Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14]O)=[N:6][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4]1>ClCCl>[CH3:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][Br:1])=[N:6][C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4]1
Reactant: Br
Reactant: Cn1nc(-c2ccccc2)nc1-c1ccccc1CO
Solvent: ClCCl
Product: Cn1nc(-c2ccccc2)nc1-c1ccccc1CBr
Yield: 84 %

Procedure:
To 300 ml. of dichloromethane saturated with dry hydrogen bromide 7 g. of 1-methyl-3-phenyl-5-(2-hydroxymethylphenyl)-1,2,4-triazole are added. The solution is allowed to stand at room temperature for a night and after washing with aqueous sodium bicarbonate and then with water it is dried over sodium sulfate. Evaporation of the solvent and crystallization from hexane afford the title compound. M.p. 83°-85° C. Yield 84%.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[CH:6][CH2:7][CH3:8])[CH:3]1[C:9](O)=[O:10].S(Cl)([Cl:15])=O>CN(C)C=O.CCCCCC>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[CH:6][CH2:7][CH3:8])[CH:3]1[C:9]([Cl:15])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CCC=CC1C(C(=O)O)C1(C)C
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCC=CC1C(C(=O)Cl)C1(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
Fifty grams (50 g) of 2,2-dimethyl-3-(1-butenyl)cyclopropanecarboxylic acid, 350 ml of hexane and 0.6 g of N,N-dimethylformamide were mixed together. At 50° C., 39 g of thionyl chloride was eye-dropped thereto over 30 minutes. Subsequently, the reaction mixture was stirred for 1 hour at 50° C. The reaction mixture was then concentrated under reduced pressure to provide 48 g of 2,2-dimethyl-3-(1-butenyl)cyclopropane carboxylic chloride.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1.C([Mg]Br)(C)C.[O:19]1CCC[CH2:20]1.CN(C)C=O.Cl>O1CCCC1>[CH2:7]([C:5]1[S:6][C:2]([CH:20]=[O:19])=[CH:3][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: CCOC(=O)c1cc(Br)sc1CC
Reactant: C1CCOC1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C=O)sc1CC
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of ethyl 5-bromo-2-ethylthiophene-3-carboxylate (10.0 g) synthesized in Example 69 (4) in tetrahydrofuran (100 was added dropwise 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (45.6 mL) at −45° C., and the mixture was stirred for 2 hr under an argon atmosphere. N,N-Dimethylformamide (8.80 mL) was added, and the mixture was stirred at −45° C. for 1 hr, and then at room temperature for 2 hr. 1N Hydrochloric acid was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to give the title compound (7.82 g, 97%) as a yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.O[CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3[NH:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:33][CH:32]=3)[NH:23][C:22](=[O:46])[C:21]=2[CH:47]=1.[CH2:48]([NH:50][CH2:51][CH2:52][OH:53])[CH3:49]>C(Cl)Cl>[CH2:48]([N:50]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][C:28]=3[NH:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:35][CH:36]=3)[NH:23][C:22](=[O:46])[C:21]=2[CH:47]=1)[CH2:51][CH2:52][OH:53])[CH3:49]
Reactant: CCNCCO
Reactant: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4cc(CO)ccc4c23)cc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CCO)Cc1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
DIEA (0.03 mL, 0.19 mmol) and methanesulfonyl chloride (0.01 mL, 0.09 mmol) were added to a solution of 273 (27 mg, 0.06 mmol) in CH2Cl2 and stirred for 2 h at room temperature. 2-(Ethylamino)ethanol (17 mg, 0.19 mmol) was added, and the reaction mixture was stirred for 1 h. The crude product was purified directly via HP-LC to provide 274 (6 mg, 16% yield) as a solid. LC-MS (M+H=508, obsd.=508).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[C:12](Cl)(=[O:30])[CH2:13][CH2:14][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][CH3:29]>>[O:30]=[C:12]([O:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:8][C:12](=[O:30])[CH2:13][CH2:14][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][CH3:29])[CH2:13][CH2:14][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][CH3:29]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1OC(=O)CCCCCCCCCCCCCCCCC

Procedure:
Using this procedure, the reaction of 4-nitrocatechol with octadecanoyl chloride gave 3,4-bis [(1-oxooctadecyl)oxy]nitrobenzene (mp 68°-70°) The structure was confirmed by the nmr spectrum.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH2:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12.C(N(CC)CC)C>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[CH2:16][S:17][C@H:12]12)=[O:8]
Reactant: O=C(Cl)Cc1cccs1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 2 h

Procedure:
To a solution of 100 milligrams (0.6 millimole) of 2-thiopheneacetyl chloride in 5 milliliters of absolute methylene chloride was added slowly a slurry of 137 milligrams (0.5 millimole) of 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and 86 milligrams (0.9 millimole) of triethylamine in 10 milliliters of absolute methylene chloride. The addition was carried out at -15° C., with stirring. After the addition, stirring was continued for two hours at -15° C. and for one and one-half hours at room temperature. The reaction mixture was then cooled and filtered to separate the precipitated solid. The solid, 80 milligrams, was analyzed on bioautogram. Bioautogram showed that approximately 50 percent of the sample was 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid and another 50 percent was the desired 7-(2-(2-thienyl)acetamido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[Cl:8][C:5]1[N:4]=[N:3][C:2]([N:1]=[CH:11][N:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc(Cl)nn1
Product: CN(C)C=Nc1ccc(Cl)nn1
Yield: 81.2 %

Procedure:
A mixture of 3-amino-6-chloropyridazine (1.3 g, 10 mmol) and dimethylformamide dimethylacetal (1.35 mL, 10.2 mmol) was heated at reflux for 2 h and concentrated in vacuo to afford a brown solid. After recrystallization with EtOAc, 1.5 g of N′-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine was obtained in 81% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[N:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:23]=[S:24]>CN(C)C=O>[C:25]1([NH:22][C:23]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:12]2)=[S:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Reactant: S=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(C(=S)Nc3ccccc3)c3ncccc23)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.8 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo-[2,3-b]pyridine 1 (50 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (4 mL). Sodium hydride (10 mg, 0.24 mmol, 60% dispersion in mineral oil) was added. The reaction mixture was stirred for 15 minutes at room temperature. 1-Isothiocyanatobenzene (35 μL, 0.29 mmol) was added and the reaction mixture was stirred for 40 minutes at room temperature. The product was concentrated and the residue was partitioned between brine and ethyl acetate. The organic portion was dried over anhydrous sodium sulfate, filtered, and concentrated to provide a solid. The solid was washed with a minimum of methanol and dried in vacuo to provide 41, (38 mg, 49%). MS(ESI) [M+H+]+=390.2.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[C:20]([F:23])[CH:19]=[CH:18][CH:17]=3)=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1)(=O)=O.[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC.[Li+].[Cl-]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:10]1[N:9]=[C:8]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[C:20]([F:23])[CH:19]=[CH:18][CH:17]=3)[C:7]([CH:26]=[CH2:27])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a mixture of 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl trifluoromethanesulfonate (2.50 g, 6.3 mmol), tributyl(vinyl)stannane (2.41 g, 7.6 mmol) and anhydrous LiCl (805 mg, 19.0 mmol) in DMF (50 mL), Pd(PPh3)2Cl2 (222 mg, 0.3 mmol) was added under N2 protection. The reaction mixture was stirred at 60° C. for 1 h. Then it was concentrated in vacuo, the residue was purified by column chromatography (PE:EA=400:1-100:1) to give the product of 2-(6-chloro-3-vinylpyridin-2-yl)-4-fluoro-1H-indole (1.20 g, yield: 69%). 1H-NMR (CDCl3, 400 MHz) δ 9.63 (br s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.28˜7.11 (m, 4H), 7.04 (s, 1H), 6.84˜6.72 (m, 1H), 5.77 (d, J=17.2 Hz, 1H), 5.60 (d, J=11.2 Hz, 1H). MS (M+H)+: 273.
Reaction SMILES: [K].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:20](Cl)[N:19]=[C:18]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[Ba+2].[OH-].[CH2:41]([OH:44])[CH2:42][OH:43]>C1(C)C=CC=CC=1>[CH3:3][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:20]([O:43][CH2:42][CH2:41][OH:44])[N:19]=[C:18]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCO
Agent: [Ba+2]
Agent: [K]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Temperature: 110 °C
Reaction time: 4 h

Procedure:
5 gms of p-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-[2,2′-bipyrimidin]-4-yl]benzenesulfonamide potassium salt and barium hydroxide (0.75 gms) were charged to a reaction vessel. Ethylene glycol (15 ml) and toluene (75 ml) were added thereto. The reaction mass was heated at a temperature of 110° C. for 2 hours. Further, 0.75 gms of barium hydroxide was added and heating was continued for another 4 hours. After completion of the reaction, the solid was filtered and isolated as barium salt of bosentan. It was further purified by crystallizing with a mixture of methanol and isopropyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[C:11](=O)(OC(Cl)(Cl)Cl)[O:12]C(Cl)(Cl)Cl.O1CCOCC1>CO>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([F:10])[C:3]=1[N:4]=[C:11]=[O:12]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cc(Cl)cc1Br
Solvent: C1COCCO1
Solvent: CO
Product: O=C=Nc1c(F)cc(Cl)cc1Br
Temperature: 100 °C

Procedure:
2-Bromo-4-chloro-6-fluoroaniline (5 mmol, 1.125 g), bis(trichloromethyl) carbonate (1.7 mmol, 0.50 g) and 1,4-dioxane (10 ml) were mixed together and the mixture was heated to 100° C. for 15 minutes; the mixture was then cooled to room temperature and it was filtered. The filtrate was concentrated to afford a mixture of products (2.2 g) containing the title compound, M++MeO=283 (LC-MS run in methanol).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1.[CH2:15](I)[CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[F:3][C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C1COc2cc(F)ccc2N1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)COc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
To 3.96 g (99 mmol) of hexanes washed 60% sodium hydride in 150 ml of N,N-dimethylformamide was added portionwise as a solid 15 g (90 mmol) of 7-fluoro-2H-1,4-benzoxazin-3(4H)-one. When the addition was complete the reaction was stirred at room temperature for 10 min, after which time 19.8 g (108 mmol) of isobutyl iodide was added. The reaction was then stirred overnight before quenching into 200 ml of water. The aqueous phase was extracted with EtOAc (2×150 ml) and the combined organics were dried over Na2SO4, filtered and evaporated in vacuo to give the desired alkylated product, as a yellow oil (13 g, 65% yield).
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-])=O)=[C:9]([CH:12]=1)[CH:10]=O.O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(OCC)C.C(O)C.[Cl-].[Zn+2].[Cl-]>[Br:4][C:5]1[CH:12]=[C:9]2[C:8](=[CH:7][CH:6]=1)[N:13]=[C:17]([CH3:24])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10]2
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc2cc(Br)ccc2nc1C
Temperature: 70 °C
Yield: 54.5 %

Procedure:
A 2.2 M solution of zinc(II)chloride (9.88 mL, 21.74 mmol) in diethyl ether was added to tin(II)chloride (4.12 g, 21.74 mmol) and activated 4 Å molecular sieve pellets (1.00 g) in ethanol (10 mL) under argon. Then, 5-bromo-2-nitro-benzaldehyde (1.00 g, 4.35 mmol) and ethyl 3-oxobutanoate (594.0 mg, 4.56 mmol) in ethanol (12 mL) were added to the reaction mixture via canula. The mixture was heated at 70° C. in an oil bath for three hours, then allowed to cool to room temperature, and carefully quenched with saturated sodium bicarbonate. Ethyl acetate was added and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:6 ethyl acetate:hexanes to give 697.9 mg (55%) of ethyl 6-bromo-2-methyl-3-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.84 (s, 1H), 8.42 (d, J=2 Hz, 1H), 7.95 (dd, J=9, 2 Hz, 1H), 7.91 (d, J=9 Hz, 1H), 4.38 (q, J=7 Hz, 2H), 2.84 (s, 3H), 1.37 (t, J=7 Hz, 3H). ESI-LCMS m/z 294 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[C:8]([CH:19]=1)[O:9][CH2:10][CH:11]([OH:18])[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)([O-:3])=[O:2].[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]([F:26])([F:25])[C:21]([F:22])([F:23])[F:24])=[C:8]([CH:19]=1)[O:9][CH2:10][CH:11]([O:18][C:27](=[O:29])[CH3:28])[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC(O)CN2CCCC2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)OC(COc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F)CN1CCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Dissolved 1-(5-nitro-2-pentafluoroethyl-phenoxy)-3-pyrrolidin-1-yl-propan-2-ol (3.5 g) in CH2Cl2 (15 ml) added TEA (2.55 ml) and cooled to 0° C. Acetyl chloride (781.3 μl) was added dropwise, forming a suspension. The mixture was warmed to RT and stirred for 1.5 h. Additional acetyl chloride (200 μl) was added and the mix was stirred for another h. The mixture was diluted with CH2Cl2 and washed with sat. NaHCO3. The organic layer was removed, washed with brine and back extracted with CH2Cl2. Dried the combined organic layers over Na2SO4, filtered and concentrated in vacuo. The residue was purified over silica gel column (5:94.5:0.5 MeOH:CH2Cl2:NH4OH) to provide acetic acid 2-(5-nitro-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-ylmethyl-ethyl ester as a yellow brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:17][C:16]=2[OH:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][Cl:40]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])=[CH:17][C:16]=2[O:30][CH2:38][CH2:39][Cl:40])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccccc3)cc2O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccccc3)cc2OCCCl)CC1
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To a solution of 4-(4-benzenesulfonyl-2-hydroxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.192 g., 0.444 mmol) in 1 mL acetonitrile is added potassium carbonate (0.245 g., 1.776 mmol) and then 1-bromo-2-chloro-ethane (0.044 mL, 0.535 mmol) dropwise. The suspension is refluxed under nitrogen for 3 hours, at which time is added 1-bromo-2-chloro-ethane (0.044 mL, 0.535 mmol) dropwise. Reflux is continued for another 1.5 hours. The reaction mixture is concentrated in vacuo and the resulting oil is dissolved in 75 mL ethyl acetate, washed with 2×50 mL water and 50 mL brine, then dried over sodium sulfate and concentrated in vacuo. The resulting crude oil is purified by flash chromatography (10% -30% ethyl acetate in hexanes) to give 0.175 g (0.35 mmol, 80%) of 4-[4-benzenesulfonyl-2-(2-chloro-ethoxy)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester as a clear oil. MS: 439 (M−tBu+H)+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]([C:20]1[N:25]=[CH:24][C:23]([CH:26]([CH:30]([CH3:32])[CH3:31])[C:27]([OH:29])=[O:28])=[CH:22][N:21]=1)([CH3:19])[CH3:18].[C:33]([CH:35](O)[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=1)#[CH:34]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:19][C:17]([C:20]1[N:21]=[CH:22][C:23]([CH:26]([CH:30]([CH3:32])[CH3:31])[C:27]([O:29][CH:35]([C:33]#[CH:34])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:37]=2)=[O:28])=[CH:24][N:25]=1)([CH3:16])[CH3:18]
Reactant: CC(C)C(C(=O)O)c1cnc(C(C)(C)C)nc1
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC(OC(=O)C(c1cnc(C(C)(C)C)nc1)C(C)C)c1cccc(Oc2ccccc2)c1
Yield: 90.5 %

Procedure:
A solution of N,N'-dicyclohexylcarbodiimide (0.2 g) in dichloromethane (5 cm3) was added to a stirred mixture of (RS)-2-[2-(2-methylprop-2-yl)pyrimidin-5-yl]-3-methylbutyric acid (0.26 g), (RS)-α-ethynyl-3-phenoxybenzyl alcohol (0.224 g), 4-dimethylaminopyridine (0.02 g) and dry dichloromethane (5 cm3) and the resultant mixture stirred for 2 hours. The precipitate which formed was removed by filtration and the filtrate concentrated by evaporation of the solvent under reduced pressure. The residual oil was purified by column chromatography using a silica column eluted with a mixture of ethyl acetate (1 part by volume) and petroleum ether (boiling range 60° to 80° C., 1 part by volume) to yield (RS)-1-ethynyl-1-(3-phenoxyphenyl)methyl (RS)-2-[2-(2-methylprop-2-yl)-pyrimidin-5-yl]-3-methylbutyrate (0.4g), as a mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH2:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18].[OH-].[Na+]>C(O)C>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:12]=1)=[O:18]
Reactant: Nc1cc(-c2ccc(Cl)cc2)no1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1cc(-c2ccc(Cl)cc2)no1)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
3-(4-Chlorophenyl)-5-aminoisoxazole (1 gram) and 2,6-dichlorobenzoylchloride (5 grams) were placed in a 100 ml. reaction vessel and heated to near reflux for 11/2 hours. The mixture was then cooled to room temperature and treated with 25 ml. of 2 N NaOH and 25 ml. ethanol. After refluxing for 2 hours, the ethanol was slowly removed at reduced pressure. A solid precipitate was collected by filtration. The remaining solution was treated with activated charcoal, filtered, and cooled to room temperature. The aqueous solution was extracted with chloroform. The chloroform was washed with water and dried (Na2SO4). Removal of the solvent afforded an oily product which was recrystallized from ether/hexane, m.p. 208°-209° C.
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:23][CH2:24][CH2:25][OH:26]>O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:26][CH2:25][CH2:24][Br:23])=[CH:4][CH:5]=1
Reactant: OCCBr
Reactant: Fc1ccc(C(Br)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(C(OCCBr)c2ccc(F)cc2)cc1
Temperature: 130 °C
Reaction time: 15 h
Yield: 73.2 %

Procedure:
A mixture of 49.5 g (0.175 mole) of bromo bis(4-fluoro phenyl)methane, 22.4 g (0.21 mole) of sodium carbonate and 26.9 g (0.21 mole) of 2-bromoethanol was stirred at 130° C. for 15 hours. After cooling, the reaction mixture was taken up with water and extracted with ether. The ethereal phase was washed, dried on sodium sulfate and then concentrated dry. Distillation of the residue yielded 41.9 g (yield: 69.4%) of 1-[bis(4-fluorophenyl) methoxy]-2-bromoethane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1ccc(O)c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2F)c(C)n1
Temperature: 140 °C

Procedure:
2,6-Dimethyl-pyridin-3-ol (3.0 g, 24.35 mmol) and cesium carbonate (15.87 g, 48.71 mmol) were added to a solution of 3,4-difluoronitrobenzene (3.87 g, 24.35 mmol) in DMF (30 ml). The mixture was heated at 140° C. for 2 hours. After cooling to room temperature it was filtered through diatomaceous earth and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 2% methanol/DCM as eluent) to yield intermediate D14 (5.88 g, 92%).
Reaction SMILES: [C:1](=S)(OCC)[S-:2].[K+].[NH2:8][C:9]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[C:12]([O:19][CH3:20])=[CH:11][C:10]=1[OH:21]>C(O)C>[SH:2][C:1]1[O:21][C:10]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:9]=2[N:8]=1
Reactant: CCOC(=S)[S-]
Reactant: COc1cc(O)c(N)c(OC)c1OC
Agent: [K+]
Solvent: CCO
Product: COc1cc2oc(S)nc2c(OC)c1OC
Yield: 64.2 %

Procedure:
Potassium O-ethyl dithiocarbonate (321 mg, 2.0 mmol) was added to a solution of the aminophenol (199 mg, 1.0 mmol) in ethanol (5 ml) and the mixture was heated to reflux for 16 hours. The reaction solution was concentrated, water (30 ml) was added thereto and the mixture was adjusted to pH, 3-4 with diluted hydrochloric acid the separated matter was collected by filtration, dried by heating in vacuo and recrystallized from methanol, ether and hexane to provide 155 mg (yield 64%) of 2-mercapto-4,5,6-trimethoxybenzoxazole as reddish-purple needles.