Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:36]=[C:35]2[C:31]([CH:32]=[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34]2)=[CH:30][CH:29]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:27][C:28]3[CH:36]=[C:35]4[C:31]([CH:32]=[C:33]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34]4)=[CH:30][CH:29]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CCOC(=O)c1cc2ccc(N)cc2[nH]1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(NC(=O)C(CCOC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1

Procedure:
100 mg (265 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate), 54.2 mg (265 μmol, 1.0 eq.) of ethyl 6-amino-1H-indole-2-carboxylate, 37.7 mg (265 μmol) of Oxima and 41.4 μl (265 μmol) of DIC in 5.5 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by preparative HPLC (column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water/0.1% formic acid and acetonitrile/0.1% formic acid, gradient 10% acetonitrile to 90% acetonitrile). Yield: 85 mg (54% of theory)
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[CH:5]=2.[Cl:16][CH2:17][CH:18]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>COCCOC>[Cl:16][CH2:17][CH2:18][N:10]1[CH2:9][CH2:8][C:7]2[CH:13]=[C:14]3[N:15]=[C:2]([CH3:1])[O:3][C:4]3=[CH:5][C:6]=2[CH2:12][CH2:11]1
Reactant: O=CCCl
Reactant: Cc1nc2cc3c(cc2o1)CCNCC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc2cc3c(cc2o1)CCN(CCCl)CC3
Yield: 36 %

Procedure:
A mixture 2-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (1 mmol), chloroacetaldehyde (2 mmol), NaBH(OAc)3 (2 mmol) in dry DME (10 ml) was stirred at room temperature for 3 h. The mixture was partitioned between aqueous Na2CO3 (0.5 M) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to provide the title compound (36% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([Cl:18])=[O:10])=[CH:4][CH:3]=1
Reactant: C=CC[C@H](C(=O)O)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC[C@H](C(=O)Cl)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
Combine (S)-2-(4-fluorophenyl)pent-4-enoic acid (3.61 g, 18.6 mmol), dichloromethane (20 mL), and dimethylformamide (2 drops). Add oxalyl chloride (1.94 mL, 22.3 mmol). After 2 hours, evaporate in vacuo to give (S)-2-(4-fluorophenyl)pent-4-enoyl chloride. Combine with toluene (10 mL) and slowly add, with vigorous stirring, to a cooled (ice bath) aqueous solution of methylamine (4 mL, 40%). After 1 hour, partition the reaction mixture between water and dichloromethane. Separate the layers, extract the organic layer with a saturated aqueous sodium bicarbonate solution. Dry the organic over MgSO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with hexane to give a solid. Collect the solid by filtration and dry to give (S)-2-(4-fluorophenyl)pent-4-enoic acid, N-methyl amide: mp; 104-105° C. Rf =0.42 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7](O)=[O:8])[O:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:17].C(Cl)(Cl)(Cl)Cl>C1CCCCC1>[CH2:1]1[O:12][C:11]2[C:3](=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:10]=2)[C:7]([Cl:17])=[O:8])[O:2]1
Reactant: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)c1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
Reaction of 31.7 g of 4,5-methylenedioxy-2-nitrobenzoic acid and 31.2 g of phosphorus pentachloride in 250 ml of cylohexane at reflux for 30 minutes followed by treatment of the crude oil twice with carbon tetrachloride gave 4,5-methylenedioxy-2-nitrobenzoyl chloride. The acid chloride was dissolved in 50 ml of tetrahydrofuran and added to a warm solution of 30.9 g of 5-aminotetrazole monohydrate in 750 ml of tetrahydrofuran and 30 ml of water. The solution was stirred for 30 minutes and then diluted with 3 liters of water. The solid which formed was separated by filtration and dried to give 4,5-methylenedioxy-2-nitro-N-(1H-tetrazol-5-yl)benzamide melting at about 279° C. after recrystallization from a mixture of dimethylformamide and water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[I:9]N1C(=O)CCC1=O>CC(O)=O>[I:9][C:7]1[C:3]([O:2][CH3:1])=[N:4][O:5][C:6]=1[CH3:8]
Reactant: COc1cc(C)on1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: COc1noc(C)c1I
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 3-Methoxy-5-methyl-isoxazole (0.60 g, 5.0 mmol) in AcOH (15 mL) is added N-iodosuccinimide (1.10 g, 5.00 mmol) at 60° C. under nitrogen. Then the reaction mixture is stirred at 60° C. for 2 h. The mixture is concentrated in vacuo to give an oil. This oil is purified by column chromatography on silica gel to give the desired compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[NH2:22].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][C:21]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:19]([O:18][CH3:17])[CH:20]=3)=[C:3]([C:15]#[N:16])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3cc(OC)c(OC)c(OC)c3)c(C#N)cnc2cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
A mixture of 4-chloro-7-fluoro-6-methoxy-3-quinolinecarbonitrile (500 mg, 2.11 mmol), 3,4,5-trimethoxyaniline (515 mg, 2.81 mmol) and pyridine hydrochloride (270 mg , 2.33 mmol) in 20 mL of 2-ethoxyethanol is heated at reflux for 4 hours then cooled to room temperature. The reaction mixture is poured into aqueous sodium bicarbonate and stirred at room temperature for 15 minutes. The solid is collected by filtration and partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration of the residue with ethyl acetate and diethyl ether provides 512 mg of 7-fluoro-6-methoxy-4-[(3,4,5-trimethoxyphenyl)amino]-3-quinolinecarbonitrile, mp 215-217° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.C1(C)C=CC=CC=1>CO>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)([O-:31])(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Clopidogrel base was dissolved in methanol, p-Toluene sulphonic acid was added to the solution at 20° C. The reaction mixture was heated to reflux temperature for 2 hrs. The solution was cooled to room temperature and the methanolic solution was added dropwise to hot toluene. The resulting solution was refluxed for an additional 20 minutes. The solution was cooled to room temperature and was stirred for 24 hrs. The solvent was evaporated under reduced pressure to dryness to obtain Clopidogrel tosylate, similar to that obtained above.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:13]([O-])=[O:14].[Na+].OS(O)(=O)=O>[OH-].[Na+]>[N:13](=[C:11]1[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1])[OH:14]
Reactant: O=N[O-]
Reactant: Oc1cc(O)c2ccccc2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2ccccc2C(=O)C1=NO
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a mixture of 3.21 g (19.9 mmol) of 2,4-dihydroxyquinoline and 1.87 g (27.1 mmol) of NaNO2 in 60 mL of 0.2N NaOH in an ice-bath was added dropwise 40 mL of aqueous 2N H2SO4. The mixture was stirred in an ice bath for 1 h after addition of H2SO4, filtered and dried to leave 3.41 g of orange solid which was crystallized by boiling with 150 mL of ethanol (95%) and filtered. The filtrate was cooled to and kept at room temperature for 5 h. The crystalline precipitate was filtered and dried to leave 1.88 g (50%) of 10a as a red solid, mp 206° C. (decomposed, lit 208° C., dec.). 1H NMR (CDCl3 +DMSO-d6), 6.65-6.78 (m, 2), 7.15 (m, 1), 7.556 (d, 0.30, J=8.1), 7.605 (d, 0.70, J=8.1), 10.887 (s, 0.3), 11.346 (s, 0.7). MS, 190 (100, M+), 173 (25), 146 (55). High resolution MS, Calcd for C9H6N2O3, 190.0375, found 190.0400.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.Br[C@@H:18]([CH3:22])[C:19]([OH:21])=[O:20]>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C@H:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH2:13][CH2:14]2)=[N:7][CH:8]=1
Reactant: C[C@H](Br)C(=O)O
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: ClCCl
Product: C[C@H](C(=O)O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A solution of 1-(5-trifluoromethyl-pyridin-2-yl)-piperazine (2.77 g, 11.99 mmoles) in DCM (42 mL) and TEA (4.2 mL) was treated with (2S)-2-bromo-propionic acid (1.19 mL, 13.2 mmoles) and stirred overnight at 35° C. The DCM was removed under reduced pressure to provide crude title compound.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.[NH2:15]O>N1C=CC=CC=1.C(O)C>[CH2:1]([C:7]1[CH:8]=[C:9]([C:12]#[N:15])[S:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NO
Reactant: CCCCCCc1csc(C=O)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCCCc1csc(C#N)c1
Yield: 84.5 %

Procedure:
A mixture solution of 4-hexylthiophene-2-carbaldehyde (11.8 g, 60.0 mmol) and hydroxylamine hydrochloride salt (6.3 g, 90 mmol) in pyridine/ethanol (60 mL, 1/1 v/v) was stirred at 80° C. overnight. Then the solvent was removed and the residue was dissolved in chloroform (100 mL). The solution was washed with distilled water (2×50 mL) and dried over anhydrous magnesium sulphate. The solvent was removed and the viscous liquid residue was refluxed in acetic anhydride (30 mL) containing potassium acetate (0.2 g) for 3 h. Then the mixture was poured into distilled water (100 mL) and extracted with hexanes (3×50 mL). The combined organic phase was washed three times with water (50 mL), dried over anhydrous magnesium sulfate before the solvent was removed by rotary evaporation. The yellow liquid residue was purified by silica-gel column chromatography (EtOAc/hexane=7/93, v/v, Rf=0.4) to yield a clear light yellow liquid product. (9.8 g, 84.5% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.43 (d, 1H, J=1.4 Hz); 7.17 (d, 1H, J=1.4 Hz); 2.60 (t, 2H, J=8.0 Hz); 1.59 (m, 2H); 1.22-1.36 (m, 6H); 0.87 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 144.04, 138.22, 127.41, 114.48, 109.28, 31.45, 30.18, 29.86, 28.67, 22.46, 13.96. HRMS EI calcd for C11H15S 193.0925, found 193.0915.
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([Cl:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:25]([C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])[OH:26])[CH:14]=2)[N:9]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:7][C:8]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:16]([Cl:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:25]([C:27]3[C:28]([CH3:33])=[N:29][O:30][C:31]=3[CH3:32])=[O:26])[CH:14]=2)[N:9]=1
Reactant: Cc1noc(C)c1C(O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1noc(C)c1C(=O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
THF (5 mL) was added to a mixture of 6-bromo-2,4-dichloro-3-phenylquinoline (363 mg, 1.03 mmol, Intermediate 1, step c) and 3,5-dimethylisoxazole-4-carbaldehyde (180 mg, 1.44 mmol) under a nitrogen atmosphere. The resulting colorless solution was cooled in a dry ice/acetone bath. n-BuLi (1.6 M in hexane, 0.771 mL, 1.23 mmol) was added dropwise and the mixture was stirred at −78° C. for 30 min, then moved to an ice bath and stirred for 30 min. The reaction was quenched by addition of saturated aqueous NH4Cl and was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated to afford crude (2,4-dichloro-3-phenylquinolin-6-yl)(3,5-dimethylisoxazol-4-yl)methanol which was used without further purification in the next step. 1,4-dioxane (7.5 mL) and manganese (IV) dioxide (447 mg, 5.14 mmol) were added to the crude alcohol from the prior step. The resulting black suspension was heated in a 100° C. oil bath in a sealed tube overnight. The mixture was allowed to cool, was diluted with DCM, and was filtered through Celite®. The filtrate was concentrated and the residue was purified by flash column chromatography—(silica gel, 3-15% EtOAc-heptane) to isolate the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[O:12]1[CH2:31][CH:13]1[CH2:14][O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([O:26][CH2:27][CH:28]1[O:30][CH2:29]1)=[O:25])=[O:17]>C1C=CC=CC=1>[OH:12][CH:13]([CH2:31][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([OH:1])[CH2:3][C:4]1([CH3:11])[CH3:10])[CH2:14][O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([O:26][CH2:27][CH:28]([OH:30])[CH2:29][N:5]1[C:4]([CH3:11])([CH3:10])[CH2:3][CH:2]([OH:1])[CH2:7][C:6]1([CH3:9])[CH3:8])=[O:25])=[O:17]
Reactant: O=C(OCC1CO1)C1CCCCC1C(=O)OCC1CO1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Solvent: c1ccccc1
Product: CC1(C)CC(O)CC(C)(C)N1CC(O)COC(=O)C1CCCCC1C(=O)OCC(O)CN1C(C)(C)CC(O)CC1(C)C
Reaction time: 5 h

Procedure:
A mixture of 11.0 g of 4-hydroxy-2,2,6,6-tetramethylpiperidine and 7.0 g of bis(2,3-epoxypropyl)1,2-cyclohexanedicarboxylate was heated, with stirring, at 170°-180° C. for 5 hours. After completion of the reaction, benzene was added to the reaction mixture and then the benzene solution was washed with water and dried over anhydrous potassium carbonate. The solvent was evaporated under reduced pressure from the benzene solution, leaving a residue, which was then purified by column chromatography through silica gel eluted with a 16:2:1:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine, giving the desired Compound No. 90 as a vitreous solid. The Compound had an Rf value of 0.32 on thin-layer chromatography on silica gel developed with a 16:2:3:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26](O)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[CH3:35][S:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])=[O:37]>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26]([N:42]3[CH2:43][CH2:44][N:39]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:40][CH2:41]3)=[O:27])=[C:17]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)O)c3n2)cn1
Product: CS(=O)(=O)N1CCN(C(=O)CCn2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)CC1

Procedure:
3-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)propanoic acid (50 mg) was reacted with 1-(methylsulfonyl)piperazine via General Procedure F followed by Boc deprotection via General Procedure E to give 33.8 mg 112 as white solid following reverse phase purification. MS (Q1) 517.2 (M)+
Reaction SMILES: [CH3:1][C:2]12[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][C:7]1=[CH:6][C:5](=[O:16])[CH2:4][CH2:3]2.[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:17]1[CH2:18][O:19][CH:4]2[CH:5]([CH2:6][C:7]3[C:2]([CH3:1])([CH2:3]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]=3)[O:16]1
Reactant: CC12CCC(=O)C=C1CCc1ccccc12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC12CC3OCCOC3CC1=CCc1ccccc12

Procedure:
A solution of 4a-methyl-4,4a,9,10-tetrahydro-2(3H)-phenanthrone 1 (7 g, 33 mmol; prepared by the method of A. L. Campbell and J. D. McChesney, Syn. Commun. 1979, 9, 471-479) is dissolved in anhydrous benzene (300 mL) and ethylene glycol (16 mL) and p-toluenesulfonic acid (0.7 g, 4 mmol) added. The solution is refluxed with the removal of water in a Dean-Stark trap according to the method of A. J. Vila, R. A. Spanevello, A. C. Olivieri, M. G. Sierra, and J. D. McChesney, Tet. Lett. 1989, 45, 4951-4960 to form the ketal, 2-ethylenedioxy-4a-methyl- 1,2,3,4,4a,9-hexahydrophenanthrene 2.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=1)=[O:5])C.[OH-].[Li+]>CO.O>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2)c2ccccc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccccc32)cc1

Procedure:
Experimental conditions analogous to those described for Step 4 of Example 60, from 3.10 g (8.80 mmol) of 1-(4-methoxy-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester, 40 mL of 1:1 methanol-water mixture and 0.44 g (18.3 mmol) of lithium hydroxide with a work-up consisting only of thorough evaporation of solvents.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH3:19][O:18][C:12]1[CH:17]=[CH:16][C:15]([C:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:14][CH:13]=1
Reactant: COc1ccccc1
Reactant: CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CC(C)C)cc1
Reaction time: 0.67 h
Yield: 98.6 %

Procedure:
While 40 g of isovaleryl chloride and 44 g of aluminum chloride were added to 140 ml of dichloromethane and stirred, 32.6 ml of anisole were slowly added in droplets at −10° C. or lower, and stirring was continued at room temperature for 40 min. Subsequently, 36.6 ml of isovaleryl chloride were slowly added in droplets, and stirring was further continued at room temperature for 18 hr. After the reaction was completed, the resultant reaction mixture was added with 200 ml of dichloromethane, and then washed with a saturated aqueous solution of sodium bicarbonate and water, in that order, after which the dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, thus obtaining 56.9 g (yield: 98.6%) of a title compound as light yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=O)[NH:14][N:15]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.Cl[C:27]1[N:28]=[N:29]C(C2C=CC([N+]([O-])=O)=C(C(F)(F)F)C=2)=CC=1.C(NN)=O>C(O)CCC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:27]=[N:28][N:29]=3)[N:15]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2]
Reactant: O=c1ccc(-c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)n[nH]1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(Cl)nn2)cc1C(F)(F)F
Agent: NNC=O
Solvent: CCCCO
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2ccc3nncn3n2)cc1C(F)(F)F

Procedure:
A mixture of 7.0 g. of 6-[4-nitro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone and 80 ml. of phosphorus oxychloride is heated on a steam bath for 18 hours. The solvent is removed and ice water added to the residue. Filtration gives 7.2 g. of 3-chloro-6-[4-nitro-3-(trifluoromethyl)phenyl]pyridazine as tan crystals, m.p. 129°-135° C. Recrystallization from dichloromethane-hexane gives cream colored crystals, m.p. 151°-155° C. The preceding compound is reacted with formylhydrazine in refluxing n-butanol for 24 hours to give the product of the example.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC([O-])=O)C=CC=1OC.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O)[CH3:27].C(OP([CH2:53][C:54]#[N:55])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:53][C:54]#[N:55])[CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH3:27]
Reactant: CCOc1cc(C(=O)c2ccccc2)ccc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1ccc(C(=CC(=O)[O-])c2ccc(OC)c(OC)c2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOc1cc(C(=CC#N)c2ccccc2)ccc1OC

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile was prepared analogously to 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3-ethoxy-4-methoxybenzophenone (1.3 g, 5 mmol), diethylcyanomethylphosphonate (0.9 mL, 5.5 mmol) and lithium hexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, methylene chloride) to afford 1.35 g (96%) of a mixture of the E and Z isomers as a white solid: mp 74-77° C.; 1H NMR (CDCl3) δ 7.50-7.24 (m, 10 H), 7.07-6.75 (m, 6 H), 5.67 (s, 1 H), 5.60 (s, 1 H), 4.15-3.95 (m, 4 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 1.50-1.36 (m, 6 H) 13C NMR (CDCl3) δ 162.8, 162.7, 151.4, 150.9, 148.1, 147.1, 147.9, 139.3, 137.1, 131.3, 130.2, 129.9, 129.5, 129.3, 128.6, 128.5, 128.4, 123.1, 122.0, 118.3, 118.2, 113.9, 112.5, 110.9, 93.3, 92.9, 64.4, 55.9, 55.9, 14.6; Anal. Calcd for C18H17NO2. Theoretical: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.14; H, 6.06; N, 4.75.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH3:6][C:7]([C:10]1[CH:15]=[C:14]([SH:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[OH:21])([CH3:9])[CH3:8].[CH3:22][C:23]1([CH3:26])[O:25][CH2:24]1>C(O)C>[CH3:18][C:17]([C:12]1[CH:13]=[C:14]([S:16][CH2:22][C:23]([OH:25])([CH3:26])[CH3:24])[CH:15]=[C:10]([C:7]([CH3:6])([CH3:8])[CH3:9])[C:11]=1[OH:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC1(C)CO1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(C)(O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of sodium ethoxide, freshly prepared from sodium (1.31 g, 57.2 mmole) in ethyl alcohol (200 ml), was added 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (6.8 g, 28.6 mmole) and the mixture was stirred for one hour. After cooling to 5° C. with an ice bath, 1,1-dimethylethylene oxide (2.06 g, 28.6 mmole) was added and the ice bath removed. After stirring for 5.5 hours the reaction mixture was poured into 10% hydrochloric acid. The ethyl alcohol was removed in vacuo and the aqueous residue was extracted with ethyl acetate. The extracts were combined, dried over sodium sulfate, filtered, and concentrated to give 2,6-bis (1,1-dimethylethyl)-4-[(2-hydroxy-2-methylpropyl)thio]phenol. Trifluoroacetic acid (3 ml) was added to a solution of the phenol intermediate (2.2 g, 7 mmole), followed by addition by syringe of methyl thioglycolate (0.7 g, 6.7 mmole). After three hours the mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel gave the title dithio compound, m.p. 64°-68°.