Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:26]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])[C:7]=2[OH:26])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:15]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2cccc(F)c2)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(Cc3cccc(F)c3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(3-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 403 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:37][CH3:38])=[CH:34]/[CH:35]=O)[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:58](Br)(Br)([Br:60])[Br:59]>[Zn]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:37][CH3:38])=[CH:34]/[CH:35]=[C:58]([Br:60])[Br:59])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:19])[CH3:20])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC/C(=C\C=O)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC/C(=C\C=C(Br)Br)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1

Procedure:
In a manner analogous to example 2g, by reaction of 9 g (16.3 mmol) of (E)-3-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)-phenyl]ethyl}phenyl)pent-2-enal (prepared in example 1j) with 2.1 g (32.5 mmol) of zinc powder, 8.5 g (32.5 mmol) of triphenylphosphine and 108 g (32.5 mmol) of carbon tetrabromide. A yellow oil is obtained (m=11.3 g; Y=98%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[C:32]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]O)#[N:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:32]([C:34]1[CH:35]=[C:36]([CH2:37][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:39]=[CH:40][CH:41]=1)#[N:33]
Reactant: N#Cc1cccc(CO)c1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (900 mg, 3.0 mmol), as prepared in step (c) of Example 1, 3-cyanobenzyl alcohol (400 mg, 3.0 mmol; Yoon et al., J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (2:1 ethyl acetate/hexane) to give the title compound as a white solid (1.10 g, 89%). 1H-NMR (300 MHz, CDCl3) δ 2.26 (s, 3 H), 4.99 (s, 2 H), 6.55 (t, 1 H, J=2.3 Hz), 6.60 (t, 1 H, J=0.7 Hz), 6.67 (t, 1 H, J=0.7 Hz), 7.39 (m, 1 H), 7.50 (t, 1 H, J=7.7 Hz), 7.61 (m, 5 H), and 7.96 (d, 1 H, J=1.3 Hz).
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:27](=[O:28])([O:17][CH2:16][C:3]1([Si:2]([CH3:19])([CH3:18])[CH3:1])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: C[Si](C)(C)C1(CO)c2ccccc2-c2ccccc21
Solvent: c1ccccc1
Product: C[Si](C)(C)C1(COC(=O)Nc2ccccc2)c2ccccc2-c2ccccc21
Temperature: 80 °C
Yield: 91.9 %

Procedure:
A mixture of 1.0 g of 9-trimethylsilyl-9-fluorenemethanol and 0.4 mL of phenyl isocyanate in 2.0 mL of dry benzene was heated in an oil bath at 80° C. for seven hours. The mixture was cooled to room temperature and triturated with 20 mL of Skelly F. The crystals deposited were removed by filtration, rinsed with Skelly F, and recrystallized from Skelly B to give 1.31 g (91.9%) of the urethane as white crystals, m.p. 137°-138° C.; IR(KBr): 3300 (NH), 1700 (C=O) cm-1 ; 1H NMR (CDCl3) 5 -0.12 (s, 9H, SiMe3), 5.07 (s, 2H, CH2), 6.21 (b, 1H, NH), 6.80-8.00 (m, 13H, aryl).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41]>C(Cl)Cl>[Br:41][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)c1cc(CO)cc(OS(C)(=O)=O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(CBr)cc(OS(C)(=O)=O)c1
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)-5-[(methylsulfonyl)oxy]benzoate (0.284 g, 0.939 mmol) in DCM (5 mL) was added triphenylphosphine (0.370 g, 1.41 mmol) and carbon tetrabromide (0.467 g, 1.41 mmol). After 2 hours, reaction mixture was concentrated in vacuo and purified by flash chromatography (25 g silica, 0-20% EtOAc/hexanes) to give 0.21 g (61%) of tert-butyl 3-(bromomethyl)-5-[(methylsulfonyl)oxy]benzoate. 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 4.50 (s, 2H), 3.20 (s, 3H), 1.60 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([NH2:19])=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.Br[CH2:30][CH2:31][CH2:32][CH2:33]Br>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N:19]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)cc12
Reactant: BrCCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N3CCCC3)cc12

Procedure:
383 mg of 6-amino-beta-carboline-3-carboxylic-acid-ethylester in 15 ml of ethanol is heated together with 0.58 ml of ethyldiisopropylamine and 0.18 ml of 1,4-dibromobutane for 6 h under nitrogen at the reflux. This is followed by an addition of 0.4 ml of 1,4-dibromobutane and reflux for 3 h. After evaporation, the mixture is washed with water and boiled with ethanol. 128 mg of 6-(1-pyrrolidinyl)-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 259°-261° C. is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.CN[C@@H]1CCCC[C@H]1NC.[CH3:41][OH:42]>[Cu]I>[OH:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([O:42][CH3:41])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Reactant: CO
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Product: COc1ccc(Cc2cc3c(=O)n([C@@H]4CCCC[C@H]4O)cnc3c3ccccc23)cn1
Temperature: 25 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.150 g, 0.357 mmol) in 3 mL of MeOH under an atmosphere of nitrogen was added trans-N,N′-dimethylcyclohexane-1,2-diamine (1.7 mg, 0.012 mmol), and copper(I) iodide (2.3 mg, 0.012 mmol). The mixture was irradiated in a microwave reactor at 160° C. for 4 h, cooled to rt and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-100% ethyl acetate in hexanes, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 416.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.03-8.99 (m, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 8.02-7.99 (m, 2H), 7.70-7.65 (m, 2H), 7.37-7.34 (m, 1H), 6.62 (d, J=8.5 Hz, 1H), 4.82 (br s, 1H), 4.39 (s, 2H), 4.01 (br s, 1H), 3.90 (s, 3H), 2.30-2.23 (m, 1H), 2.18-2.12 (m, 1H), 1.99-1.84 (m, 3H), 1.53-1.42 (m, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C([S-])C.[Na+].CN(C)C=O.Cl>O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=Cc2ccc(N(c3ccc(C)cc3)c3ccc(C)cc3)cc2)cc1
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccc(O)cc3)cc2)cc1
Reaction time: 5 h

Procedure:
The obtained 4-methoxy-4′-(di-p-tolylamino)stilbene and two equivalent amounts of sodium ethanethiolate were dissolved into N,N-dimethylformamide, allowing reaction to proceed at 130° C. for 5 hours. The solution was cooled, added in water, and neutralized with hydrochloric acid, and the target product was extracted with ethyl acetate. The extract liquid was washed with water and dried, and solvent was removed to obtain a crude product, which was then purified by column chromatography on silica gel to give 4-hydroxy-4′-(di-p-tolylamino)stilbene (CTP-1), a target product.
Reaction SMILES: O1C=CC(C2C(OC)=C(C(CS(C3C=CC=CC=3)(=[N:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=O)=CC=2)C(OC)=O)=C1.[C:34]1([S:40]([CH2:42][C:43]2[C:48]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[C:47]([O:56][CH3:57])[C:46]([C:58]3[CH:62]=[CH:61][O:60][CH:59]=3)=[CH:45][CH:44]=2)=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[O:60]1[CH:61]=[CH:62][C:58]([C:46]2[C:47]([O:56][CH3:57])=[C:48]([C:43]([CH2:42][S:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[N:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[O:41])=[CH:44][CH:45]=2)[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[CH:59]1
Reactant: COc1c(-c2ccoc2)ccc(CS(=O)c2ccccc2)c1C(=O)OC(C)(C)C
Reactant: COC(=O)c1c(CS(=O)(=NC(=O)C(F)(F)F)c2ccccc2)ccc(-c2ccoc2)c1OC
Product: COc1c(-c2ccoc2)ccc(CS(=O)(=NC(=O)C(F)(F)F)c2ccccc2)c1C(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 215, starting from t-butyl 6-(benzenesulphinylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 221).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH:4]([CH3:25])[CH:5]([C:8]1[CH:9]=[C:10]([O:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH:11]=[CH:12][CH:13]=1)[CH2:6][CH3:7].CO.[OH-].[Na+].[Cl-].[Na+]>O>[CH3:26][N:2]([CH3:1])[CH2:3][CH:4]([CH3:25])[CH:5]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH2:6][CH3:7]
Reactant: CCC(c1cccc(OS(=O)(=O)c2ccc(C)cc2)c1)C(C)CN(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(c1cccc(O)c1)C(C)CN(C)C
Temperature: 31.5 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
To a stirred solution of [1RS,2RS]-toluene-4-sulfonic acid 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenyl ester (9 g, 0.02 mol) and methanol (27 ml), a solution of sodium hydroxide (4 g, 0.10 mol) and water (18 ml) was added at 20-25° C. and mixture was stirred at 28-35° C. for 20 hours. Reaction mixture was further stirred at 45-50° C. for 6 hours and solvent was distilled off. Resulting residue was dissolved in demineralised water (30 ml) at ambient temperature and washed with isopropyl ether (2×10 ml). Aqueous layer was separated and aqueous hydrochloric acid (7.3 ml, 30%) was added at 20-25° C. reaction mixture was saturated with sodium chloride and extracted with ethyl acetate (2×50 ml). All ethyl acetate extracts were combined, washed with water, dried and solvent was distilled off to give 4.24 g of title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)=[O:21])=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[ClH:29].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:14][CH:15]=2)=[O:21])=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)Nc3ccc(Cl)cn3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2CCNC2)cc1)Nc1ccc(Cl)cn1
Temperature: 60 °C
Yield: 187.7 %

Procedure:
To a stirred solution of (RS)-3-{4-[3-(5-chloro-pyridin-2-yl)-ureido]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (210 mg) in THF (4 ml) was added dropwise a solution of hydrogen chloride in dioxane (1.89 ml, 4 M solution) and the mixture was heated at 60° C. overnight. The mixture was then cooled to 0° C. and the ensuing crystals were collected by filtration, washing with ethyl acetate, and were dried in vacuo at 60° C. to afford (RS)-1-(5-chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)-urea hydrochloride (167 mg, 94%) as a beige crystalline solid. MS (ISP): 319.1 ([{37Cl}M+H]+), 317.2 ([{35Cl}M+H]+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][C:12]([C@@H:15]([NH2:17])[CH3:16])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.[F:20][C@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31](F)[N:30]=1)[CH3:22].CCN(C(C)C)C(C)C>CS(C)=O>[F:20][C@H:21]([C@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:17][C@H:15]([C:12]2[N:11]=[CH:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:8]=3)=[CH:14][CH:13]=2)[CH3:16])[N:30]=1)[CH3:22]
Reactant: C[C@H](F)[C@H]1COC(=O)N1c1ccnc(F)n1
Reactant: C[C@H](N)c1ccc(-c2ccnc(C(F)(F)F)c2)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)F)n1)c1ccc(-c2ccnc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A solution of (S)-1-(2′-(trifluoromethyl)-[3,4′-bipyridin]-6-yl)ethanamine (27 mg, 0.10 mmol), (R)-4-((S)-1-fluoroethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (23 mg, 0.10 mmol) and DIPEA (52.4 μl, 0.30 mmol) in DMSO (500 μl) was heated at 110° C. for 1 hr. The solution was then cooled to rt and RP-HPLC purification (acetonitrile:water) provided the 32 mg of the major product as a white solid. 1H NMR (400 MHz, MeOD) δ 8.98 (s, 1H), 8.79 (d, J=5.1 Hz, 1H), 8.23 (dd, J=8.2, 2.4 Hz, 1H), 8.17 (br s, 1H), 8.17-8.12 (m, 1H), 7.98 (dd, J=5.1, 1.7 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.40 (d, J=5.8 Hz, 1H), 5.11 (br s, 1H), 4.69 (br d, J=27.2 Hz, 1H), 4.55-4.12 (m, 3H), 1.60 (d, J=7.1 Hz, 3H), 1.03 (br s, 3H); HRMS (B) m/z 477.1699 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([S:7][CH3:8])[CH2:5][NH:4][CH2:3]1.[CH:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11]>CO>[CH3:9][C:10]([CH3:13])([CH3:12])[CH:11]=[N:1][C@H:2]1[C@H:6]([S:7][CH3:8])[CH2:5][NH:4][CH2:3]1
Reactant: CS[C@@H]1CNC[C@H]1N
Reactant: CC(C)(C)C=O
Solvent: CO
Product: CS[C@@H]1CNC[C@H]1N=CC(C)(C)C
Reaction time: 0.5 h

Procedure:
1.32 g (10 mmol) of trans-3-amino-4-methylthio-pyrrolidine are initially introduced into 5 ml of methanol, and 1.23 ml (11 mmol) of 97% strength pivalaldehyde are added dropwise, after which the temperature rises from 25° to 36° C. The mixture is subsequently stirred for a further 30 minutes, without cooling, the batch is then concentrated and the residue is distilled. Yield: 1.50 g (75% of theory),
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19]S(C2C=CC=CC=2)(=O)=O)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:6]=1)#[N:4].CC1CCCO1.[F:39][C:40]([F:56])([F:55])[C:41]1[CH:46]=[C:45]([NH:47][C:48]2[CH2:53][CH2:52][CH2:51][C:50](=[O:54])[CH:49]=2)[CH:44]=[CH:43][N:42]=1>O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:19][C:49]2[C:50](=[O:54])[CH2:51][CH2:52][CH2:53][C:48]=2[NH:47][C:45]2[CH:44]=[CH:43][N:42]=[C:41]([C:40]([F:39])([F:55])[F:56])[CH:46]=2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([S:29]([CH3:32])(=[O:30])=[O:31])[CH:6]=1)#[N:4]
Reactant: CC(C)(C)OC(=O)N(CS(=O)(=O)c1ccccc1)c1ccc(C#N)cc1S(C)(=O)=O
Reactant: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1=C(Nc2ccnc(C(F)(F)F)c2)CCCC1=O)c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 153 mg, 3.84 mmol) is added in portions to a mixture of tert-butyl (4-cyano-2-(methylsulfonyl)phenyl)(phenylsulfonyl)methylcarbamate (step 1, 1.60 g, 3.20 mmol based on 90% purity) and 2-methyltetrahydrofuran (15 mL), and the mixture is stirred at room temperature for 20 min. 3-(2-(Trifluoromethyl)pyridin-4-yl-amino)cyclohex-2-enone (intermediate 55, 940 mg, 3.70 mmol) is added, and the mixture is stirred for 2 h. Water is added, and the phases are separated. The organic layer is washed with water and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient dichloromethane/methanol 99:1 to 97/3). Yield: 2.10 g; ESI mass spectrum [M+H]+=565; Retention time HPLC: 0.67 min (X012_S02).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[CH2:14])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:18]1[CH2:17][CH2:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])([C:10]([O:12][CH3:13])=[O:11])[CH2:19]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of methyl 2-(tert-butoxycarbonylamino)acrylate (16.5 g, 82.0 mmol) and N-(Methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (19.5 g, 82.0 mmol) in DCM (400 mL) was added dropwise TFA (0.32 mL) at 0° C. under nitrogen. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3% MeOH in DCM) to give methyl 1-benzyl-3-(tert-butoxycarbonylamino)pyrrolidine-3-carboxylate (21.7 g, 79%).
Reaction SMILES: [OH:1][CH:2]([CH:8]([N:15]([CH3:23])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5]CC)=O.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:3](=[O:5])[CH:2]([OH:1])[CH:8]([N:15]([CH3:23])[C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:25]
Reactant: CCN
Reactant: CCOC(=O)C(O)C(c1ccccc1)N(C)c1ccc(C)cc1
Product: CCNC(=O)C(O)C(c1ccccc1)N(C)c1ccc(C)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
A mixture of ethyl (2RS,3RS)-2-hydroxy-3-[methyl(4-methylphenyl)amino]-3-phenylpropanoate (Example 12, step 1, 948 mg, 3.03 mmol) and methanolic ethylamine solution (2.0 M in methanol, 25 mL) was stirred at 120° C. in a sealed tube for 48 hours. After cooling, all volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-15% ethyl acetate/hexane) and recrystallized (warm chloroform/hexane/−25° C.) to yield 537 mg (57%) of (2RS,3RS)-N-ethyl-2-hydroxy-3-[methyl(4-methylphenyl)amino]-3-phenylpropanamide as a white solid. MS (ESI) m/z 313 ([M+H]+); HRMS: calculated for C19H24N2O2+H, 313.1911; found (ESI, [M+H]+), 313.1908.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17][S:59]([CH3:58])(=[O:61])=[O:60])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 3 h
Yield: 100 %

Procedure:
To an ice-bath cooled solution of Intermediate 167a (316 mg, 0.49 mmol) in DCM (5.0 mL) was added DIPEA (339 μL, 1.95 mmol) followed by methanesulfonyl chloride (76 μL, 0.97 mmol). The reaction mixture was stirred for 3 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative, assumed 0.49 mmol). The isolated product was used in the following step without further purification. LCMS (Method 4): Rt 3.61 min, m/z 727 [MH+].
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:7]=1[CH2:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:36])=O.CN(C=O)C>C(Cl)Cl>[C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:7]=1[CH2:26][C:27]([CH3:31])([CH3:32])[C:28]([Cl:36])=[O:29])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)Cl)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3-[3-tert-butylsulfanyl-1-(4-chloro-benzyl)-5-isopropyl-1H-indol-2-yl]-2,2-dimethyl-propionic acid (prepared according to the procedures described in U.S. Pat. No. 5,081,138 issued Jan. 14, 1992; 0.25 g, 0.53 mmol) suspended in CH2Cl2 (5 mL) was added oxalyl chloride (48 uL, 0.56 mmol) and catalytic DMF. The reaction was stirred at room temperature for 3 hours, and then concentrated to give I-1, which was used without further purification.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][N:3]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:2]12.N1C=CC=CC=1.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>ClCCl>[C:27]1([CH3:28])[CH:29]=[CH:30][C:24]([S:21]([O:10][CH2:9][CH2:8][CH2:7][N:6]2[CH2:5][CH2:4][N:3]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:2]3[CH2:1]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCN1CCN2CCCCC2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCN2CCN3CCCCC3C2)cc1

Procedure:
A solution of 4.5 g of the compound obtained in Step B, 2.5 ml of pyridine, and 4.8 g of tosyl chloride in 100 ml of dichloromethane is stirred for 24 hours at room temperature, and then washed with 100 ml of water and finally purified over a silica gel chromatography column, eluted with a mixture of CH2Cl2/MeOH (95/5), enabling the expected product to be isolated.