Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:15](ON1C(=O)CCC1=O)([CH3:17])=[O:16].CN1CCOCC1>CN(C=O)C>[NH:1]([C:15]([CH3:17])=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)N[C@@H](COCc1ccccc1)C(=O)O

Procedure:
The same compound was also prepared by a different route. Thus, H-Ser(Bzl)-OH (18.6 g, 95.4 mmol) was dissolved in 45 ml Triton B, evaporated to dryness, and the residue re-evaporated twice with DMF (100 ml each). The residue was then stirred with Ac-OSu (16.9 g, 95.4 mmol) in 150 ml DMF for 20 hours. N-Methylmorpholin was added from time to time in order to maintain the reaction slightly basic. Removal of the solvent and extraction of the product into EtOAc followed by washing with small volumes of 10% HOAc, H2O (the product is water soluble, use a small volume of H2O), dried over Na2SO4, evaporation to dryness again gave a clear oil (14.5 g, Ac-Ser(Bzl)-OH). The compound failed to crystallize. It was thus dissolved in a mixture of MeOH and H2O (300 ml:30 ml), titrated to pH 7.0 with 20% Cs2CO3 and evaporated to a solid mass. The salt was re-evaporated twice more with DMF and stirred with benzyl bromide (15.4 g, 91 mmol) in 250 ml DMF for 18 hours. On evaporation of the solvent, the residue was taken up in H2O (600 ml) and the oily product formed was extracted into EtOAc. It was washed with H2O, dried over Na2SO4 and evaporated to a syrup which on seeding crystallized immediately. It was recrystallized from EtOAc and petroleum ether to yield, 10.42 g (32.2% overall); mp 89°-91°.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:24])[CH2:21][NH:22][CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34]Br)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:24])[CH2:21][N:22]([CH2:34][CH2:33][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CNCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCNC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.2 %

Procedure:
500 mg (1.42 mmol) of sarcosine benzyl ester p-toluenesulfonate, 478 mg (2.13 mmol) of 2-(tert-butoxycarbonylamino)-ethyl bromide, and 0.25 mL (2.13 mmol) of diisopropyl-ethylamine were dissolved in methylene chloride (10 mL), and then stirred at room temperature for approximately three days. After completion of the reaction, the reaction solution was concentrated and the residue obtained was purified by silica gel column chromatography (ethyl acetate) to yield 175 mg (38%) of {[2-(tert-butoxycarbonylamino)-ethyl]-methyl-amino}-acetic acid benzyl ester as a colorless viscous oil.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]1([SH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>O>[NH2:15][C:16]1[CH:21]=[C:20]([S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: Sc1ccccc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
2.53 G. 57% sodium hydride in oil suspension in 20 ml. dimethylformamide is treated with 6.2 ml. thiophenol under nitrogen. 5.0 G. 2-amino-4-chloro-1-nitrobenzene is added and the mixture stirred for three hours. Water is added and the product filtered off and washed with water and hexane. Recrystallization from methanol gives pure 2-amino-4-phenylthio-1-nitrobenzene.
Reaction SMILES: [F:1][C:2]([CH:5]=[C:6]=[CH:7][C:8]([F:11])([F:10])[F:9])([F:4])[F:3].[O:12]([CH3:14])[Na].O>CO>[C:2]([CH:5]=[C:6]([CH2:7][C:8]([F:9])([F:10])[F:11])[O:12][CH3:14])([F:4])([F:3])[F:1]
Reactant: CO[Na]
Reactant: FC(F)(F)C=C=CC(F)(F)F
Solvent: CO
Solvent: O
Product: COC(=CC(F)(F)F)CC(F)(F)F
Reaction time: 0.25 h
Yield: 88 %

Procedure:
21.1 g (0.12 mol) of bis(trifluoromethyl)allene were added to 20 mL 0.5 N NaOCH3 in methanol (8 mol % relative to allene) over 1 h with water bath cooling, keeping the reaction temperature at 10-20° C. Stirring was continued for 15 min. and the mixture poured into 80 mL cold water. The lower layer was separated and the aqueous portion extracted with 20 mL CH2Cl2. The combined organic layers were washed with 5 mL brine, dried (Na2SO4) and distilled to give 21.9 g (88% yield) of CF3CH=C(OCH3)CH2CF3, boiling point 110-111° C. IR: 1672 cm-1. Major MS fragments: 208 (75.9), 189 (30.2), 158 (31.6), 125 (60.5), 111 (82.4), 91 (100), 31 (91.2). 1H NMR:4.95 (q,1H, J=7.5 Hz), 3.65 (s, 3H), 3.18 (q, 2H, J=9.8 Hz) ppm. 19FNMR: -54.4(d,3 F), -63.9 (t, 3 F) ppm. Anal. Calcd for C6H6F6O: C, 34.61; H, 2.91. Found: C, 34.59; H. 2.85.
Reaction SMILES: FS([O-])(=O)=[O:3].Cl[C:7]1[C:11]([Cl:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][N+:8]=1[CH3:18]>C([O-])([O-])=O.[K+].[K+]>[Cl:12][C:11]1[C:7](=[O:3])[N:8]([CH3:18])[S:9][C:10]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1s[n+](C)c(Cl)c1Cl
Reactant: O=S(=O)([O-])F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1sn(C)c(=O)c1Cl
Yield: 37.6 %

Procedure:
3,4-Dichloro-5-ethoxycarbonyl-2-methylisothiazolium fluorosulfonate (4.2 g, 0.012 mol) was added to 50 ml of saturated K2CO3 solution. The aqueous phase was extracted wih 3×50 ml of CH2Cl2. The combined extracts were dried (MgSO4), filtered and conc. to yield a solid. Recrystallization from heptane yielded 1.0 g (35%) of 4-chloro-5-ethoxycarbonyl-2-methyl-4-isothiazolin-3-one, mp 142-147.
Reaction SMILES: [C:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14]([OH:33])([C:19]3[CH:24]=[CH:23][C:22]([O:25][Si](C(C)(C)C)(C)C)=[CH:21][CH:20]=3)[CH2:15]2)[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>C1COCC1>[CH2:1]([N:9]1[CH2:18][CH2:17][C@H:16]2[C@@H:11]([CH2:12][CH2:13][C:14]([OH:33])([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[CH2:15]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2(O)CC[C@H]3CN(C(=O)c4ccccc4)CC[C@@H]3C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1ccc(C2(O)CC[C@H]3CN(Cc4ccccc4)CC[C@@H]3C2)cc1
Temperature: 25 °C

Procedure:
A mixture of trans-2-benzoyl-6-hydroxy-6-(4'-t-butyldimethylsilyloxyphenyl)decahydroisoquinoline (Example 48, 740 mg, 1.61 mmol) and lithium aluminum hydride (0.31 g, 8 mmol) in anhydrous THF (20 mL) was stirred at reflux temperature under a nitrogen atmosphere for 19.5 h. The reaction mixture was cooled to room temperature and quenched with excess ethyl acetate, followed by water (0.3 mL), a 1N NaOH solution (0.3 mL) and water (1 mL). The precipitate was filtered through celite; the filtrate was dried over magnesium sulfate and filtered. Removal of solvent in vacuo gave an oil. Column chromatography (ethyl acetate) gave the product, a solid (209 mg): mp 108°-109° C., NMR (CDCl3, 200 MHz): 7.4-7.2 (m, 7H), 6.8 (d, 2H, J=7), 3.55 (s, 2H), 2.95 (br d, 1H, J=8), 2.85 (br d, 1H, J=8), 2.2 (s, 2H), 2.1-1.2 (m, 11H); Anal. Calcd for C22H27NO2.O.3H2O: C, 77.06, H, 8.11, N, 4.09; Found C, 76.82, 76.83, H, 7.95, 8.15, N, 3.88, 3.80.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>ClCCl>[CH3:24][S:25]([O:23][CH2:22][CH2:21][CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCOCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
In dichloromethane (50 ml) is dissolved 3-(octadecyloxy)propanol (8.0 g). To the solution are added, under ice-cooling, methanesulfonyl chloride (4.18 g) and triethylamine (5.1 ml). The mixture is stirred at room temperature for one hour. The reaction mixture is washed with water and an aqueous solution of sodium hydrogencarbonate, successively, and then dried. The solvent is distilled off under reduced pressure to give the above-titled compound (9.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13]([NH2:15])=[O:14])=[C:4]([F:16])[CH:3]=1.[CH3:17][CH2:18][O:19][C:20]([CH:22]1[C:26](=O)[CH2:25][CH2:24][CH2:23]1)=[O:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:14])[NH:15][C:23]2[CH2:24][CH2:25][CH2:26][C:22]=2[C:20]([O:19][CH2:18][CH3:17])=[O:21])=[C:4]([F:16])[CH:3]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)Oc1cc(NC(N)=O)c(F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(OC(C)C)c(Cl)cc2F)CCC1

Procedure:
7.00 g of 4-chloro-2-fluoro-5-isopropoxyphenylurea and 4.44 g of ethyl cyclopentanone-2-carboxylate are heated at reflux temperature for 1.5 hours with 0.3 g of toluene-4-sulphonic acid monohydrate in 150 ml of benzene. The water which forms is removed with a water separator. The reaction mixture is subsequently evaporated to dryness and the residue is purified by chromatography on a silica gel column using methylene chloride as the eluent and recrystallized from diethyl ether/n-hexane. There is obtained ethyl 2-[3-(4-chloro-2-fluoro-5 -isopropoxyphenyl)-ureido]-1-cyclopentenecarboxylate, m.p. 166°-169° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:25]Br.O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([Br:25])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccs2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture containing 4-thiazol-2-yl-piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 1.9 mmol) and cesium carbonate (0.62 mmol) in chloroform (5 mL) at 0° C., bromine (110 mL) was added through a syringe. After the addition, the reaction mixture was stirred at room temperature for 1 hour. Water was added and the organic layer was collected and dried over sodium sulfate. After removal of solvent, 0.6 g of product was obtained (95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccc(-n2cccc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 100 °C
Yield: 79.2 %

Procedure:
A 2-L three-necked flask equipped with a stirrer, a thermometer, a condenser tube and a nitrogen inlet tube was charged with 134.6 g (0.500 mol) of 2,5-dichloro-4′-fluorobenzophenone, 50.3 g (0.750 mol) of pyrrole, 76.0 g (0.550 mol) of potassium carbonate and 840 ml of dehydrated N,N′-dimethylacetamide. The reaction solution was heated under a nitrogen atmosphere in an oil bath at 100° C. for 3 hours. After thin layer chromatography confirmed that the materials showed no peaks, the reaction liquid was allowed to cool to room temperature. The reaction liquid was slowly added to 3 L of water, and the product was precipitated. The liquid was then filtered. The product obtained by the filtration was dissolved in 2.5 L of toluene. The solution was washed with salt solution using a separating funnel until the water phase became neutral. The organic phase was dried over magnesium sulfate, and the solvent was evaporated with an evaporator. A crude product weighing 133.3 g was obtained. The crude product was subjected to recrystallization using a hexane/ethyl acetate mixed solvent, and the resultant crystal was isolated. As a result, 125.3 g (0.396 mol) of an objective purified product was obtained with a yield of 79.3%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([S:13][CH2:14][CH2:15][CH2:16]Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>>[C:7]1([S:13][CH2:14][CH2:15][CH2:16][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCSc1ccccc1
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(SCCCN2CCNCC2)cc1

Procedure:
To 1 liter 50% aqueous alcohol are added 3 moles piperazine, 1 mole 3-phenylthio-1-chloropropane, 1 mole 10N sodium hydroxide. The mixture is refluxed for 24 hours, with stirring. The methanol is then evaporated off, and the resulting material is extracted with methylene chloride. The organic phase is thoroughly washed with water, and is then concentrated and distilled, to give 1-(3-phenylthiopropyl)piperazine, bp0.5 mm =140°-142° C.
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][C:6]([CH3:8])=O)C.[CH3:10][CH:11]([NH:19][NH2:20])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>C(O)C>[CH3:8][C:6]1[NH:20][N:19]([CH:11]([CH3:10])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:4](=[O:9])[CH:5]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(C(C)NN)cc1
Solvent: CCO
Product: Cc1ccc(C(C)n2[nH]c(C)cc2=O)cc1

Procedure:
26 g of acetoacetic acid ethyl ester were dissolved in 20 ml of absolute ethanol. 30.0 g of α-methyl-4-methylbenzylhydrazine in a little absolute ethanol were slowly added to this solution under nitrogen. After the exothermic reaction had subsided, the mixture was heated for 2 hours under reflux. On cooling, the crude product crystallized out and was purified by recrystallization from methanol. Melting point 144°- 146°C; yield 28 g (65% of theory).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:1][C:2]([F:29])([F:30])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1)[CH2:6][CH:7]1[C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: FC(F)(F)c1cc(C=C2c3ccccc3CCc3ccccc32)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(CC2c3ccccc3CCc3ccccc32)cc(C(F)(F)F)c1
Reaction time: 17 h

Procedure:
Add 5-(3,5-bis-trifluoromethyl-benzylidene)-10,11-dihydro-5H-dibenzo [a,d]cycloheptene (0.28 g, 0.67 mmol) to a mixture of 10% Pd/C (0.08 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (4.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite. Evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product. MS (m/e): 420 (M+); Analysis for C24H18F6: Calcd: C, 68.56 H, 4.31. Found: C, 68.55 H. 4.01.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:9]([CH3:20])[CH2:8]1.[C:22]([O:26][C:27]([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH:9]([CH3:20])[CH2:8]1)=[O:44])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC1CN(c2c(N)cnn2C)CCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.6 %

Procedure:
To a solution of tert-butyl (±)-4-(4-amino-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (400 mg, 2.05 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (630 mg, 2.46 mmol), HATU (0.83 g, 8.19 mmol) in DMF (15 mL) was added TEA (1.5 mL). The reaction mixture was stirred at 25° C. for 20 hours and poured into water (100 mL). The mixture was extracted with EtOAc (50 mL×2). The combined organic layers was washed with water (50 mL×2) and brine (30 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography using DCM/MeOH (1:1) as eluting solvents to afford tert-butyl (±)-4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (280 mg, 52%) as white solid. 1H NMR (500 MHz, CDCl3) δ (ppm): 10.32 (s, 1H), 8.70 (s, 1H), 7.80 (s, 1H), 7.38-7.35 (m, 1H), 7.06-7.03 (m, 2H), 4.34 (s, 1H), 3.94-3.97 (m, 1H), 3.81 (s, 3H), 3.67-3.40 (m, 1H), 3.20-3.25 (m, 2H), 3.04-3.06 (m, 1H), 2.88-2.90 (m, 1H), 1.55 (s, 9H), 1.47 (s, 9H), 1.34-1.36 (d, J=6.4 Hz, 3H); MS (ESI) m/z=434 (M+H+).
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][C@H:7]([NH:35]C(=O)OC(C)(C)C)[C:8](=[O:34])[N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([C:20]4[CH:29]=[CH:28][C:27]5[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=5[CH:21]=4)[N:19]=3)[CH2:11][CH2:10]2)[NH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:35][C@@H:7]([CH2:6][C:4]1[NH:3][CH:2]=[N:1][CH:5]=1)[C:8]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]=4[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N1CCC(c2nc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)cs2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(C(=O)[C@@H](N)Cc5cnc[nH]5)CC4)n3)ccc21

Procedure:
250 mg (0.42 mmol) of tert-butyl ((S)-1-(3H-imidazol-4-ylmethyl)-2-oxo-2-{4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]-piperidin-1-yl}ethyl)carbamate are dissolved in 20 ml of dichloromethane and 1 ml of trifluoroacetic acid and stirred at room temperature for 12 h. The reaction mixture is washed with 0.1 N NaOH, the organic phase is dried over sodium sulfate and purified by column chromatography on silica gel. The crude product is dissolved in acetone, and a pH of 4 is set using 1 N HCl. A white precipitate forms in the process, which is filtered off with suction, washed with ether and dried in vacuo. Yield: 200 mg of “A63” hydrochloride, white solid; ESI: 492 (M+H).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.Cl.[CH2:35]([O:42][CH:43]1[CH2:49][CH:48]2[NH:50][CH:44]1[CH2:45][O:46][CH2:47]2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].CC#N>CCOC(C)=O>[CH2:35]([O:42][CH:43]1[CH2:49][CH:48]2[N:50]([CH2:6][C@H:7]3[CH2:12][N:11]([S:13]([C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]3[C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=3)[CH:44]1[CH2:45][O:46][CH2:47]2)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: c1ccc(COC2CC3COCC2N3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2C(OCc2ccccc2)C3)cc1)C(F)(F)F
Temperature: 150 °C

Procedure:
A 10 mL vial was charged with ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (0.207 g, 0.391 mmol, Intermediate B), 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (endo) (0.100 g, 0.391 mmol, J. Org. Chem. 2010, 75, 1643), potassium carbonate (0.162 g, 1.173 mmol), and 3 mL of MeCN. The tube was sealed and heated in a microwave reactor (Emrys Optimizer Automated Microwave Synthesizer, Uppsala, Sweden) at 150° C. for 1 h. The mixture was diluted with EtOAc, filtered and the filtrate was concentrated and purified via column chromatography on silica gel (0 to 50% EA/Hex) to 2-(4-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of four endo isomers (0.130 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([CH2:11][NH2:12])[CH2:7][C:8](Cl)=[O:9].[CH3:13][OH:14]>N1C=CC=CC=1>[CH3:13][O:14][C:8](=[O:9])[CH2:7][CH:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[CH2:11][NH2:12]
Reactant: CO
Reactant: NCC(CC(=O)Cl)c1ncc[nH]1
Solvent: c1ccncc1
Product: COC(=O)CC(CN)c1ncc[nH]1

Procedure:
0.01 mol of the compound obtained in stage A of Example 16 is dissolved in 30 cm3 of pyridine. 1 cm3 of methanol is added. The whole is heated under reflux for five hours, the reaction medium is evaporated in vacuo on a water bath. The residue is dried and purified by chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH2:10])[CH3:9])[N:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.[F:21][C@H:22]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30]1[CH:35]=[CH:34][N:33]=[C:32](F)[N:31]=1)[CH3:23].CCN(C(C)C)C(C)C>CS(C)=O>[F:21][C@H:22]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([NH:10][C@H:8]([C:6]2[N:5]=[CH:4][C:3]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=3)=[C:2]([CH3:1])[CH:7]=2)[CH3:9])[N:31]=1)[CH3:23]
Reactant: Cc1cc([C@H](C)N)ncc1-c1ccnc(C(F)(F)F)c1
Reactant: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc([C@H](C)Nc2nccc(N3C(=O)OC[C@@H]3[C@H](C)F)n2)ncc1-c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A solution of (S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine (28.1 mg, 0.1 mmol), (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (22.9 mg, 0.100 mmol) and DIPEA (52.4 μl, 0.300 mmol) in DMSO (Volume: 500 μl) was heated at 110° C. for 1 hr. The solution was then cooled to rt, and RP-HPLC (acetonitrile:water) purification provided a white solid. This material was purified again with flash column chromatography (0-10% MeOH/EtOAc) to give 14 mg (R)-4-((S)-1-fluoroethyl)-3-(2-(((S)-1-(4-methyl-2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a white solid. 1H NMR (400 MHz, MeOD) δ 8.81 (d, J=5.0 Hz, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.69 (dd, J=5.0, 1.6 Hz, 1H), 7.44 (s, 1H), 7.41 (d, J=5.8 Hz, 1H), 5.08 (br s, 1H), 4.73 (br d, J=26.0 Hz, 1H), 4.56-4.27 (m, 3H), 2.32 (s, 3H), 1.58 (d, J=7.1 Hz, 3H), 1.12 (br s, 3H); HRMS (B) m/z 491.1782 (M+H)+. Anal. RP-HPLC tR=3.42 min. Purity 100%/100%.