Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C([N:18](CC)CC)C.[Br:23][CH2:24][C:25](Br)=[O:26]>C1COCC1>[Br:23][CH:24]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15])[C:25]([NH2:18])=[O:26]
Reactant: CCN(CC)CC
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Solvent: C1CCOC1
Product: NC(=O)C(Br)c1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64.1 A solution of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to C. F. Bigge et al., patent application WO 2003045912) in 150 ml THF was treated with 5.8 ml triethylamine and 3.2 ml bromoacetyl bromide. The reaction mixture was stirred overnight at r.t., then again treated with 2.1 ml bromoacetyl bromide. After stirring overnight at r.t., the solid was filtered off and washed with THF. Then it was dissolved 1 l EtOAc and washed 2× with 100 ml H2O. The organic layer was dried over MgSO4, filtered and concentrated to give 3.0 g 2-bromo-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-acetamide as off-white solid. MS 325.1 ([M+H]+)
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[O-:2].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O+]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)C.[CH2:33]([C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].NC1C=CC=CC=1>C(#N)C>[S:1](=[O:3])(=[O:2])([OH:5])[O-:4].[CH2:33]([C:43]1[CH:44]=[CH:45][C:46]([N+:47]2[C:12]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:14]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:48][CH:49]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCc1ccc(N)cc1
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Agent: O=S(=O)([O-])O
Solvent: CCO
Solvent: Nc1ccccc1
Solvent: CC#N
Product: CCCCCCCCCCc1ccc(-[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)cc1

Procedure:
In a 500-ml round-bottom flask is placed 2.03 g (0.005 mole) of 2,4,6-triphenylpyrylium bisulfate. To this is added 150 ml of ethanol followed by 2.34 g (0.01 mole) of p-decylaniline. This mixture is refluxed for about 8 hours and allowed to cool. A quantity of the starting aniline precipitates and is removed by filtration. The ethanol is then removed to give a yellow waxy material which is washed with ether to give a white powder. This material is then dissolved in acetonitrile to cause the remaining aniline to precipitate. The acetonitrile is removed to give the desired product which is then rinsed with ether to remove any residual acetonitrile. The yield is 1.77 g (0.0028 mole) of 2,4,6-triphenylpyridinium bisulfate as confirmed by nuclear magnetic resonance (1H) and elemental analysis.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][C:6]#[N:7].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]([CH2:2][CH:3]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][C:6]#[N:7])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCC(CO)CCC#N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(CCC#N)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 66 h
Yield: 82.7 %

Procedure:
To a mixture of 45.50 g (0.323 mol) of crude 4-(hydroxymethyl)heptanenitrile and 53.5 g of t-butyldimethylsilyl chloride in 450 mL of methylene chloride at 3°-4° C., under argon, was added a solution of 67.5 mL (50.1 g, 0.388 mol) of diisopropylethylamine in 67.5 mL of methylenechloride dropwise over 10 min. 3.94 g (32.2 mmol) of 4-dimethylaminopyridine was then added and after stirring at room temperature for 66 hr, the dark reaction mixture was washed with 150 mL of 2N hydrogen chloride solution, 150 mL of water and 150 mL of saturated brine, dried (MgSO4), filtered, and concentrated. The residue was redissolved in methylene chloride, 180 g of silica gel was added and the solvent was removed under vacuum. The residual powder was placed on top of a 23/8"×9" column of 270 of silica gel and eluted, sequentially, with 1 L of hexane, 1 L of 1:19 ethyl acetate:hexane and I L of 1:9 ethyl acetate:hexane; 500-mL fractions were collected. Fractions 3-7 were combined and concentrated in vacuo, and the residue was distilled to give 68.22 g (82.9%) of 4-(t-butyldimethylsiloxymethyl)heptanenitrile, bp 114°-117° C. (0.9-1.0 mm Hg).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[Si]([N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CN1CCN([Si](C)(C)C(C)(C)C)CC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Yield: 312 %

Procedure:
0.5 g (1.85 mmol) of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (II, R1 : ethyl; X: chloro) and 1.07 g (0.50 mmol) of 4-(t-butyldimethylsilyl)-1-methyl piperazine (III, R2, R3 and R4 : methyl; R5 : t-butyl) are added to 100 ml of acetonitrile and then heated with stirring. A solution of 1.60 g (0.50 mmol) of tetrabutyl ammonium fluoride trihydrate in 5 ml of acetonitrile is added dropwise to the reaction mixture. After heating with stirring for 3 hours,the solvent is stripped off and water is added thereto to give a solid. After filtering and drying, 0.52 g (85% yield) of a solid compound is afforded.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]([O:22]C)=[O:21])[CH:13]=2)[O:9][N:8]=1.[OH-].[Na+]>CO.O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]([OH:22])=[O:21])[CH:13]=2)[O:9][N:8]=1
Reactant: COC(=O)c1cc(OC)cc(-c2nc(-c3ccccn3)no2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A stirred suspension of 3-(2-pyridyl)-5-(3-methoxycarbonyl-5-methoxyphenyl)-1,2,4-oxadiazole (191.3 mg, 0.62 mmol) in methanol-tetrahydrofuran (1:1, 10 mL) was treated with 1M sodium hydroxide (1.5 mL, 1.5 mmol). The reaction was stirred at 50° C. for 5 hours and the solvent then removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH 4-5) by the addition of 2 N hydrogen chloride. The precipitate was collected and dried to afford 131.8 (72%) of 3-(2-pyridyl)-5-(3-carboxy-5-methoxyphenyl)-1,2,4-oxadiazole: 1H NMR (DMSO): δ-8.81 (d, 1H), 8.28 (s, 1H), 8.21 (d, 1H), 8.06 (t, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.65 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:22][CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34]>N1C=CC=CC=1.O>[O:34]=[C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32](=[O:33])[N:24]1[CH2:23][CH2:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([CH2:12][NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:14]=2)[NH:18][CH:17]=1
Reactant: NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(CNS(=O)(=O)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzenesulphonyl chloride (0.33 ml) was added to an ice-cooled, stirred solution of 2-[2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione, hemisulphate, hydrate (0.84 g) in dry pyridine (25 ml). After 2 h with ice cooling, the mixture was stirred at room temperature for 1 h. Water (5 ml) was added and the solution was stirred for 1 h. The mixture was diluted to 100 ml with water and the yellow solid (0.8 g) filtered off, m.p. 214°-6°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:14]([C:20]5[CH:25]=[CH:24][C:23]([C:26]6([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]6)=[CH:22][CH:21]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1.[ClH:44].CCOC(C)=O>CO.C(Cl)Cl>[ClH:44].[ClH:44].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:14]([C:20]5[CH:21]=[CH:22][C:23]([C:26]6([NH2:30])[CH2:27][CH2:28][CH2:29]6)=[CH:24][CH:25]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)nc4ccn23)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(N)CCC6)cc5)nc4ccn23)c1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl (1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)carbamate (1-8) (2.52 g, 4.41 mmol) in MeOH (5 mL) and DCM (15 mL) was added a 4N solution of HCl in EtOAc (22 mL, 88 mmol). The sealed reaction mixture was permitted to stir at room temperature. After 4 hours the reaction mixture was concentrated in vacuo to give 1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine dihydrochloride (1-9) as a yellow solid. HRMS (M+H)+: observed=472.2249, calculated=472.2244.
Reaction SMILES: [F:1][C:2]1[C:7]([SiH:8]([C:13]2[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=2[F:23])[O:9][CH2:10][CH2:11]Cl)=[C:6]([F:24])[C:5]([F:25])=[C:4]([F:26])[C:3]=1[F:27].[C:28]1([Li])[C:37]([F:38])=[C:35]([F:36])[C:33]([F:34])=[C:31]([F:32])[C:29]=1[F:30]>CCOCC>[F:38][C:37]1[C:28]([C:11]([C:13]2[C:14]([F:23])=[C:15]([F:22])[C:16]([F:21])=[C:17]([F:20])[C:18]=2[F:19])([C:28]2[C:37]([F:38])=[C:35]([F:36])[C:33]([F:34])=[C:31]([F:32])[C:29]=2[F:30])[CH2:10][O:9][SiH3:8])=[C:29]([F:30])[C:31]([F:32])=[C:33]([F:34])[C:35]=1[F:36].[Si:8]([O:9][CH2:10][CH3:11])([C:28]1[C:29]([F:30])=[C:31]([F:32])[C:33]([F:34])=[C:35]([F:36])[C:37]=1[F:38])([C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[F:23])[C:7]1[C:6]([F:24])=[C:5]([F:25])[C:4]([F:26])=[C:3]([F:27])[C:2]=1[F:1]
Reactant: [Li]c1c(F)c(F)c(F)c(F)c1F
Reactant: Fc1c(F)c(F)c([SiH](OCCCl)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: CCOCC
Product: CCO[Si](c1c(F)c(F)c(F)c(F)c1F)(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Product: Fc1c(F)c(F)c(C(CO[SiH3])(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Temperature: 25 °C

Procedure:
88.54 g (0.200 mol) of di(pentafluorophenyl)chloroethoxysilane in Et2O is slowly added to solution of C6F5—Li (0.200 mol, 34.80 g, prepared in situ) in Et2O at −78° C. The solution is stirred for over night allowing it to warm up to room temperature. Formed clear solution is filtered and evaporated to dryness to result tri(pentafluorophenyl)ethoxysilane, (C6F5)3SiOEt.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]C(O)=O)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].CN(C1C2C([N:29]([CH3:31])C)=CC=CC=2C=CC=1)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:39])C=CC=CC=1.C(OCC)C>C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:29]=[C:31]=[O:39])=[CH:10][CH:11]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)COc1ccc(CC(=O)O)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)COc1ccc(CN=C=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-isobutoxyphenylacetic acid (7.6 g, 36.5 mmol) was dissolved in THF (50 mL). Proton Sponge™ (8.2 g, 38 mmol) was added, and the mixture was stirred for 15 min. Diphenylphosphoryl azide (10.6 g, 38 mmol) was added dropwise and the mixture was heated to reflux for 4 h. The mixture was cooled to room temperature and placed in the freezer at −18° C. for 20 h. The resulting white precipitate was vigorously stirred with diethyl ether (250 mL) for 15 min and filtered. The filtrate was evaporated to give crude 4-isobutoxybenzyl isocyanate (1.97 g, 9.6 mmol), which was dissolved in dichloromethane (50 mL) and added to a solution of 50ELH85 (2.91 g, 9.6 mmol) in dichloromethane (50 mL). The reaction mixture was stirred for 20 h and concentrated. The crude product was purified by flash chromatography (0-5% methanol in dichloromethane) to give N-(4-fluorobenzyl)-N-[1-(trifluoroacetyl)piperidin-4-yl]-N′-(4-isobutyloxybenzyl)carbamide (76ELH17, 3.90 g, 91%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:21]1[C:26](C(O)=O)=[C:25]([CH3:30])[NH:24][C:23]([CH3:31])=[C:22]1[C:32]([O:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:33].C1(C)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:21]1[C:26]([C:1]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[O:2])=[C:25]([CH3:30])[NH:24][C:23]([CH3:31])=[C:22]1[C:32]([O:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:33]
Reactant: CC1=C(C(=O)O)C(c2c(F)cccc2Cl)C(C(=O)OC2CCCC2)=C(C)N1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1=C(C(=O)OC2CCCC2)C(c2c(F)cccc2Cl)C(C(=O)n2ccnc2)=C(C)N1

Procedure:
13.6 g (83 mmol) of carbonyldiimidazole are added to 33.0 g (83 mmol) of 4-(2-chloro-6-fluorophenyl)-3-cyclopentyloxycarbonyl-1,4-dihydro-2,6-dimethylpyridine-5-carboxylic acid in 350 ml of tetrahydrofuran and the mixture is heated to reflux for 3 h. Thin-layer chromatographic checking (silica gel, toluene/ethyl acetate 1:1) shows complete reaction, after which the reaction mixture is concentrated, the residue is taken up in ethyl acetate, and the solution is washed twice with water, dried over sodium sulphate and concentrated again. The target compound precipitates from ether in the form of white crystals of m.p. 150° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22]Br)[CH:16]=1>C(O)C>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1
Reactant: Clc1ccc(Br)cc1CBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1ccc(Br)cc1COc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 7.1 g phenol and 11.1 g potassium carbonate in 100 mL ethanol are added 19.5 g 4-bromo-2-bromomethyl-1-chloro-benzene. The mixture is stirred at ambient temperature over night. The ethanol is evaporated, and water is added to the residue. The resulting mixture is extracted with ethyl acetate, the combined extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 70:30).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH:8]=[CH2:9])[CH:5]=[O:6])[CH2:2][CH3:3].[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[CH:5]=[O:6])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: C=CCC(C=O)CCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(C=O)CCC

Procedure:
A Parr hydrogenation bottle was charged with 10% palladium on carbon (0.1 equivalent) and ethyl acetate. A solution of 2-propylpent 4 enal, prepared as in Example 5, in ethyl acetate was added. The mixture was hydrogenated at 300N/m2 hydrogen in a Parr hydrogenation apparatus at room temperature until hydrogen uptake ceased. The catalyst was removed by filtration through celite. The filtrate was concentrated to give the desired product as a colorless oil. The product was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][S:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])C.Cl>[OH-].[Na+]>[C:12]1([NH:11][C:10]2[S:9][N:8]=[N:7][C:6]=2[C:4]([OH:5])=[O:3])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1nnsc1Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nnsc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester(0.1 g, 0.4 mmol, prepared as above) in 10 ml of 10% NaOH solution was stirred at room temperature for 1.5 h. The pH of the solution was adjusted with 5% HCl solution to about 2. The solution was extracted with CHCl3 (2×20 mL). The organic layer was dried with anhydrous Na2SO4. The product was obtained as an off-white solid after the removal of the solvent (0.06 g, 67%). m.p.: 165° C. (decomp.). 1H NMR (ppm, DMSO—d6): 10.22 (s, br., 1H), 7.3-7.7 (m, 5 H). FTIR (cm−1, KBr pellet): 3407, 3024, 1673, 1524, 1501, 1464, 1340, 1266, 1090, 784, 754.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1.C(OC(=O)C)(=O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)c1ccc(C)nc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(/C=C/c2ccc(OC)cc2)nc1
Reaction time: 12 h
Yield: 21.3 %

Procedure:
4-Methoxybenzaldehyde (210 mg, 1.52 mmol), methyl 6-methylnicotinate (230 mg, 1.52 mmol), acetic anhydride (310 mg, 3.04 mmol) and catalytic amount of zinc chloride were heated at 140° C. with stirring for 12 h. Ethyl acetate and brine were added to the cooled reaction mixture and the product was extracted. The organic layers were combined, dried (MgSO4) and the solvent removed under reduced pressure. The crude product was applied to a silica gel column and the product was eluted with ethyl acetate/n-hexane (1:1 RF=0.60 fluorescent under the UV lamp). Fractions containing the required product were collected and the solvents removed under reduced pressure to give the sub-title compound as a yellow solid (87 mg, 21%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].[NH2:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=1>O1CCOCC1>[F:19][C:18]1[C:13]([NH2:12])=[N:14][C:15]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[N:16][CH:17]=1
Reactant: Nc1nc(Cl)ncc1F
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 4-fluorobenzyl alcohol (2.56 g, 20.3 mmol) in 1,4-dioxane (20 mL) was added 60% NaH (0.813 g, 20.3 mmol) in several portions over a period of 10 min. To the magnetically stirred solution was added 4-amino-2-chloro-5-fluoropyrimidine* (2.00 g, 13.6 mmol) and the mixture was stirred at room temperature until gas evolution subsided. The reaction mixture was then heated in a CEM Discover microwave reactor at 120° C. for 90 min. The cooled reaction mixture was partitioned between ethyl acetate and water, the organic phase was concentrated, and the product was purified by column chromatography (hexane/ethyl acetate gradient) to yield 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amine (1.66 g, 52% yield) as a white solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J=2.6 Hz, 1H), 7.42 (m, 2H), 7.03 (m, 2H), 5.27 (s, 2H), 5.05 (br s, 2H); MS (ESI) m/z 238 (M+H)+. *4-Amino-2-chloro-5-fluoropyrimidine can be purchased commercially or can be prepared through known literature methods. 1. Hayashi, T.; Kawakami, T. JP Patent 2005126389 2. Durr, G. J. J. Med. Chem. 1965, 8(2), 253.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[C:21]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:20]2)[CH:12]=[CH:11][C:10]=1[N+:39]([O-:41])=[O:40].O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[C:21]([C:32]([OH:34])=[O:33])=[CH:20]2)[CH:12]=[CH:11][C:10]=1[N+:39]([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)c1cn(CCCNc2ccc([N+](=O)[O-])c(N)n2)cc1-c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Nc1nc(NCCCn2cc(C(=O)O)c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
In a vial, TFA (catalytic amount) was added to a stirred mixture of tert-butyl ester pyrrole 7 (1 eq), water (0.1%), and CH2Cl2 at rt. The vial stirred at room temperature until done (−12 h. The reaction was then concentrated under reduced pressure at room temperature and dried in vacuo. The crude residue was dissolved again in CH2Cl2 and concentrated under reduced pressure at rt. The material was used in the final coupling step without further purification as the TFA salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=O.[C:13]1([C:19](=O)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:28][C:29]([NH2:31])=[O:30].Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:31][C:29](=[O:30])[NH:28]2)[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10]
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc(F)c1O
Temperature: 80 °C
Yield: 28 %

Procedure:
A mixture of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (50 mg, 0.294 mmol), 1,2-diphenylethanone (57.7 mg, 0.294 mmol), urea (52.9 mg, 0.882 mmol), and concentrated HCl solution (0.5 mL) in ethanol (2 mL) was refluxed at 80° C. for 52 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by preparative HPLC to give Compound 68 (32.1 mg, yield 28%). 1HNMR (DMSO-d6 400 MHZ): δ 9.25 (s, 1H), 8.70 (s, 1H), 7.49 (s, 1H), 7.32-7.26 (m, 5H), 7.11-7.05 (m, 3H), 6.88 (d, J=1.6 Hz, 2H), 6.86-6.79 (m, 2H), 5.11 (d, J=2.8 Hz, 1H), 3.79 (s, 3H); MS (ESI): m/z 391.0 [M+H]+.
Reaction SMILES: ClC(OCC)=O.[CH2:7]([N:14]1[C@H:18]([C:19](OC)=[O:20])[C@H:17]([C:23](O)=[O:24])[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15]1=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1>[CH2:26]([N:16]1[C@H:17]2[CH2:23][O:24][C:19](=[O:20])[C@H:18]2[N:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]1=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A solution of ethyl chloroformate (0.54 g) in tetrahydrofuran (2 ml) wasd added dropwise to a mixture of (4R,5S)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 149°-150° C., [α]36525 =-27.4° at c=1 in DMF, 1.84 g), triethylamine (0.51 g) and tetrahydrofuran (10 ml) at -5° C. The mixture was stirred at the same temperature for 30 minutes. Precipitated triethylamine hydrochloride was filtered off and the filtrate was added dropwise to a solution of sodium borohydride (0.24 g) in 90% aqueous tetrahydrofuran (10 ml) at -15° C. After reacting, the mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by chromatography on silica gel column to give (3aS,6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (1.04 g). M.P., 114°-117° C. [α]D20 =+59.0° (c=1, CHCl3).