Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[CH2:4][N:5]1[C:9]([CH2:10]O)=[CH:8][N:7]=[CH:6]1.C(N(CC)CC)C.S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[Cl:26][CH2:10][C:9]1[N:5]([CH2:4][C:3]2[C:2]([Cl:1])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:16])[CH:6]=[N:7][CH:8]=1
Reactant: OCc1cncn1Cc1c(Cl)cccc1Cl
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClCc1cncn1Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
45 mg (0.18 mmol) of the compound from Example 36A together with 27 mg (0.26 mmol) of triethylamine were dissolved in 1 ml of toluene, and 25 mg (0.21 mmol) of thionyl chloride were added dropwise at RT. The mixture was stirred at RT for 1 h. Under reduced pressure, the reaction mixture was freed from all volatile components. This gave 48 mg (99% of theory) of the target compound, which was reacted further without any further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[N:8]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:9](=[O:21])[N:10]([C@H:14]([CH3:20])[CH2:15][S:16](Cl)(=[O:18])=[O:17])[C:11](=[O:13])[CH:12]=1.O.[NH3:33].O>C(#N)C.C(OCC)(=O)C>[CH3:6][C:7]1[N:8]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:9](=[O:21])[N:10]([C@H:14]([CH3:20])[CH2:15][S:16]([NH2:33])(=[O:18])=[O:17])[C:11](=[O:13])[CH:12]=1
Reactant: Cc1cc(=O)n([C@H](C)CS(=O)(=O)Cl)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cc1cc(=O)n([C@H](C)CS(N)(=O)=O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of the compound prepared in Reference Example 253 (1.0 g) in acetonitrile (20 ml) was added phosphorus oxychloride (1.3 ml) and the resulting mixture was stirred at 60° C. for three hours (note: it was confirmed a formation of the above-mentioned intermediate, (R)-2-(4-methyl-2,6-dioxo-3-(3-(trifluoromethyl)phenyl)-2,3-dihydropyrimidin-1(6H)-yl)propane-1-sulfonylchloride; UPLC/MS 41.3 (M+H)/0.980 min). The reaction solution was cooled to 0° C. and thereto was added ammonia water (5.0 ml) dropwise and the resulting mixture was stirred for one hour. To the reaction mixture was added water (30 ml) and thereto was added ethyl acetate (20 ml×3) such that the intended products were extracted into an organic layer. The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried on anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the above-mentioned (R)-2-(4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl)propane-1-sulfonamide (560 mg). UPLC/MS 392 (M+H)/0.753 min. (measurement condition 9)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[C:19]([CH2:29][C:30](O)=[O:31])=[CH:20][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)(=[O:11])=[O:10])[O:4][N:3]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[C:50]([NH2:54])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl.CCOC(C)=O>[CH3:51][C:50]([NH:54][C:30](=[O:31])[CH2:29][C:19]1[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:9]([N:8]([C:5]2[O:4][N:3]=[C:2]([CH3:1])[C:6]=2[CH3:7])[CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])(=[O:11])=[O:10])=[CH:23][CH:22]=[C:21]([C:24]2[O:25][CH:26]=[CH:27][N:28]=2)[CH:20]=1)([CH3:53])[CH3:52]
Reactant: CC(C)(C)N
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the title compound of Step (C) (85 mg, 0.16 mmol) and 0.004 ml DMF in 1.6 ml CH2Cl2, oxalyl chloride (2M in CH2Cl2, 0.20 ml, 0.40 mmol) was added. The mixture was stirred at room temperature for 0.5 hr and concentrated. To the residue, 2 ml CH2Cl2 and tert-butylamine (t-BuNH2, 69 mg, 0.94 mmol) were added. The reaction was stirred at room temperature overnight, diluted with EtOAc, washed with H2O and brine, dried and concentrated. The residue was chromatographed on silica gel using 1:2 hexane/EtOAc to afford the title compound of this step (45 mg, 48%) as a colorless gum.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][OH:24])[CH:18]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].I(C1C(C(OO)=O)=CC=CC=1)(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CS(C)=O>[F:31][C:2]([F:1])([F:30])[C:3]([C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH:23]=[O:24])[CH:18]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(CO)c1
Agent: O=C(OO)c1ccccc1I(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(C=O)c1
Yield: 49.7 %

Procedure:
To a solution of (4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)pyridin-2-yl)methanol (110 mg, 446 μmol) in dimethylsulfoxide (3 mL), 2-iodoxyperbenzoic acid (136 mg) was added at room temperature, and the resultant mixture was stirred. After completion of the reaction, the reaction solution was added with a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate at room temperature, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (100 mg, yield 92%) was obtained as a colorless oil.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[C:8]([C:10]2[C:11]([C:15]([F:18])([F:17])[F:16])=[N:12][NH:13][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:19]1([CH2:23]Br)[CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:19]1([CH2:23][S:1][C:2]2[CH:9]=[C:8]([C:10]3[C:11]([C:15]([F:16])([F:18])[F:17])=[N:12][NH:13][CH:14]=3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:22][CH2:21][CH2:20]1
Reactant: BrCC1CCC1
Reactant: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC1CCC1
Yield: 21.6 %

Procedure:
0.9 g (3.3 mmol) of 2-mercapto-4-(3-trifluoromethylpyrazolyl)benzonitrile, 0.5 g (3.3 mmol) of cyclobutylmethyl bromide and 0.55 g (4.0 mmol) of potassium carbonate were stirred in 5 ml of N,N-dimethylformamide at room temperature overnight. The resulting reaction mixture was poured into 50 ml of water and the organic matters were extracted with 20 ml of ethyl acetate twice. The ethyl acetate layers were combined, then washed with 30 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.24 g of 2-cyclobutylmethylthio-4-(3-trifluoromethylpyrazolyl)benzonitrile (yield 21.2%) as a pale yellow powder (m.p. 102-103° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[N:5]/[OH:6].[H-].[Na+].[CH3:24]OS(OC)(=O)=O.Cl>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:21])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[N:5]/[O:6][CH3:24]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.5 %

Procedure:
E-α-hydroxyimino-2-(4-methylphenoxy)pheylacetic acid methyl ester (0.71 g, 0.0025 mole) was dissolved in dried tetrahydrofuran (10 ml), followed by the addition of 60% sodium hydride (0.13 g, 0.033 mole). Then, the mixture was stirred at room temperature for 20 minutes and to this was added dropwise a solution of dimethylsulfate (0.44 g, 0.0035 mole) dissolved in dried THF (2.5 ml) under ice cooling, followed by stirring for 1.75 hours under ice cooling. After completion of the reaction, water was added to the reaction mixture which was adjusted to pH 1 with conc. hydrochloric acid. The mixture was extracted twice with methylene chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain E-α-methoxyimino-2-(4-methylphenoxy)phenylacetic acid methyl ester (0.61 g, yield: 81.3%) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[CH:8][N:7]=1)=[CH2:5])C.Cl>CC(C)=O>[C:4]([C:6]1[N:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[CH:8][N:7]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1nccc(OCC)n1
Agent: Cl
Solvent: CC(C)=O
Product: CCOc1ccnc(C(C)=O)n1
Temperature: 40 °C
Reaction time: 16 h
Yield: 77.9 %

Procedure:
A solution of 1-ethoxy-1-(4-ethoxypyrimidin-2-yl)-ethylene (2.7 g) in acetone (20 ml) was treated with hydrochloric acid (6 ml of a 2M solution). The reaction mixture was allowed to stand for 16 hours, then warmed at 40° C. for 11/2 hours, and concentrated. The residue was diluted with water and neutralised with sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (×2) and the combined extracts were washed with brine, dried and concentrated to give 2-acetyl-4-ethoxypyrimidine (1.8 g, 78% yield) as a colourless oil which partially solidified on standing, and was used without further purification; IR maximum (film): 1717cm-1 ; 1H NMR (270 MHz): δ1.45(3H,t), 2.74(3H,s), 4.53(2H,q), 6.85(1H,d), 8.60(1H,d) ppm.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH:17]C(=O)C)[CH:9]=[C:10]([F:16])[C:11]=2[CH3:15])[C:6]1=[O:21])(=[O:3])[CH3:2].Cl.C(=O)([O-])[O-].[K+].[K+].[O-][Si]([O-])=O.[Mg+2]>O>[C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[C:10]([F:16])[C:11]=2[CH3:15])[C:6]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(F)c(C)c2c1C(=O)C(NC(C)=O)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=[Si]([O-])[O-]
Solvent: O
Product: CC(=O)NC1CCc2c(C)c(F)cc(N)c2C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To 8.0 g of 2,8-diacetylamino-6-fluoro-5-methyl-1 -tetralone, 120 ml of a 20% aqueous solution of hydrochloric acid were added and the mixture was stirred at an external temperature of 60° C. for 2 hours. After the completion of the reaction, the reaction mixture was cooled and was added with 100 ml of water. The resulting mixture was filtered through a Kiriyama funnel. To the filtrate, further 100 ml of water were added, followed by extraction with chloroform. To the chloroform layer so obtained, potassium carbonate and Florisil were added and they were stirred for a while. The resulting mixture was filtered and then, the solvent was removed under reduced pressure. The residue so obtained was recrystallized from chloroform-diethyl ether, whereby 3.4 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccco1
Yield: 87.8 %

Procedure:
5.0 g of ethyl 2-[2-(4-fluorophenyl)-5-(2-furyl)-4-oxazolyl]acetate, 70 ml of methanol, 10 ml of water and 1.5 g of sodium hydroxide are treated in the same manner as described in Example 16. 4.0 g of 2-[2-(4-fluorophenyl)-5-(2-furyl)-4-oxazolyl]acetic acid are thereby obtained. Yield: 87.7%
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[C:7]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:8][CH2:9][CH3:10]>C1COCC1.C(OCC)C>[OH:4]/[CH:2]=[C:8](\[CH2:9][CH3:10])/[C:7]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCCC(=O)OCC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)/C(=C/O)CC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of potassium tert-butoxide (3.86 g, 34.4 mmol) in THF (20 mL) under nitrogen at room temperature was added a solution of ethyl butanoate (2.275 mL, 17.22 mmol) in diethyl ether (20.0 mL). The reaction mixture was stirred at rt for 3 hrs. The mixture was quenched and concentrated to give the title compound. LCMS: rt=2.34 min, [M+H+]=143
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:16])=[C:7]([Cl:15])[CH:8]2[S:12][C:11]([SH:13])=[N:10][CH:9]2[CH:14]=1)=[O:4].CI.[CH3:19]CN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:16])=[C:7]([Cl:15])[CH:8]2[S:12][C:11]([S:13][CH3:19])=[N:10][CH:9]2[CH:14]=1)=[O:4]
Reactant: CCN(CC)CC
Reactant: COC(=O)C1=CC2N=C(S)SC2C(Cl)=C1N
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1=CC2N=C(SC)SC2C(Cl)=C1N

Procedure:
This compound is prepared as described in Acta. Chim. Slov. 2002, 49, 871 using the crude 6-amino-7-chloro-2-mercapto-3a,7a-dihydro-benzothiazole-5-carboxylic acid methyl ester as starting material. Methylation is performed with MeI and Et3N in DMF. The 6-amino-7-chloro-2-methylsulfanyl-3a,7a-dihydro-benzothiazole-5-carboxylic acid methyl ester is obtained, after column chromatography purification over silica gel, in 59% over 3 steps from 2,5-diamino-3-chloro-4-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester (step d in example H17); LC/MS: 289/291 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[CH3:18][C:19](=[CH2:21])[CH3:20].C(=O)(O)[O-].[Na+]>O1CCOCC1.COC(C)(C)C>[C:19]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][Br:1])([CH3:21])([CH3:20])[CH3:18]
Reactant: O=C(O)Cc1ccccc1CBr
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)Cc1ccccc1CBr
Temperature: -15 °C
Reaction time: 4 h

Procedure:
To a solution of 80 g (0.349 mol) 2-bromomethylphenylacetic acid in 700 mL 1,4-dioxane in a 2 L heavy-walled flask was added 84 mL (1.571 mol) concentrated sulfuric acid at ambient temperature. The reaction mixture was chilled to −15° C., and 580 mL isobutylene was condensed directly into the reaction vessel. The sealed pressure flask was shaken mechanically at room temperature for 4 h (the pressure inside the flask rises to ca. 20 psi during this step). The mixture was carefully quenched by slowly pouring it into a 0-5° C. stirred mixture of 1.2 L tert-butyl methyl ether and 336 g (4.0 mol) solid sodium bicarbonate before slow dilution with 1.2 L ice-water. The separated organic phase was washed with 0.8 L brine, dried with sodium sulfate, filtered concentrated in vacuo to give an oil, which was used without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:29])[C:17]3[C:30](=[O:34])[NH:31][C:32](=[O:33])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:35])[CH:11]=[CH:10][C:9]1=2)(=O)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.COC1C=CC2NC3C=C(C(OCC4C=CC=CC=4)=O)C4C(=O)NC(=O)C=4C=3C=2C=1>>[Cl:29][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=1[C:18]1[C:17]2[C:30](=[O:34])[NH:31][C:32](=[O:33])[C:16]=2[C:15]2[C:14]3[CH:13]=[C:12]([OH:35])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:7][CH2:6][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:20]=2[CH:19]=1
Reactant: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCOS(C)(=O)=O
Reactant: C1COCCN1
Agent: COc1ccc2[nH]c3cc(C(=O)OCc4ccccc4)c4c(c3c2c1)C(=O)NC4=O
Product: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCN1CCOCC1
Yield: 81 %

Procedure:
Reaction of 2-(4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-1,3-dioxo-2,3-dihydropyrrolo[3,4-c]carbazol-6 (1H)-yl)ethyl methanesulfonate (VII; Ar=2-chloro-6-methoxyphenyl, n=2, mesylate) (114) prepared as described in example 66 with morpholine using the procedure described in example 179 of Scheme 3 gave 4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-[2-(4-morpholinyl)ethyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VIII; Ar=2-chloro-6-methoxyphenyl, n=2, Z=4-morpholinyl) (115) in an 81% yield as a yellow powder; mp 185° C. 1H NMR δ [(CD3)2SO] 10.99 (br s, 1H), 9.34 (br s, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.3, 8.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.14–7.10 (m, 2H), 4.53 (t, J=6.1 Hz, 2H), 3.66 (s, 3H), 3.41 (t, J=4.5 Hz, 4H), 2.64 (t, J=6.1 Hz, 2H), 2.37 (m, 4H). Found: C, 63.57; H, 4.71; N, 8.06. C27H24ClN3O5.1/4H2O requires C, 63.53; H, 4.84; N, 8.23.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:20](OCC)=[O:21].[O-]S([O-])(=O)=O.[Mg+2].[OH-].[K+]>C(OCC)C.C(OCC)(=O)C.C(OC)(C)(C)C.CCCCCCC.C(OCC)(=O)C>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:20][OH:21]
Reactant: CCOC(=O)c1nc(-c2ccc(C)cc2)oc1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Cc1ccc(-c2nc(CO)c(C)o2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
In a dry four-necked flask with stirrer motor, internal thermometer, dropping funnel with pressure equalizer and reflux condenser with argon inlet (aspirator with tap), 9.3 g of LiAlH4 are covered with 600 ml of diethyl ether. The suspension is cooled to 0° C. 30 g of ethyl 5-methyl-2-p-tolyloxazole-4-carboxylate are dissolved in 100 ml of diethyl ether and added dropwise to the suspension. After one hour of stirring at room temperature, the reaction has ended (TLC (heptane/ethyl acetate 1:1): Rf, starting material=0.66, Rf, product=0.18). 80 g of MgSO4, 300 ml of methyl tert-butyl ether and 30 ml of ethyl acetate are added successively, and the suspension is stirred at room temperature. The mixture is then cooled to 0° C., 90 ml of 10N KOH are added dropwise and the mixture is stirred for another 60 min. The solids are filtered off, the residue is washed three times with ethyl acetate and the filtrate is concentrated, giving 24 g of 5-methyl-2-p-tolyl-oxazole-4-methanol as a yellow solid. C12H13NO2 (203.24), LCMS(ESI): 204.1 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][OH:7].C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH2:15][CH2:16][CH3:17]>C(#N)C>[CH2:14]([N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][OH:7])[CH2:15][CH2:16][CH3:17]
Reactant: OCC1CCCN1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCCC1CO

Procedure:
To 10.1 g (0.1 mol) of 2-pyrrolidinemethanol and 13.8 g (0.1 mol) of potassium carbonate in 200 mL of acetonitrile add 13.7 g (0.1 mol) of butyl bromide. Heat the reaction mixture at reflux with stirring under a nitrogen atmosphere. Follow the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction remove the solvent in vacuo then dissolve the residue in water. Make the aqueous mixture acidic (pH=1) with concentrated hydrochloric acid. Extract the aqueous acid solution with 3×50 mL of hexanes. Make the aqueous solution basic (pH=12) with 20% sodium hydroxide solution and extract with 3×100 mL of methylene chloride. Dry the combined methylene chloride extracts over anhydrous sodium sulfate. Filter the drying agent and evaporate the filtrate in vacuo to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24](=[O:26])[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCCC1

Procedure:
Starting from (S)-N2-(benzyloxycarbonyl)-N5-(tert-butyloxycarbonyl)-ornithine and pyrrolidine, the expected product is obtained according to the procedure described in Step A of Example 3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.C([O-])(=O)C.[K+].CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([B:22]([OH:23])[OH:21])=[CH:3][C:4]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(B(O)O)cnc1Cl
Temperature: 90 °C
Reaction time: 5 h
Yield: 111.7 %

Procedure:
N-(5-Bromo-2-chloro-3-pyridinyl)methanesulfonamide (5 g, 17.51 mmol), potassium acetate (5.16 g, 52.5 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (4.89 g, 19.26 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (1.281 g, 1.751 mmol) were placed in 1,4-dioxane (51 ml) and the mixture heated for 16 h at 90° C. The reaction was left stirring at 90° C. for a further 5 h. Further catalyst (0.3 g), potassium acetate (1.7 g) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (1.5 g) were added and the mixture stirred at 95° C. overnight. The mixture was cooled to room temperature then the mixture was filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was partitioned between water (250 ml) and dichloromethane (250 ml). the organic layer was collected and the solvent removed in vacuo. The residue was columned on silica (3×100 g) cartridges eluting with 0-25% methanol in dichloromethane over 40 mins gave the title compound as a dark brown oil (4.9 g).
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=O)=O.O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCCCC(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)C(F)(F)CCCCCI
Yield: 85.8 %

Procedure:
Sodium iodide (27.37 g, 182.58 mmol) was added to a solution of 1-methanesulfonyloxy-6,6,7,7,7-pentafluoroheptane (17.3 g, 60.86 mmol) in acetone (500 ml), followed by heating under reflux for 12 hours. Water was added to the reaction mixture, which was then extracted twice with ether. The combined organic layers were washed with 1% aqueous sodium thiosulfate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-iodo-6,6,7,7,7-pentafluoroheptane (16.5 g, Yield 86%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[S:27])[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[K]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=3)[S:27][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(=S)Nc2ccc(OCc3ccccc3)cc2)ccc1Cl
Agent: [K]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1cc(-c2nc3ccc(OCc4ccccc4)cc3s2)ccc1Cl
Temperature: 130 °C

Procedure:
N-(4-Benzyloxy-phenyl)-4-chloro-3-nitro-thiobenzamide (2 g, 5 mmol) was dissolved in methanol (100 ml). Sodium hydroxide (1.6 g in 5 ml water) was added followed by Triton B (2.1 ml, 5 mmol, commercially available). The mixture was cooled in an ice-bath. Potassium ferri(III) cyanide (13.2 g in 50 ml water) was added drop wise with vigorous stirring. The reaction mixture was allowed to warm up overnight and was further warmed to 130° C. for 1 hour. The reaction mixture was cooled and extracted with ethyl acetate/water. The organic phase dried and the solvent removed under reduced pressure. The product, compound was purified by flash chromatography with Hexane/Ethyl acetate as eluent.