, 2H) 2.84-3.03 (m, 2H) 4.22-4.44 (m, 3H) 5.26 (br s, 2H) 6.77 (s, 1H) 7.65 (s, 1H) 7.73-7.79 (m, 1H) 7.92 (s, 1H).
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2>>[CH:1]1([S:7][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1CCCCC1
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Product: O=C1CCc2cc(OCCCCSC3CCCCC3)ccc2N1

Procedure:
Prepared analogous to Example 1 from cyclohexyl-mercaptan and 6-(4-chloro-butoxy)-3,4-dihydro-carbostyril
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH:23]1[CH2:29][C:27](=[O:28])[NH:26][C:24]1=[O:25].N1CCCCC1>CCO>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([CH:21]=[C:29]4[NH:23][C:24](=[O:25])[NH:26][C:27]4=[O:28])=[C:14]3[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)Oc1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)Oc1cccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)c1
Temperature: 70 °C

Procedure:
To 5-(3-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (80 mg, 0.270 mmol) in EtOH was added hydantoin (27 mg, 0.270 mmol) and piperidine (27 μL, 0.270 mmol). The mixture was heated at 70° C. for several hours. The solid produced was isolated by filtration to yield 5-((5-(3-isopropoxyphenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=379)