Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].CC(C)([O-])C.[K+].[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:27]=[C:28]2[S:32][C:31](SC)=[N:30][C:29]2=[O:35])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14]>C(O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([CH:27]=[C:28]2[S:32][C:31](=[N:1][CH2:2][C:3]([OH:5])=[O:4])[NH:30][C:29]2=[O:35])[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]=1[OH:22])([CH3:12])[CH3:14]
Reactant: NCC(=O)O
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2SC(=NCC(=O)O)NC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
A mixture of glycine (2.25 g, 0.03 mole), potassium-t-butoxide (2.81 g, 0.025 mole), and ethanol (700 mL) is stirred at room temperature for 15 minutes. 5-[(3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylene]-2-(methylthio)-4(5H)-thiazolone (7.27 g, 0.02 mole) is added to it and the mixture is refluxed with stirring for 20 hours. The mixture is then filtered and the solvent removed at 40° C. under reduced pressure. The residue is treated with ice-water, acidified with 1N aqueous hydrochloric acid and extracted with ether. The organic layer is washed with water, dried, and the solvent removed to give 7.75 g of a solid. The crude solid is recrystallized from tetrahydrofuran-ether to give 2.95 g (38%) of pure N-[5-[3,5-[bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4-oxo-2-thiazolidinylidene]glycine, (Z)-, mp 260° C. (dec). Anal. for C20H26N2O4S.0.25C4H8O: Calcd: C, 61.74; H, 6.91; N, 6.86; S, 7.85. Found: C, 61.82; H, 7.08; N, 6.50; S, 7.55.
Reaction SMILES: [F:1][C:2]1[CH:50]=[CH:49][C:5]([C:6]([N:8](C(=O)C2C=CC(F)=CC=2)[C:9]2[N:13]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]3)[C:12]3[CH:26]=[C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[CH:28]=[CH:29][C:11]=3[N:10]=2)=[O:7])=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[N:13]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]3)[C:12]3[CH:26]=[C:27]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[CH:28]=[CH:29][C:11]=3[N:10]=2)=[O:7])=[CH:49][CH:50]=1
Reactant: COc1ccc(COc2ccc3nc(N(C(=O)c4ccc(F)cc4)C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)NC(C)C)CC4)c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc3nc(NC(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)NC(C)C)CC4)c3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-N-(4-fluorobenzoyl)-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-2-yl)benzamide (442 mg, 0.649 mmol, as a mixture with the mono-acylated material) in MeOH (3.2 mL) and dioxane (3.2 mL) was added a flake of sodium hydroxide (46.7 mg, 1.169 mmol), and the mixture was stirred at RT for 1 hour. The mixture was evaporated and the residue diluted with DCM, washed with 1 N aqueous NaOH, brine, and the organic layer dried over Na2SO4. The residue was purified via flash chromatography using a linear gradient of 0% to 50% EtOAc in hexanes. The title compound was collected as a white solid (275 mg, 76% yield). M/Z calc'd for C32H35FN4O4: 558.65. found 559 [M+H].
Reaction SMILES: Cl[C:2]1[N:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([F:11])=[CH:6]2.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=1>CN1CCCC1=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:26][C:2]2[N:3]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[N:4]=[C:5]3[C:10]=2[CH:9]=[CH:8][C:7]([F:11])=[CH:6]3)[CH:23]=[CH:24][CH:25]=1
Reactant: Fc1ccc2c(Cl)n(-c3ccc(Cl)cc3)nc2c1
Reactant: Nc1cccc(Cl)c1
Solvent: CN1CCCC1=O
Product: Fc1ccc2c(Nc3cccc(Cl)c3)n(-c3ccc(Cl)cc3)nc2c1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-6-fluoro-2H-indazole (example 40.2) was reacted with 3-chloro-phenylamine ([108-42-9]) in N-methyl 2-pyrrolidone for 72 h at 175° C. in a sealed tube to give the title compound as colorless crystals. MS: m/e=372.1 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[CH:14]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:3]([CH2:2][O:19][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:4]([CH:9]=1)[C:5]([OH:7])=[O:6]
Reactant: OC1CCCC1
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1COC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
A mixture of methyl 2-(bromomethyl)-5-chlorobenzoate (200 mg, 0.80 mmol), cyclopentanol (379 mg 4.4 mmol), and potassium tert-butoxide (448 mg, 4.0 mmol) in tetrahydrofuran (8 mL) was stirred at room temperature for 3 hours. The mixture was acidified with 2 N hydrochloric acid and the acidic aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1/1) to afford 100 mg (49%) of the title compound:
Reaction SMILES: [CH3:1][N:2]1[CH2:13][CH2:12][C:5]2([NH:9]C(=O)N[C:6]2=[O:11])[CH2:4][CH2:3]1.[OH2:14].O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[NH2:9][C:5]1([C:6]([OH:11])=[O:14])[CH2:4][CH2:3][N:2]([CH3:1])[CH2:13][CH2:12]1
Reactant: O
Reactant: CN1CCC2(CC1)NC(=O)NC2=O
Agent: [Ba+2]
Agent: [OH-]
Product: CN1CCC(N)(C(=O)O)CC1
Yield: 379.5 %

Procedure:
1-Methylpiperidine-4-spiro-5'-hydantoin (9.75 g. 0.0533 mole) and barium hydroxide octahydrate (28.8 g, 0.9913 mole) in water (150 ml) were heated at 160° C. in a bomb for 3 hr. The content of four such batches were combined and the precipitated barium carbonate was filtered off. The filtrate was neutralized with solid CO2 and the precipitate removed by filtration. Concentration of the filtrate gave 4-amino-1-methyl-piperidine-4-carboxylic acid (32.0 g, 95%) mp. 275°-280° C. (dec.).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]1[N:5]=[CH:6][O:7][CH:8]=1.[CH2:10]([O:12][C:13](=[O:33])[N:14]([C:22]1[CH:27]=[C:26](Br)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:11]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:10]([O:12][C:13](=[O:33])[N:14]([C:22]1[CH:27]=[C:26]([C:6]2[O:7][CH:8]=[C:4]([CH2:3][N:2]([CH3:9])[CH3:1])[N:5]=2)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:11]
Reactant: CN(C)Cc1cocn1
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(-c2nc(CN(C)C)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using dimethyl-oxazol-4-ylmethyl-amine (128 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (200 mg) and palladium bis(triphenylphosphine)dichloride (71 mg), giving the product (99 mg) as a yellow gum.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[OH:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:41]2[CH:42]=[C:37]([OH:36])[CH:38]=[CH:39][CH:40]=2)=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(O)c3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (6.8 mg, yield 15%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[CH3:11][N:12]=[C:13]=[O:14]>>[CH3:11][NH:12][C:13]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:14]
Reactant: CN=C=O
Reactant: NCCSCc1cc[nH]n1
Product: CNC(=O)NCCSCc1cc[nH]n1

Procedure:
By the procedure of Example 24, 3-[(2-aminoethyl)-thiomethyl]pyrazole is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)(=[O:3])[CH3:2].[Cl:12]N1C(=O)CCC1=O>C(O)(=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:12])=[C:8]([CH2:10][OH:11])[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Nc1nc(CO)cs1
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CO)c(Cl)s1
Temperature: 40 °C
Yield: 86.9 %

Procedure:
A mixture of 2-acetylamino-4-hydroxymethylthiazole (7.0 g) and N-chlorosuccinimide (6.5 g) in acetic acid (70 ml) was heated at 40° C. for 3.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was added the aqueous sodium bicarbonate. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1), washed with water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was triturated with isopropyl ether. The precipitates were collected by filtration, washed with isopropyl ether and dried in vacuo to give 2-acetylamino-5-chloro-4-hydroxymethylthiazole (7.3 g, yield : 78.5%). mp: 145°-146° C. IR (Nujol) : 3150, 1690, 1550, 1285 cm-1
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:6]=[CH:5][C:4]=1[Cl:20].[I-].[Na+].[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>CCC(C)=O>[Cl:20][C:4]1[C:3]([CH2:2][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[N:8][C:7]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:6][CH:5]=1
Reactant: CCOP(OCC)OCC
Reactant: O=C1c2ccccc2C(=O)N1c1ccc(Cl)c(CBr)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOP(=O)(Cc1nc(N2C(=O)c3ccccc3C2=O)ccc1Cl)OCC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The product from Example 26 was dissolved in MEK (180 mL) and placed in a 500 mL flask under a N2 atmosphere. Sodium iodide (catalytic) was added to the reaction which was subsequently stirred at room temperature for 20 min. Triethyl phosphite (3.66 g, 22 mmol) was added to the reaction. The reaction was heated to reflux for 6 h, cooled to room temperature, and stirred an additional 16 h. The reaction was filtered and all solvent removed in vacuo to yield the crude title compound. Purification via flash chromatography (96/4 CHCl3 /EtOH) produced the pure title product.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:38](Br)[CH2:39][CH2:40][CH2:41][CH3:42]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH:21]4[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16]4)[C:10]=3[N:9]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)C1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCCCOc2cccc3c2nc(COc2ccc(Cl)cc2)n3CCCC2CCCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C

Procedure:
A solution of (RS) 2-(4-chlorophenoxymethyl)-4-hydroxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15 mmol, 1.0 eq) in dry N,N-dimethylformamide (1.0 ml) was treated with sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting mixture was stirred at room temperature for thirty minutes, after which time 5-[1-(t-butoxycarbonyl)piperidin-4-yl)]pentyl bromide (0.18 mmol, 1.2 eq) was added. The resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to give a crude product. The title product was further purified by flash chromatography to provide a crystalline product.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[H-].[Na+].O>CS(C)=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[S:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(-c2nsc(Cl)n2)cc1
Reactant: c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ccc(-c2nsc(-n3cccc3)n2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 44.7 %

Procedure:
The 5-chloro-1,2,4-thiadiazole compound (102 mg, 0.445 mmol) was dissolved in DMSO (2 mL) and pyrrol (300 mg, 2.22 mmol) added at room temperature. The mixture was heated for 18 h to 55° C. ext. temperature, however no conversion was found (sample tested by 1H-NMR). Sodium hydride (55% wetted with mineral oil, 20 mg, 0.467 mmol) was added and the mixture heated to 80° C. ext. temperature for 5 h. As the conversion was not complete (sample tested by 1H-NMR) the mixture was heated to 100° C. ext. temperature for 6 h. The reaction mixture was poured into water (10 mL) and crude product isolated by filtration. The purification by column chromatograpy (SiO2, 0-10% ethyl acetate inheptanes) afforded 3-(4-chlorophenyl)-5-(1H-pyrrol-1-yl)-1,2,4-thiadiazole (52 mg, 0.199 mmol, 45%), which was 98% pure (HPLC 254 nm). 1H-NMR spectra is in accordance with the chemical structure.
Reaction SMILES: Br[C:2]1[C:3](C)=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:11][S:12]([NH:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:13]>>[CH3:8][N:6]1[C:5](=[O:9])[CH:4]=[CH:3][C:2]([C:20]2[CH:21]=[C:16]([NH:15][S:12]([CH3:11])(=[O:13])=[O:14])[CH:17]=[CH:18][CH:19]=2)=[CH:7]1
Reactant: Cc1cc(=O)n(C)cc1Br
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: Cn1cc(-c2cccc(NS(C)(=O)=O)c2)ccc1=O

Procedure:
5-Bromo-1,4-dimethylpyridin-2-one was treated with [3-(methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.43 (t, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 6.69 (s, 1H), 3.67 (s, 3H), 3.07 (s, 3H), 2.16 (s, 3H). LCMS (M+H)+ 293.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:9]([N:12]=[C:13]=[O:14])[CH:10]=[CH2:11]>CN(C)C=O>[CH2:9]([NH:12][C:13]([N:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[N:6][C:5]1=[O:8])=[O:14])[CH:10]=[CH2:11]
Reactant: C=CCN=C=O
Reactant: O=c1ncc(Br)c[nH]1
Solvent: CN(C)C=O
Product: C=CCNC(=O)n1cc(Br)cnc1=O
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of 5-bromopyrimidin-2-one (2 mmol) and allylisocyanate (3 mmol) in dimethyl formamide (2 ml) was stirred together at room temperature until a clear solution resulted (ca. 3 h) before the solvent was distilled off at 1 mmHg, the residue triturated with ether and then with water; the residue was the title compound, yield 59%. MS (70 eV) m/e: 257/255 (M,O), 176 (31), 174 (33), 148 (9), 106 (8), 104 (8), 95 (60), 83 (20), 56 (100).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:31]([NH2:33])=[O:32])[CH:3]=1.C=O.[OH-].[Na+].[C:38](OCC)(=[O:40])C>COCCOC>[OH:40][CH2:38][NH:33][C:31]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH:8]([S:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=1)=[O:32]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)(F)F)nc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)(F)F)nc1
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of 4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-trifluorophenyl)methyl]pyridine-2-carboxamide (147 mg, 0.300 mmol) in ethylene glycol dimethyl ether (0.8 ml), an aqueous solution of formaldehyde (37%, 0.200 ml) and 1 N aqueous sodium hydroxide (0.200 ml) were added at room temperature, and the mixture was stirred for 16 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethyl acetate and diethyl ether, and then was collected by filtration to obtain the title compound (113 mg, 0.218 mmol, 73%) as a white solid.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])C1C=CC=CC=1.C1CCCCC=1>CCO.[Pd]>[NH2:8][CH:9]([P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])[P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(OCC)C(N(Cc1ccccc1)Cc1ccccc1)P(=O)(OCC)OCC
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Yield: 119.5 %

Procedure:
Compound 1 (2.00 g, 4.14 mmol) was dissolved in EtOH (40 mL). To this solution was added palladium on carbon (10%, 1.5 g) and cyclohexene (2.5 mL, 24.7 mmol). The reaction mixture was refluxed under argon for 15 hours, filtered through celite and evaporated to give 2 as a slightly impure pale yellow oil (1.50 g, 119%), which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 1.35 (t, J=7.0, 12H), 3.58 (t, J=20.3, 1H), 3.65-3.90 (br s, 2H), 4.20-4.28 (m, 8H).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH2:9]([C:11]1[NH:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][CH:12]=1)[CH3:10].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:8][C:12]1[N:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:15][C:11]=1[CH2:9][CH3:10]
Reactant: CCOC(=O)c1ncc(CC)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 25 °C
Reaction time: 28 h
Yield: 44.8 %

Procedure:
NCS (3.15 g, 23.59 mmol) was added to a solution of ethyl 5-ethyl-1H-imidazole-2-carboxylate obtained in Example (1b) (3.35 g, 19.92 mmol) in chloroform (100 mL), and the mixture was stirred at room temperature for 28 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 3/1) to obtain 1.81 g of the title compound as a pale yellow solid (45%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O1CCOCC1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>[OH-].[Na+]>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([N:2]([CH3:1])[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N(C)[C@@H](Cc2ccccc2)C(=O)O)cc1
Reaction time: 1 h
Yield: 45.6 %

Procedure:
N-Methyl-L-phenylalanine (500 mg, 2.79 mmol) was dissolved in 1N NaOH (6 mL). Dioxane (9 mL)) was added, followed by p-toluenesulfonyl chloride (532 mg, 2.79 mmol) and the mixture was vigorously stirred for 1 hr. The volatiles were removed in vacuo and the residue was dissolved in water (30 mL) and washed with Et2O (2×30 mL) before making acidic with 1N HCl. The mixture was extracted with CHCl3 (3×30 mL) and the extracts were evaporated in vacuo to give N-(toluene-4-sulfonyl)-N-methylphenylalanine as a solid (424 mg, 45%). N-(Toluene-4-sulfonyl)-N-methylphenylalanine was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 (400 mg, 62%). The title compound was prepared via hydrolysis of the ethyl ester using NaOH in ethanol. Proton and carbon NMR analyis indicated a mixture of diastereomers.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.Cl[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C)C=O>[CH3:28][O:27][C:25](=[O:26])[CH2:24][N:10]1[C:8]2[N:9]=[C:4]([NH2:3])[N:5]=[CH:6][C:7]=2[CH:13]=[C:12]([C:14]2[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[C:11]1=[O:22]
Reactant: COC(=O)CCl
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Yield: 60.7 %

Procedure:
To a suspension of NaH (60% in mineral oil, 38 mg) in 6 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (203 mg, 0.66 mmol). The mixture was heated at 50° C. for 40 minutes resulting in a clear solution. Methyl chloroacetate (90 μL, 1.03 mmol) was added, and the solution was heated at 50° C. for 20 minutes, then cooled to room temperature and poured onto 30 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The aqueous filtrate was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate, filtered, and concentrated. The solids were combined and purified by flash chromatography, eluting with a gradient of 1:1 hexane:ethyl acetate to all ethyl acetate to provide 152 mg (61%) of [2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]-acetic acid methyl ester; mp 188°-190° C.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>C1COCC1>[N:17]1[C:3]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:2][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12
Reactant: Nc1ccccn1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cn2ccccc2n1
Yield: 26.9 %

Procedure:
A mixture of ethyl 4-chloro-3-oxobutanoate (15 g, 91 mmol) and pyridin-2-amine (8.58 g, 91 mmol) in THF (80 mL) was refluxed overnight. Then, the reaction mixture was concentrated and the residue purified by silica gel chromatography (PE:EA=1:1) to afford ethyl 2-(imidazo[1,2-a]pyridine-2-yl)acetate (5 g, yield 26.9%).