Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[C:13]([C:20]([F:23])([F:22])[F:21])=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[H][H]>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH:13]([C:20]([F:23])([F:22])[F:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: [H][H]
Reactant: CCOC(=O)C=C(c1c(C)[nH]c2ccc(OC)cc12)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(c1c(C)[nH]c2ccc(OC)cc12)C(F)(F)F
Yield: 99.8 %

Procedure:
A solution of the indole from Step 2 (23 g, 70 mmol) in 200 mL EtOH was treated with 60 psi hydrogen over 5% palladium on carbon (2.3 g) in a Parr shaker for 18 h. The mixture was filtered through celite and evaporated to give 23 g of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]#[N:8])=[O:6])[CH3:3]>>[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C#N
Agent: Cl
Product: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1

Procedure:
Hydrogen chloride gas was bubbled through neat ethylcyanoformate (0.997 ml, 10.1 mmol) until the solution became a white solid, approximately 2 hours. The solid was partitioned between CH2Cl2 and water. The CH2Cl2 layer was collected dried (MgSO4) and concentrated to a white solid. The product was crystallized from hot absolute ethanol to give the title compound (m. p. 169-170° C.). 1H NMR (CDCl3) δ1.42 (t, 9H, 3× CH3), 4.50 (q, 6H, 3× CH2). 13C NMR (DMSO) δ14.06 (CH3), 64.02 (CH2), 161.27 (CO), 166.86 (Triazine Ar).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N+:9]2[O-])(=[O:3])[CH3:2].C(OC(=O)C)(=[O:25])C>>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:25])[NH:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2c1ccc[n+]2[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 40 °C
Reaction time: 2 h

Procedure:
5-Acetyl-8-benzyloxyquinoline-N-oxide (10 gms/0.034 moles) was charged in acetic anhydride (20 ml) at 25-30° C. The resulting slurry was heated to 40° C. and stirred for 2 hours at 40° C. After completion of reaction, the reaction mass was cooled to 25-30° C., chilled to 0-5° C. and stirred for 30 minutes at 0-5° C. The resulting 5-Acetyl-8-benzyloxycarbostyril was isolated by filtration and washed with diisopropyl ether (50 ml), dried under vacuum at 60-65° C. for 2-3 hours. Yield-7 gms.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14](C(O)=O)([C:17]([OH:19])=[O:18])[CH2:15][CH2:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(C(=O)O)CCc2onc(-c3ccc(Cl)cc3)c2C1
Solvent: CCO
Product: O=C(O)C1CCc2onc(-c3ccc(Cl)cc3)c2C1
Yield: 77.6 %

Procedure:
1 g of 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2-benzisoxazole-5,5-dicarboxylic acid was heated to 200°-210° C. for 5 minutes until effervescence had ceased. The residue was dissolved in ethanol and there was obtained from the solution 0.67 g of 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2-benzisoxazole-5-carboxylic acid of melting point 203°-205° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:52](I)[CH3:53].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([N:9]([CH2:52][CH3:53])[S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NS(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Reactant: CCI
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(N(CC)S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 250 mg of methyl 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate, 0.081 mL of ethyl iodide, 142 mg of potassium carbonate, and 2.5 mL of DMF was stirred at 60° C. overnight. To the reaction mixture was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 243 mg of methyl 4-(2-{-4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl](ethyl)sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate as a yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=2[O:22][CH3:23])=[C:8]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:7]=1>C(Cl)Cl>[Cl:3][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:9]2[C:8]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:7][C:6]([NH2:5])=[N:11][C:10]=2[CH3:12])=[C:15]([O:22][CH3:23])[CH:16]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.239 mL) was added portionwise to a solution of the product from step (v) (0.94 g) in DCM (20 mL) under nitrogen. The resulting solution was stirred at rt for 1 h. The solvent was evaporated under reduced pressure to give the subtitle compound as a colourless gum 0.99 g that was used without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[NH2:17].O.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:17][C:3]1[CH:4]=[C:5]([N:8]([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:6]=[CH:7][CH:2]=1
Reactant: Nc1cc(N(C(F)(F)F)C(F)(F)F)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cccc(N(C(F)(F)F)C(F)(F)F)c1
Yield: 44.4 %

Procedure:
26.5 g of 4-chloro-3-amino-N,N-bistrifluoromethyl-aminobenzene were dissolved in 50 g of toluene and reacted at 350° C. The reaction products were introduced into 150 ml of water. The two-phase mixture obtained was made alkaline with 20% strength by weight aqueous sodium hydroxide solution, and the toluene phase was separated off, to give 10.3 g of 3-amino-N,N-bistrifluoromethyl-aminobenzene of boiling point 76° to 78° C. at 20 mbar by distillation.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C:10]1([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][S:30][C:31]3[NH:35][C:34]4[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=4[N:32]=3)[C:24]=2[CH3:40])[O:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][O:11]1)[CH3:9].ClC1C=CC=C(C(OO)=[O:49])C=1>CO>[CH2:8]([C:10]1([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][S:30]([C:31]3[NH:35][C:34]4[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=4[N:32]=3)=[O:49])[C:24]=2[CH3:40])[O:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][O:11]1)[CH3:9]
Reactant: CCC1(CCOc2ccnc(CSc3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a toluene (10.8 ml) and methanol (1.2 ml) solution of the 2-(((4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (380 mg, 0.81 mmol) obtained in the step (4h), a toluene (2.7 ml) and methanol (0.3 ml) solution of 3-chloroperbenzoic acid (192 mg, 0.73 mmol as the content was regarded as 65%) was added dropwise at −70 to −60° C. for 10 minutes in a nitrogen atmosphere. The mixture was stirred for one hour in the same conditions. The reaction was terminated by adding a saturated aqueous solution (15 ml) of sodium hydrogen carbonate at the same temperature. The mixture was extracted with chloroform (50 ml) twice and the organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (NH silica gel: elusion solvent: ethyl acetate/methanol=1/0-4/1 gradient) and desired fractions were concentrated. The obtained foamy product was re-precipitated with chloroform and diethyl ether and filtered. The operation was repeated four times and the obtained solid was washed with diethyl ether and then dried to obtain the title compound (188 mg, 47.9% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CN(C)C=O.Br[CH2:18][C:19]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=1[Cl:29].Cl.CO>CO>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:18][C:19]2[CH:24]=[C:23]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:22]=[CH:21][C:20]=2[Cl:29])[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: CS(=O)(=O)c1ccc(Cl)c(CBr)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)c1ccc(Cl)c(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 2.8 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in 35 N,N-dimethylformamide (3 ml) was added 2-(bromomethyl)-1-chloro-4-(methylsulfonyl)benzene (0.30 g), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was quenched with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by silica gel chromatography (ethyl acetate100%→ethyl acetate:methanol=4:1) to give a yellow solid. The obtained solid was dissolved in methanol, and 2N hydrochloric acid-methanol solution (0.1 ml) was added. The solvent was concentrated under reduced pressure and the residue was crystallized from methanol-ethyl acetate to give the title compound (5 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1I.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:4][C:3]=1/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: C=CC(=O)OCC
Reactant: Cc1cc(-n2cnnn2)cc(I)c1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cc(-n2cnnn2)cc(C)c1N

Procedure:
To a solution of 1-(4-amino-3-iodo-5-methylphenyl)tetrazole (5 g) in acetonitrile (80 cm3) was added ethyl acrylate (2 g), triethylamine (2 g) and palladium acetate (0.1 g). The mixture was heated under reflux for 11/2 hours, cooled and then partitioned between water (100 cm3) and dichloromethane (100 cm3). The aqueous phase was re-extracted with more dichloromethane (100 cm3) and the combined organic phases were dried (MgSO4), filtered and evaporated in vacuo. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane: methanol, 20:1. Combination and evaporation of appropriate fractions gave a solid which on recrystallisation from ethyl acetate/methanol afforded yellow needles of trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol-1-yl]phenyl)prop-2-enoate, m.p. 210°-211°, (3.45 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)c2cccnc2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.1 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid (2.6 g) and 4-nitrophenol (1.42 g) in 35 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (1.91 g). The mixture was stirred at room temperature for 18 hours, and after the usual work up. the ester was crystallized from ether to give 3.65 g of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid 4-nitrophenyl ester 51°-56° C. Recrystallization of a portion from ether afforded the analytical specimen, mp 54°-56° C.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Br:39][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][CH:36]=1
Reactant: CN(C[C@@H](N)c1cccc(Br)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cccc(Br)c1

Procedure:
Compound 65 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-bromo-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound. LC/MS [401,403 (M+H)]1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.19 (s, 1H), 9.01 (d, 1H), 8.55 (s, 1H), 8.39 (d, 1H), 8.19 (s, 1H), 7.70 (m, 1H), 7.52-7.38 (m, 3H), 7.29 (m, 1H), 5.48 (s, 1H), 3.15 (dd, 1H), 2.91 (dd, 1H), 2.31 (s, 3H)
Reaction SMILES: O[C:2]1([CH2:19][O:20][C:21](=[O:35])[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3]1.C(N(S(F)(F)[F:42])CC)C>C(Cl)Cl>[F:42][C:2]1([CH2:19][O:20][C:21](=[O:35])[N:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)COc1cccc2c1CCC(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2
Solvent: ClCCl
Product: CCOC(=O)COc1cccc2c1CCC(F)(COC(=O)N(c1ccccc1)c1ccccc1)C2
Reaction time: 0.5 h

Procedure:
To a solution of 2-hydroxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene (100 mg) in CH2Cl2 (10 ml) was added diethylaminosulfur trifluoride (0.5 ml) at -78° C. After being stirred for 30 minutes, the mixture was washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 2-fluoro-2-(N,N-diphenylcarbamoyloxymethyl)-5-ethoxycarbonylmethyloxy-1,2,3,4-tetrahydronaphthalene (40 mg).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH-:6].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+]>>[CH2:1]([O:6][CH2:1][CH:3]1[O:5][CH2:4]1)[CH:3]1[O:5][CH2:4]1
Reactant: ClCC1CO1
Reactant: [OH-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: C(OCC1CO1)C1CO1
Temperature: 37.5 °C
Reaction time: 7 h
Yield: 63 %

Procedure:
A 6.8 g (14 mmol) quantity of 1,3-bis(4,4′-dimethyl-diphenylamino)-4-hydroxybenzene and 32 ml (0.4 mol) of epichlorohydrin (commercially obtained from Aldrich, Milwaukee, Wis.) were added to a 50 ml 3-neck round bottom flask equipped with reflux condenser, thermometer and mechanical stirrer to form a reaction mixture. The reaction mixture was stirred vigorously at 35-40° C. for 7 hours. While the reaction mixture was stirring, 2.7 g (0.04 mol) of powdered 85% potassium hydroxide and 0.7 g (5 mmol) of anhydrous sodium sulfate were added in two portions, with a temporary cooling of the reaction mixture to 20-25° C. prior to each addition. After termination of the reaction, the mixture was cooled to room temperature and filtered. The organic part of the mixture was treated with diethylether and washed with distilled water until the wash water had a neutral pH. After the organic solution was dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered, the solvent was removed. The residue was purified by column chromatography (silica gel, grade 62, 60-200 mesh, 150 Å, Aldrich) using a mixture of acetone:hexane in a volume ratio of 1:4 as the eluant. Fractions containing the product were collected and the solvent was evaporated to afford 4.8 g (63%) of glycidyl ether of 1,3-bis(4,4′-dirnethyldiphenylamino)phenol (Compound 2). A 1H NMR spectrum (250 MHz, CDCl3) yielded chemical shifts, in ppm, of: 7.05-6.70 (m, 19H, Ar); 3.84 (d, J=4.0 Hz, OCH2); 2.84 (m, 1H, CH); 2.33 (dd, 1H, one of CH2 of oxirane); and 2.27 (s, 12H, CH3). An elemental analysis resulted in the following values in weight %: C 82.08; H 6.61; N 5.07, which compared with calculated values for C37H36N2O2 in weight percent of: C82.19; H 6.71; N 5.18.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]([CH3:18])=[N:16][C:15]2[N:11]([N:12]=[C:13]3[CH2:21][N:20]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[O:23])[CH2:19][C:14]3=2)[C:10]=1[CH3:37]>C(Cl)Cl>[Cl:8][C:9]1[C:17]([CH3:18])=[N:16][C:15]2[N:11]([N:12]=[C:13]3[CH2:21][N:20]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH:31]4[CH2:36][CH2:35][N:34]([C:1](=[O:3])[CH3:2])[CH2:33][CH2:32]4)=[O:23])[CH2:19][C:14]3=2)[C:10]=1[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNCC1)C3
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ccccc2C(=O)N2Cc3nn4c(C)c(Cl)c(C)nc4c3C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
Acetic anhydride (27 μL; 0.28 mmol; 1.2 eq.) was added to a suspension of Example 3 (100 mg; 0.23 mmol; 1 eq.) and TEA (82 μL; 0.59 mmol; 2.5 eq.) in DCM (3 mLl) and the resulting mixture was stirred at room temperature for 2 hours. The solution was diluted with DCM, washed with 0.1M HCl and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (72 mg, 66%) as a white solid. 1H NMR (CDCl3) δ 7.42-7.35 (m, 2H), 7.11-7.04 (m, 1H), 7.02-6.97 (m, 1H), 5.01-4.99 (m, 2H), 4.71-4.58 (m, 3H), 3.75-3.68 (m, 1H), 3.60-3.46 (m, 2H), 3.40-3.32 (m, 1H), 2.91 (s, 2H), 2.85 (s, 1H), 2.69 (s, 1H), 2.62 (s, 2H), 2.04 (s, 3H), 1.90-1.74 (m, 4H). HPLC (max plot) 99.4%, Rt 3.16 min. UPLC/MS: (MS+) 468.4 ([M+H]+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C([NH+](CC)CC)C.[CH2:13]([CH:20]1[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22][C:21]1=[O:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([C:20]1[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22][C:21]=1[O:28][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1NC(=O)C(Cc2ccccc2)C(=O)N1
Reactant: CS(=O)(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Oc1[nH]c(=O)[nH]c(=O)c1Cc1ccccc1
Yield: 36.2 %

Procedure:
A solution of methanesulfonyl chloride (1.4 ml) in DMF (20 ml) was dropped into a stirred suspension of the triethylammonium salt of 5-benzyl-2,4,6-(1H,3H)-pyrimidinetrione (g 5) in DMF (210 ml). After an hour most of the solvent was removed in vacuo. The residual suspension was then poured into a ice-water mixture, and the precipitated white solid was collected by filtration, to yield, after drying, the title product, (4 g, 36.2% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]=[O:11])[CH3:2].[OH-:12].[K+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11])[CH3:2]
Reactant: CCc1ccccc1CC=O
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1ccccc1CC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of the crude (2-ethylphenyl)acetaldehyde in 20 ml of EtOH was added a solution of 2.29 g (13.52 mmol) of AgNO3 in 7.5 ml of water and a solution of 2.08 g (37.2 mmol) of KOH in 13 ml of water at 0° C. The reaction mixture was stirred at 0° C. for 2 h and was filtered to remove the solid. The filtrate was extracted with CH2Cl2 (20 ml×3) to remove impurity. The aqueous was acidified with 6N HCl to PH=1 and was extracted with CH2Cl2 (50 ml×3). The combined organic layers were dried MgSO4 and concentrated to give 2-ethylphenylacetic acid.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:22]O>>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([O:16][CH3:22])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccccc1
Yield: 96 %

Procedure:
A mixture of 3-(5-phenyl-4-isoxazolyl)propionic acid (18.62 g), conc. sulfuric acid (0.2 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-(5-phenyl-4-isoxazolyl)propionate (19.03 g, yield 96%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.59–2.71 (2H, m), 2.95–3.06 (2H, m), 3.68 (3H, s), 7.42–7.56 (3H, m), 7.64–7.74 (2H, m), 8.22 (1H, s).
Reaction SMILES: [CH3:1][Mg]I.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14].O.Cl>CCOCC>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]([OH:14])[CH3:1]
Reactant: C[Mg]I
Reactant: CCCCC(C=O)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCCCC(c1ccc(Cl)cc1Cl)C(C)O
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To 14.3 g (0.088 mole) of methylmagnesium iodide in 75 ml of ether is slowly added at less than 10°, 14.5 g (0.059 mole) of the α-(2,4-dichlorophenyl) hexanal. When the addition is complete, the reaction is stirred for 1 hour then heated up to reflux for 2 hours. The reaction is cooled and poured into water. The mixture is acidified with hydrochloric acid and the oil which separates is extracted out with ether. The ether solution is dried and concentrated to give 11.7 g (76%) of the crude product.