Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=O)=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[N:7]=1.O.[NH2:27][NH2:28]>C(O)C>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[C:3]2[C:2](=[N:7][C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:5][N:4]=2)[NH:28][N:27]=1
Reactant: NN
Reactant: O=C(c1ccccc1Cl)c1ncc(Oc2ccc(F)cc2F)nc1Cl
Solvent: CCO
Solvent: O
Product: Fc1ccc(Oc2cnc3c(-c4ccccc4Cl)n[nH]c3n2)c(F)c1
Yield: 42.1 %

Procedure:
To a solution of [3-chloro-5-(2,4-difluorophenoxyl)pyrazin-2-yl]-(2-chlorophenyl)methanone (0.73 g, 1.9 mmol, 1.0 eq) in ethanol was added hydrazine hydrate (0.19 mL, 3.8 mmol, 2.0 eq). The resulting mixture was refluxed under nitrogen for 0.5 hours. The reaction mixture was cooled and filtered to give 3-(2-chlorophenyl)-6-(2,4-difluorophenoxy)-1H-pyrazolo[3,4-b]pyrazine (0.285 g, 0.8 mmol, 42% yield) as a solid. MP=240.5-241.5° C. Mass spec. M+1=359.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[CH2:3][CH2:2]1.C1C=CC=CC=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C(N(CC)CC)C>[CH2:19]([NH:21][C:22]([O:12][N:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH2:2][CH2:3]1)=[O:23])[CH3:20]
Reactant: CCN=C=O
Reactant: ON=C1CCOc2ccccc21
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)ON=C1CCOc2ccccc21
Reaction time: 8 h

Procedure:
4-Chromanone oxime (20 g, 0.12 mole) was added to benzene (260 ml) and refluxed for 45 min. in a flask equipped with a Dean-Stark trap. The solution was cooled to 25°-30°, triethylamine (0.5 ml) was added, followed by ethyl isocyanate (8.5 g, 0.12 mole). The solution was refluxed for 3 hrs. and stored overnight at room temperature. The mixture was filtered and the filtrate was stripped of solvent under reduced pressure. Anhydrous ether (100 ml) was added to the residue and the mixture was cooled for 3 hrs. The product was collected by filtration, yield: 20 g (79%). A sample was recrystallized from isopropanol, m.p. 110°-111°.
Reaction SMILES: C([OH:5])CCC.N1C=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:13]([O:15][CH:16]([CH3:27])[CH2:17][C:18]([CH3:26])([O:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:19])=[O:14]>C(OCC)C>[C:13](=[O:5])([O:14][CH2:7][CH2:8][CH2:9][CH3:10])[O:15][CH:16]([CH3:27])[CH2:17][C:18]([CH3:26])([O:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:19]
Reactant: c1ccncc1
Reactant: CCCCO
Reactant: CC(CC(C)(C)OOC(C)(C)C)OC(=O)Cl
Solvent: CCOCC
Product: CCCCOC(=O)OC(C)CC(C)(C)OOC(C)(C)C

Procedure:
To a solution of 8.1 g. (0.11 mole) of n-butyl alcohol and 7.9 g. (0.1 mole) of pyridine in diethyl ether cooled to 10°±1° C. was added a solution of 27.0 g. (0.1 mole) 1,3-dimethyl-3-(t-butylperoxy)butyl chloroformate. The reaction temperature was controlled at 15°±1° C. during the addition.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH3:13][N:14]([CH3:25])[CH2:15][CH2:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.O.ClCCl>O1CCOCC1>[CH3:13][N:14]([CH3:25])[CH2:15][CH2:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: CN(C)CCOc1ccc(N)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN(C)CCOc1ccc(Nc2ccn3ncc(C=O)c3n2)cc1
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in dioxane was added 4-(2-(dimethylamino)ethoxy)aniline (149 mg, 0.829 mmol). The mixture was heated in microwave 100 minutes at 120° C. Water and dichloromethane were added, and the product was extracted into dichloromethane. The organic layer was dried over Na2SO4 and concentrated under reduced pressured to yield 5-(4-(2-(dimethylamino)ethoxy)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=408)
Reaction SMILES: Cl[C:2](Cl)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19]>CC#N>[S:18]([N:22]=[C:2]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:20])(=[O:19])[NH2:21]
Reactant: NS(N)(=O)=O
Reactant: ClC(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: NS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
Dichlorodiphenoxymethane (1 g, 3.72 mmol) and sulfamide (0.72 g, 7.44 mmol) were dissolved in MeCN (10 ml) and stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and purified by flash chromatography (20-40% EtOAc/hexanes) to afford diphenyl sulfamoylcarbonimidate (0.69 g, 2.34 mmol, 63%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:12][C:13]([S:15][CH3:16])=[NH:14])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24]([O:27][CH2:28][C:29](Cl)=[O:30])(=[O:26])[CH3:25]>ClCCl>[C:24]([O:27][CH2:28][C:29]([N:14]=[C:13]([NH:12][C:10]([NH:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:11])[S:15][CH3:16])=[O:30])(=[O:26])[CH3:25]
Reactant: CSC(=N)NC(=O)NCc1ccc(Cl)cc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC(=NC(=O)COC(C)=O)NC(=O)NCc1ccc(Cl)cc1
Yield: 61.8 %

Procedure:
To a dichloromethane solution (2.0 mL) of methyl N-({[(4-chlorobenzen-1-yl)methyl]amino}carbonyl)-carbamimidothioate (257 mg, 1.00 mmol) synthesized in Reference Synthesis Example 326, triethylamine (279 μL, 2.00 mmol) and 2-chloro-2-oxoethyl acetate (162 μL, 1.50 mmol) were added and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (221 mg, yield 62%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11](=[CH:17][N:18](C)C)[C:12]2=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29]N)=[CH:25][CH:24]=1>C(O)C>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([C:11]3[CH:17]=[N:18][N:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[C:12]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=C1C(=O)C2CC1CN(Cc1ccccc1)C2
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: Fc1ccc(-n2ncc3c2C2CC3CN(Cc3ccccc3)C2)cc1
Yield: 38.3 %

Procedure:
To a solution of 3-benzyl-7-dimethylaminomethylene-3-aza-bicyclo[3.2.1]octan-6-one (0.6 mmol) in ethanol (3 mL) was added (4-fluoro-phenyl)-hydrazine hydrochloride (0.7 mmol). The reaction mixture was heated at reflux overnight, cooled, concentrated and the residue was treated with dichloromethane and aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane and the organic layer was dried and stripped to provide an oil that was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes to yield product (0.23 mmol). 1H NMR (CDCl3, 400 MHz) δ 7.55 (m, 2H), 7.40 (s, 1H), 7.20–6.90 (m, 7H), 3.50 (br s, 2H), 3.25 (br s, 1H), 3.10 (br s, 1H), 2.95–2.6.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CCO.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:5]1[CH:4]=[CH:3][C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 100 °C
Yield: 97 %

Procedure:
To a mixture of 5-bromo-2-fluorobenzoic acid (3 g, 13.2 mmol, 1.0 eq) and 3-fluorophenyl boronic acid (2.1 g, 15.1 mmol, 1.1 eq) in water (15 mL), EtOH (15 mL) and DMF (60 mL) was added Na2CO3 (5.81 g, 54.8 mmol, 4.1 eq) and Pd(PPh3)4 (1.58 g, 1.37 mmol, 0.1 eq). The reaction mixture was heated at 100° C. under nitrogen for 4 h, then cooled to room temperature. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extracts were combined, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white powder (3 g, 97%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.Cl.[CH3:13]O>CO>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O:10][CH3:13])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
p-Tolylacetic acid (10 g) was dissolved in 30 ml of absolute methanol, followed by addition of 10% hydrogen chloride-methanol (10 ml), and stirred overnight at room temperature. The reaction solution was concentrated and dissolved in chloroform, followed by washing in saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, to distill off the solvent. Methyl p-tolylacetate (11 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][N:11]1[CH2:14][CH:13]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12]1.C(N(S(F)(F)[F:33])CC)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:33])[CH2:10][N:11]1[CH2:14][CH:13]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12]1
Reactant: O=S(=O)(CC1CN(CC(O)c2ccc(F)cc2F)C1)c1ccc(F)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(CC1CN(CC(F)c2ccc(F)cc2F)C1)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A stirred suspension of the alcohol from Step 1 (130 mg, 0.33 mmol) in dichloromethane (4 mL) under nitrogen was cooled to −10° C. (Diethylamino)sulfur trifluoride (54 μL, 0.41 mmol) was added dropwise and after 30 minutes the cooling bath was removed. After a further 15 minutes, the reaction was quenched with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative TLC (50% ethyl acetate/isohexane) to give the title compound (64 mg, 50%). 1H NMR (500 MHz, CDCl3) δ 7.91–7.89 (2H, m), 7.40–7.34 (1H, m), 7.27–7.23 (2H, m), 6.90 (1H, t, J=8.2 Hz), 6.79 (1H, t, J=9.5 Hz), 5.70–5.58 (1H, m), 3.49 (2H, q, J=7.4 Hz), 3.38–3.36 (2H, m), 2.95 (2H, q, J=6.7 Hz), 2.90–2.70 (3H, m); m/z (ES+) 388 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:22]=[C:15]2[C:16]([CH2:20][OH:21])=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[CH:22]=[C:15]2[C:16]([CH:20]=[O:21])=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1
Reactant: Cc1cc2c(CO)cccn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(C=O)cccn2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
Under nitrogen atmosphere, to a solution of oxalyl chloride (18.9 mL, 216 mmol) in dichloromethane (200 mL) was added dimethyl sulfoxide (35.4 mL, 499 mmol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added a solution of (2-methylpyrazolo[1,5-a]pyridin-4-yl)methanol (27.0 g, 166 mmol) in dichloromethane (133 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (117 mL, 831 mmol) at −78° C., and the mixture was stirred for 1 hr and warmed to room temperature. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (7.00 g, yield 26%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[OH:25].[OH-].[K+]>C(#N)C>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[CH:14]\[O:15][CH3:16])/[C:10]([O:12][CH3:13])=[O:11]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CO/C=C(/C(=O)OC)c1ccccc1CBr
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)ccc1C
Yield: 80.9 %

Procedure:
(E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (20 g, 70.1 mmol) was reacted with 2,5-dimethylphenol (8.56 g, 1.0 eq) in 400 mL of acetonitrile (CH3CN) in the presence of potassium hydroxide (4.65 g, 1.1 eq) at room temperature for 4 hours, followed by removing the reaction solvent by concentration in a vacuum. The residue was stirred in water (200 mL) and the aqueous layer was extracted twice with 200 mL of dichloromethane. The organic layer thus obtained was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to remove the solvent. The residue was purified using silica gel chromatography to give (E)-methyl 2-(2-((2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (18.5 g, yield 81%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15]Br)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2
Reactant: C1CCNC1
Reactant: Nc1ncnn2c(CCCCBr)cc(Br)c12
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCCCN3CCCC3)cc(Br)c12
Temperature: 55 °C
Yield: 80.3 %

Procedure:
To a solution of 5-bromo-7-(4-bromobutyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (597 mg, 1.72 mmol) in DMF (10 mL) was added pyrrolidine (158 μL, 1.89 mmol), triethylamine (717 μL, 5.15 mmol), and sodium iodide (26 mg, 0.17 mmol). The reaction was heated (55° C.) for 22 h and then cooled to rt. The mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous phase was further extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (1×50 mL), brine, dried (Na2SO4) and evaporated to afford 467 mg (80%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.81 (s, 1 H), 6.60 (s, 1 H), 2.81 (t, 2 H), 2.40-2.31 (m, 6 H), 1.70-1.59 (m, 6 H), 1.50-1.40 (m, 2 H); ES-MS m/z 338.1 [M+H]+, HPLC RT (min) 1.12.
Reaction SMILES: [O:1]([CH:9]([CH3:49])[CH2:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][CH:16]=[N:15][C:14]=2[N:13]([C@@H:21]2[O:36][C@H:35]([CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=3[Cl:47])[C@@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[C@@:22]2([CH3:48])[OH:23])[CH:12]=1)[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>C1COCC1>[Cl:20][C:18]1[C:19]2[C:11]([CH2:10][CH:9]([OH:1])[CH3:49])=[CH:12][N:13]([C@@H:21]3[O:36][C@H:35]([CH2:37][O:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=4[Cl:47])[C@@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[Cl:34])[C@@:22]3([CH3:48])[OH:23])[C:14]=2[N:15]=[CH:16][N:17]=1
Reactant: CC(Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(O)Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
To a solution of compound 4.2 (800 mg, 1.01 mmol) in THF (20 mL) was added a 1.0 M solution of tetrabutylammonium fluoride in THF (1.5 mmol) at room temperature. The colorless solution was stirred for 4 hr at room temperature and then diluted by addition of 150 mL of CH2Cl2 and water (50 mL). The aqueous layers were extracted three times with CH2Cl2, and then dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography using 1-2% MeOH in CH2Cl2 as eluent gave the desired compound 4.3 (460 mg, 67%) as a white solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[N:13]1([CH2:18][CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=5)=[CH:37][CH:36]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:23][CH2:22]2)[CH:17]=[CH:16][N:15]=[CH:14]1>C(OCC)(=O)C>[N:13]1([CH2:18][CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[C:32](=[O:33])[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[C:47]5[NH:3][C:4](=[O:7])[O:5][N:48]=5)=[CH:37][CH:36]=4)=[C:30]([CH2:49][CH2:50][CH3:51])[N:29]4[N:52]=[CH:53][N:54]=[C:28]34)[CH2:23][CH2:22]2)[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCn3ccnc3)CC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCCn3ccnc3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.44 g), sodium hydrogen carbonate (0.71 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(4-{trans-4-[2-(1H-imidazol-1-yl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.24 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.083 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was adjusted to pH 7 with 1 N hydrochloric acid and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.086 g, 33%).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]2>CCOCC.C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21][CH3:1])=[O:20])=[CH:14][CH:13]=[CH:12]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cccc2cc(O)ccc12
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cccc2cc(O)ccc12
Reaction time: 1.5 h
Yield: 56 %

Procedure:
A solution of (trimethylsilyl)diazomethane (4.0 mL of a 2.0 M solution in Et2O, 8.0 mmol) was added slowly to a solution of 6-hydroxy-1-naphthoic acid (commercially available from TCI, 1.50 g, 8.0 mmol) in THF (40 mL) at 0° C. After 1.5 h at 0° C., the reaction mixture was concentrated in vacuo and absorbed onto silica. The resulting residue was purified on 80 g silica gel (100% hexanes→100% EtOAc, gradient) to afford 910 mg (56%) of methyl 6-hydroxy-1-naphthoate.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.B(F)(F)F.[CH3:17][CH2:18]OCC.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:17][CH3:18])=[O:9])=[CH:11][CH:12]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)cc1

Procedure:
A solution of 5.0 g. 4-aminohydrocinnamic acid in 50 ml. of absolute ethanol containing 8 ml. of boron trifluoride etherate is heated to reflux for 48 hours. The solution is then cooled, poured into 5% aqueous sodium carbonate, and extracted with methylene chloride. Evaporation of the organic extracts yields ethyl 4-aminohydrocinnamate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:7]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([F:20])[CH:5]=1.[CH:21](OCC)=[O:22].Cl>O1CCCC1>[Cl:3][C:4]1[C:9]([O:10][CH:11]([CH3:12])[CH3:13])=[CH:8][C:7]([CH:14]([CH:21]=[O:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([F:20])[CH:5]=1
Reactant: CCOC(=O)Cc1cc(OC(C)C)c(Cl)cc1F
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)c1cc(OC(C)C)c(Cl)cc1F
Reaction time: 0.5 h

Procedure:
Then, 1.1 g of sodium hydride (60% in oil) was suspended in 50 ml of tetrahydrofuran, and the mixture was cooled to 5° C., to which a solution of 7.2 g of ethyl 4-chloro-2-fluoro-5-isopropoxyphenylacetate in 80 ml of tetrahydrofuran was slowly added dropwise. The mixture was stirred for 30 minutes with a gradual temperature increase to room temperature, to which 10 ml of ethyl formate was added at room temperature, followed by stirring for 3 hours. Then, the reaction mixture was cooled to 5° C., to which diluted hydrochloric acid was added. The reaction mixture was concentrated, and the residue was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 8.0 g of ethyl 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-2-formylacetate.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]1[C:31](=[O:32])[N:30]([CH3:33])[C:23]2[N:24]=C(SC)[N:26]=[CH:27][C:22]=2[CH:21]=1.[CH3:34][S:35]([CH3:37])=[O:36]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]1[C:31](=[O:32])[N:30]([CH3:33])[C:23]2[N:24]=[C:34]([S:35]([CH3:37])(=[O:9])=[O:36])[N:26]=[CH:27][C:22]=2[CH:21]=1
Reactant: CS(C)=O
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reaction time: 8 h

Procedure:
A quantity of 0.346 g (1.00 mmol) of 50% to 60% m-chloroperbenzoic acid (assuming 50% peracid was present) was added at 25° C. to a stirred solution of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 in 15 mL of chloroform, and the solution was stirred overnight. A quantity of 0.25 g (3.20 mmol) of dimethylsulfoxide was added to reduce any excess peracid. After 15 minutes, the chloroform solution was washed with 30 mL of saturated sodium bicarbonate and then with water. The separated organic layer was dried over sodium sulfate, filtered, and concentrated to ca. 5 mL volume. Crystals separated. Added ca. 5 mL of petroleum ether and filtered; wt 0.165 g (92%); mp >290° C.