Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.CC(C)([O-:35])C.[K+].C(OC)(=O)CO>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[S:23][CH:24]=[C:20]([CH2:19][S:18][C:4]3[C:5]([C:16]#[N:17])=[C:6]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[C:7]([C:8]#[N:9])=[C:2]([OH:35])[N:3]=3)[N:21]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Agent: COC(=O)CO
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(O)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1N1CCCCC1
Temperature: 25 °C

Procedure:
400 mg (0.82 mmol) of the compound from Example 4A are initially charged in 8 ml of dry DMF. After addition of 110 mg (0.99 mmol) of potassium tert-butoxide, the mixture is stirred at RT for RT. A solution of 74 mg (0.82 mmol) of methyl glycolate in 1 ml of dry DMF is then added dropwise, and the reaction mixture is stirred at RT for 20 h. The solvent is then removed on a rotary evaporator and the residue is directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH:1]([N:4]([CH3:13])[CH:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:32][CH2:33][CH2:34][NH2:35])=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH2:32][CH2:33][CH2:34][NH:35][C:6](=[O:8])[C@@H:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:27][CH:26]=1
Reactant: CC(C)CC(C(=O)O)N(C)C(C)C
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A solution of 297 mg (1.68 mmol) 2-(isopropyl-methyl-amino)-4-methyl-pentanoic acid, 0.88 mL (5 mmol) N,N-diisopropylethylamine, and 636 mg (1.68 mmol) O-Benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate in 4 mL dry DMF was stirred at 3° for 60 minutes, at which time 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride was added and the reaction stirred an additional 10 minutes at 3°, then warmed to 25° C. for 40 minutes at which time it was diluted with 20 mL diethyl ether and washed with 20 mL saturated aqueous sodium bicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 60% ethyl acetate in hexanes as eluant, followed by conversion to the hydrochloride salt by treating with excess diethyl ether which had been saturated with hydrogen chloride gas to give 648 mg (83%) of titled compound: mp 155-156° C. APCI-MS m/z 431.4 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:33])=[C:9]([CH2:11][O:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([OH:30])=[N:19]3)=[CH:15][CH:14]=2)[N:10]=1.[H-].[Na+].I[CH2:37][CH3:38].O>CN(C)C=O>[CH2:37]([O:30][C:20]1[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][N:18]([CH2:17][C:16]2[CH:31]=[CH:32][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:33])=[CH:14][CH:15]=2)[N:19]=1)[CH3:38]
Reactant: CCI
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-3-hydroxy-1H-pyrazol-4-yl]propionate (452 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 40.0 mg) was added at 0° C., and the solution was stirred at room temperature for 30 minutes. Iodoethane (0.240 ml) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionate (348 mg, yield: 73%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(#N)C.O.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[S:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C.O>[C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:32]1([C:22]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:30]3[C@H:26]([CH2:27][NH:28][CH2:29]3)[S@:25](=[O:31])[CH2:24][CH2:23]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: O=C(O)[C@@H](O)c1ccccc1
Solvent: CC#N
Solvent: O
Product: O=[S@@]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reaction time: 48 h
Yield: 19.6 %

Procedure:
15.8 g of (S)-(+)-mandelic acid and 750 cm3 of a mixture of acetonitrile and water (99/1 by volume) are added to 32.3 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide, followed by 5.0 cm3 of water. After making lukewarm, the solution obtained is allowed to stand for 48 hours at room temperature. The crystalline suspension is filtered, and the filtrate, concentrated to dryness, gives a meringue which is taken up in 200 cm3 of the boiling acetonitrile-water mixture. The solution obtained is allowed to stand for about 20 hours at room temperature. The crystals are drained, washed with acetonitrile, dried and then again taken up in 200 cm3 of an acetonitrile-water mixture (98/2 by volume). The resulting solution is allowed to stand for about 20 hours at room temperature. The crystals are drained and dried. 9.4 g of (1R*,4aR*,7aR*)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide (S)-(+)-mandelate are obtained; [α]D 20 =+337°(c=0 45; acetic acid)
Reaction SMILES: C(C1C=CC=CC=1C=C)=C.[CH2:11]([CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12].[Cl:21][CH:22]([SiH3:24])[Cl:23]>>[Cl:21][CH:22]([SiH2:24][CH2:12][CH2:11][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[Cl:23]
Reactant: CCC=Cc1ccccc1
Reactant: [SiH3]C(Cl)Cl
Agent: C=Cc1ccccc1C=C
Product: ClC(Cl)[SiH2]CCC=Cc1ccccc1
Reaction time: 48 h

Procedure:
A 500 ml three-neck, round bottom flask equipped with a magnetic stirrer, a condenser and an addition funnel was charged with 60 ml (0.337 mol) of divinylbenzene (Aldrich Chemical Co., Milwaukee, Wis.); mixture of 80% m- and p- isomers and 20% ethylvinylbenzene) under an argon atmosphere and at room temperature (RT). While stirring, 200 ml of distilled and dried hexanes were added followed by 0.5 ml of the above described platinum catalyst solution (SIP6830.0 from Gelest). Dichloromethylsilane (39.0 ml; 0.371 mol) was placed in the addition funnel, the argon supply was disrupted and a drying tube was attached to the system. The dichloromethylsilane was added dropwise at room temperature and the reaction was monitored by 1H NMR spectroscopy. After 48 hours, it was determined that hydrosilation was complete, the addition funnel and condenser were replaced by a distillation head and the crude product was purified by fractional distillation. The desired product was obtained as a mixture, 77% thereof corresponding to a combination of meta- and para-(2-dichloromethylsilyl-ethyl)-styrene (DSiSt) of the formula
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:6])[NH2:4].[Na].[F:23][CH2:24][C:25](O)=[O:26].[I-].ClC1C=CC=CN1C>CN(C)C=O.C(N(CC)CC)C>[F:23][CH2:24][C:25]([NH:4][C@H:3]([C@@H:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:6])[CH2:2][OH:1])=[O:26]
Reactant: O=C(O)CF
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Agent: CN1C=CC=CC1Cl
Agent: [I-]
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO)NC(=O)CF

Procedure:
5.0 gr of sphingosine (16.70) mM), prepared according to Example 4, are reacted with 2.1 gr of the sodium salt of fluoroacetic acid (20.88 mM), in the presence of 5.3 gr of 2-chloro-1-methylpyridine iodide (20.88 mM) and 5.8 cc of triethylamine (42.00 mM) in 80 cc of dimethylformamide, at room temperature overnight. The solvent is evaporated, and the residue is gathered in CH2Cl2 and washed with H2O. It is anhydrified and purified by chromatography, eluting with a mixture of CH2Cl2 /ethyl acetate/CH3CH 70:30:1 v/v/v.
Reaction SMILES: F[C:2]1[C:3]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:3]([C@@H:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: O[C@H]1CCC[C@@H](c2nccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@H]1CCC[C@@H](c2nccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 150 °C

Procedure:
A mixture of (rac)-cis-3-(3-fluoropyrazin-2-yl)cyclohexanol, prepared according to Scheme 35a, (48 mg, 0.245 mmol), 4-(pyridin-2-ylamino)phenol (91 mg, 0.489 mmol), and cesium carbonate (159 mg, 0.489 mmol) in NMP (2 mL) was heated in a Biotage™ microwave reactor at 150° C. for 0.5 h. The mixture was partitioned between H2O (10 ml) and CH2Cl2 (20 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-cis-3-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol as a light yellow solid. MS (ESI, pos. ion) m/z: 363.0 (M+1). IC50 (uM) 0.02837.
Reaction SMILES: CO[C:3]([C:5]1([CH3:22])[CH2:21][N:8]2[CH2:9][CH:10](C)[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=O)[CH:7]2[CH2:6]1)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:29]1COCC1>>[OH:4][CH2:3][C:5]1([CH3:22])[CH2:21][N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:29]=3)[CH2:12][CH:7]2[CH2:6]1
Reactant: C1CCOC1
Reactant: COC(=O)C1(C)CC2C(=O)N(c3ccccc3)C(C)CN2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(CO)CC2CN(Cc3ccccc3)CCN2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of 3.33 g (11 mmol) of (7RS,8aSR)-7-methoxycarbonyl-7-methyl-2-phenyl-methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazin-1-one (Jones, R. C. F., Howard, K. J., J. Chem. Soc., Perkin Trans. 1, 1993, 2391) in 125 mL of dry THF was added dropwise to a stirred suspension of 1.26 g (33 mmol) of lithium aluminum hydride in 125 mL of dry THF. The solution was stirred for 2 hours at room temperature, and carefully quenched with 1.26 mL of water, 1.26 mL of 15% NaOH, and 3.78 mL of water. After stirring for 30 minutes, the mixture was filtered through Celite, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography eluting with 9:1 chloroform:methanol gave 1.67 g (58%) of the title compound. 13C NMR (base, CDCl3): δ 25.3, 39.7, 41.8, 51.1, 51.6, 57.1, 62.3, 62.9, 63.3, 71.3, 127.0, 128.2, 128.7, 129.2, 138.3. m/z (MH+) 261.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][C:10](=[O:13])[CH2:11][CH3:12])[C:3]=1[C:14]([CH3:20])([CH3:19])[CH2:15][C:16]([OH:18])=[O:17].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:48]2[CH:52]=[N:51][N:50]=[N:49]2)=[C:26]([CH:47]=1)[CH2:27][NH:28][C:29]([C@H:31]1[N:35]([C:36](=[O:46])[C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)O)[N:34]=[CH:33][CH2:32]1)=[O:30].C(Cl)CCl>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][C:10](=[O:13])[CH2:11][CH3:12])[C:3]=1[C:14]([CH3:19])([CH3:20])[CH2:15][C:16]([O:18][C@H:37]([C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1)[C:36]([N:35]1[C@H:31]([C:29](=[O:30])[NH:28][CH2:27][C:26]2[CH:47]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=2[N:48]2[CH:52]=[N:51][N:50]=[N:49]2)[CH2:32][CH:33]=[N:34]1)=[O:46])=[O:17]
Reactant: CCC(=O)Oc1cc(C)cc(C)c1C(C)(C)CC(=O)O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CC=NN1C(=O)[C@H](O)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(=O)Oc1cc(C)cc(C)c1C(C)(C)CC(=O)O[C@@H](C(=O)N1N=CC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.8 %

Procedure:
To a solution of 3-(2,4-dimethyl-6-(propionyloxy)phenyl)-3-methylbutanoic acid (160 mg, 0.57 mmol) and (S)—N-(5-chloro-2-(1H-tetrazol-1-yl)benzyl)-1-((R)-2-(4-fluorophenyl)-2-hydroxyacetyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (263 mg, 0.57 mmol) in DCM (3 mL) and DMF (3 mL) was added EDC (165 mg, 0.86 mmol) and DMAP (7 mg, 0.06 mmol). The clear colorless solution was stirred at rt for 48 h. The mixture was diluted with DCM and washed with water, 1M HCl and sat NaHCO3. The organic phase was dried, filtered, evaporated and purified by flash chromatography (DCM/EtOAc gradient from 4:1 to 2:1) to give (R)-2-((S)-5-(5-chloro-2-(1H-tetrazol-1-yl)benzylcarbamoyl)-4,5-dihydro-1H-pyrazol-1-yl)-1-(4-fluorophenyl)-2-oxoethyl 3-(2,4-dimethyl-6-(propionyloxy)phenyl)-3-methylbutanoate (380 mg, 92%) as a semisolid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[O:12](C)[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14]>C(Cl)Cl>[F:17][C:16]([F:19])([F:18])[S:13]([O-:15])(=[O:14])=[O:12].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([CH3:16])[CH:6]=[CH:5]2
Reactant: Brc1ccc2cnccc2c1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C[n+]1ccc2cc(Br)ccc2c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Yield: 167.7 %

Procedure:
A solution of 6-bromoisoquinoline (618 mg, 3 mmol) in CH2Cl2 (35 mL) was cooled to 0° C. under argon. Methyl triflate (0.38 mL, 3.3 mmol) was added dropwise and the mixture was warmed to rt. The precipitate was filtered, triturated with ether and dried to give the title compound as a yellow solid (1.03 g, 93%). 1H NMR (400 MHz, CD3OD) δ 9.83 (s, 1H), 8.64-8.56 (m, 2H), 8.41 (d, J=7.0 Hz, 1H), 8.36 (d, J=8.8 Hz, 1H), 8.20 (d, J=9.03 Hz, 1H), 4.53 (s, 3H).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[C@@:14]12([OH:23])[N:21]([CH3:22])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]=[CH:15]2.O[C:25]1([C:38]([O-:40])=[O:39])[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2.O.C([O-])(O)=O.[Na+]>ClCCl>[C@@:14]12([OH:23])[N:21]([CH3:22])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]=[CH:15]2.[F:11][C:25]1([C:38]([O-:40])=[O:39])[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: O=C([O-])C1(O)c2ccccc2-c2ccccc21
Agent: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C([O-])C1(F)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.66 mL (0.009 mol) of bis-(2-methoxyethyl)aminosulfur trifluoride are placed in 10 mL dichloromethane and within 20 minutes at 15°–20° C., a solution of 2.4 g (0.007 mol) of 4a in 25 mL dichloromethane is added dropwise thereto. The mixture is stirred for 20 hours at ambient temperature, cooled to 0° C., and carefully combined with 80 mL of water with thorough stirring. Then the mixture is carefully adjusted to pH 8 with aqueous NaHCO3 solution, the organic phase is separated off, the aqueous phase is extracted again with dichloromethane, the combined organic phases are washed with water, dried over magnesium sulfate, and evaporated to dryness. The hydrochloride is precipitated and recrystallized from acetonitrile-diethyl ether. Then the free base is liberated again using 10% aqueous sodium carbonate solution. Yield: 1.05 g bright yellow crystals (53% of theoretical yield).
Reaction SMILES: N[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[N:5]=[C:4]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:3]=1.C(Br)(Br)[Br:25]>>[Br:25][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[N:5]=[C:4]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:3]=1
Reactant: BrC(Br)Br
Reactant: Cc1nc2c(N)nc(SCc3cccc(F)c3F)nc2[nH]c1=O
Product: Cc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]c1=O

Procedure:
The sub-titled compound was prepared from the product of example 35, step (a) (1.5 g) and bromoform (30 ml) using the method of Example 3, step (b).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=3[CH:22]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[O:29]=[S:26]1(=[O:30])[CH2:27][CH2:28][N:23]([C:19]([C:17]2[O:18][C:14]3[CH:13]=[CH:12][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]4)=[CH:22][C:15]=3[CH:16]=2)=[O:21])[CH2:24][CH2:25]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)N1CCC(Oc2ccc3oc(C(=O)O)cc3c2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3oc(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Yield: 72.3 %

Procedure:
In a flask were mixed together the above prepared 5-(1-isopropyl-piperidin-4-yloxy)-benzofuran-2-carboxylic acid (1.25 g, 3.92 mmol, calculated as 73%), thiomorpholine 1,1-dioxide (0.636 g, 1.2 eq.), (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (2.081 g, 1.2 eq.) and 2.4 eq. of N-ethyldiisopropylamine (1.60 mL) in 24 mL of abs. THF and allowed to react during one night at ambient temperature. Pouring onto crashed ice/AcOEt/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=2/98) and trituration in hexane/AcOEt=7/3 yielded 1.192 g of the title compound as off-white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]CCC(N)=O)=[C:10]([C:20]([F:23])([F:22])[F:21])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].[C:30]([C:32]1([NH:35][C:36]([C@H:38]2[N:42]([C:43]([C:45]3([C:48]([F:51])([F:50])[F:49])[CH2:47][CH2:46]3)=[O:44])[CH2:41][C@@H:40](OS(C3C=CC=CC=3)(=O)=O)[CH2:39]2)=[O:37])[CH2:34][CH2:33]1)#[N:31]>O1CCCC1.CN(C)C(=O)C.O>[C:30]([C:32]1([NH:35][C:36]([C@@H:38]2[CH2:39][C@@H:40]([S:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][C:10]=3[C:20]([F:22])([F:21])[F:23])[CH2:41][N:42]2[C:43]([C:45]2([C:48]([F:51])([F:49])[F:50])[CH2:46][CH2:47]2)=[O:44])=[O:37])[CH2:33][CH2:34]1)#[N:31]
Reactant: Cc1cc(-c2ccc(SCCC(N)=O)c(C(F)(F)F)c2)ccn1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(C(F)(F)F)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2ccc(S[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)N(C(=O)C4(C(F)(F)F)CC4)C3)c(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.6 %

Procedure:
3-[4-(2-Methyl-pyridin-4-yl)-2-trifluoromethyl-phenylsulfanyl]-propionamide (200 g, 588 mmol) was dissolved in tetrahydrofuran (1.0 L) before sodium tert-butoxide (55.5 g, 578 mmol) was added and the fine suspension was stirred for 2 h at room temperature. N,N-dimethylacetamide (500 mL) was added and the solution was stirred for further 1.5 h. A solution of benzenesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (237.5 g, 504 mmol) in N,N-dimethylacetamide (500 mL) was added and the brown, clear solution was stirred for 40 h. The mixture was diluted with water (3 L) and extracted with tert-butyl methyl ether (1×2 L, 3×1 L). The combined organic extracts were washed with an aqueous sodium carbonate solution (1 M, 1.0 L) and brine (1.0 L), dried over sodium sulfate, and concentrated in vacuo to yield the title compound as a brown gum (327.8 g). The crude product (containing dimethylacetamide) was used in the next step without further purification. For characterization purposes, a 4 g sample of crude material was purified by filtration over silica gel (20 g, eluent: ethyl acetate (200 mL)). 3.3 g of purified material were obtained as an off-white solid. MS (EI): m/z=583.1 [M+H]+. 1H NMR (CDCl3, 300 MHz): δ 1.10-1.36 (m, 6H), 1.49-1.58 (m, 2H), 1.99-2.12 (m, 1H), 2.65 (s, 3H), 2.90-3.02 (m, 1H), 3.92 & 4.02 (ABX, JAB=11.9 Hz, JAX=4.8 Hz, JBX=5.8 Hz, each 1H), 4.12-4.22 (m, 1H), 4.71 (dd, J=4.7 Hz, 7.8 Hz, 1H), 7.31 (d, J=5.3 Hz, 1H), 7.37 (br s, 1H), 7.60-7.69 (m, 2H), 7.80 (d, J=8.3 Hz, 1H), 7.93 (s, 1H), 8.60 (d, J=5.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[O:23]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)=[O:29])[CH2:24]1.C(Cl)CCl>CN(C=O)C>[O:23]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[NH:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[O:14])=[CH:32][CH:31]=2)=[O:29])[CH2:24]1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Reactant: Nc1ccc(C(=O)N2CCOC2)cc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C(=O)N2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (44 mg, 0.14 mmol) and 4-(oxazolidin-3-ylcarbonyl)phenylamine (25 mg, 0.13 mmol) in DMF (3 mL), EDC (75 mg, 0.39 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (20 mg). MS 493.2 and 495.2 (M+H, Cl pattern).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH:15]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH3:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C(=CN(C)C)C(C)=O
Yield: 93.9 %

Procedure:
Ethyl acetoacetate (15 g, 115 mmol) and N,N-Dimethylformamide dimethyl Acetal (13.7 g, 115 mmol) stirred at rt for overnight. After completion of the reaction, reaction mixture distilled on rotavapour to obtain the crude. Crude was purified by column chromatography over 60-120 mesh silica gel using EtOAc and petether (10:90) as eluent to obtain the title compound (20 g).