Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[C:30]1(=[CH:34][C:35]#[N:36])[CH2:33][CH2:32][CH2:31]1.N12CCCN=C1CCCCC2>C(#N)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([C:30]5([CH2:34][C:35]#[N:36])[CH2:33][CH2:32][CH2:31]5)[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: N#CC=C1CCC1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C2(CC#N)CCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
To a solution of 1-[(1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (10 mg, 0.022 mmol, chiral intermediate from Example 1, Step 7) in acetonitrile (0.1 mL) was added cyclobutylideneacetonitrile (4.1 mg, 0.044 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (13 μL, 0.087 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with acetonitrile and purified by preparative RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (4.3 mg, 41%). The product was isolated as a single enantiomer. LCMS calculated for C25H31ClN7O (M+H)+: m/z=480.2; Found: 480.0.
Reaction SMILES: [N+:1]([CH:4]1[CH2:8][N:7]([CH2:9][CH3:10])[N:6]([CH2:11][CH3:12])[CH2:5]1)([O-])=O.C(O)C>C1(C)C=CC=CC=1.[Ni]>[NH2:1][CH:4]1[CH2:8][N:7]([CH2:9][CH3:10])[N:6]([CH2:11][CH3:12])[CH2:5]1
Reactant: CCN1CC([N+](=O)[O-])CN1CC
Agent: [Ni]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN1CC(N)CN1CC
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To a solution of approximately 3.0 g (0.016 mole) of 4-nitro-1,2-diethyl-pyrazolidine in 100 ml of toluene was added 60 ml of anhydrous ethanol and 2 g Raney nickel (washed three times with anhydrous ethanol). The mixture was added and hydrogenated for three hours at about 30 psi. The mixture was filtered to give a light yellow solution. The solvents were evaporated at reduced pressure giving the colorless liquid, 1.95 g of the title product, b.p. 113°-115° C./40 mm. The dimaleate salt melted at 119°-120° C.
Reaction SMILES: Cl[C:2](=[CH2:26])[CH2:3][N:4]([CH2:17][CH:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[OH:27]S(O)(=O)=O>C(Cl)Cl.O>[N+:14]([C:11]1[CH:10]=[CH:9][C:8]([S:5]([N:4]2[CH2:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][C:2](=[O:27])[CH2:3]2)(=[O:7])=[O:6])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: C=C(Cl)CN(CC(O)c1ccccc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: O=C1CC(c2ccccc2)CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-(2-chloroprop-2-enyl)-N-(2-hydroxy-2-phenylethyl)-4-nitrobenzenesulfonamide (1-3, 6.6 g, 16.6 mmol) was dissolved in 40 mL CH2Cl2 and cooled to −78° C. The resulting solution was treated dropwise with conc. H2SO4 (20 mL) and H2O (2 mL). The reaction was placed in a 0° C. bath and stirred 1 h to completion. The reaction was diluted carefully with CH2Cl2 (200 mL) and H2O (400 mL) and the organic layer was separated, dried (MgSO4) and filtered. Concentration of the organic layer followed by flash column chromatography (SiO2, 0-100% EtOAc-hexanes graident over 40 min) provided 1-[(4-nitrophenyl)sulfonyl]-5-phenylpiperidin-3-one (1-4) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J=8.8 Hz, 2H), 7.94 (d, J=8.8 Hz, 2H), 7.34 (m, 3H), 7.16 (m, 2H), 4.13 (d, J=15.9 Hz, 1H), 3.98 (m, 1H), 3.42 (d, J=15.9 Hz, 1H), 3.36 (m, 1H), 3.00 (dd, J=12.2, 10.4 Hz, 1H), 2.80 (m, 1H), 2.61 (dd, J=16.2, 11.3 Hz, 1H); MS 361.1 found 361.4 (M+H+) required (ionizes poorly).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5].F[B-](F)(F)F.CN(C)[C:31]([C:37](OCC)=O)=[CH:32][CH:33]=[N+](C)C.C([Li])CCC.C1(SCC(OC2CCCCC2)=O)C=CC=CC=1>CCCCCC.O1CCCC1>[CH3:23][N:2]([CH3:1])[C:3](=[CH:9][CH:10]=[C:11]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:12]([O:14][CH:15]1[CH2:33][CH2:32][CH2:31][CH2:37][CH2:16]1)=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: F[B-](F)(F)F
Agent: O=C(CSc1ccccc1)OC1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=S)C(=CC=C(C(=O)OC1CCCCC1)c1ccccc1)N(C)C

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (13.7 g), a 1.6M solution (33.1 cc) of n-butyllithium in hexane and cyclohexyl (phenylthio)acetate (12 g) in tetrahydrofuran (150 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (80:20 by volume) as eluent, 1-ethyl 6-cyclohexyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate (9.7 g) is obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH2:21])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)C(N)(CO)CO>ClCCCl>[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH:21][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: O=S(=O)(NC1Cc2cc(Cl)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was synthesized as part of library using the following procedure in a parallel synthesis fashion using 48 well red and blue minireactors. Typical procedure: To a solution of 22B (14 mg, 0.05 mmol) in DCE (0.5 mL) at RT was added NMM (0.109 mL, 0.1 mmol), followed by addition of benzene sulfonylchloride (17.6 mg, 0.1 mmol) in DCE (0.5 μL). The reaction mixture was shaken at RT for 24 h, and treated with 100 mg of PS-Trisamine (4 mmol/g loading) for 2 h to remove excess sulfonyl chloride. Contents were filtered into a synthesis tube rack (STR) and the solvent was dried in a speed vac. The resulting residue was chromatographed using Prep HPLC (conditions: Xterra MS-C18 (30×50 mm); Eluted with 10% to 100% B, 6 min gradient. (A=100% water−0.1% TFA and B=acetonitrile with 0.1% TFA); Flow rate at 30 mL/min. UV detection at 220 nm) to give compound 50 (13.8 mg, 69%). HPLC: 99% at 1.74 min (retention time) (Conditions: Xterra MS-C18 (2.1×50 mm); Eluted with 0% to 100% B, 2.75 min gradient. (A=100% water−0.1% TFA and B=acetonitrile with 0.1% TFA); Flow rate at 1 mL/min. UV detection at 220 nm). MS (ES): m/z 413 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[OH:26][C:27]1C(C2C3=NC=CC=C3N(CCCCC)C2=O)=CC2OCOC=2C=1>>[OH:1][C:2]1[C:3]([C:11]2([CH2:27][OH:26])[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2cnccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ncccc21
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2cnccc21

Procedure:
Following the procedure described in PREPARATION 2E, and making non-critical variations using 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one to replace 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one, the title compound was obtained: MS (ES+) m/z 371.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:18]([O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH:32]1[CH2:34][O:33]1)([CH3:21])([CH3:20])[CH3:19]>C(O)(C)C>[C:18]([O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][C@@H:32]([OH:33])[CH2:34][N:13]1[CH2:12][CH2:11][CH:10]([N:6]2[C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH2:15][CH2:14]1)([CH3:20])([CH3:19])[CH3:21]
Reactant: CC(C)(C)OC(=O)c1ccccc1OCC1CO1
Reactant: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)c1ccccc1OC[C@@H](O)CN1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Yield: 98.9 %

Procedure:
A solution of 5-fluoro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (235 mg, 0.5 mmol) and 2-oxiranylmethoxy-benzoic acid tert-butyl ester (250 mg, 1.0 mmol) in isopropanol (iPrOH) (10 mL) was stirred at 70° C. for 14 h, after which the solvent was removed in vacuo. The residue was purified by gradient flash chromatography on silica gel (CH2Cl2 to EtOH), yielding an off-white solid (240 mg, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:21][OH:22])[CH:5]=[C:6]([F:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1.Cl[C:24]1[CH:34]=[C:28]2[N:29]([CH3:33])[CH2:30][CH2:31][CH2:32][N:27]2[C:26](=[O:35])[N:25]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:17])([F:18])[F:19])[CH:10]=1)[CH2:21][O:22][C:24]1[CH:34]=[C:28]2[N:29]([CH3:33])[CH2:30][CH2:31][CH2:32][N:27]2[C:26](=[O:35])[N:25]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(F)c(C(F)(F)F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(F)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluoro-4-(4-fluoro-3-(trifluoromethyl)phenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[NH2:12])=[CH:5][CH:4]=1)#[N:2].[C:15](OC)(=[O:18])[C:16]#[CH:17]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:10]2[CH:17]=[CH:16][C:15](=[O:18])[NH:12][C:11]=2[CH3:13])=[O:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(N)=CC(=O)c1ccc(C#N)cc1
Reactant: C#CC(=O)OC
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)ccc1C(=O)c1ccc(C#N)cc1
Reaction time: 24 h

Procedure:
was prepared following the procedure described in Example A-2 using 24.3 g of 3-(4-cyanophenyl)-1-methyl-3-oxo-1-propenamine, 12.5 ml of methyl propiolate and 100 ml of dimethylformamide. After a refluxing period of 24 hours, the reaction mixture was cooled whereupon the product precipitated, was collected, washed with ethanol and dried in a vacuum oven at 90° C. There was thus obtained 12.2 g of product, m.p. 267°-269° C., which was recrystallized from dimethylformamide using decolorizing charcoal, washed with ethanol and dried in a vacuum oven at 90° C. to yield 7.4 g of 5-(4-cyanobenzoyl)-6-methyl-2(1H)-pyridinone, m.p. 268°-270° C.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[CH2:27][CH2:26][N:25]2[CH3:37])[CH2:23][CH2:22]1.C(N(CC)CC)C>CCOCC>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([O:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:32]=3)[CH2:27][CH2:26][N:25]2[CH3:37])[CH2:23][CH2:22]1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Agent: Br
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)Oc1cc2c(cc1OC)CCN(C)C2C1(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Decanoyl chloride (0.45 g) was added to a mixture of (+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (1 g, prepared in a similar manner to that described in Example 77), triethylamine (0.7 g) and ether (30 ml). The mixture was stirred at ambient temperature for 24 hours, then washed with water, 10% aqueous sodium hydroxide solution, and brine. The organic layer was dried over magnesium sulphate, filtered and concentrated to yield a gum which was purified by chromatography on a silica gel column using a 1:3 mixture of ether and light petroleum as eluant. The relevant fractions were concentrated in vacuo to yield (+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.95 g) as a gum; having specific optical rotation αD of +21.47°.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([C:19]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]2[C:22]([CH:23]3[CH2:33][CH:24]3[CH2:25][O:26]2)=[CH:21][CH:20]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[N+:16]([O-])=O)(=[O:8])=[O:7])=[O:4].C(O)(=O)C>C(O)C.[Zn]>[CH3:1][O:2][C:3]([N:5]([C:19]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]2[C:22]([CH:23]3[CH2:33][CH:24]3[CH2:25][O:26]2)=[CH:21][CH:20]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH2:16])(=[O:7])=[O:8])=[O:4]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])ccc2c1OCC1CC21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2N)ccc2c1OCC1CC21
Yield: 80 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[N-(methoxycarbonyl)-N-(4-fluoro-2-nitrobenzene-sulfonyl)amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 111, 0.2 g), zinc (0.54 g) and acetic acid (0.5 g) in ethanol (20 mL) was stirred and heated at reflux for 1 hour. After cooling, the solid was filtered off and the filtrate was evaporated to dryness. The residue was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether with a gradient of 30-50% to give methyl (1aRS,7bSR)-5-[N-(methoxycarbonyl)-N-(2-amino-4-fluorobenzenesulfonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.15 g) as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH:13]1[CH2:16][N:15]([C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:20])[CH3:19])[C:14]1=[O:25].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:5]([O:4][C:2]([NH:12][CH:13]1[CH2:16][N:15]([C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:19])[CH3:20])[C:14]1=[O:25])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(=C(C)C)N1CC(N)C1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C(=C(C)C)N1CC(NC(=O)OCc2ccccc2)C1=O
Yield: 80.6 %

Procedure:
Benzyl chloroformate (7.9 g.) was dissolved in methylene chloride (50 ml.). A methylene chloride (20 ml.) solution containing 3-amino-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone (2.42 g.) and triethylamine (3.7 g.) was added dropwise to the solution at -15° to -10° C. in the course of 1.33 hours with stirring, whereafter the mixture was stirred at the same temperature for 1.25 hours. The reaction mixture was evaporated to dryness under reduced pressure to give a residue, which was dissolved in ethyl acetate (150 ml.). The solution was washed three times with 5% hydrochloric acid and once with an aqueous sodium chloride, and then dried over magnesium sulfate. The solvent was removed by distillation and a residue (7.3 g.) was treated with n-hexane to give crude object compound, 3-benzyloxycarbonylamino-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone (3.27 g.). The compound (3.71 g.) thus obtained was subjected to column chromatography on silica gel (60 g.), and elution was carried out with chloroform and a mixture of chloroform and methanol (volume ratio; 10:1). The fractions containing the desired compound were collected and the solvent was distilled off from the eluate under reduced pressure to give the purified object compound (3.05 g.).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]#[N:9].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:7][C:5]1[S:6][C:2]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[C:3]([C:8]#[N:9])[N:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc(C#N)c(Br)s1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(C#N)c(C#C[Si](C)(C)C)s1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
5-Bromo-2-methyl-thiazole-4-carbonitrile (4.8 g, 23.6 mmol) was suspended in 50 ml triethyl amine. Trimethylsilylacetylene (4.64 g, 47.3 mmol), triphenylphosphine (186 mg, 0.7 mmol) and bis(triphenylphosphine)palladium(II)chloride (0.83 g, 1.18 mmol) were added and this mixture was evacuated and purged with argon several times to remove oxygen from the solution. Copper(I)iodide (45 mg, 0.24 mmol) was added and the reaction mixture was stirred at 70° C. for 5 hrs. The residue was taken up in water, extracted three times with ethyl acetate and several times with water. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (heptane/ethyl acetate 90:10->1:1 gradient). The desired product was obtained as a black solid (4.1 g, 79%).
Reaction SMILES: C([O:8][C:9](=[O:44])[CH:10]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:35])[NH:26][O:27]CC3C=CC=CC=3)=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:40]([O:39][C:37]([NH:36][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:35])[NH:26][OH:27])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[C:9]([OH:44])=[O:8])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)NOCc3ccccc3)cc2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)NO)cc2)cc1)C(=O)O
Yield: 71.6 %

Procedure:
Palladium on carbon (5%, 0.3 g) was added to a degassed solution of the benzyl hydroxamate 7 (0.4 g) in MeOH (25 mL) and the suspension was treated with hydrogen at atmospheric pressure for 4 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 8 (0.2 g, 72%). 1H NMR (DMSO-d6): 11.20 (s, 1H), 9.02 (br, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.10 (ddd, J=12.8 10.0, and 4.4 Hz, 1H), 3.03 (dd, J=13.6 and 4.4 Hz, 1H), 2.82 (dd, J=13.6 and 10.4 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:18][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)([OH:20])[CH3:21])[C:4]=2[CH2:3]1
Reactant: CC1(c2cccnc2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CN(C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 22.4 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (1 g, 5 mmol) was dissolved in 15 mL DMF and stirred for 10 min at 0° C. Sodium hydride (600 mg, 15 mmol) was added portionwise at RT and stirred for 10 min. 3-(2-Methyl-oxiranyl)-pyridine (1.01 g, 7.5 mmol) was added dropwise at the same temperature and the mixture stirred for 12 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (4×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated and the residue was crystallized in EtOH and ether to obtain 375 mg of 1-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-3-yl-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.76 (d, 1H), 8.55 (dd, 1H), 7.703 (d, 1H), 7.24 (s, 1H), 7.23 (dd, 1H), 7.15 (d, 1H), 6.95 (d, 1H), 4.13 (d, 1H), 4.08 (d, 1H), 3.38 (dd, 2H), 2.79 (q, 2H), 2.74 (q, 2H), 2.46 (s, 3H), 2.43 (s, 3H), 1.64 (s, 3H). Separation by chiral HPLC provided enantiomers 14a and 14b. Optical rotations: Compound 14a, (+)31.28 (c 0.58, Chloroform, 96.04% HPLC purity); Compound 14b, (−)27.23 (c 0.57, Chloroform, 96.09% HPLC purity).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([SH:10])[CH:5]=1.[H-].[Na+].[F:14][C:15](I)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17]>CN(C=O)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:15]([F:14])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:5]=1
Reactant: COC(=O)c1cccc(S)c1
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccc(SC(F)(C(F)(F)F)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
To a stirred solution of 3-mercaptobenzoic acid methyl ester (2.32 g, 13.8 mmol) in DMF (15 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 608 mg, 15.2 mmol) in small portions. After stirring for 10 min at 0° C., and a further 30 min at room temperature, perfluoroisopropyl iodide (2.16 mL, 15.2 mmol, 1.1) was added to the reaction. Following the addition, the reaction was stirred for 10 min at room temperature and then heated to 60° C. After 90 min at 60° C. the reaction was cooled to room temperature, diluted with ethyl ether (150 mL), washed with brine (2×200 mL), saturated aqueous NaHCO3 (200 mL), brine (100 mL), dried over MgSO4 and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5% EtOAc in hexanes as an eluent to furnish 3-(1,2,2,2-tetrafluoro-1-trifluoromethylethylthio)benzoic acid methyl ester (3.13 g).