Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C@H:3]1[C:14]([OH:16])=[O:15].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.P(O)(O)([O-])=O.[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C@H:3]1[C:14]([O:16][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: BrCc1ccccc1
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A solution of 25 g of (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid in 250 ml of tetrahydrofuran were added at 10° C. to a mixture of 2.6 g of sodium hydride in 100 ml of tetrahydrofuran and the mixture was stirred at 15° C. for 30 minutes. A solution of 35 ml of benzyl bromide in 100 ml of tetrahydrofuran was added to the mixture which was heated at 50° C. for 48 hours and then was cooled and poured into aqueous monosodium phosphate solution. The mixture was extracted with isopropyl ether and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 9-1 hexane-isopropyl ether mixture to obtain 30 g of benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:64]1([CH2:70][SH:71])[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:70]([S:71][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([Br:12])[CH:3]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: SCc1ccccc1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(Br)cc(SCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
1,3-Dibromo-5-tert-butylbenzene (2.89 g, 10 mmol) in dioxane (160 mL) was stirred under Ar. Then DIPEA (3.09 mL, 16 mmol), Xantphos (0.28 g, 0.48 mmol) and Pd2(dba)3 (0.24 g, 0.24 mmol) were added and the reaction was heated to 100° C. Phenyl-methanethiol (0.94 mL, 8 mmol) was slowly added and the reaction was stirred for 6 h, quenched by the addition of H2O (15 mL) and extracted with EA (3×). The combined organic layers were washed with water, dried over Na2SO4, filtered, evaporated and purified by CC to afford compound P21a (1.7 g, 72%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[NH:8][N:7]=1.P(Cl)(Cl)([Cl:19])=O>ClC(Cl)C>[Cl:19][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][N:8]=1
Reactant: O=c1[nH]nc(-c2ccco2)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Clc1nnc(-c2ccco2)c2ccccc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1.0 g of 4-(2-furyl)-1-phthalazinone and 5 ml of phosphorus oxychloride were dissolved in 5 ml of dichloroethane, and the solution was stirred at 100° C. for 3 hours. The reaction solution was distilled off, and a 1-N aqueous NaOH solution was added thereto under cooling with ice. The solution was extracted with chloroform, dried and concentrated to obtain 910 mg of 1-chloro-4-(2-furyl)phthalazine.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](O)(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C=O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([Cl:21])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 6 h

Procedure:
The sulphonic acid intermediate (2b) was then dissolved in an excess of thionyl chloride, a catalytic amount of DMF (few drops) was added, and the resulting mixture was stirred for 6 h at reflux. The solvent was evaporated and the residue dissolved in Et2O (40 mL). The ether solution was washed with 5% aqueous NaOH (3×40 mL) and water (6×40 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. After drying in high vacuum overnight, the pure product was obtained as a white solid. Yield: 1.04 g, 3.63 mmol, 72% (white solid). 1H-NMR (CDCl3): δ 7.99 (d, 3J=9.1 Hz, 2H, ArH), 7.19-7.02 (m, 6H, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.CCN(CC)CC.[C:17](Cl)([CH3:19])=[O:18]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:17](=[O:18])[CH3:19])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: NCc1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1ccc(Br)cn1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of (5-bromopyridin-2-yl)methanamine (500 mg, 2.67 mmol) in DCM (10 mL) was added Et3N (405 mg, 4.0 mmol) and AcCl (250 mg, 3.18 mmol) at 0° C. The mixture was then warmed to room temperature for 2 h when the reaction was quenched with water and extracted with DCM. The organic layer was concentrated to give the crude product which was used in next step without further purification. (540 mg, Yield 90%). LCMS (m/z): 229.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:34][S:35][C:36]1[O:37][C:38]2[CH:44]=[C:43]([CH:45]=O)[CH:42]=[CH:41][C:39]=2[N:40]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:45][C:43]2[CH:42]=[CH:41][C:39]3[N:40]=[C:36]([S:35][CH3:34])[O:37][C:38]=3[CH:44]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CSc1nc2ccc(C=O)cc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NCc2ccc3nc(SC)oc3c2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methoxy-2-nitroaniline (500 mg, 2.99 mmol) and TFA (3.07 mL) in DCM (15 mL) at 5° C. was added NaBH(OAc)3 (1.9 g, 8.97 mmol). To the resulting mixture at 0° C. was added a solution of 2-(methylthio)benzo[d]oxazole-6-carbaldehyde (630 mg, 3.29 mmol) in DCM (10 mL), and. the mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with DCM and washed sequentially with H2O, aq NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 4-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline as a light brown solid (1.08 g, quantitative). 1H NMR (300 MHz, DMSO-d6) δ 8.62 (t, 1H), 7.64 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J=9.3 Hz, 1H), 7.18 (d, J=6.0 Hz, 1H), 6.93 (d, J=9.3 Hz, 1H), 4.71 (d, J=5.7 Hz, 1H), 3.72 (s, 3H), 2.75 (s, 3H). LCMS (ESI) m/z 346 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:19]2[O:21][CH2:20]2)=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3]
Reactant: C#CCOc1ccc(O)c2c1NC(=O)CC2
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCOc1ccc(OCC2CO2)c2c1NC(=O)CC2
Yield: 68.3 %

Procedure:
To 78 g of 8-(2-propynyloxy)-5-hydroxy-3,4-dihydrocarbostyril were added 102 g of epichlorohydrin, 60 g of potassium carbonate and 600 ml of methanol, and the resulting mixture was heated while refluxing for 2.5 hours on a water bath. After completion of the reaction, the methanol was evaporated, and water was added to the residue followed by extracting with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residual crystals were recrystallized from isopropanol to obtain 67 g of 8-(2-propynyloxy)-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril having a melting point of 142°-143.5° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH:14]1([C@H:17]([NH2:39])[C:18]([N:20]2[CH2:24][C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])=[CH:22][C@H:21]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:19])[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:14]1([C@H:17]([NH:39][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C:18]([N:20]2[CH2:24][C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])=[CH:22][C@H:21]2[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:19])[CH2:16][CH2:15]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
4-nitrophenyl chloroformate (171 mg, 0.85 mmol, 1.5 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7, 200 mg, 0.564 mmol, 1 equiv) and N,N-diisopropylethylamine (172 μL, 0.988 mmol, 1.75 equiv) in dichloromethane (5 mL) at 0° C., and the resulting mixture was stirred for 15 minutes, then warmed to 23° C. and stirred for an additional 30 minutes. Additional 4-nitrophenyl chloroformate (1.0 equiv) and N,N-diisopropylethylamine (1.0 equiv) were added and the mixture was stirred for 2.5 hours, then partitioned between water (55 mL) and dichloromethane (2×45 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 4-nitrophenyl(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethylcarbamate (26-1) as a light yellow oil. LRMS m/z (M+H) 520.4 found, 520.2 required.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:5].Cl[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>C(Cl)Cl>[Cl:12][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][NH:2][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: NCC(=O)c1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)NCC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A mixture of 2-amino-1-(3-chlorophenyl)ethanone hydrochloride from Step 79a (2.83 g, 13.7 mmol, 1 eq), ethyl chlorooxoacetate (1.87 g, 13.7 mmol, 1 eq), and CH2Cl2 (40 mL) is cooled in an ice-H2O bath. The mixture is treated with a solution of TEA (4.0 mL, 29 mmol, 2.1 eq) in CH2Cl2 (20 mL), and the reaction is warmed to room temperature overnight. Water is added and the organic layer is separated, dried over MgSO4, filtered., and evaporated. The resulting solid is triturated with hexane/2-propanol and dried in vacuo to provide the title compound (2.70 g, 72%). MS (ESI) for C12H12ClNO4 m/z 270 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[CH:5]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:11][S:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:12])=[O:2]
Reactant: COC(=O)c1cccc(SC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1cccc(C(=O)O)c1
Yield: 96.4 %

Procedure:
3-Methylsulfanyl-benzoic acid methyl ester (684 mg, 3.8 mmol) and 1N NaOH (5.6 mL, 5.6 mmol) in methanol (8 mL) and THF (8 mL) were heated at 70° C. for 1 hour. The reaction mixture was concentrated and then the residue was diluted with water. After acidification with 1N HCl to pH˜2, the aqueous layer was extracted with ethyl acetate and then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-methylsulfanyl-benzoic acid (616 mg, 97%, white solid). 1H NMR (DMSO), δ (ppm): 13.1 (bs, 1H), 7.76 (s, 1H), 7.70 (d, 1H), 7.51 (d, 1H), 7.44 (t, 1H), 2.52 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2)([OH:19])=[O:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:23]1[C:22]2[C:26](=[CH:27][CH:28]=[C:20]([C:17]([OH:19])=[O:18])[CH:21]=2)[NH:25][C:24]1=[O:29])([CH3:3])[CH3:2]
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(C(=O)O)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-carboxy-2-oxindole to give 0.4 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid as a yellow-orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>C(#N)C.C(N(CC)CC)C>[CH3:12][C:4]1[N:3]=[C:2]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:22][CH:21]=2)[N:7]=[C:6]([NH2:8])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1nc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)nc(N)c1[N+](=O)[O-]
Temperature: 120 °C
Yield: 94.1 %

Procedure:
A mixture of 2-chloro-6-methyl-5-nitropyrimidin-4-ylamine (300 mg, 1.591 mmol), 4-trifluoromethylbenzylamine (369 mg, 2.107 mmol) in acetonitrile (3 ml) and triethylamine (0.5 ml) were flashed with argon, sealed in the Emrys process vial and heated at 120° C. for 2 min under microwave irradiation. The obtained suspension was quenched with 10% aqueous sodium carbonate (2 ml) and organic volatiles were evaporated under reduced pressure. Methanol (5 ml) and water (100 ml) were added to the residue. The product was separated by filtration, washed with water and dried in vacuo to give 490 mg of yellow solid. Yield 94%. LC-MS (m/z) 328.1 (MH+); tR=2.58. 1H NMR (500 MHz, DMSO-d6): ca. 3:1 mixture of two rotamers, 2.54 (s, 3H), 4.57 (d, 1.5H), 4.63 (d, 0.5H), 7.52 (t, 2H), 7.68 (d, 2H), 7.81 (s, 0.5H, NH2), 8.0 (s, 1.5H, NH2), 8.17 (t, 0.25H, NH), 8.48 (t, 0.75H, NH).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]#[N:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]#[N:8]
Reactant: N#Cc1sccc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1sccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
3-Bromothiophene-2-carbonitrile was coupled with 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane using the conditions described in Example 1 to give 3-(2-fluoro-5-nitrophenyl)thiophene-2-carbonitrile as an off-white solid. This in turn was reduced using the conditions outlined in Example 1 to give 3-(5-amino-2-fluorophenyl)thiophene-2-carbonitrile: δH (400 MHz, CDCl3) 3.67 (2H, s), 6.68-6.72 (1H, m), 6.90 (1H, dd, J 6 and 3), 7.00 (1H, dd, J 9 and 1), 7.30 (1H), dd, J 5 and 2), 7.60 (1H, d, J 5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Cl[I:10].[OH-].[Na+]>C(O)(=O)C.O>[Cl:8][C:5]1[CH:6]=[C:7]([I:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: ClI
Reactant: Nc1ccc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1I
Reaction time: 2 h
Yield: 60.1 %

Procedure:
The solution of 2-amino-5-chloropyridine (10.0 g, 77.8 mmol) potassium acetate (7.63 g, 77.8 mmol) in 100 mL of acetic acid was heated to 85° C. and ClI (12.6 g, 77.8 mmol) in 50 mL of acetic acid was added dropwise. Reaction mixture was kept 2 h at this temperature, diluted with 1 L of water, neutralized with NaOH 1N solution to pH 7 and extracted with ethyl acetate (4×75 mL). Organic fraction were combined, washed with NaHCO3, filtered through celite and evaporated. The residue was subjected to column chromatography on silica (eluent—hexane/ethyl acetate 1/1) providing 5-chloro-3-iodopyridin-2-amine as yellow solid (11.9 g, 60%).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][S:4][N:3]=1.[S:13](Cl)(=[O:16])(=[O:15])[NH2:14].C(N(C(C)C)CC)(C)C>C(#N)C>[C:7]1([C:6]2[C:2]([O:1][S:13](=[O:16])(=[O:15])[NH2:14])=[N:3][S:4][N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1nsnc1-c1ccccc1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)Oc1nsnc1-c1ccccc1

Procedure:
A slurry of 3-hydroxy-4-phenyl-1,2,5-thiadiazole (15.0 g, 0.084 mole) in acetonitrile (100 ml) was treated by the simultaneous dropwise addition of a sulfamoy l chloride solution in acetonitrile (0.20 mole, 66 ml of 3M) and a diisopropylethylamine solution (0.22 mole in enough 1:1 acetonitrile/methylene chloride to make 66 ml). High Pressure Liquid Chromatography analysis indicated a maximum of 85% conversion of starting material to product. The reaction was worked up by concentration of the reaction mixture and partitioning the residue between ethyl ether and water. Concentration of the ether fraction gave a white paste from which desired product was separated by dissolving in a small amount of acetonitrile. The product was crystallized from the acetonitrile to give 2.8 g (13%) of the title compound as a white powder, mp 128°-130° C.
Reaction SMILES: [N:1]([C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:13][CH:14]([CH2:27][O:28][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)/[CH:15]=[CH:16]/[P:17]([O:23][CH:24]([CH3:26])[CH3:25])([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>O1CCCC1>[CH:20]([O:19][P:17](/[CH:16]=[CH:15]/[CH:14]([CH2:27][OH:28])[CH2:13][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][CH:11]=[N:12][C:4]=2[NH2:1])([O:23][CH:24]([CH3:25])[CH3:26])=[O:18])([CH3:21])[CH3:22]
Reactant: CC(C)OP(=O)(/C=C/C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cn1cnc2c(N=[N+]=[N-])ncnc21)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OP(=O)(/C=C/C(CO)Cn1cnc2c(N)ncnc21)OC(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 65.5 %

Procedure:
* Mixture of Azido and Tetrazolo Tautomers c) A solution of (E)-6-azido-9-[2-(t-butyldiphenylsilyloxy)methyl-4-(diisopropoxyphosphoryl)but-3-enyl]purine (320 mg, 494 μmol) and triphenylphosphine (194 mg, 741 μmol) in tetrahydrofuran (15 ml) was stirred at room temperature for 21 h. The solution was heated to 70° C. and 5M hydrochloric acid (258 μl, 1.29 mmol) added. After 2 h, the solvent was removed and the residue was dissolved in 3% methanolic hydrogen chloride (10 ml) and the solution stirred at room temperature for 2 h. The solvent was removed, the residue dissolved in water and the solution neutralised by addition of aqueous sodium bicarbonate solution. The solution was evaporated to dryness and the residue purified by column chromatography on silica gel eluting with dichloromethane-methanol (9:1, 6:1) to give the title compound as a white solid (124 mg, 63%), m.p. 130° C.; λmax (EtOH) 261 (13,074)nm; υmax (KBr) 3325, 2980, 1645, 1600, 1475, 1420, 1240 and 990 cm-1 ; δH [(CD3)2SO] 1.10 (12H, m, CH3), 3.07 (1H, m, CH), 3.50 (2H, t, J 5Hz, CH2O), 4.10 (1H, m, CH(CH3)2)), 4.27 (3H, m, CH2N and CH(CH3 )2), 4.99 (1H, t, J 5Hz, D2O exchangeable, OH), 5.59 (1H, dd, J 17 Hz and 21 Hz, PCH=CH), 6.52 (1H, ddd, J 8 Hz, 17 Hz and 22 Hz, PCH=CH), 7.16 (2H, br.s, D2O exchangeable, NH2), 8.07 (1H, s, H-2/H-8), 8.12 (1H, s, H-2/H-8); CIMS 384 (MH+) (Found: C, 48.92; H, 6.90; N, 17.58%. C16H26N5O4P.0.5 H2O requires C, 48.97; H, 6.94; N, 17.85%).
Reaction SMILES: [C:1]([F:4])([F:3])=O.[F:5][C:6]([F:11])([F:10])[C:7]([F:9])=O>>[F:5][C:6]([F:11])([F:10])[C:7]([F:9])=[C:1]([F:4])[F:3]
Reactant: O=C(F)C(F)(F)F
Reactant: O=C(F)F
Product: FC(F)=C(F)C(F)(F)F

Procedure:
The procedure described in Example 9 is employed in which 10.2 grams hexafluoropropylene is condensed in at high pressure and 12 grams liquid carbon dioxide is added. The temperature is raised to 60° C., and the cell is charged with molecular oxygen to approximately 2,500 psi. Oxygen is supplied continuously to the reactor. 0.5 grams of a clear fluid is collected in the cold trap corresponding to a 5% yield of perfluoropolyether (based on hexafluoropropylene). Analysis using 19F NMR spectroscopy is consistent with a perfluoropolyether structure. Analysis of portions of the gaseous products shows evidence of carbonyl fluoride and trifluoroacetyl fluoride in addition to other low molar mass fluorooxy compounds.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([S:14](Cl)(=[O:16])=[O:15])[N:4]=1)[CH3:2].[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:20]=1[NH2:21]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:20]=1[NH:21][S:14]([C:5]1[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1)(=[O:16])=[O:15]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CCc1nc(S(=O)(=O)Cl)nn1-c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)nn1-c1ccccc1
Yield: 30.4 %

Procedure:
5-Ethyl-1-phenyl-1,2,4-triazole-3-sulphonyl chloride (2.7 g), prepared by a method analogous to that of Example A, was added to a stirred solution of 2,6-dichloroaniline (1.8 g), and 4-dimethylaminopyridine (0.1 g) in dry pyridine (15 ml). After 48 hours at 25° C. most of the pyridine was removed in vacuo, and the residue was dissolved in dichloromethane. The solution was extracted with dilute hydrochloric acid and then re-evaporated. The residue was treated with 4M sodium hydroxide solution (25 ml) at 80° C. for 1 hour and then filtered. The filtered solid was washed with warm water, the filtrate was acidified with concentrated hydrochloric acid, and the product was recrystallised from ethanol to give 1.2 g of desired product, mp 185°-187° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[CH:5][N:4]=1)#[N:2].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncc(Cl)nc1C#N
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ncc(Sc2ccccc2)nc1C#N
Yield: 47.8 %

Procedure:
2,3-Dicyano-5-chloropyrazine (0.83 g; 0.005 mole) was dissolved in 25 ml of acetone. The solution was cooled to 0° to 3° C., and with stirring, a solution prepared from 0.55 g (0.005 mole) of thiophenol, 0.21 g (0.005 mole) of sodium hydroxide, 1 ml of water, and 20 ml of acetone was added dropwise over the period of 10 minutes. Then, the reaction mixture was worked up in the same way as in Example 7, and recrystallized from benzene to afford 0.57 g (yield 48%) of 2,3-dicyano-5-(phenylthio)pyrazine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:23][CH2:22][CH2:21][C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=[N+]([O-])c1ccc(CCCBr)cc1
Product: O=C(O)c1cc(NCCCc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 50.4 %

Procedure:
According to the similar procedure to Synthesis Example 1, by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 3-(4-nitrophenyl)propyl bromide (950 mg, 3.92 mmole), 520 mg (50% yield) of 2-hydroxy-5-[3-(4-nitrophenyl)-n-propylamino]-benzoic acid was obtained as a pale yellow solid. Melting point 229-231° C.