Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH2:20]1>CS(C)=O>[CH2:34]1[O:33][C:30]2[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][N:21]3[CH2:22][CH2:23][CH2:24][C@H:20]3[CH2:19][N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)=[CH:28][C:29]=2[O:35]1
Reactant: Cl[C@@H]1CCCN(CCc2ccc3c(c2)OCO3)C1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)COc1ccccc1N2C[C@@H]1CCCN1CCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
Sixty-percent sodium hydride (0.11 g, 2.8 mmols) was washed with petroleum ether, and then suspended in 10 ml of dimethyl sulfoxide. To the suspension were added 450 mg (2.3 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 0.56 g (2.1 mmols) of (R)-(-)-3-chloro-1-(3,4-methylenedioxyphenethyl)piperidine [[α]D25 =-11.9° (c=1.0, ethanol)] in 5 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 12 hours and at 40° C. for 4 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:5. This mixed solvent was distilled off under reduced pressure. Further, the thus-obtained residue was subjected to column chromatography, and eluted with a mixed solvent of chloroform and methanol at a ratio of 200:1. This mixed solvent was then distilled off under reduced pressure to give 0.46 g of (S)-(-)-5,11-dihydro-5-[1-(3,4-methylenedioxyphenethyl)-2-pyrrolidinyl-methyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 51%.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22](C)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N[C@@H](C1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)CO.[F:37][C:38]([F:50])([F:49])C1C=C(S(Cl)(=O)=O)C=CC=1>>[F:37][C:38]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([S:8]([O:11][CH2:12][C@H:13]([C:14]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[NH:15][S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([C:38]([F:50])([F:49])[F:37])[CH:24]=2)(=[O:17])=[O:18])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: N[C@H](CO)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=S(=O)(N[C@H](COS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)c1cccc(C(F)(F)F)c1

Procedure:
Proceeding as described for (45), but using (S)-2-amino-2-(4-fluorophenyl)ethanol and 3-trifluoromethylbenzenesulfonyl chloride afforded (S)-2-(4-fluorophenyl)-2-(3-(trifluoro-methyl)benzenesulfonamido)ethyl 3-(trifluoromethyl)benzenesulfonate (47). MS m/z: 572.3 (M+H) (Calc'd for C22H16F7NO5S2: 571.48).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1.CCN(C(C)C)C(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:12][CH2:13]2)[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncc(C2CCNCC2)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(c2cnc(N)c(Br)n2)CC1
Reaction time: 1 h

Procedure:
To 3-bromo-5-(piperidin-4-yl)pyrazin-2-amine (50 mg, 0.194 mmol) in DCM (2 mL) in ice bath was added DIEA (340 μl, 1.945 mmol) and methanesulfonyl chloride (16.67 μl, 0.214 mmol). The reaction mixture was stirred for 60 min. The reaction mixture was extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. (30 mg, 46%). LCMS (m/z): 335.2/337.2 (MH+), 0.572 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=O.Cl.[C:19]([O:23][C:24](=[O:37])[C@H:25]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH2:26])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[C:19]([O:23][C:24](=[O:37])[CH:25]([NH:26][C:9](=[O:11])[CH:8]([C:7](=[O:13])[NH:6][CH2:5][C:4]1[CH:14]=[C:15]([F:17])[CH:16]=[C:2]([F:1])[CH:3]=1)[CH3:12])[CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-(3,5-Difluoro-benzyl)-2-methyl-malonamic acid (3.00 g, 12.3 mmol), L-tryptophan-tert-butylester hydrochloride (3.66 g, 12.3 mmol), TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate, 3.96 g, 12.3 mmol) and triethylamin (3.74 g, 3.70 mmol) were dissolved in DMF (15 ml) and stirred for 5 h at r.t. The reaction mixture was poured into water and the product mixture was extracted with ethyl acetate. The organic layers were dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e=486.4 (M+H+), (6.45 g, quant.) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2Cl2).
Reaction SMILES: [Si](O[C@H:9]1[CH2:13][C@@H:12]([OH:14])[CH:11]=[CH:10]1)(C(C)(C)C)(C)C.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.CC[O:23]CC>C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[O:23][CH:12]1[CH2:13][CH2:9][CH2:10][CH2:11][O:14]1
Reactant: CCOCC
Reactant: C1=COCCC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C=C[C@H](O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of (1R,4S)-4-(tert-butyldimethylsilyl)oxy-2-cyclopentenol (9.70 g, 40 mmol) (J. Amer. Chem. Soc., 1991, 113, 9851,), dihydropyran (4.40 g, 53.0 mmol) and p-toluenesulfonic acid (100 mg) in dry ether (50 ml) was stirred for 10 h at room temperature. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution (50 ml) and brine (50 ml). The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford 14.2 g of crude tetrahydropyranyl ether of (1R,4S)-4-(tert-butyldimethylsilyl)oxy-2-cyclopentenol as a colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=2)[CH:2]=1.[H][H]>[Pd].CO>[NH:14]1[CH2:15][CH2:16][CH:11]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc3ccccc3c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: c1ccc2ncc(C3CCNCC3)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
A catalytic amount of 50% wet 10% palladium on carbon was added to a mixture of tert-butyl 4-(quinolin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (260 mg, 0.84 mmol) in methanol (10 mL). Reaction vessel was placed on a Parr apparatus and charged with 10 psi of hydrogen gas. Reaction shook at room temperature for 4 hours. Mixture was filtered to removed catalyst. Filtrate was concentrated in vacuo. Residue was dissolved in dichloromethane (4 mL). Trifluoroacetic acid (1 mL) was added to the mixture. Reaction stirred at room temperature for 2 hours. Reaction mixture was concentrated in vacuo. Residue was dissolved in dichloromethane (20 mL). Mixture was washed with aqueous sodium bicarbonate (20 mL). Aqueous layer was back extracted with dichloromethane (30 mL). Organic layers were combined, dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as yellow oil in 45% yield. MS m/e (M+H)+=213.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O)=[O:12].P(Br)(Br)[Br:22].C(=O)(O)[O-].[Na+]>CCOCC>[Br:22][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12]
Reactant: BrP(Br)Br
Reactant: O=C(CCCCCCCO)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CCCCCCCBr)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
To a solution of 7-(2-naphthoyl)-1-heptanol 71 (175 mg, 0.606 mmol) in ether (5 mL) at 0° C. was added a solution of phosphorous tribromide (86 μL, 0.908 mmol) in ether (1 mL) dropwise and the reaction mixture was stirred at room temperature for 6 hours. Saturated sodium bicarbonate solution was added slowly and the mixture was extracted with ether (2×20 mL). The combined organic layers were washed with brine and dried (MgSO4). The solvents were removed in vacuo to give the title compound 72 (141 mg, 70%). 1H NMR (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.12 (m, 1H), 7.99 (m, 3H), 7.62 (m, 2H), 3.50 (t, 2H), 3.11 (t, 2H), 1.65 (m, 2H), 1.55 (m, 2H),1.31 (m, 6H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][CH2:3]2.[Li][CH3:22].[CH2:23]1C[O:26][CH2:25][CH2:24]1>C(Cl)Cl>[OH:20][C@:12]1([CH3:22])[CH2:13][CH2:14][C@@:15]2([CH3:16])[C@@H:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C@@H:3]2[O:26][CH2:25][C:24]#[CH:23])[CH2:11]1
Reactant: [Li]C
Reactant: C1CCOC1
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CC[C@H]3CC(=O)CC[C@]3(C)[C@H]1CC2
Solvent: ClCCl
Product: C#CCO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of 17β-propynyloxy)-5α-androstan-3-one (230 mg, 0.7 mmol) in dry THF (20 mL) was treated with MeLi (5 mL, 1M in THF, 5 mmol) at −70° C. After stirring the mixture at −70° C. for 0.5 hr, the cooling bath was removed and it was warmed to 10° C. The mixture was then quenched with NH4Cl solution (5 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (98:2) gave 3α-hydroxy-3β-methyl-17β-(2-propynyloxy)-5α-androstane (40 mg); TLC Rf (toluene:acetone 95:5)=0.31; and then 3β-hydroxy-3α-methyl-17β-(2-propynyloxy)-5α-androstane (70 mg) as a colorless solid; TLC Rf (hexane:acetone 7:3)=0.27.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1([CH2:39][N:40]2[C:45](=[O:46])[C:44](COS(C)(=O)=O)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.N1(C(OC(C)(C)C)=O)CCNCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:44]2[C:45](=[O:46])[N:40]([CH2:39][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[N:41]=[C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)[CH:43]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CCCC3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 78.8 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 78.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=O.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:51][C@@H:52]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[C:72]([F:75])([F:74])[F:73])[CH2:53][N:54]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]1=[O:64]>C(Cl)Cl>[O:63]=[C:62]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55](=[O:64])[N:54]1[CH2:53][C@@H:52]([NH:51][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[C:2]([F:1])[CH:3]=1)[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[C:72]([F:74])([F:73])[F:75]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1ccc(C(=O)O)cc1F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1F
Reaction time: 16 h
Yield: 67.8 %

Procedure:
To a solution of 3-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzoic acid (66 mg, 0.3 mmol), PyBrOP (169 mg, 0.37 mmol) and diisopropylethyl amine (263 μL, 1.5 mmol) in DCM (3 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (105 mg, 0.3 mmol)[prepared according to Preparation 3]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (112 mg, 68%) as a white solid: LC-MS (ES) m/z=551 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH:20]1([NH:23][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]3[O:12][C:13]([CH3:18])([CH3:19])[C:14]([CH3:16])([CH3:17])[O:15]3)[CH:4]=2)[CH2:22][CH2:21]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (WO200700565, 5.47 g, 20.87 mmol) in N,N′-dimethylformamide (55 mL) were added cyclopropylamine (1.76 mL, 25.08 mmol), diisopropylethylamine (8.00 mL, 45.93 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.62 g, 20.04 mmol). The clear solution was stirred at room temperature overnight. The mixture was then concentrated in vacuo and the residue was taken up with ethyl acetate and the organic phase was washed with 4% aqueous sodium bicarbonate solution, water, brine, dried (MgSO4) and concentrated to afford an oily residue. The oil was triturated with a mixture of hexanes and diethyl ether to give the title compound (5.78 g, 96%) as a white solid.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.CSC.[CH2:12]([O:19][C:20]1[C:25]([CH2:26]O)=[C:24]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:23]=[C:22]([CH3:37])[N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20]1[C:25]([CH2:26][Cl:8])=[C:24]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:23]=[C:22]([CH3:37])[N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CO)c(OCc2ccccc2)n1
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CCl)c(OCc2ccccc2)n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
To a 0° C. solution of NCS (70.2 mg, 0.515 mmol) in DCM (2 mL) was added DMS (34.9 mg, 0.562 mmol). The reaction mixture was cooled to −40° C., then a solution of [2-(benzyloxy)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-methylpyridin-3-yl]methanol (Cpd J, 175 mg, 0.468 mmol) in DCM (1 mL) was added drop-wise keeping the internal temperature below −30° C. Upon complete addition the reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed with brine, dried with MgSO4, filtered, then concentrated under vacuum. The residue was purified by column chromatography (0-30% EtOAc/heptane) to give the title compound (Cpd K, 120 mg, 65%) as an oil. 1H NMR (400 MHz, chloroform-d) δ 7.50 (d, J=7.3 Hz, 2H), 7.44-7.29 (m, 3H), 6.94 (s, 1H), 5.46 (s, 2H), 4.83 (s, 2H), 4.70 (s, 2H), 2.47 (s, 3H), 0.97 (s, 9H), 0.14 (s, 6H); MS 392 [M+H].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:34]#[N:35])([NH:14][C:15](=[O:33])[CH:16]([NH:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36]>O1CCOCC1>[ClH:36].[C:34]([C:11]1([NH:14][C:15]([CH:16]([NH:24][C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:33])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)#[N:35]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNCC1
Reaction time: 1 h

Procedure:
4-Cyano-4-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-piperidine-1-carboxylic acid t-butyl ester (1000 mg, 2.03 mmol) was dissolved in 20 mL of 4 M HCl in dioxane and stirred for 1 hour at which time the volatiles were remove in vacuo. The resulting residue was triturated with 100 mL of diethyl ether and the resulting solid was collected by filtration under inert atmosphere (the solid is very hygroscopic) and washed 2×50 mL of diethyl ether and dried in vacuo to yield the title compound as a bright white powder (802 mg); MS, m/z 392, M-35).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].C[N+]1C=CN([C:25](=[O:34])[N:26]([CH3:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)C=1>>[CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:25](=[O:34])[N:26]([CH3:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC1CCCCC1)Nc1ccc(O)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(NC(=O)CC2CCCCC2)cc1)c1ccccc1
Yield: 77.5 %

Procedure:
The title compound (284 mg, 77% yield, white crystals) was prepared from 2-cyclohexyl-N-(4-hydroxy-phenyl)-acetamide (233 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl—carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=367 (M+1); Rt=4.51 min
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(Cl)ncnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncnc2cc(CBr)ccc12
Yield: 51.3 %

Procedure:
To a solution of 4-chloro-7-methylquinazoline (7.0 g, 39 mmol) in carbon tetrachloride (140 mL) is added N-bromosuccinimide (8.0 g, 45 mmol), and benzoyl peroxide (0.8 g, 3.3 mmol). The solution is refluxed for 8 hours. After this time, the solution is filtered. The filtrate is concentrated and the residue is stirred with ether to give the title compound as an off-white solid (5.1 g, 20 mmol). 1H NMR (CDCl3, 300 MHz) δ9.10 (s, 1H), 8.30 (d, 1H), 8.10 (s, 1H), 7.82 (d, 1H), 4.68 (s, 2H). MS (EI): m/z 237 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:15]([OH:17])=[O:16])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:23]([Si:27]([CH3:30])([CH3:29])Cl)([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:13][O:14][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:30])[CH3:29])[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(CO)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
1.50 g (6.27 mmol) of N-[(benzyloxy)carbonyl]-(DL)-serine was dissolved in 10 ml of N,N-dimethylformamide. 885 mg (13.2 mmol) of imidazole and 1.98 g (13.2 mmol) of t-butyldimethylchlorosilane were added to the obtained solution at 0° C., and they were stirred overnight. Water was added to the reaction mixture and they were stirred for 10 minutes. After extracting with ethyl acetate 3 times followed by the drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].[CH3:20][Si:21]([CH3:34])([CH3:33])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O.CO>COCCOC.O>[CH3:20][Si:21]([CH3:34])([CH3:33])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH2:31][C:11]#[N:12]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: C[Si](C)(C)CCOCn1ccnc1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccnc1CC#N
Temperature: -60 °C
Reaction time: 2 h
Yield: 4151.6 %

Procedure:
1.73 g (8.84 mmol) tosylmethylisocyanide were solved in 10 ml DME and cooled down to −60° C. At this temperature first 1.98 g potassium tert-butoxide was added then slowly a solution of 2.00 g (8.84 mmol) 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde in 5 ml DME. After 2 hours stirring at −60° C. the reaction was allowed to reach 0° C. and 5 ml methanol (123.60 mmol) was added to the solution. The reaction was stirred for further 24 hours at ambient temperature and for 2 hours at 40° C. Excess water was added and the solution was extracted 3 times with dichloromethane. The organic phase was dried over Na2SO4, after evaporation of the solvent under reduced pressure the raw material was purified by reverse phase column chromatography (water 0.1% TFA/acetonitrile=80/20 to yield 0.87 g (0.367 mol) of the SEM-protected imidazole-acetonitrile.
Reaction SMILES: OC(C(F)(F)F)=O.[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([CH3:25])[C@@H:13]1[C:26]([N:28]1[CH2:33][CH:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([O:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[CH2:15][N:14]([CH3:25])[C@@H:13]1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11]
Reactant: [H][H]
Reactant: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CC=C(c2ccccc2)CC1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCC(c2ccccc2)CC1
Yield: 91.2 %

Procedure:
A mixture of (2S,3S,5S)-N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide TFA salt (4 mg, 0.00001 mol) in 1 mL of MeOH was hydrogenated in the presence of 5% Pd/BaSO4, under balloon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was concentrated to dry to yield the titled compound (4 mg, 100%). MS (ESI): (M+H)+=439.2.