Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:14]([O:13][C:11]([N:5]1[C@@H:4]([CH2:3][CH2:2][O:1][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:8][O:7][C:6]1([CH3:10])[CH3:9])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CCOc2ccc(Cl)cc2)COC1(C)C
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
To a stirred solution of tert-butyl(S)-4-(2-hydroxyethyl)-2,2-dimethyloxazolidine-3-carboxylate (411 mg; CAS 147959-18-0) in THF (6 ml) were added 4-chlorophenol (283 mg), triphenylphosphine (630 mg) and diethyl azodicarboxylate (40% in toluene, 0.92 ml). The resulting yellow solution was placed in a microwave oven at 100° C. for 20 min. Sodium hydroxide solution (1M) and ethyl acetate were added, after separation the organic layer was washed a second time with 1M sodium hydroxide solution, dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0→90:10) to give (S)-4-[2-(4-chloro-phenoxy)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (540 mg, 76%) as a light yellow oil. MS (ISP): 356.1 ([M+H]+)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COCCC(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: COCCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 1 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 18 mg, 50 μmol) and 3-methoxypropanoyl chloride (18 mg, 150 μmol). Yield 17 mg (74%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12](O)=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([O:19]C2CCCC2)=[CH:7][CH:6]=1)=[O:4].P(Cl)(Cl)([Cl:27])=O>>[CH3:1][O:2][C:3]([C:5]1[C:10]2[C:11]3[C:12]([Cl:27])=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:9]=2[C:8]([OH:19])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(OC2CCCC2)c2oc3ccnc(O)c3c12
Product: COC(=O)c1ccc(O)c2oc3ccnc(Cl)c3c12

Procedure:
A solution of Methyl-1-hydroxy-6-cyclopentyloxybenzo[4,5]furo[3,2-c]pyridine-9-carboxylate (16.0 g) and phosphorous oxychloride (320 mL) was refluxed for 15-16 hours. Phosphorous oxychloride (300 mL) was removed under vacuo. Water (20.0 ml) was added at 60-70° C. Then after water (200 mL) was added, the solid obtained was filtered, washed with water (2×100 mL) and dried to get 8.8 g of product as yellow solid.
Reaction SMILES: [ClH:1].C(O[NH:7][CH:8]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9](=C=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C>C(OCC)C>[ClH:1].[CH3:20][Si:18]([CH3:19])([CH3:21])[CH:8]([NH2:7])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)ONC(C(=C=O)c1ccccc1)[Si](C)(C)C
Agent: Cl
Solvent: CCOCC
Product: C[Si](C)(C)C(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 3N solution of HCl in diethyl ether (3 ml) was added at room temperature to a mixture of N-tertbutoxy-carbonyl-α-(trimethylsilyl)benzeneethanamine (0.150g, 0.51 mmol) in diethyl ether (3 ml). The mixture was stirred at room temperature for 48 hours. The resulting solid was filtered off and dried, invacuo, to yield 0.106 g of the expected α-(trimethylsilyl)-benzeneethanamine hydrochloride,
Reaction SMILES: [CH:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][C:9]([CH3:32])([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25]C3CCCCO3)=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]([C:4]1[CH:34]=[CH:33][C:7]([O:8][C:9]([CH3:32])([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccc(C(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(C)(Cc1ccc(OCCO)cc1)Oc1ccc(C(C)C)cc1
Yield: 75.8 %

Procedure:
In a similar manner to that described in Reference example 3(t), a reaction was carried out using ethyl 2-(4-isopropylphenoxy)-2-methyl-3-[4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl]propionate (1.06 g), which is the product of Reference example 9(c), and p-toluenesulfonic acid monohydrate (0.60 g) and the reaction mixture was treated to afford the desired compound (0.66 g) as a syrup.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:8]=[C:9]([CH3:15])[C:10](=[CH:12][C:13]=1[CH3:14])[NH2:11].[Br:21]Br>ClCCl>[Br:21][C:12]1[C:13]([CH3:14])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=2)[CH:8]=[C:9]([CH3:15])[C:10]=1[NH2:11]
Reactant: BrBr
Reactant: Cc1cc(Oc2cccc(C(F)(F)F)c2)c(C)cc1N
Solvent: ClCCl
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)c(C)c(Br)c1N

Procedure:
To a stirred solution of the product from stage b) above (1.12 g) in dichloromethane (20 ml) was added dropwise bromine (0.64 g) in dichloromethane (5 ml) at 0° C. The mixture was washed with sodium bicarbonate solution, dried (MgSO4), filtered and evaporated to give a crude oil which was purified by silica gel chromatography eluting with ethyl acetate/light petroleum (b.p. 60-80° C.) (1:4) to give the title product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([SH:15])[N:9]=1.[CH3:16]I>CC(C)=O>[CH3:16][S:15][C:10]1[N:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH3:7])[N:9]=1
Reactant: Cc1cc(C)nc(S)n1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1nc(C)cc(C)n1
Yield: 82.3 %

Procedure:
A suspension of potassium carbonate (27.6 g, 0.2 mol) in a solution of 4,6-dimethyl-2-mercaptopyrimidine (14 g, 0.1 mol) and methyl iodide (18.7 ml, 0.3 mol) in acetone (200 ml) was heated under reflux for 3 hours. The reaction mixture was allowed to cool before being filtered and then evaporated in vacuo. Distillation of the mixture at a pressure of 0.01 mmHg afforded 12.7 g 2-methylthio-4,6-dimethylpyrimidine as a white solid. A portion of this solid (4.42 g, 28.7 mmol) was dissolved in dichloromethane (200ml) and m-chloroperoxybenzoic acid (50%, 22.8 g, 66.0 mmol) was added in portions. The resulting mixture was stirred for a period of 5 days at the end of which it was first filtered and then evaporated in vacuo. Purification by flash column chromatography upon silica gel using diethyl ether as eluant afforded 3.35 g 2-methylsulphonyl-4,6-dimethylpyrimidine as a white solid, m.pt., 81° C.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.[Si:25]([O:42][CH2:43][C@H:44](I)[CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:1]([S:3][C@H:44]([CH2:43][O:42][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: COC(=O)CC[C@@H](I)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)SC(C)=O
Reaction time: 18 h

Procedure:
Thioacetic acid (1 mL, 13.2 mmol) was added to 20 mL of toluene under a nitrogen atmosphere. A 1M solution of tetrabutylammonium hydroxide in methanol (11 mL, 11 mmol) with a washing of 1 mL methanol was added to the thioacetic acid solution. The methanol was removed azeotropically with toluene and residual salt redissolved in 30 mL toluene. The salt solution with a washing of 20 mL toluene was added to a solution of 8 (4.75 g, 9.6 mmol) in 50 mL toluene and stirred under nitrogen for 18 hours. After removal of solvent and precipitated salts, the crude product was purified by flash chromatography with 6:1 hexane/ethyl acetate. Yield 3.47 g (81%) of a viscous oil [α]D25 -16.0° (C=0.7, CDCl3); FAB MS 445 (M+H)+, 387 (M-t-butyl)+ ; 1H NMR (CDCl3) δ 7.65 (m, 4, ArH), 7.4 (m, 6, ArH), 3.8 (m, 1, H-4), 3.7 (s, 3, OCH2), 3.7 (m, 2, CH2), 2.35 (m, 2, CH2), 2.3 (s, 3, acetyl CH2), 2.2 (m, 1, H-2), 1.9 (m, 1, H-2), 1.05 (s, 9, t-butyl).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH2:8](O)[CH3:9]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)[CH3:9]
Reactant: CCO
Reactant: O=C1C=CC(O)N1
Product: CCOC1C=CC(=O)N1

Procedure:
A mixture of 2.3 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one in 140 cm3 of ethanol and 100 g of Amberlite resin IR-120 (H) is taken to reflux for 30 minutes. After allowing to cool, filtering off the resin and distilling the ethanol off under reduced pressure, 2.76 g of the expected product is obtained, m.p. 50°-52° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9](Cl)[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].C(C1[N:35](CCCCSC2C=CC=CC=2)C2C3C=CC=CC=3N=C(SC3C=CC=CC=3)C=2N=1)CCC.N.C>CO.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:35])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(Sc3ccccc3)nc3ccccc3c2n1CCCCSc1ccccc1
Reactant: CCCCc1nc2c(Cl)nc3ccccc3c2n1CCCCSc1ccccc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCSc1ccccc1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A 3:1 mixture of 2-butyl-4-chloro-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinoline to 2-butyl-4-(phenylthio)-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinoline (1.38 g) and a solution of 7% ammonia in methanol (30 mL) were combined in a bomb and heated to 150° C. The reaction was judged to be complete after 5 hours. The volatiles were removed under reduced pressure and the resulting residue was stirred in water and made basic (pH 10) with solid sodium carbonate. The aqueous mixture was extracted with chloroform (3×). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a yellow crystalline solid. The solid (0.8 g) was dissolved in ethyl acetate (50 mL) and brought to reflux. Activated charcoal (0.4 g) was added; the resulting mixture was heated at reflux for 5 minutes and then the charcoal was removed by filtration through fluted paper to provide a colorless solution. The solution was concentrated under reduced pressure to give a solid that was recrystallized from ethyl acetate and hexanes to provide 2-butyl-1-[4-(phenylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.51 g, 1.25 mmol) as white needles, m.p. 118-120° C.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][N:3]=[N:2]1.[CH2:10]([N:12]=[C:13]=[S:14])[CH3:11]>C(O)C>[CH2:10]([NH:12][C:13]([N:2]1[N:3]=[CH:4][C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1]1)=[S:14])[CH3:11]
Reactant: C1CCC2(C1)CN=NC2
Reactant: CCN=C=S
Solvent: CCO
Product: CCNC(=S)N1CC2(C=N1)CCCC2
Yield: 0.3 %

Procedure:
1.05 g (1 mol equiv.) 2,3-diaza-spiro[4.4]non-2-ene (synthesized as described in WO 2008/034863) and 0.95 mL (1.3 mol equiv.) ethyl isothiocyanate were added to 10 mL ethanol. The reaction mixture was refluxed for 2.5 hours under magnetic stirring. Silica gel was added and volatiles were removed in vacuo. The product was purified by flash chromatography on silica gel (Et2O:PA=1:2) and, after evaporation of the volatiles, stirred with diisopropylether and collected by filtration to yield 0.57 g (32%) of 2,3-diazaspiro[4.4]non-3-ene-2-carbothioic acid ethylamide. 1H NMR (400 MHz, CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 1.64-1.86 (m, 8H), 3.68 (dq, J=7.2, 5.5 Hz, 2H), 4.00 (s, 2H), 6.80 (s, 1H), 7.08-7.18 (br.s., 1H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][N:11]([CH3:25])[C:12](=[O:24])/[CH:13]=[CH:14]/[C:15]1[C:20]2[CH2:21][CH2:22][O:23][C:19]=2[CH:18]=[CH:17][CH:16]=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:9][O:10][N:11]([CH3:25])[C:12]([C@@H:13]1[CH2:2][C@H:14]1[C:15]1[C:20]2[CH2:21][CH2:22][O:23][C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:24]
Reactant: CON(C)C(=O)/C=C/c1cccc2c1CCO2
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@@H]1C[C@H]1c1cccc2c1CCO2
Temperature: 37.5 °C
Reaction time: 3 h

Procedure:
Trimethylsulfoxonium iodide (9.9 g, 45 mmol) was added in small portions to a suspension of sodium hydride (1.8 g, 45 mmol) in DMF (120 mL). After the foaming had subsided (10 min), a solution of (trans)-N-methoxy-N-methyl-3-(2,3-dihydrobenzofuran-4-yl)propenamide (3.5 g, 15 mmol) in DMF (60 mL) was added dropwise, with the temperature maintained between 35-40° C. The mixture was stirred for 3 h at room temperature. Saturated NH4Cl (50 mL) was added dropwise and the mixture was extracted three times with ethyl acetate. The organic extracts were combined, washed with H2O and brine, dried over K2CO3, and concentrated in vacuo to give a white wax (3.7 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([OH:17])[N:11]=[CH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([O:17][CH3:20])[N:11]=[CH:10]2)=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1c(O)ncn1Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ncn(Cc2ccc([N+](=O)[O-])cc2)c1C(N)=O
Temperature: 50 °C

Procedure:
3.93 g (15 mmol) of the derivative 3-(4-nitrobenzyl)-5-hydroxy-3H-imidazole-4-carboxamide are added to 80 ml of DMF in a three-necked flask under argon, followed by addition of 8.29 g (60 mmol; 4 eq.) of potassium carbonate. The stirred medium is maintained at 50° C. for 30 minutes and then cooled to room temperature. Methyl iodide (5.75 g; 40.5 mmol; 2.7 eq.) is then added.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C.O1CCCCC1[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]3[O:38][C:39]4[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][C:40]=4[CH:41]=3)[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>O>[F:49][C:46]([F:47])([F:48])[C:43]1[CH:44]=[CH:45][C:39]2[O:38][C:37]([CH2:36][O:35][CH:32]3[CH2:33][CH2:34][N:29]([C:26]4[CH:27]=[CH:28][C:23]([OH:22])=[CH:24][CH:25]=4)[CH2:30][CH2:31]3)=[CH:41][C:40]=2[CH:42]=1
Reactant: FC(F)(F)c1ccc2oc(COC3CCN(c4ccc(OC5CCCCO5)cc4)CC3)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Oc1ccc(N2CCC(OCc3cc4cc(C(F)(F)F)ccc4o3)CC2)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.84 g) was added to an ethanol solution (40 ml) of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(5-trifluoromethylbenzofuran-2-ylmethoxy)piperidine (2.1 g) and the mixture was heated at reflux for 1 hour. After being cooled to room temperature, water was added to the reaction mixture and filtered through Celite, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was washed with ether and dried to afford the title compound as a white powder (1.4 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[BrH:14].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[Br:14][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: Br
Reactant: OCc1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccnc2cc(CBr)ccc12
Temperature: 120 °C

Procedure:
7-Hydroxymethyl-4-chloroquinoline (0.2 g, 0.97 mmol) is treated with 48% HBr and heated to 120° C. for 1 hours. The resulting solution is cooled with ice, diluted with water and treated with ethyl acetate and sodium bicarbonate until basic to pH paper. The layers are separated and the organic layer is washed with water, dried (Na2SO4) and concentrated to give 7-bromomethyl-4-chloroquinoline (0.23 g, 0.9 mmol). MS m/z: M+=255; 1H NMR (CDCl3, 300 MHz) δ8.75 (d, 1H), 8.25 (d, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 4.7 (s. 2H).
Reaction SMILES: N#N.O1C=CC=C1CC1C=C(OC)N=C(N)C=1N.[CH3:19][CH:20]([NH2:22])[CH3:21].[Br:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Br:23][CH2:24][CH2:25][C:26]([NH:22][CH:20]([CH3:21])[CH3:19])=[O:27]
Reactant: CC(C)N
Reactant: O=C(Cl)CCBr
Agent: COc1cc(Cc2ccco2)c(N)c(N)n1
Agent: N#N
Solvent: ClCCl
Product: CC(C)NC(=O)CCBr
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To a stirred and cooled (0°-10° C.) mixture of 59 parts of 2-propanamine and 650 parts of dichloromethane were added dropwise 94.2 parts of 3-bromopropanoyl chloride. Upon completion, stirring was continued for 5 minutes. The whole was washed with water. The organic layer was separated, dried, filtered and evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and hexane. The product was filtered off and dried, yielding 70 parts (73%) of 3-bromo-N-(1-methylethyl)propanamide; mp. 60° C. (67).
Reaction SMILES: C(OC(Cl)=O)C(C)C.[NH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:10]([C:14]([OH:16])=O)[C@@H:11]([CH3:13])[OH:12].CN1CCOCC1.[NH2:31][C@H:32]([C:43]([NH:45][C@H:46]([CH2:50][OH:51])[C@@H:47]([CH3:49])[OH:48])=[O:44])[CH2:33][S:34][CH2:35][C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1.FC(C(O)=O)(F)F>C1COCC1>[NH:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:10]([C:14]([NH:31][C@H:32]([C:43]([NH:45][C@H:46]([CH2:50][OH:51])[C@@H:47]([CH3:49])[OH:48])=[O:44])[CH2:33][S:34][CH2:35][C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)=[O:16])[C@@H:11]([CH3:13])[OH:12]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(CSC[C@H](N)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: Cc1ccc(CSC[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Temperature: -25 °C
Reaction time: 0.08 h

Procedure:
5.9 ml chloroformic acid isobutyl-ester are added drop-wise to a solution of 9.7 g Boc-Thr-OH and 9.4 ml N-methyl-morpholine in 50 ml THF pre-cooled to -25° C. The solution is stirred for 5 min. at -15° C. and a solution of 20 g H-Cys(MBzl)-Thr-ol trifluoroacetate and 9.8 ml N-methylmorpholine in 50 ml THF, pre-cooled to -10° C. are added. The reaction mixture is stirred for 2 hrs. at 0° C., and for 2 hrs. at room temperature. 20 ml 10% KHCO3 are added and the mixture concentrated under vacuum. The product is diluted with AcOEt and washed with 2 N citric acid, 10% KHCO3 solution and then 30% NaCl solution. The AcOEt phase is dried over Na2SO4 and evaporated under vacuum, and the residue re-crystallised from MeOH/AcOEt/hexane. The title compound is obtained after further filtration, washing with ether and drying:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)([CH3:20])[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH:32]([CH3:34])[CH3:33]>>[CH:32]([C:31]1[N:28]=[C:27]([N:24]2[CH2:23][CH2:22][CH:21]([C@@:18]3([CH3:20])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:26][CH2:25]2)[O:29][N:30]=1)([CH3:34])[CH3:33]
Reactant: CC(C)C(=N)NO
Reactant: C[C@@]1(C2CCN(C#N)CC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Product: CC(C)c1noc(N2CCC([C@]3(C)Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from (S)-4-[5-(4-methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (Intermediate 33; the configuration of the stereocenter is arbitrarily assigned) and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 4): tR=1.13 min; Mass spectrum (ESI+): m/z=483 [M+H]+.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH:22]=[CH:23][C:24](=[O:33])[CH2:25][CH:26]([OH:32])[CH2:27][C:28]([O:30][CH3:31])=[O:29].O.CCOCC>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH2:23][C:24](=[O:33])[CH2:25][CH:26]([OH:32])[CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CC(O)CC(=O)C=Cc1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(O)CC(=O)CCc1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 81.5 %

Procedure:
Tributyltin hydride (450 μL, 1.7 mmol) was added dropwise over 1-1/2 hours to a stirred solution of the ene-one ester from Step A (320 mg, 1 mmol) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol) in dry THF (5 mL) at ambient temperature under N2. After standing at 20° C. overnight the light-brown solution was distributed between water (100 mL) and ether (150 mL). The organic layer was separated and washed with water (2×100 mL), dried and evaporated. The residual oil (1 major spot on TLC with Rf 0.39 vis-a-vis 0.35 for the starting ene-one ester on Whatman MK6F silica using CHCl3 -MeOH; 99:1 as eluent) was chromatographed on a Still column to obtain the product (260 mg, 81%) as a pale amber gum; NMR (CDCl3) δ: 2.5-2.525 (2H, m, --C2CO2 --), 2.57-2.73 (2H, m, -- COC2C(OH)--), 2.77 (2H, t, J=7.5 Hz, AR-CH2CH2CO-), 2.98 (2H, t, J=7.5 Hz, Ar-CH2CH2CO-), 3.71 (3H, s, --CO2C3), 4.45-4.51 (H, m, --CH(OH)--).