Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:37])([CH3:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C@@H:21]([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([OH:45])[CH2:41][CH2:40]2)[CH2:20]1)(=[O:18])=[O:17].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:37])([CH3:36])[C:32]([F:33])([F:34])[F:35])=[CH:27][CH:26]=2)[C@@H:21]([CH2:38][N:39]2[CH2:40][CH2:41][C:42](=[O:45])[CH2:43][CH2:44]2)[CH2:20]1)(=[O:17])=[O:18]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCC(O)CC2)cc1)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCC(=O)CC2)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
A solution of 2.0 M solution of oxalyl chloride in CH2Cl2 (162 μL, 0.323 mmol, Sigma-Aldrich, St. Louis, Mo.) was diluted with CH2Cl2 and then chilled to −78° C. To this solution was added DMSO (45.9 μL, 0.647 mmol). The mixture was stirred for 30 min, and then a solution of 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinol (115 mg, 0.216 mmol) in CH2Cl2 was added to slowly to the mixture. The reaction was stirred for 1 h at −78° C. and then triethylamine (150 μl, 1.078 mmol) was added. Afterwards, the mixture was stirred for 15 min and allowed to slowly warm to room temperature and stirred for additional 4 h. Saturated aqueous NaHCO3 was added and the mixture was concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 1-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)-4-piperidinone (40 mg) as a mixture of two isomers.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[CH:21]=[C:20]([CH3:22])[S:19][CH:18]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:18]2[S:19][C:20]([CH3:22])=[CH:21][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=Cc1csc(C)c1)CC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(OC(C)=O)c2sc(C)cc2c1
Yield: 41.7 %

Procedure:
Sodium acetate (30 g, 0.36 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-3-thienyl)but-3-enoic acid (30 g, 0.12 mol) in 300 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 250 mL of dichloromethane. The combined solutions were washed by 350 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (250×150 mm) with hexane/ethyl acetate mixture (3:1) to give the desired product 14 g (50 mmol, 42%) as a solid.
Reaction SMILES: [CH2:1]([C:3]1([NH2:12])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH2:28]Br)=[CH:23][C:22]=1[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH2:28][NH:12][C:3]2([CH2:1][CH3:2])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[CH:23][C:22]=1[NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCC1(N)Cc2ccccc2C1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Solvent: CC#N
Product: CCC1(NCC(=O)c2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)Cc2ccccc2C1

Procedure:
A mixture of 2-ethyl-indan-2-ylamine and N-(2-benzyloxy-5-bromoacetyl-phenyl)-methanesulfonamide is stirred in acetonitrile at room temperature for 20 hours. The product is isolated by filtration. ES+MS m/e 479 (MH+)
Reaction SMILES: [Cl:1][CH:2]([C:6](=O)[CH3:7])[C:3](=O)[CH3:4].[NH2:9][C:10]([NH2:12])=[O:11]>C(O)C.Cl>[ClH:1].[OH:11][C:10]1[N:12]=[C:6]([CH3:7])[C:2]([Cl:1])=[C:3]([CH3:4])[N:9]=1
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: Cc1nc(O)nc(C)c1Cl
Temperature: -10 °C

Procedure:
A solution of 134.5 g (1 mole) of the 3-chloropentane-2,4-dione prepared as in (i) and 75 g (1.25 moles) of urea in 800 ml of ethanol and 100 ml of concentrated hydrochloric acid was heated for 10 hours under reflux. It was then cooled to -10° C., whereupon a precipitate formed, which was filtered off and dried. 114 g (58% of theory of 2-hydroxy-5-chloro-4,6-dimethylpyrimidine hydrochloride were obtained in the form of colorless crystals of melting point >210° C. ##STR57##
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9](N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:9])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CC1C(=O)CCC1=O
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1(C)C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of enone (1) (0.25 mM) and Thiol (0.25-0.275 mM) in dry chloroform (5 ml) was added catalytic amount of triethyl amine (20 μl) at room temperature and the reaction mixture was stirred at room temperature for 1-3 days under nitrogen atmosphere. The chloroform was removed under vacuum and residue was purified by flash column chromatography over silica using ethyl acetate in hexane as eluent to afford the title compound 2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:28])[N:5]([CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][C:14](=[O:16])[CH3:15])[C:6]2=[O:11].[Cl:29][CH2:30][C:31](Cl)=[O:32]>O1CCCC1>[Cl:29][CH2:30][C:31]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:28])[N:5]([CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1)[CH2:13][C:14](=[O:16])[CH3:15])[C:6]2=[O:11])=[O:32]
Reactant: CCOc1cc(C(CC(C)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(C)=O)N2C(=O)c3cccc(NC(=O)CCl)c3C2=O)ccc1OC
Yield: 99.6 %

Procedure:
A mixture of 4-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]isoindoline-1,3-dione (0.9 g, 2.34 mmol) and chloroacetyl chloride (0.29 g, 2.57 mmol) in tetrahydrofuran (20 mL) was heated to reflux for 10 minutes. The mixture was concentrated in vacuo to give 2-chloro-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-oxobutyl]-1,3-dioxoisoindolin-4-yl}acetamide (1.07 g, 100%); 1H NMR (CDCl3) δ 10.56 (s, 1H), 8.71 (d, J=8.4 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.53 (d, J=7.3 Hz, 1H), 7.09-7.05 (m, 2H), 6.82 (d, J=8.0 Hz, 1H), 5.75-5.69 (dd, J=5.3 and 9.8 Hz, 1H), 4.22 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 4.04-3.93 (m, 1H), 3.83 (s, 3H), 3.31-3.21 (dd, J=5.2 and 18.0 Hz, 1H), 2.18 (s, 3H), 1.45 (t, J=7.0 Hz, 3H).
Reaction SMILES: B#B.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=O)[CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1>C1COCC1>[ClH:3].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:15]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CCc1ccccc1)N1CCN(c2cccc(Cl)c2)CC1
Agent: B#B
Solvent: C1CCOC1
Product: Cl
Product: Clc1cccc(N2CCN(CCCc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 132.7 %

Procedure:
To a stirred solution of diborane:dimethyl sulfide complex (2M) in THF (30 mL) was added drop wise a solution of dry THF (25 mL) and 1-(3-chlorophenyl)-4-(3-phenylpropionyl)piperazine (1.28 g, 3.86 mmol). The reaction mixture was stirred at room temperature for 18 h, quenched by the addition of MeOH-HCl (25 mL), and the solvents removed under reduced pressure. Additional MeOH was added and removed under reduced pressure to give a tan solid. This was dried for 18 h under vacuum then recrystallized from MEK to give 0.9 g (67%) of colorless crystals, mp 168-169° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]1[C:5]([C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([Cl:25])=[C:8]([N:11]2[N:15]=[C:14]([C:16]#[N:17])[C:13]([S+:18]([O-:23])[C:19]([F:22])([F:21])[F:20])=[C:12]2[NH2:24])[C:9]=1[Cl:10].C=O>CO>[C:16]([C:14]1[C:13]([S:18]([C:19]([F:22])([F:20])[F:21])=[O:23])=[C:12]([NH:24][CH2:1][OH:2])[N:11]([C:8]2[C:7]([Cl:25])=[CH:6][C:5]([C:26]([F:27])([F:29])[F:28])=[CH:4][C:9]=2[Cl:10])[N:15]=1)#[N:17]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Reactant: C[O-]
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCO)c1S(=O)C(F)(F)F

Procedure:
5 equivalent of a sodium methylate (30% solution in methanol) was rapidly added to a suspension of 0.437 g of Fipronil and 1.4 equivalent of paraformaldehyde in 3 mL of methanol to provide the 3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydroxymethylamino-4-trifluoromethylsulfinylpyrazole (Compound V) after 3 hour at 20° C. and 1 hour at 60° C. Then 1 equivalent of sodium borohydride was added to the medium which provide after classical extraction and chromatography separation the 3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfinylpyrazole (Compound I).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 40.2 %

Procedure:
To a solution of benzhydryl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (6.79 g) in methylene chloride (68 ml) were added trifluoroacetic acid (29.1 g) and anisole (11.02 g) at 0° C., and the mixture was stirred at ambient temperature for 65 minutes. After the reaction mixture was evaporated, to the residue were added ethyl acetate and water, followed by adjusting to pH 7 with an aqueous solution of sodium bicarbonate. The separated aqueous solution was adjusted to pH 3.0 with 10% hydrochloric acid, and the precipitated substance was collected by filtration to give 7-[2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (1.88 g), mp 104°-116° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:23]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccc(Cl)c4)cc3c2C1
Yield: 24.8 %

Procedure:
Beginning with 10.6 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.8 μL (0.063 mMol) 3-chlorobenzoyl chloride, 4.2 mg (25%) of the title compound were recovered as a brown solid.
Reaction SMILES: OCCN(C)[C:5](=[O:11])[O:6][C:7]([CH3:10])(C)C.[CH3:13][O:14][CH2:15]C(Cl)=O.[N:19]1C=CC=C[CH:20]=1>C(OCC)(=O)C>[CH3:13][O:14][CH2:15][C:5]([O:6][CH2:7][CH2:10][NH:19][CH3:20])=[O:11]
Reactant: c1ccncc1
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: COCC(=O)Cl
Solvent: CCOC(C)=O
Product: CNCCOC(=O)COC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) were added methoxyacetyl chloride (1.20 g) and pyridine (0.97 mL). After stirring at room temperature for 3 hrs., ethyl acetate (70 mL) was added to the reaction mixture. The mixture was washed with water (20 mL), a saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (5 mL), and a 4N hydrogen chloride—ethyl acetate solution (10 mL) was added. After stirring at room temperature for 1 hr., the mixture was concentrated under reduced pressure. Water (60 mL) and diethyl ether (30 mL) were added to the residue. After stirring, the aqueous layer was separated and taken. The aqueous layer was basified with sodium hydrogen carbonate and extracted twice with ethyl acetate (40 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (1.00 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([CH3:10])=[CH:8][C:6]([NH2:7])=[C:5]([CH3:11])[C:4]=1[CH3:12].[CH:13]([C:15]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCl.O>[CH3:1][O:2][C:3]1[C:9]([CH3:10])=[CH:8][C:6]([NH:7][CH2:13][C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)=[C:5]([CH3:11])[C:4]=1[CH3:12]
Reactant: CCOC(=O)C1(C=O)CCC1
Reactant: COc1c(C)cc(N)c(C)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1(CNc2cc(C)c(OC)c(C)c2C)CCC1
Reaction time: 3.5 h

Procedure:
To a solution of 4-methoxy-2,3,5-trimethylaniline (400 mg) in dichloromethane (24 mL) was added ethyl 1-formylcyclobutanecarboxylate, prepared as described in Step 1 (377.8 μL). Then NaBH(OAc)3 (771.4 mg) and acetic acid (152.2 μL) were added sequentially. After 3.5 h, water was added. The two layers were separated and the aqueous layer was extracted with more dichloromethane. The combined organic phases were washed with brine, dried and evaporated. Elution of the residue on a silica column (EtOAc/DCM, 0-5%) gave ethyl 1-((4-methoxy-2,3,5-trimethylphenylamino)methyl)-cyclobutanecarboxylate (400 mg) as an oil. 1H-NMR, (300 MHz, CDCl3) δ=6.37 (s,1H), 4.262-3.974 (q, 2H), 3.63 (s, 3H), 3.745-3.474 (br s, 1H), 3.41 (s, 2H), 2.693-2.339 (m, 2H), 2.27 (s, 3H), 2.21, (s, 3H), 2.14-1.818, (m, 4H), 2.02, (s, 3H), 1.333-1.174 (t, 3H) ppm., 13C-NMR, (75 MHz, CDCl3) δ=176.51, 142.52, 129.68, 128.09, 119.78, 110.29, 60.85, 60.37, 50.67, 47.2, 28.43, 16.38, 15.9, 14.3, 12.94, 12.85 ppm.
Reaction SMILES: Cl.CC1C=CC([N+]([O-])=O)=CC=1NC(N)=N.[N+]([O-])(O)=O.CC1C=CC([N+]([O-])=O)=CC=1NC(N)=N.[C:34]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)(=[O:36])[CH3:35].CO[CH:45](OC)[N:46]([CH3:48])[CH3:47]>>[CH3:45][N:46]([CH3:48])[CH:47]=[CH:35][C:34]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:36]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccnc1
Agent: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Agent: Cl
Solvent: O=[N+]([O-])O
Product: CN(C)C=CC(=O)c1cccnc1

Procedure:
In other aspects the invention provides a process for the preparation of N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine comprising: (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; and (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine.
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:27]=[CH:26][C:10]([O:11][C:12]2[CH:13]=[C:14]([C:22]([O:24][CH3:25])=[O:23])[CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=1.N([O-])=[O:29].[Na+]>O>[OH:29][C:7]1[CH:27]=[CH:26][C:10]([O:11][C:12]2[CH:13]=[C:14]([C:22]([O:24][CH3:25])=[O:23])[CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1cc(Oc2ccc(N)cc2)cc(C(=O)OC)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(O)cc2)cc(C(=O)OC)c1
Temperature: 50 °C
Yield: 52 %

Procedure:
Into a 1 liter four-necked flask equipped with a thermometer, a stirrer and a dropping funnel, 450 ml of ion-exchanged water, 75 ml of a concentrated sulfuric acid and 45.20 g (0.15 moles) of dimethyl 5-(4-aminophenoxy)isophthalate obtained in accordance with the same procedures as those conducted in Example 5 were placed and the resultant mixture was stirred. The flask was cooled at a temperature of 50° C. or lower. Into the cooled flask, a solution prepared by dissolving 12.42 g (0.18 moles) of sodium nitrite into 25 ml of distilled water was added dropwise over 20 minutes. The resultant mixture was stirred at a temperature of 5° C. or lower for 40 minutes and at 100° C. for 2 hours. The formed precipitates were separated by filtration and, after a treatment with active carbon in methanol, recrystallized from methanol. The formed solid substance was separated by filtration and dried at 50° C. for 1 day under a reduced pressure and 23.58 g of a product was obtained (the yield: 52%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(Cl)([Cl:16])=O.[CH3:18]O>>[ClH:16].[NH2:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([I:13])=[CH:11][CH:12]=1)[C:3]([O:5][CH3:18])=[O:4]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](Cc1ccc(I)cc1)C(=O)O
Product: COC(=O)[C@@H](N)Cc1ccc(I)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 92 (2.00 g, 6.87 mmol) in MeOH (10 mL) at 0° C. was added thionyl chloride (2 mL) and the resulting solution was allowed to stir for 16 h whilst equilibrating to RT. The reaction was evaporated to dryness in vacuo to yield the title compound (2.25 g, 6.80 mmol, 99%) as a white solid, which had spectral data in agreement with that reported.93 [α]D21 −9.3 (c. 0.15, HCl). Mp 195-198° C. (lit. 199.5-200.5° C.)93 1H NMR (CD3OD, 300 MHz): δ 7.72 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 7.06 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 4.33 (dd, J=6.3, 6.9 Hz, 1H, H2); 3.80 (s, 3H, OCH3); 3.23 (dd, J=6.6, 14.4 Hz, 1H, H3a); 3.15 (dd, J=7.2, 14.4 Hz, 1H, H3b). Mass Spectrum (ES, +ve) m/z 306 (100%) [M+]. HRMS calcd for C10H13INO2 305.9986 found 305.9980.
Reaction SMILES: [Br-].[C:2]1([C:8]([PH3+])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)C=CC=CC=1.[CH2:22]([Li])[CH2:23][CH2:24]C.C1(=O)CCCCCCCC=CCCCCCC1>C(OCC)C>[CH2:2]=[C:8]1[CH2:9][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:24][CH:23]=[CH:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:15]1
Reactant: [PH3+]C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Agent: O=C1CCCCCCC=CCCCCCCC1
Agent: [Br-]
Solvent: CCOCC
Product: C=C1CCCCCCC=CCCCCCCC1
Reaction time: 4 h

Procedure:
10.7 g of triphenylmethylphosphonium bromide are added at room temperature to a mixture of 20 ml of n-butyllithium (1.55 molar in hexane) and 60ml of diethyl ether. After the mixture has been held at room temperature for 4 hours, 7.3 g of 8-cyclohexadecen-1-one are added dropwise, and the mixture is refluxed for 18 hours. After filtration, the solvent is removed by distillation, the residue is purified by chromatography (SiO2, hexane/ethyl acetate 95:5), giving 2.5 g of 1-methylene-8-cyclohexadecene, identified by a 1H-NMR spectrum:
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7](Cl)(=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[C:7]([C:4]1[S:3][C:2]([Br:1])=[CH:6][CH:5]=1)(=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Brc1cccs1
Reactant: CCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCCCCC(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Bromothiophene (1.63 g, 10.0 mmol) and heptanoyl chloride (1.78 g, 12.0 mmol) were dissolved in dry benzene (15 mL) and AlCl3 was added in portions with stirring over 10 min. The resulting dark brown solution was refluxed for 1 hr and left to cool down to room temperature. The mixture was quenched with 2M HCl (15 mL) carefully while stirred. The organic layer was separated, washed with 2M HCl, 2M NaOH, and water, and passed through silica column (d=3 cm, I=8 cm). The solution was dried over MgSO4, and concentrated in vacuo (2.40 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[N:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1nc(O)ncc1F
Solvent: c1ccncc1
Product: Nc1nc(OS(=O)(=O)c2ccccc2)ncc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
To a suspension of 4-amino-5-fluoro-pyrimidin-2-ol (0.177 g, 1.4 mmol) in pyridine (5 mL) was added benzene sulfonyl chloride (0.284 g, 1.6 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the crude material purified by reverse phase chromatography to yield the title compound (0.106 g, 29% yield) as a white solid: mp 145-146° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.05-8.00 (m, 3H), 7.9-7.75 (m, 3H), 7.70-7.63 (m, 2H); HPLC-MS (ESI) m/z 270 (M+H)+, 268 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([OH:21])[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[N:28]1([C:32]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])=[O:33])[CH2:31][CH2:30][CH2:29]1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:37]3[CH:38]=[CH:39][C:34]([C:32]([N:28]4[CH2:31][CH2:30][CH2:29]4)=[O:33])=[C:35]([F:41])[CH:36]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:35]3[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=3[C:32]([N:28]3[CH2:31][CH2:30][CH2:29]3)=[O:33])[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: O=C(c1ccc(F)cc1F)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cn1ccc(NC(=O)c2cc(Oc3cc(F)ccc3C(=O)N3CCC3)c3c(c2)OC(C)(C)C3)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Temperature: 160 °C
Yield: 5 %
Yield: 46 %

Procedure:
4-Hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (31a) (421 mg, 1.47 mmol) and Cs2CO3 (965 mg, 2.96 mmol) was added to a solution of azetidin-1-yl(2,4-difluorophenyl)methanone (33a) (292 mg, 1.48 mmol). The reaction mixture was heated to 160° C. for 2 hr in a microwave. The mixture was filtered and concentrated, The residue was purified by SFC chromatography to give 4-[4-(azetidine-1-carbonyl)-3-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (315 mg, 46% yield) and 4-[2-(azetidine-1-carbonyl)-5-fluoro-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (34 mg, 5% yield) as white solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH:4]([CH3:5])[CH2:3][O:2]1>CO>[C:1](=[O:7])([O:6][CH3:4])[O:2][CH3:3].[CH2:3]([OH:2])[CH:4]([OH:6])[CH3:5]
Reactant: CC1COC(=O)O1
Solvent: CO
Product: CC(O)CO
Product: COC(=O)OC

Procedure:
A single stage transesterification of propylene carbonate and methanol to form dimethyl carbonate and propylene glycol was conducted in a manner similar to that set forth in Example 1. The single stage experiment was conducted by combining a stream containing 61.25 weight percent of propylene carbonate and 38.76 weight percent of methanol with the potassium carbonate catalyst in a glass reaction tube. The results of the single stage transesterification of propylene carbonate and methanol are presented in Table 1.