Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:9]=1)=[O:3].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[CH:9]=[C:4]([C:2]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:3])[CH:5]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cc(C(=O)Cl)cc(-c2ccc(C)cc2)c1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl 5-(chlorocarbonyl)-4′-methylbiphenyl-3-carboxylate (5.5 g, 18 mmol) in methylene chloride (100 mL) at 0° C. were slowly added pyrrolidine (2.6 g, 36 mmol) and triethylamine (7.6 mL, 54 mmol). The mixture was stirred at room temperature for 2 h, and then washed with brine, aq. Na2CO3 solution and water. The separated organic phase was dried (Na2SO4), and concentrated. The residue was purified by silica gel column (30-100% EtOAc/hexane) to afford the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH:18]1[C:26]2[C:21](=[CH:22][N:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:18]1[C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[CH:20]=[CH:19]1)=[O:6]
Reactant: c1cc2[nH]ccc2cn1
Reactant: O=C(O)c1c(F)cccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1c(F)cccc1Cl)n1ccc2cnccc21
Reaction time: 0.25 h
Yield: 39.7 %

Procedure:
To a stirred solution of 2-chloro-6-fluorobenzoic acid (2.5 g, 14.32 mmol) in dichloromethane (20 mL), oxalyl chloride (3.029 ml, 28.64 mmol) was added at 0° C. After stirring at the same temperature for 15 min, dimethylfromamide (2-3 drops) was added, and the reaction was allowed to stir at room temperature for 1.5 hours. The reaction mixture was cooled and concentrated on rotary evaporator. The residue was taken up in dichloromethane (20 mL) and treated with 5-azaindole (1.72 g, 14.51 mmol) and triethylamine (6.1 mL, 43.52 mmol). The resulting reaction mixture was allowed to stir at room temperature for 20 hours. The reaction mixture was concentrated under vacuum, diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under rotary evaporator. The product was isolated by silica gel column chromatography using ethyl acetate (25%) in hexanes as eluent to yield (2-chloro-6-fluorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (1.56 g, 39.5%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:13].Br[CH2:34][CH2:35][CH2:36][CH2:37][Cl:38]>O1CCCC1>[Cl:38][CH2:37][CH2:36][CH2:35][CH2:34][O:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:13]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)N1CCCCC1CCO
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC(=O)N1CCCCC1CCOCCCCCl

Procedure:
Sodium hydride is added to tetrahydrofuran solution of octadecyl 2-(2-hydroxyethyl)piperidinecarboxylate and the mixture is reacted at 0° C. Then, 1-bromo-4-chlorobutane is added to the reaction mixture and reacted to obtain octadecyl 2-(4-chlorobutoxyethyl)piperidinecarboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:18]COC(C)=O.CCCCCCC>CO>[CH3:18][O:12][C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCCCCCC
Solvent: CO
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a mixture of 2-(4-nitrophenyl)acetic acid (1 g, 5.52 mmol) dissolved in methanol (100 mL) cooled to 0° C., was added thionyl chloride (1.31 mL, 11 mmol) dropwise slowly. The mixture was stirred at 0° C. for 30 min then 25° C. for 1 h. TLC Rf=0.5 PDT (50% EtOAc/heptane; Rf=0.2 for SM). The mixture was concentrated under reduced pressure to afford (4-nitro-phenyl)-acetic acid methyl ester (1.1 g, 100%). 1H NMR (CDCl3) δ 8.2 (d, 1H), 7.5 (d, 1H), 3.79 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([NH:22][C:23](=[O:35])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]4[CH2:34][CH2:33][CH2:32][NH:31]4)[CH:25]=3)=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:43]([C:45]1[CH:46]=[C:47]([N:51]=[C:52]=[O:53])[CH:48]=[CH:49][CH:50]=1)#[N:44].[N-]=C=O>CN(C=O)C>[CH2:2]([O:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([NH:22][C:23](=[O:35])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:52](=[O:53])[NH:51][C:47]4[CH:48]=[CH:49][CH:50]=[C:45]([C:43]#[N:44])[CH:46]=4)[CH:25]=3)=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: O=C(Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2)c1cccc(C2CCCN2)c1
Agent: Cl
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cccc(NC(=O)N2CCCC2c2cccc(C(=O)Nc3ccc4c(c3)CN(C(=O)OCc3ccccc3)CC4)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.1 %

Procedure:
To a solution of 7-(3-pyrrolidin-2-yl-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester HCl (238 mg, 0.387 mmol) in DMF (5 mL) add Et3N (0.082 mL, 0.581 mmol) followed by 3-cyanophenyl isocyanate (69 mg, 0.464 mmol). Stir the solution at room temperature for 48 h. LCMS analysis indicates the presence of starting material. Add more isocyanate (69 mg, 0.464 mmol) and stir the reaction at room temperature 24 h more. Quench the reaction with sat. NH4Cl (100 mL) and extract with EtOAc (2×150 mL). Wash the organic layers with water (100 mL), dry (Na2SO4) and concentrate to an oil. Purify the crude product by silica gel chromatography eluting with 10% to 75% EtOAc/hexane to afford 186 mg 7-{3-[1-(3-cyanophenylcarbamoyl)-pyrrolidin-2-yl]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a solid foam.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:13][C:14]1[C:18](B(O)O)=[C:17]([CH3:22])[O:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C(OCC)(=O)C.O>[CH3:13][C:14]1[C:18]([C:2]2[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])=[C:17]([CH3:22])[O:16][N:15]=1
Reactant: COc1ccc([N+](=O)[O-])cc1I
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1-c1c(C)noc1C
Temperature: 90 °C
Yield: 83.3 %

Procedure:
3-Iodo-4-(methoxy) nitrobenzene (65 g, 233 mmol, Matrix Scientific), (3,5-dimethyl-4-isoxazolyl)boronic acid (36.1 g, 256 mmol) and cesium carbonate (152 g, 466 mmol) were combined with DME (80 ml) and water (40 ml) and the mixture was degassed with nitrogen for 10 min, then PEPPSI™ catalyst (3.96 g, 5.82 mmol) was added and the mixture heated at 90° C. for 4 h, then cooled and diluted with ethyl acetate (800 ml). The resulting suspension was filtered through Celite and the filtrate washed with water (2×500 ml). The solvent was dried (sodium sulphate), filtered and evaporated to give a brown solid which was triturated with ether (30 ml). The solid product was washed with ether (100 ml) to give 3,5-dimethyl-4-[2-(methyloxy)-5-nitrophenyl]isoxazole as beige solid (48.2 g).
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].CN(C)C=O.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(OCC)C.O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a stirred solution containing 11.5 g (0.05 mole) of 3,5-ditrifluoromethylphenol, 3.3 g (0.05 mole) of 85% potassium hydroxide, 200 ml of N,N-dimethylformamide and 10 ml of water, 0.055 mole of ethyl 4-bromobutyrate was added in one portion. The stirred reaction mixture was heated at 80°-90° C. for 24 hours. After cooling to 25° C., 500 ml of water and 500 ml of ethyl ether were added; and stirring was continued for 15 minutes. The separated ether layer was washed with water until neutral to litmus and dried over sodium sulfate. The ether was removed in vacuo at a maximum temperature of 80°-90° C. at 1-2 mm of Hg. A product with a ND25 =1.4281 was obtained with a 95% yield.
Reaction SMILES: Cl[C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[NH2:20][C:18]1[S:19][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:3]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][CH:2]=2)[N:17]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1ccc(Cl)cc1
Yield: 75.2 %

Procedure:
To a cold (5° C.) vigorously stirred mixture of 121.87 g (0.936 mole) of ethyl acetoacetate, 314 ml. of benzene and 626 ml. of water was added 41.25 ml. of 33% sodium hydroxide. To the above mixture was added simultaneously in two dropping funnels 177.0 g (1.01 mole) of p-chlorobenzoyl chloride and 188.8 ml. of 33% sodium hydroxide in 2 hours. The reaction mixture became pasty. The reaction mixture was heated at 35° C. for 1 hour, cooled and filtered to give 170.0 g of sodium salt of ethyl 2-benzoylacetoacetate. Part (150 g) of this salt was added to a mixture of 39.0 g (0.729 mole) of ammonium chloride and 78 ml. of concentrated ammonium hydroxide in 780 ml. of water. The mixture was stirred at 40°-50° C. for 3 hours and cooled in an ice bath. The precipitate was filtered to give 115.5 g of yellow solid which was Kugelrohr distilled to give 76.0 g (38% based on ethyl acetoacetate) of crude ethyl p-chlorobenzoylacetate. A mixture of 40.0 g (0.175 mole) of crude ethyl p-chlorobenzoylacetate, 24.2 g (0.18 mole) of sulfuryl chloride and some chloroform was held at reflux for 6 hours, cooled and concentrated to give 49.0 g of crude ethyl 2-chloro-p-chlorobenzoylacetate. A mixture of 46.0 g (0.174 mole) of crude ethyl 2-chloro-p-chlorobenzoylacetate, 13.25 g (0.174 mole) of thiourea, and 174 ml. of ethanol was held at reflux for 2 hours and cooled. The precipitate was filtered and neutralized with saturated sodium bicarbonate. The insoluble material was filtered to give 37.0 g (80%) of ethyl 2-amino-4-p-chlorophenyl-5-thiazolecarboxylate, m.p. 198°-200° C. To a cold (-5° C.) mixture of 11.3 g (0.04 mole) of ethyl 2-amino-4-p-chlorophenyl-5-thiazolecarboxylate and 80 ml. of 85% phosphonic acid was added 40 ml. of 70% nitric acid. To the above mixture was added with vigorous stirring, 4.0 g (0.0434 mole) of sodium nitrite in 20 minutes at -5°-0° C. The reaction mixture was stirred at -5°-0° C. for 10 minutes and poured into a mixture of 4.0 g (0.04 mole) of cuprous chloride, 20 ml. of concentrated hydrochloric acid and 20 ml. of water. The reaction mixture was stirred at room temperature for 30 minutes, after which time evolution had subsided. The precipitate was filtered to give 10.5 g of solid which was Kugelrohr distilled (145° C. at 0.05 mm Hg) to give 6.0 g of solid, m.p. 113°-120° C., which was recrystallized from hot ethanol to give 4.4 g (37%) of ethyl 2-chloro-4-p-chlorophenyl-5-thiazolecarboxylate as a white solid, m.p. 119°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[NH:11][C:10](=O)O[C:7](=[O:8])[C:6]2=[CH:13][C:14]=1[O:15][CH3:16].CSC(=N)[NH:20][S:21]([CH2:24]Cl)(=[O:23])=[O:22].[N:27]12CCCC1=NCCC2.Cl>O1CCOCC1>[CH3:16][O:15][C:14]1[CH:13]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:11]=[C:10]1[NH:20][S:21](=[O:22])(=[O:23])[CH2:24][N:27]1[C:7]2=[O:8]
Reactant: CSC(=N)NS(=O)(=O)CCl
Reactant: C1CN=C2CCCN2C1
Reactant: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2nc3n(c(=O)c2cc1OC)CS(=O)(=O)N3

Procedure:
To a stirred slurry of 4,5-dimethoxyisatoic anhydride (4.46 g, 20 mmol) and S-methyl-N-(chloromethanesulfonyl)isothiourea (4.06 g, 20 mmol) in dioxane (30 ml) is added 1,5-diazabicyclo[4.3.0]non-5-ene (2.5 ml). The mixture is refluxed for 4 hr under nitrogen, then cooled and poured into 0.3N aqueous hydrochloric acid. The precipitate is collected by filtration and recrystallized from DMSO to provide the title compound as a light yellow solid, mp >300° C. (445 mg, 7.5%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C:13]1[C:14]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:15]([CH2:38][CH2:39][CH3:40])[N:16]2[C:21]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][C:18]([N:28]1[CH2:37][CH2:36][C:31]3(OCC[O:32]3)[CH2:30][CH2:29]1)=[N:17]2)=[O:12])[CH3:9].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH2:8]([O:10][C:11]([C:13]1[C:14]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:15]([CH2:38][CH2:39][CH3:40])[N:16]2[C:21]=1[C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:19][C:18]([N:28]1[CH2:29][CH2:30][C:31](=[O:32])[CH2:36][CH2:37]1)=[N:17]2)=[O:12])[CH3:9]
Reactant: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCC4(CC3)OCCO4)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCC(=O)CC3)nn12
Temperature: 50 °C

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of 2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-phenyl-7-propyl-pyrrolo[1,2-b]pyridazine-5,6-dicarboxylic acid diethyl ester (99) (245 mg, 0.47 mmol) in THF (10 mL) and water (1 mL). The reaction mixture was heated to 50° C. for 4 h, poured into aqueous NaHCO3 solution. The mixture was extracted with EtOAc and the organic layer was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 35% EtOAc/hexane) provided the title compound. 1H NMR (DMSO-d6) δ 1.05-1.11 (m, 6H), 1.38 (t, 2H, J=7.0 Hz), 1.83-1.89 (m, 2H), 2.63-2.67 (m, 4H), 3.34 (t, 2H, J=7.8 Hz), 3.71 (q, 2H, J=7.2 Hz), 4.08-4.11 (m, 4H), 4.35 (q, 2H, J=7.2 Hz), 7.05 (s, 1H), 7.60-7.66 (m, 5H). Mass Spectrum (ES+) m/e=478.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC)=O)[CH:12]([CH3:20])[CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[K+].CC(O)C>O>[ClH:1].[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH:12]([CH3:20])[CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC1CC(n2c(=O)[nH]c3cc(Cl)ccc32)CCN1
Product: Cl

Procedure:
A mixture of 20 parts of methyl 4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-2-methyl-1-piperidinecarboxylate, 20 parts of potassium hydroxide, 160 parts of 2-propanol and 3 parts of water is stirred and refluxed for 36 hours. The reaction mixture is evaporated and water is added to the residue. The whole is acidified with a hydrochloric acid solution. Then it is basified with ammonium hydroxide and the free base is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-propanol. The salt is filtered off and dried, yielding 5-chloro-1,3-dihydro-1-(2-methyl-4-piperidinyl)-2H-benzimidazol-2-one hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Cl:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:12][C:7]1[CH:8]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:6]
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Cl)cc(F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Chloro-4-fluoro-6-nitroaniline was prepared using an adaptation of the method of Mitchell, et al. (Mitchell, R. H. et al., J. Org. Chem. 44:4733 (1979)). To a solution of 4-fluoro-2-nitroaniline (500 mg, 3.2 mmol) in dry DMF (10 mL) under N2 was added dropwise a solution of N-chlorosuccinimide (426 mg, 3.2 mmol) in dry DMF (16 mL). The reaction was allowed to stir overnight. The solution was then poured into 100 mL H2O and the resulting cloudy suspension extracted with 4×25 mL ethyl acetate. The combined organic phases were washed with 4×25 mL H2O and 25 mL saturated NaCl solution and dried (MgSO4). The MgSO4 was vacuum filtered and the solvent rotary evaporated to yield a brown crystalline solid which was purified further by flash chromatography (2:1 hexanes:ethyl acetate) to yield 424 mg of an orange crystalline solid (69.5%) 1H NMR (CDCl3) δ6.46 (br s, 2H, NH2), 7.42 (dd, JH5-3 =3 Hz, JH3-F =7.2 Hz, H-4), 7.85 (dd, JH5-3 =3 Hz, JH5-F =8.7 Hz, H-5)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[CH3:13].N1C=CC=CC=1.[O:20](S(C(F)(F)F)(=O)=O)[S:21]([C:24]([F:27])([F:26])[F:25])(=O)=[O:22].C(OCC)(=O)C>C(Cl)Cl>[CH3:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:22])=[O:20])[CH:3]=2)[O:8][C:7](=[O:12])[CH:6]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(=O)oc2ccc(O)cc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(=O)oc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Hydroxy-4-methyl-chromen-2-one (25 mg, 0.142 mol) and pyridine (300 mL) were dissolved in CH2Cl2 (200 mL) at room temperature and the reaction mixture was cooled to 0° C. and then treated with Tf2O (40 mL). After 1 hour, ethyl acetate (900 mL) was poured into the reaction mixture and the reaction mixture was transferred into a separation funnel. The reaction mixture was then washed with 5% sodium bicarbonate (2×450 ml), water (450 ml) and then brine. The organic layer was dried over sodium sulfate and concentrated. Flash column chromatography on silica gel eluted with 20-50% ethyl acetate in hexane yielded the title compound as a foam.
Reaction SMILES: O[C:2](C)(C#C)[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=[N:8][CH:9]=1.[H-].[Na+].C1(C)C=CC=CC=1.CC(C)=O>C1(C)C=CC=CC=1>[C:3]([C:4]1[CH:5]=[C:6]([CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=[N:8][CH:9]=1)#[CH:2]
Reactant: C#CC(C)(O)Cc1cncc(C2CCCN2C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#Cc1cncc(C2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
5-(2-Hydroxy-2-methyl-3-butynyl)-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine (495 mg, 1.5 mmol) was dissolved in toluene (30 mL) and catalytic sodium hydride (10 mg) was added. The solution was heated until several milliliters of toluene-acetone mixture was removed by distillation. The mixture was cooled to 25° C. and water (20 mL) and ethyl acetate (40 mL) were added. The organic phase was separated and the aqueous layer extracted with ethyl acetate (2×40 mL) and the combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography with ethyl acetate:hexane (1:3) as eluant to afford 5-ethynyl-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine as an oil (250 mg, 61%). LRMS (EI) m/e 217 (M+ +H--isobutylene), 216 (M+ --isobutylene); 1H NMR (CDCl3, 300 MHz): δ 8.59 (b-s, 1H), 8.42 (d, J=1.5 Hz, 1H), 7.59 (b-s, 1H), 4.94 (b-m, 0.5H), 4.77 (b-m, 0.5H), 3.64 (b-m, 2H), 3.21 (s, 1H), 2.39 (m, 1H), 1.75-2.0 (b-m, 3H), 1.46 (s, 3H), 1.21 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])=[C:20]([O:30][CH3:31])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.N1C=NC=N1.C(N(C(C)C)[P:41]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(C)C.[OH:61]O.O>C(Cl)Cl>[P:41]([O:29][C:26]([CH3:28])([CH3:27])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15]3[S:16][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:9][C:10]=3[N:11]=[CH:12]2)=[CH:19][C:20]=1[O:30][CH3:31])([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:61]
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)O
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Reactant: OO
Agent: c1nc[nH]n1
Solvent: ClCCl
Solvent: O
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
A suspension of 6-(4-chlorophenyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (Example 82) (3.00 g; 6.56 mmol), 1,2,4-triazole (1.36 g; 19.7 mmol) and dibenzyl N,N-diisopropylphosphoramidite (6.62 mL; 19.7 mmol) in 40 mL of CH2Cl2 was heated at reflux for 16 h. The solution was cooled to rt, 30% H2O2 in water (4.00 mL; 35.3 mmol) was added and the solution stirred at rt for 2.5 h. The solution was diluted with CH2Cl2, washed with 1M sodium metabisulfite, 1N HCl, water and brine, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, Hexanes/EtOAc; 100:0 to 0:100 gradient) to afford 3.79 g (80%) of the title compound as a white solid. 1H NMR (CDCl3) δ 1.65 (s, 6H), 3.75 (s, 3H), 4.07 (s, 2H), 5.04-5.06 (m, 4H), 6.87-6.96 (m, 3H), 7.29-7.35 (m, 10H), 7.44 (d, J=8.24 Hz, 2H), 7.53 (s, 1H), 7.66 (d, J=8.25 Hz, 2H), 8.10 (s, 1H); 13C NMR (CDCl3) δ 22.56, 25.04, 56.08, 68.98, 69.03, 75.36, 82.87, 111.30, 113.91, 119.15, 120.87, 127.42, 127.67, 127.88, 128.33, 128.48, 129.47, 130.33, 131.54, 135.69, 136.07, 148.19, 149.10, 150.19, 151.63, 156.79, 157.37; HPLC (Method #1) 4.85 min retention time, (100%); MS (ES): m/z 717 [M+H]+.