Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]1[CH3:26])[CH3:16]>C(Cl)CCl>[CH2:15]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:8]([C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:11]([OH:10])=[O:12])=[O:9])=[C:18]1[CH3:26])[CH3:16]
Reactant: CCn1c(C)cc2ccccc21
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: ClCCCl
Product: CCn1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2C(=O)O)c2ccccc21
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A solution of 67.2 g (0.4 mole) of 4-nitrophthalic anhydride and 63.0 g (0.32 mole) of 80.6 percent active 1-ethyl-2-methylindole in 50 ml of ethylene dichloride was heated at reflux for two hours. The reaction mixture was then allowed to cool to room temperature. The yellow precipitate which separated was collected by filtration, washed with fresh ethylene dichloride and dried to obtain 64.5 g of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-5-nitrobenzoic acid (Formula VIII: R°=R2 =R3 =Y1 =H; R1 =NO2 ; R5 =CH3 ; R6 =CH2CH3) having a melting point of 203°-204° C.
Reaction SMILES: [CH3:1][NH2:2].Br.[CH3:4][O:5][C:6]([C:8]1[C:9]([CH3:23])=[N:10][S:11][C:12]=1[NH:13][C:14]([O:16]C1C=CC=CC=1)=O)=[O:7]>C(O)C.O>[CH3:4][O:5][C:6]([C:8]1[C:9]([CH3:23])=[N:10][S:11][C:12]=1[NH:13][C:14]([NH:2][CH3:1])=[O:16])=[O:7]
Reactant: CN
Reactant: COC(=O)c1c(C)nsc1NC(=O)Oc1ccccc1
Agent: Br
Solvent: O
Solvent: CCO
Product: CNC(=O)Nc1snc(C)c1C(=O)OC

Procedure:
A warm solution of methyl 3-aminocrotonate (prepared according to the method of Conrad and Epstein, Chemische Berichte, 1887, 20, 3054, 10.4 g.) in toluene (20 ml.) was added with stirring to a solution of phenoxycarbonylisothiocyanate (16 g.) in toluene (50 ml.). The temperature of the mixture rose from 20° C. to 35° C. The mixture was then stirred for 11/2 hours at ambient temperature, filtered and the solid residue washed with light petroleum (b.p. 40°-60° C.) to give 3-imino-2-methoxycarbonyl-N-phenoxycarbonylthiobutyramide (8.6 g.) in the form of an orange solid, which was then dissolved in ethyl acetate (100 ml.). To this solution, a solution of bromine (1.67 ml.) in ethyl acetate (5 ml.) was added over 15 minutes at 2°-5° C. The mixture was stirred at ambient temperature for 11/2 hours and the solid product filtered off to give 4-methoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole hydrobromide (9.6 g.) m.p. 170°- 173° C. A solution of methylamine in ethanol (30% w/v; 20 ml.) was added to 4-methoxycarbonyl-3-methyl-5-phenoxycarbonylaminoisothiazole hydrobromide (9.0 g.). The mixture was heated under reflux for 15 minutes, diluted with water (30 ml.), filtered and the solid residue dried at 100° C., to give 1-(4-methoxycarbonyl-3-methylisothiazol-5-yl)-3-methylurea (4.1 g.), m.p. 236°-237° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1F)([O-:3])=[O:2].CO[C:16]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19](OC)=[C:18]([CH3:26])[C:17]=1[OH:27]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[O:27][C:17]1[C:18]([CH3:26])=[CH:19][C:20]([CH3:23])=[C:21]([CH3:22])[CH:16]=1)([O-:3])=[O:2]
Reactant: COc1c(C)c(C)c(OC)c(O)c1C
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(F)c1
Product: Cc1cc(C)c(Oc2cc([N+](=O)[O-])ccc2[N+](=O)[O-])cc1C

Procedure:
The process was carried out as described in point 5.4 above, using 0.812 g (4.362 mmol) of 2,5-dinitrofluorobenzene and 0.856 g (4.362 mmol) of 2,5-dimethoxy-3,4,6-trimethylphenol. The title product was obtained in the form of a yellow solid (1.412 g, 89%) after column chromatography using, as eluent, a 75:25 mixture of light mineral spirit (60-80° C.):diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1O[C@@](CCCO)(c2ccc(F)cc2)CCN1[C@H]1CCCNC1
Reactant: N#Cc1ccc(Br)nc1
Product: N#Cc1ccc(N2CCC[C@H](N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)C2)nc1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one and 2-bromo-5-cyanopyridine following a procedure analogous to that described in Example 508. LC-MS Method 2 tR=1.218 min, m/z=439.1; 1H NMR (CDCl3) 1.21-1.36 (m, 1H), 1.62 (m, 1H), 1.78 (m, 3H), 1.56 (m, 2H), 1.86-2.00 (m, 2H), 2.19 (m, 1H), 2.29 (m, 1H), 2.67-2.86 (m, 3H), 3.20 (m, 1H), 3.50 (t, 2H), 3.79 (m, 1H), 4.12 (m, 1H), 4.30 (d, 1H), 6.53 (m, 1H), 7.01 (t, 2H), 7.24 (m, 2H), 7.51 (d, 1H), 8.30 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([CH:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:4][N:3]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[O:26])=[CH:4][N:3]=1
Reactant: COc1ccc(CNc2nc(Cl)ncc2C(O)c2ccccn2)cc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(Cl)ncc2C(=O)c2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-[(hydroxy)(2-pyridyl)methyl]pyrimidine (prepared in the above (2)) 46 mg, manganese dioxide 230 mg and chloroform 2.3 ml is stirred at room temperature for 3 hours. After removal of insoluble substances by filtration, the filtrate is concentrated in vacuo to give 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylcarbonyl)pyrimidine 39 mg. mp 117–119° C. (recrystalization from diethyl ether), MS(m/z): 389(M+H)+
Reaction SMILES: [CH:1]1([C:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.COC(C1C(C(F)(F)F)=NC(Br)=C(C2C=CC([Cl:54])=C(Cl)C=2)N=1)=O>>[CH:1]1([C:4]([OH:32])([CH3:31])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:16])[F:17])=[N:13][C:12]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23]3)=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([Cl:54])=[C:26]([Cl:30])[CH:25]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(Cl)c2)c(Br)nc1C(F)(F)F
Reactant: CC(O)(CNC(=O)c1nc(-c2cccc(Cl)c2)c(OCC2CC2)nc1C(F)(F)F)C1CC1
Product: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)c(Cl)c2)c(OCC2CC2)nc1C(F)(F)F)C1CC1

Procedure:
In analogy to example 7 (3-chloro-phenyl)-5-cyclopropylmethoxy-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide) the title compound was prepared by substituting 5-bromo-6-(3-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester with 5-bromo-6-(3,4-dichloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[NH2:21][CH2:22][CH2:23][P:24](=[O:27])([O-:26])[O-:25].[OH-].[Na+]>C(O)C.O>[P:24]([CH2:23][CH2:22][NH:21][C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6])([OH:27])([OH:26])=[O:25]
Reactant: NCCP(=O)([O-])[O-]
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncnc2c1nc(NCCP(=O)(O)O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 110 °C

Procedure:
A mixture of 8-bromoadenosine (1 mmol), aminoethylphosphonate (2 mmol), and sodium hydroxide (2 mmol) in ethanol-water in a sealed tube was warmed at 110° C. under nitrogen. After 24 h the cooled reaction mixture was purified through preparative HPLC to give 8-(2-phosphonoethylamino)-adenosine (4.1). mp 175° C.;
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:3][C:4]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc(C)c1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C)c1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride is added to a solution of methyl 2-hydroxy-3-methylbenzoate (694 mg, 4.18 mmol) in 15 mL of DMF at 0° C. The reaction is stirred for 15 minutes after which 4-trifluoromethyl-benzyl bromide (1.0 g, 4.18 mmol) is added. The reaction is allowed to warm up to room temperature and stirred overnight. The mixture is partitioned between ethyl acetate and water. The organic phase is washed with brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on silica gel using 4% ethyl acetate in hexane as the eluent to obtain methyl 2-(4-trifluoromethylbenzyloxy)-3-methylbenzoate as a clear liquid.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:10]=2)[C:5]1=[O:20]>C(O)(=O)C>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:10]=2)[C:5](=[O:20])[N:4]([CH3:3])[CH:13]=1
Reactant: BrBr
Reactant: Cn1ccc2cc(-c3ccccn3)ccc2c1=O
Solvent: CC(=O)O
Product: Cn1cc(Br)c2cc(-c3ccccn3)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.3 %

Procedure:
At 0° C., bromine (78 mg, 0.49 mmol) in acetic acid (0.3 mL) was added dropwise to 2-methyl-6-pyridin-2-ylisoquinolin-1-one (115 mg, 0.49 mmol) in acetic acid (20 mL). The mixture was stirred at room temperature for 20 min. Extractive work up with CH2Cl2 and purification by silica gel chromatography (PE:EA=5:1-1:1) gave the title compound (73.0 mg, 47.7%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.79 (d, J=4.4 Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 8.44 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.85 (t, J=7.2 Hz, 1H), 7.42 (s, 1H), 7.36-7.34 (m, 1H), 3.64 (s, 3H). LCMS: 314.9 (M+H)+
Reaction SMILES: [CH3:1][C@H:2]1[C@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][NH:3]1.[CH3:17][N:18]=[C:19]=[O:20].O>O1CCCC1>[CH3:17][NH:18][C:19]([N:3]1[CH2:4][C@@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[C@@H:2]1[CH3:1])=[O:20]
Reactant: CN=C=O
Reactant: C[C@@H]1NC[C@H]1Oc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1C[C@@H](Oc2cccc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
A stirred solution of 6 g (0.015 mole) of crude trans-2-methyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of tetrahydrofuran was treated with 0.94 g (0.0165 mole of methyl isocyanate added dropwise and stirred for 16 hr under a blanket of nitrogen. Dilution of the reaction mixture with water produced an oil which solidified. After decanting the aqueous tetrahydrofuran phase, the solid residue was recrystallized from ethanol-water to yield 3.95 g (91.4%) of fine white crystals, m.p. 104.5°-106° C.
Reaction SMILES: Cl.[P:2]([C:6]1[C:7]([C:12]([OH:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)([OH:5])([OH:4])=[O:3]>O=[Pt]=O.C(O)(=O)C>[P:2]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH:7]1[C:12]([OH:14])=[O:13])([OH:4])([OH:5])=[O:3]
Reactant: O=C(O)c1ncccc1P(=O)(O)O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C1NCCCC1P(=O)(O)O

Procedure:
A mixture of 348 mg of 3-phosphonopyridine-2-carboxylic acid hydrochloride and 100 mg of Adams catalyst in dilute aqueous acetic acid is hydrogenated at 3 atmospheres pressure and room temperature to yield 3-phosphonopiperidine-2-carboxylic acid, mp 150° dec.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[CH2:27][C:28]([NH2:30])=[O:29]>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:30]=[C:28]([CH2:27][C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[Cl:19])[O:29][CH:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Product: O=C(O)COc1ccc(Br)cc1-c1coc(Cc2ccc(F)cc2Cl)n1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 2-(2-chloro-4-fluorophenyl)acetamide according to GP5 and GP3: LC/MS (an 10p8) Rt 2.75 min, m/z 440 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]1([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:20]([O:23][CH:24](C)[CH2:25][CH2:26][CH2:27]I)(=[O:22])[CH3:21].Cl>O1CCCC1>[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)CCCI
Reactant: CCOC(=O)Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(CCCCOC(C)=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
Diisopropylamine (2.4 g, 23.8 mmole) was dissolved in anhydrous tetrahydrofuran (50 ml) under argon, and the solution was cooled at -70° C. 1.6M n-butyllithium-hexane solution (14.8 ml, 23.7 mmole) was added dropwise to the solution, followed by stirring at -70° C. for 10 minutes. Tetrahydrofuran (10 ml) solution containing ethyl phenylacetate (3.24 g, 20 mmole) was added, while maintaining the reaction solution at not higher than -60° C. After stirring was continued for 30 minutes under the same conditions, a solution of 4-acetoxypentyl iodide (4.8 g, 20 mmole) in hexamethylphosphortriamide (4 ml) was added dropwise to the reaction solution. Following the dropwise addition, stirring was continued at -70° C. for another 1 hour, and the reaction temperature was allowed to rise to room temperature. 2N hydrochloric acid (30 ml) was added, and the product was extracted with isopropyl ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on silica gel, and development was effected with isopropyl ether:hexane (1:1) to yield ethyl 6-acetoxy-2-phenylhexanoate (5 g, 90%).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)C.[OH-].[Na+]>C1COCC1>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([C:12](=[O:11])[CH2:2][C:1]#[N:3])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cccc(OC)c1
Reactant: CC#N
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)CC#N)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.6 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 12 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5gms. of 3-methoxy-benzoic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids, and then is extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered The organic layer is concentrated in vacuo and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-(3-methoxy-phenyl)-3-oxo-propionitrile in the amount of 2.0202 gms.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=2[OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=1[CH3:32]>CN1C(=O)CCC1>[CH3:28][C:27]1[CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=[C:23]([CH3:32])[C:22]=1[O:17][C:15]1[CH:14]=[CH:13][C:12]([OH:18])=[C:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:16]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1cc(O)ccc1O
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C

Procedure:
The title B compound, 2-(4-fluorobenzenesulfonyl)benzene-1,4-diol (1.2 g, 4.48 mmol) is added to a suspension of NaH (60% dispersion in mineral oil; 0.39 g, 9.86 mmol) in 15 mL of NMP at 0° C. in one portion. The mixture is warmed to RT and after 30 min, 4-chloro-3,5-dimethylnitrobenzene (1 g, 5.38 mmol) is added and the reaction is heated at 120° C. for 1 h. The reaction is cooled to RT and quenched with aqueous 1N HCl. The mixture is partitioned between water and EtOAc, and the organic solution is washed with water and brine, dried over anhydrous Na2SO4 and concentrated. Chromatography on silica (eluant; EtOAc/hexane-1/2/1/1) affords 4-(2,6-dimethyl-4-nitrophenoxy)-2-(4-fluorobenzenesulfonyl)phenol: NMR (CDCl3) 2.11 (s, 6H), 6.85-6.96 (m, 3H), 7.00 (app t, 2H, J=9), 7.88 (dd, 2H, J=9, 5), 7.98 (s, 2H), 8.73 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][CH:20]([C:22]4[CH:23]=[CH:24][C:25](=[O:32])[N:26]([CH2:28][C:29]([OH:31])=O)[CH:27]=4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:35][CH3:36].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:37]1([NH:40][C:29](=[O:31])[CH2:28][N:26]2[C:25](=[O:32])[CH:24]=[CH:23][C:22]([CH:20]3[O:19][N:18]=[C:17]([C:12]4[N:13]=[C:14]([CH3:16])[N:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]5[CH:33]=[CH:34][C:2]([F:1])=[C:3]([O:35][CH3:36])[CH:4]=5)=[O:9])[CH:11]=4)[CH2:21]3)=[CH:27]2)[CH2:39][CH2:38]1
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(=O)n(CC(=O)O)c4)C3)nc(C)n2)ccc1F
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(=O)n(CC(=O)NC5CC5)c4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.7 %

Procedure:
To a stirred solution 2-(5-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)-2-oxopyridin-1(2H)-yl)acetic acid (0.2 g, 0.404 mmol, G.1.225) in DMF (5 mL) was added cyclopropanamine (0.046 g, 0.807 mmol, Sd Fine Chem), EDCI.HCl (0.093 g, 0.484 mmol, spectrochem), HOBT (0.093 g, 0.605 mmol, spectrochem) and DIPEA (0.157 g, 1.211 mmol, spectrochem). The reaction mixture was stirred at RT for about 12 h. The reaction mixture was diluted with ice cold water (20 mL) and the product extracted with EtOAc (2×15 mL), The organic layer was dried over sodium sulphate and evaporated under reduced pressure to afford a thick mass. Crude compound was purified by preparative TLC, eluting with 2-4% methanol in DCM to afford 6-(5-(1-(2-(cyclopropylamino)-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 21 mg (9.73%) as an off white solid. 1H NMR (400 MHz, DMSO): δ 9.519-9.487 (m, 1H), 8.282-8.273 (d, J=3.6 Hz, 1H), 8.190 (s, 1H), 7.768-7.762 (d, J=2.4 Hz, 1H), 7.558-7.529 (dd, J=9.2 Hz, 1H), 7.186-7.119 (m, 2H), 6.908-6.871 (m, 1H), 6.429-6.404 (d, J=10 Hz, 1H), 5.705-5.654 (m, 1H), 4.491-4.458 (m, 4H), 3.857-3.784 (m, 4H), 3.461-3.393 (m, 1H), 2.767 (s, 3H), 2.745-2.650 (m, 1H), 0.649-0.601 (m, 2H) 0.425-0.387 (m, 2H); MS m/z=533.3 (M−H)−.
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([CH:7]=[CH:8][N+:9]([O-:11])=[O:10])CC1.NC1C=[C:15]2[C:19](=[CH:20][C:21]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH2:18][CH2:17][CH2:16]2.Cl.CC(C)=O>O>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([C:21]1[CH:20]=[C:19]2[C:18]([CH2:17][CH2:16][CH2:15]2)=[CH:6][C:5]=1[NH:4][CH:7]=[CH:8][N+:9]([O-:11])=[O:10])=[O:30]
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1Cl)CCC2
Reactant: O=[N+]([O-])C=CN1CCOCC1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(c1ccccc1Cl)c1cc2c(cc1NC=C[N+](=O)[O-])CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
1-Morpholino-2-nitroethene (3.93 g) was added to a mixture of 5-amino-6-(2-chlorobenzoyl)indan (4.50 g), 6N HCl (15 ml) and acetone (45 ml) and the whole mixture was stirred at room temperature for one hour. To this reaction mixture was added water to give crystals of 6-(2-chlorobenzoyl)-5-(2-nitroethenylamino)indan (5.40 g, 95.2%). Recrystallization from ethanol gave yellow needles, mp. 225°-226° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])[CH2:3][CH2:2]1.[F-].[Cs+].CS(O[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O>CC(N(C)C)=O>[CH:1]1([CH2:4][NH:5][C:6](=[O:7])[NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=C(NCC1CC1)Nc1ccc(O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)NCC3CC3)cc2)CC1
Temperature: 85 °C

Procedure:
To a stirring solution of 1-(cyclopropylmethyl)-3-(4-hydroxyphenyl)urea (6.79 mmol, 1.4 g) in dimethylacetamide (50 mL) was added cesium fluoride (20.36 mmol, 3.09 g) followed by a solution of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (8.15 mmol, 2.276 g) in dimethylacetamide (50 mL). The resulting suspension was heated to 85° C. overnight. The reaction mixture was filtered and the filtrate concentrated under vacuum. The residue was dissolved in dichloromethane and washed with water. The organic layer was separated, dried over magnesium sulfate and concentrated under vacuum. The residue was dissolved in dichloromethane and purified by column chromatography (eluent 2-8% methanol in dichloromethane) to afford the title compound. MS (ESI) m/z 390.0 [M+H]+