Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:5](Br)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[NH3:20]>CO>[CH3:1][O:2][N:3]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:5]([NH2:20])[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N
Reactant: CON=C(c1ccc(Cl)cc1)C(Br)CC1CCCC1
Solvent: CO
Product: CON=C(c1ccc(Cl)cc1)C(N)CC1CCCC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 45 %

Procedure:
The 2-bromo-1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one O-methyl-oxime (1.16 g, 2.901 mmol) was dissolved in a solution of ammonia in methanol (30 mL, ˜7 N). The reaction flask was sealed with a Teflon stopper, and the reaction mixture was stirred at 55–60° C. for 2 d. It was cooled to 0° C. then the stopper was removed. The reaction mixture was concentrated to remove ammonia and methanol. The residue was partitioned between water and diethyl ether. The product was extracted with diethyl ether (2×20 mL). The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with 50–100% ethyl acetate+0.1% triethylamine in hexanes yielded 2-amino-1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one O-methyl-oxime (423 mg, 45%) as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].[C-]#N.[K+].O>CN(C)C=O>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][C:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1)=[O:6]
Reactant: C=CC(=O)OC
Reactant: O=Cc1cccc(F)c1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)c1cccc(F)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of 3-fluorobenzaldehyde (35.38 g, 285.07 mmol) in 35 mL dimethylformamide (DMF) was added to a heated (48° C.) solution of methyl acrylate (26.28 mL, 25.03 g, 290.7 mmol) and powdered KCN under Argon. The reaction mixture was stirred at 40° C. for 2 hours and then poured into 500 mL of water. This aqueous phase was extracted twice with 500 mL of Et2O and once with 250 mL of EtOAc. The combined organic layers were washed with water and saturated brine, and then dried over MgSO4. The solvent was evaporated under reduced pressure to give 50.89 g (242.2 mmol, 84.93%) of 4-(3-fluoro-phenyl)-4-oxo-butyric acid methyl ester as an oil. MS: 211 (M+H)+.
Reaction SMILES: C[O:2][CH2:3][CH2:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:33][CH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41]>ClCCl>[OH:43][C:36]1[C:35]([CH2:34][NH:33][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH:5]([CH2:4][CH2:3][OH:2])[CH3:6])=[CH:15][CH:14]=2)=[C:40]([CH3:41])[CH:39]=[C:38]([CH3:42])[N:37]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: COCCC(C)c1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)CCO)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
A mixture of 4-(4-methoxybutan-2-yl)benzoic acid (177 mg, 0.85 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (245 mg, 1.3 mmol), N-hydroxybenzotriazole (176 mg, 1.3 mmol) and triethylamine (258 mg, 2.55 mmol) in dichloromethane (50 mL) was stirred for 30 minutes at room temperature. Then to the mixture, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (130 mg, 0.85 mmol) was added. The resultant mixture was stirred at room temperature for 12 hours. Then the mixture was washed with water (30 mL×3). The organic layer was concentrated to give a residue and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(4-hydroxybutan-2-yl)benzamide (47 mg, 17%). LRMS (M+H+) m/z: calcd 324.19 found 324. 1H. NMR (300 MHz, CD3OD): δ 12.96 (s, 1H), 7.80 (s, 1H), 7.70 (d, J=7.8 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H), 5.95 (s, 1H), 4.56 (d, J=5.7 Hz, 2H), 3.20-3.14 (m, 5H), 2.93 (q, J=7.2 Hz, 1H), 2.37 (s, 3H), 2.27 (s, 3H), 1.82 (q, J=6.9 Hz, 2H), 1.23 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:17])[C:10]([F:16])([F:15])[CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl>C(OC(C)=O)(C)C.[Cl-].[Na+].O>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([F:16])([F:15])[C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(F)(F)C(=O)NCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)C
Solvent: O=S(Cl)Cl
Product: O=C1CC(F)(F)C(=O)N1Cc1ccccc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
To a solution of the crude 4-(benzylamino)-3,3-difluoro-4-oxobutanoic acid in iPrOAc (40 mL), SOCl2 (2.04 mL, 27.9 mmol, 2 eq) was added at ambient temperature. The reaction solution was stirred at 55° C. for 4 hr. The reaction was cooled to 0-5° C. Half saturated brine (50 mL) was added slowly to quench the excess SOCl2. The organic phase was washed with brine (70 mL) and 2 M Na2CO3 (about 50 mL) to pH=8-9, extracted two times with EtOAc. The combined organic layer was washed with brine (50 mL), the organic phase was dried over MgSO4, filtered and concentrated. The crude residue was diluted with CH2Cl2 and filtered to remove precipitate. The concentrated filtrate was purified by column chromatography and eluted with 2-20% EtOAc/Heptane to obtain the title compound as a clear oil (1.74 g, 65%)1H NMR (400 MHz, CDCl3) δ ppm 7.30-7.43 (m, 5 H) 4.76 (s, 2 H) 3.18 (t, J=12.53 Hz, 2 H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=O)=[CH:26]2)[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=[C:10]1[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][C:11]1=[O:16])=[CH:26]2)[CH3:35]
Reactant: CCN(CC)CCCc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCCc1ccc2[nH]c(C=C3C(=O)Nc4ccc(-c5ccccc5)cc43)cc2c1
Temperature: 95 °C
Yield: 11.7 %

Procedure:
A mixture of 5-phenyl-2-oxindole (41 mg, 0.19 mmol), 5-(3-diethylamino-propyl)-1H-indole-2-carbaldehyde (50 mg, 0.19 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 95° C. for 20 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 10 mg (11%) of the title compound as an orange crystalline solid. MS-EI m/z 449 [M+].
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:19]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl.C(O)(C(F)(F)F)=O>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.CCO>[F:27][C:5]1[CH:4]=[C:3]([F:28])[C:2]([C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)=[CH:7][C:6]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH2:19])=[N:9]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)c(F)cc3F)CO[C@H](CF)[C@H]2CS1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: NC1=N[C@@]2(c3cc(-c4cncnc4)c(F)cc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl ((4aS,5S,7aS)-7a-(5-bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (100 mg, 0.21 mmol) was dissolved in DME (1.5 mL), EtOH (0.7 mL) and water (0.5 mL). The solution was heated to 100° C. Pyrimidin-5-ylboronic acid (51.5 mg, 0.416 mmol), bis(triphenylphosphine)palladium (II) chloride (29.2 mg, 0.042 mmol) and cesium carbonate (406 mg, 1.25 mmol) were added and the reaction was stirred at 100° C. for 45 minutes. The reaction was cooled to room temperature and partitioned between DCM and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with DCM (×2). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min eluting with 20-80% EtOAc in n-hexane). The material was stirred in DCM (2 mL, 31.08 mmol) and TFA (2 mL) for 1 hour at room temperature. The solvents were removed in vacuo. The residue was passed over a 5 g SCX cartridge, washing with MeOH then 2N NH3/MeOH. The basic fractions were concentrated in vacuo and the residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min gradient 0-20% MeOH in EtOAc) to leave the title compound as a white solid.
Reaction SMILES: CN(C)C=O.S(Cl)(Cl)=O.C[N+](C)=C[Cl:13].[Cl-].O[CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])[C:18]([OH:20])=[O:19].[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([CH3:38])[NH:33]1>ClCCl.CCOCC>[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([CH3:38])[NH:33]1.[Cl:13][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29])[C:18]([OH:20])=[O:19]
Reactant: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: C[N+](C)=CCl
Agent: CC1CCCC(C)N1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: O=C(O)C(Cl)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To magnetically stirred N,N-dimethylformamide (2 ml, 25.8 mmol) cooled in ice was added slowly dropwise thionyl chloride (3 ml, 41.1 mmol), and the resulting cold Vilsmeier reagent was diluted with dichloromethane (10 ml). α-Hydroxy-2-nitrobenzenepropanoic acid (2.00 g, 9.47 mmol), followed by an additional 2 ml of dichloromethane was added. The mixture, protected from moisture, was stirred at room temperature (25° C.) overnight. The resulting solution was evaporated to a syrup. The syrup was dissolved in dichloromethane and the solution was added to stirred ice. The mixture was stirred for 1 hour during which time it warmed to room temperature. The dichloromethane solution was separated and washed (X4) with water and dried (MgSO4). Evaporation gave a syrup which was subjected to an oil pump vacuum for half an hour. The syrup was dissolved in ether and 2,6-dimethylpiperidine was added to approximate neutrality (pH 9 with pH paper). The crude titled product [2.36 g (81%), mp 138-140° C.]crystallized readily. Recrystallization (methanol-ether) with decolorization (Nuchar C-190N) gave pure product, mp 141°-143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11](O)=O)=[CH:4][C:3]=1[S:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:17])=[O:16].C(OC(=O)C)(=[O:25])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11](=[O:25])[CH:14]=2)=[CH:4][C:3]=1[S:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:17])=[O:16]
Reactant: O=C(O)CCC(=O)c1ccc(Cl)c(S(=O)(=O)N2CCCC2)c1
Reactant: CC(=O)OC(C)=O
Product: O=C1C=C(c2ccc(Cl)c(S(=O)(=O)N3CCCC3)c2)OC1

Procedure:
3.9 g of 4-[4-chloro-3-(1-pyrrolidinylsulfonyl)-phenyl]-4-oxobutanoic acid are boiled under a reflux condenser in 50 ml of acetic anhydride for 1 hour, the solvent is driven off under reduced pressure and the residue is caused to crystallize under diisopropyl ether. 5-[4-Chloro-3-(1-pyrrolidinylsulfonyl)-phenyl]-2,3-dihydro-3-oxofuran is obtained in the form of light red-colored crystals of melting point 108°-111° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.[Cl-].[C:16]([SiH:20]([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[C:16]([Si:20]([CH3:22])([CH3:21])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: OC1CCNCC1
Reactant: C[SiH](C)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
7.94 g (78.57 mmoles) of 4-hydroxypiperidine are placed in 175 mL of CH2Cl2 and 35 mL Et3N under nitrogen. At 0° C., a solution of 25 g (165 mmoles) of tert-butyldimethylsilane chloride in 350 mL of CH2Cl2 is added dropwise. The reaction medium is agitated overnight at ambient temperature then 2.36 g (15.7 mmoles) of tert-butyldimethylsilane chloride are added. After agitation for 4 h at ambient temperature, 0.69 g (0.55 mmoles) 4-dimethylaminopyridine and 2.36 g (15.7 mmoles) tert-butyldimethylsilane chloride are added. The reaction medium is agitated overnight at ambient temperature then diluted in water and extracted with CH2Cl2. After drying over MgSO4, the organic phases are evaporated and the residue obtained is purified by silica gel flash chromatography (CH2Cl2-MeOH—NH4OH, gradient 100:0:0 to 90:9:1 in 50 min). 12.71 g of intermediate 5a are thus obtained in the form of yellow oil (yield 75%). TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH—NH4OH: 90:9:1, Rf=0.47.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].N[C@H](C(O)=O)CCCCN>>[ClH:1].[NH2:2][C@@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: NCCCCC(N)C(=O)O
Agent: Cl
Agent: NCCCC[C@H](N)C(=O)O
Product: NCCCC[C@@H](N)C(=O)O
Reaction time: 0.17 h

Procedure:
Into a shaking flask having a volume of 500 ml was charged ml of a medium (pH 7.0) comprising 0.5% of DL-lysine monohydrochloride, 1.0% of polypeptone, 1.0% of a yeast extract and 0.5% of sodium chloride, and the medium was sterilized at 120° C. for 10 minutes. A loopful of Pseudomonas sp. ATCC 14676 was inoculated into the medium and cultured at 30° C. for 20 hours. The cell collected from 1000 ml of the above culture broth by centrifugation was suspended in a physiological saline and then collected by centrifugation. To the cell was added 500 ml of a 50 mM phosphate buffer (pH 7.0) containing 50 g of DL-lysine monohydrochloride, and the mixture was reacted at 30° C. for 72 hours to degrade L-lysine completely. After the reaction, the cells were removed by centrifugation, and subsequent procedures were carried out in the same manner as in Example 1 to obtain 14.2 g of D-lysine monohydrochloride.
Reaction SMILES: N#N.[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.[CH3:18]NOC.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C[Mg+].[Br-].OS([O-])(=O)=O.[K+]>CC#N>[O:16]=[C:14]([CH3:18])[CH2:13][CH2:12][CH2:11][NH:10][C:8](=[O:9])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: C[Mg+]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 4-(tert-butoxycarbonyl-amino)butyric acid (1.00 g, 4.77 mmol) in dry CH3CN (24 mL) were added N,O-dimethyl-hydroxylamine hydrochloride (475 mg, 4.77 mmol), EDC.HCl (934 mg, 4.77 mmol), HOBt (658 mg, 4.77 mmol) and N-methylmorpholine (2.68 mL, 23.86 mmol) at rt. The reaction mixture was stirred at rt until completion of the reaction. The mixture was then concentrated under reduced pressure. The residue was redissolved in EA, successively washed with water, 10% aq. KHSO4, sat. aq. NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was dissolved in dry THF (20 mL) and treated with MeMgBr (3.0M solution in Et2O, 3.25 mL, 9.75 mmol) at 0° C. The reaction mixture was stirred at 0° C. until completion of the reaction. 10% Aq. KHSO4 was then carefully added, the layers separated and the aq. layer extracted with EA (3×). The combined org. extracts were successively washed with aq. sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA 3:2) to give the title compound as a colorless oil. TLC:rf (3:2 hept-EA)=0.38.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C(Cl)Cl.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>Cl.O>[CH3:21][S:22]([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCc1ccc(F)cc1
Temperature: 2.5 °C
Yield: 102.7 %

Procedure:
A suitable reactor maintained under nitrogen was charged with 4-fluorophenethyl alcohol (2.6 kg, 18.6 mol) and 18 L of methylene chloride. The stirred solution was cooled to and maintained at 0-5° C. while triethylamine 2.85 kg (28.2 mol) was added fairly rapidly. The reaction temperature was maintained at 0-5° C. while adding methanesulfonyl chloride (2.5 kg, 21.8 mol) over 1 hour. The stirred reaction mixture was maintained at 0-5° C. for 1 hour, then it was warmed to room temperature within approximately 2 hours. The reaction mixture was diluted with a solution of 0.5 kg of 33% hydrochloric acid in 10 L of water. The organic phase was separated and washed with a solution of 0.2 kg of 33% hydrochloric acid in 5 L of water. Both acidic extracts were combined and extracted with 5 L of methylene chloride. Both organic phases were combined, washed with 2×15 L of water, then dried with sodium sulfate (2 kg). Drying agent was filtered off and washed with 2×5 L of methylene chloride. The majority of the solvent was boiled off at atmospheric pressure, with the final amount distilled off at 35° C./500 torr to give 4-fluorophenethyl alcohol methanesulfonate (4.17 kg.)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:69]=[CH:68][C:13]([O:14][CH2:15][C@@H:16]([CH2:42][O:43][C:44](=[O:67])[C@H:45]([CH3:66])[NH:46][C:47](=[O:65])[C@@H:48]([NH:57]C(OC(C)(C)C)=O)[CH2:49][C:50]([O:52]C(C)(C)C)=[O:51])[O:17][C:18](=[O:41])[C@H:19]([CH3:40])[NH:20][C:21](=[O:39])[C@@H:22]([NH:31]C(OC(C)(C)C)=O)[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:12][CH:11]=2)[C:5]([C:70]#[N:71])=[C:4]([S:72][CH2:73][C:74]2[N:75]=[C:76]([C:79]3[CH:84]=[CH:83][C:82]([Cl:85])=[CH:81][CH:80]=3)[O:77][CH:78]=2)[N:3]=1.[F:86][C:87]([F:92])([F:91])[C:88]([OH:90])=[O:89]>ClCCl>[F:86][C:87]([F:92])([F:91])[C:88]([OH:90])=[O:89].[F:86][C:87]([F:92])([F:91])[C:88]([OH:90])=[O:89].[NH2:31][C@H:22]([C:21](=[O:39])[NH:20][C@@H:19]([CH3:40])[C:18](=[O:41])[O:17][C@@H:16]([CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([C:6]2[C:5]([C:70]#[N:71])=[C:4]([S:72][CH2:73][C:74]3[N:75]=[C:76]([C:79]4[CH:80]=[CH:81][C:82]([Cl:85])=[CH:83][CH:84]=4)[O:77][CH:78]=3)[N:3]=[C:2]([NH2:1])[C:7]=2[C:8]#[N:9])=[CH:69][CH:68]=1)[CH2:42][O:43][C:44](=[O:67])[C@H:45]([CH3:66])[NH:46][C:47](=[O:65])[C@@H:48]([NH2:57])[CH2:49][C:50]([OH:52])=[O:51])[CH2:23][C:24]([OH:26])=[O:25]
Reactant: C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)[C@H](C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)[C@@H](N)CC(=O)O)C(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)[C@H](C)NC(=O)[C@@H](N)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An amount of 410 mg (0.336 mmol) of the compound from example 24A was introduced in 2 ml of dichloromethane, admixed with 0.259 ml (3.364 mmol) of trifluoroacetic acid and stirred at RT overnight. The reaction mixture was then concentrated and the residue was purified by means of preparative HPLC (eluent gradient: acetonitrile/water 10:90→95:5 with addition of 0.1% TFA). This gave 191 mg (50% of theory) of the target compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C@H:5]([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:21])([F:20])[F:19])[C:10]1=[O:22])[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[CH3:29][C:30]1([CH3:42])[O:34][C@@H:33]([C:35]2[N:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:32][O:31]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.CO>[CH3:29][C:30]1([CH3:42])[O:34][C@@H:33]([C:35]2[N:36]=[CH:37][C:38]([NH:41][C:6](=[O:7])[C@@H:5]([N:9]3[CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][C:15]=4[C:18]([F:20])([F:19])[F:21])[C:10]3=[O:22])[CH2:4][CH2:3][S:2][CH3:1])=[N:39][CH:40]=2)[CH2:32][O:31]1
Reactant: CSCC[C@@H](C(=O)O)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: CC1(C)OC[C@H](c2cnc(N)cn2)O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CSCC[C@@H](C(=O)Nc1cnc([C@H]2COC(C)(C)O2)cn1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
A solution of (S)-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyric acid (57 mg, 0.17 mmol) in methylene chloride (5 mL) and N,N-dimethylformamide (3 drops) at room temperature was treated with a solution of oxalyl chloride (2.0M in methylene chloride, 210 μL, 0.34 mmol) and stirred for 15 min. After this time, the reaction mixture was concentrated in vacuo and then diluted with methylene chloride (5 mL) and added to a flask containing a solution of 5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-ylamine (prepared as in WO2004052869, Example 54, 67 mg, 0.34 mmol), 2,6-lutidine (64 μL, 0.34 mmol) in methylene chloride (2.5 mL) at room temperature. The reaction mixture was then stirred at room temperature for a period of 2 h. After this time, the reaction mixture was treated with methanol and then diluted with methylene chloride. The reaction mixture was then transferred to a separatory funnel and washed with a 1N aqueous hydrochloric acid solution. The organic layer was then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate was concentrated with silica gel (2 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 40%-60% ethyl acetate/hexanes) to afford (S)—N-[5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-4-methylsulfanyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-butyramide (28 mg, 32%) as a colorless sticky solid.
Reaction SMILES: [CH:1]1([S:7]([CH2:10][CH2:11][CH2:12][OH:13])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][CH2:11][CH2:10][S:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:8])=[O:9])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(CCCO)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-cyclohexylsulfonyl-1-propanol (37 g) and triethylamine (30 ml) in methylene chloride (400 ml) was treated dropwise at -5° C. with methanesulfonyl chloride (15 ml). After stirring for 2 h at room temperature the mixture was washed with water and dried over magnesium sulfate. Removal of solvent in vacuo gave a viscous oil (49 g) of 3-cyclohexylsulfonyl-1-propyl methanesulfonate.