Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])=[O:15]
Reactant: Cc1ccccc1CCN
Reactant: O=C(Cl)c1ccccc1Cl
Product: Cc1ccccc1CCNC(=O)c1ccccc1Cl

Procedure:
1-Amino-2-(2-methylphenyl)ethane and 2-chlorobenzoyl chloride were reacted in the same way as in step (a) of Example 1 to afford 1-(2-chlorobenzoyl)amino-2-(2-methylphenyl)ethane having a melting point of 90.4° to 90.9° C. The product was successively reacted in the same way as in steps (b), (c), (d) and (e) to afford 1-(2-chlorophenyl)isoquinoline-5-acetonitrile having a melting point of 112.8° to 113.3° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=1.[CH2:11]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>C1COCC1>[OH:22][C:19]1([C:3]2[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[CH:4]=2)[CH2:20][CH2:21][CH:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]1
Reactant: CCCCCC1CCC(=O)CC1
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCC1CCC(O)(c2cc(F)cc(F)c2)CC1
Reaction time: 0.5 h
Yield: 110 %

Procedure:
To a mixture of magnesium (600 mmol) and 1,300 ml of THF was added dropwise 1-bromo-3,5-difluorobenzene (500 mmol) at room temperature, and stirred at the same temperature for 30 min to prepare a Grignard reagent. To this solution was added dropwise a mixture of 4-pentylcyclohexanone (600 mmol) and 200 ml of THF, and stirred at the same temperature overnight. After 600 ml of 1N hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether and dried over anhydrous magnesium sulfate. The solvent was distilled off to give a (1-hydroxy-4-pentylcyclohexyl)-3,5-difluorobenzene (550 mmol). Purification was not particularly performed.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:26]([C:30]1[CH:31]=[CH:32][C:33]([C:36](Cl)=[O:37])=[N:34][CH:35]=1)[CH2:27][CH2:28][CH3:29]>>[CH2:26]([C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[O:37])=[N:34][CH:35]=1)[CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: CCCCc1ccc(C(=O)Cl)nc1
Product: CCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)cc2)nc1
Yield: 60 %

Procedure:
The compound of example 648 was prepared analogous to the compound of example 640 by reaction of compound of example 6 with commercially available 5-butylpicolinoyl chloride (Sigma Chemical Company, USA).
Reaction SMILES: C([O:8][C:9](=[O:33])[CH:10]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:15]=1[S:24]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH2:11][CH:12]=[CH2:13])C1C=CC=CC=1.[OH-].[Na+]>CO.O>[CH3:23][O:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:14]([CH:10]([CH2:11][CH:12]=[CH2:13])[C:9]([OH:33])=[O:8])=[C:15]([S:24]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)(=[O:26])=[O:25])[CH:16]=1
Reactant: C=CCC(C(=O)OCc1ccccc1)c1cc(OC)c(OC)cc1S(=O)(=O)N1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCC(C(=O)O)c1cc(OC)c(OC)cc1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred mixture 2-[4,5-dimethoxy-2-(morpholine-4-sulfonyl)-phenyl]-pent-4-enoic acid benzyl ester (3.25 g, 6.83 mmol) in methanol (28 cm3) under an atmosphere of dry nitrogen was added sodium hydroxide (820 mg, 20.5 mmol) dissolved in water (7 cm3). The mixture completely dissolved while stirring at ambient temperature for 20 hours. The volatile fractions were removed in vacuo and water (30 cm3) was added to the mixture. The aqueous mixture acidified with 6N HCl to pH 1.0 and was extracted with dichloromethane (3×30 cm3). The combined extracts were washed with brine (30 cm3), dried over sodium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to a crude golden oil. The oil was triturated in Et2O (30 cm3), vacuum filtered, washed with Et2O (2×10 cm3) and vacuum dried to constant weight to afford the title compound as (2.30 g, 87.54%) with a positive ion ESI (M+H)+386.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:25]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7]2>CCO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[N:23][N:24]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:25]=2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:7]2
Reactant: O=C1c2c(Cl)cc(-c3cnn(Cc4ccccn4)c3)cc2CN1CC#Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C1c2c(Cl)cc(-c3cnn(Cc4ccccn4)c3)cc2CN1CCCc1ccccc1
Yield: 95.8 %

Procedure:
To a solution of 7-chloro-2-(3-phenylprop-2-ynyl)-5-(1-pyridin-2-ylmethyl-1H-pyrazol-4-yl)-2,3-dihydroisoindol-1-one (30 mg, 0.07 mmol) in EtOH (5 mL) was added 10% Pd on carbon (16.5 mg). A H2 balloon was attached to the flask. After 16 hours the reaction was filtered and concentrated to provide the title compound (29.7 mg, 98%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 8.61 (ddpg, 1H), 7.88 (m, 2H), 7.70 (t, 1H), 7.48 (d, 2H), 7.40 (d, 2H), 7.23 (m, 8H), 5.49 (s, 2H), 4.32 (s, 2H), 3.68 (t, 2H), 2.70 (t, 2H), 2.00 (tt, 2H).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:16]1([CH2:15][CH2:14][CH2:13][C@@H:12]([C:22]2[O:23][CH:24]=[C:25]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[N:26]=2)[CH2:11][C:10]([NH:9][OH:8])=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: [H][H]
Reactant: CN(C)C(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of 2-((1R)-1 -{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-N,N-dimethyl-1,3-oxazole-4-carboxamide (Preparation 66) (100 mg, 0.23 mmol) in ethanol (5 ml) was treated with 5% palladium on barium sulphate (50 mg), pressurised to 1 atm with hydrogen in a sealed vessel and the mixture was stirred at room temperature for 2 hours. The solution was filtered through Arbocel® and the solvent removed from the filtrate under reduced pressure. The residue was azeotroped from dichloromethane (×3) then dichloromethane:ether (1 ml:4 ml) to afford the title compound as a foam (75 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][NH2:11])=O)=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:4][NH:3]1.[C:18]([NH2:21])(=S)[CH3:19].C(N(CC)CC)C.N1C=CC=CC=1>C(O)CCC>[CH3:19][C:18]1[NH:21][C:8]([C:7]2[C:2](=[O:1])[NH:3][N:4]=[C:5]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:6]=2)=[N:10][N:11]=1
Reactant: NNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: CC(N)=S
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: c1ccncc1
Product: Cc1nnc(-c2cc(-c3ccncc3)n[nH]c2=O)[nH]1
Temperature: 25 °C

Procedure:
A mixture of 100 mg of 3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazine-4-carboxylic acid hydrazide, 130 mg thioacetamide, 87 mg triethylamine, 1 ml of pyridine and 5 ml of butanol is refluxed for 15 hours. After cooling and stirring at room temperature, a solid precipitated is collected by filtration, washed with cold isopropanol and dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13](=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH2:7][CH2:6]1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13](=[O:24])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:7][CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1CC[C@H](CNC(=O)Cc2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](CNC(=O)Cc2ccccc2N)CC1

Procedure:
A solution of trans-4-{[2-(2-Nitro-phenyl)-acetylamino]-methyl}-cyclohexanecarboxylic acid methyl ester (4 g) in MeOH (600 mL) was submitted to continuous flow rate hydrogenation by H-Cube (ThalesNano®) using a 10% Pd/C cartridge (small cartridge, full hydrogen mode, flux 0.6 ml/min, P=1 atm). Finally, the solvent was removed under reduced pressure to obtain the titled compound (3.64 g, quantitative yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])=[C:4]([F:17])[CH:3]=1.[CH:18]1([B-](F)(F)F)[CH2:20][CH2:19]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2.[Al]>[NH4+].[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2].O.C1(C)C=CC=CC=1>[CH:18]1([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])=[C:4]([F:17])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: F[B-](F)(F)C1CC1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(C2CC2)cc1F
Temperature: 100 °C
Yield: 106.5 %

Procedure:
To a microwave vial containing a stir bar was added (R)—N—((S)-1-(4-bromo-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 0.31 mmol) followed by the addition of potassium cyclopropyltrifluoroborate (459 mg, 3.10 mmol), cesium carbonate (506 mg, 1.55 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol) and di(1-adamantyl)-n-butylphosphine (22 mg, 0.06 mmol), toluene (2.6 mL) and finally water (0.5 mL). The vial capped and heated by microwave irradiation for 20 min at 100° C., followed by thermal heating at 100° C. in a preheated aluminum tray for 18 hours. The reaction mixture was diluted with a saturated solution of NH4Cl. The aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to afford a yellow crystalline of (R)—N—((S)-1-(4-cyclopropyl-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (116 mg, 0.33 mmol, 106% yield). LCMS m/z 284.0 (M+H)+, Rt 0.90 min.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=1)[C:3]([O:5]C)=[O:4]>Cl>[NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)Cc1ccc(C(N)C(=O)OC)cc1
Agent: Cl
Product: NC(C(=O)O)c1ccc(CC(=O)O)cc1
Yield: 99 %

Procedure:
A suspension of methyl α-amino-p-methoxycarbonylmethylphenylacetate (2.3 g, 7 mmol) in 60 ml of 6N HCl was refluxed for 12 hours. After cooling white needles were collected. The aqueous layers were extracted with ethyl acetate. The organic layers were evaporated and the solids combined to give (RS)-α-amino-p-carboxymethylphenylacetic acid (1.45 g, 83%);
Reaction SMILES: [Br-].[N:2]1([C:7]2[CH:25]=[CH:24][C:10]([C:11](=[O:23])[CH2:12][N+:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.BrCC(C1C=C[C:33]([N:36]2CCCC2)=[CH:32][CH:31]=1)=O.N1C2C(=CC=CC=2)C=CC=1>C(#N)C>[C:33]([C:32]1[CH:31]=[C:12]([C:11](=[O:23])[C:10]2[CH:9]=[CH:8][C:7]([N:2]3[CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:25][CH:24]=2)[N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=12)#[N:36]
Reactant: O=C(CBr)c1ccc(N2CCCC2)cc1
Reactant: O=C(C[n+]1cccc2ccccc21)c1ccc(N2CCCC2)cc1
Agent: [Br-]
Solvent: CC#N
Solvent: c1ccc2ncccc2c1
Product: N#Cc1cc(C(=O)c2ccc(N3CCCC3)cc2)n2c1ccc1ccccc12
Yield: 96 %

Procedure:
1-(4-Pyrrolidin-1-yl-phenacyl)-quinolinium bromide: A stirred solution of 2-bromo-1-(4-pyrrolidin-1-yl-phenyl)-ethanone (689 mg, 2.57 mmol), quinoline (250 μL, 2.11 mmol) and acetonitrile (5.0 mL) was refluxed at 96° C. for 7 h under argon. The solution was equilibrated to room temperature and the precipitate was filtered on a Buchner funnel. The solid was dried in vacuo to yield 812 mg (96%) of the title compound. 1H NMR (DMSO-d6): 9.49 (d, J=4.67 Hz, 1H), 9.42 (d, J=8.25 Hz, 1H), 8.54 (d, J=8.24 Hz, 1H), 8.30 (m, 2H), 8.22 (td, J=7.92, 1.31 Hz, 1H), 8.06 (t, J=7.41 Hz, 1H), 7.96 (d, J=8.79 Hz, 2H), 6.84 (s, 2H), 6.72 (d, J=9.07 Hz, 2H), 3.40 (t, J=6.31 Hz, 4H), 2.02 (t, J=6.46 Hz, 4H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C([O:18][C:19]([C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[C:29]1[S:33][C:32]([S:34][CH3:35])=[N:31][CH:30]=1)[CH:24]([NH:36][C:37](=[O:44])[CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)[C:23]2=[O:45])=[O:20])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>[N+](C)([O-])=O.C(Cl)Cl.C(OCC)(=O)C>[C:19]([C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[C:29]1[S:33][C:32]([S:34][CH3:35])=[N:31][CH:30]=1)[CH:24]([NH:36][C:37](=[O:44])[CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)[C:23]2=[O:45])([OH:20])=[O:18]
Reactant: CSc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: CSc1ncc(C2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A solution of aluminium chloride (1.04 g) in nitromethane (25 cc) is added in 10 minutes, to a solution, cooled to -8° C., of 2-benzhydryloxycarbonyl-3-(2-methylthiothiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.61 g) in dry methylene chloride (40 cc) containing anisole (4 cc), and the reaction mixture is stirred for 2 hours at a temperature of between -8° C. and 0° C. The reaction mixture is diluted with ethyl acetate (200 cc) and distilled water (200 cc) acidified with 4N hydrochloric acid (3 drops). After filtration to remove insoluble matter, the organic layer is decanted and is washed with distilled water (50 cc) and then extracted with a 5% strength sodium bicarbonate solution (80 cc). The aqueous solution is washed with ethyl acetate (50 cc) and then acidified to pH 3, at 0° C., with 4N hydrochloric acid. The precipitate is filtered off, washed with water (2×20 cc) and dried. 2-Carboxy-3-(2-methylthio-thiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.8 g) is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11]C)[N:7]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[CH:5]2.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[N:7]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:6]=[CH:5]2
Reactant: COc1cc2c(ccn2S(C)(=O)=O)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)n1ccc2cc(F)c(O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of 5-fluoro-1-methanesulphonyl-6-methoxyindole (0.10 g 0.41 mmol) in dry dichloromethane (3 ml) at −10° C. was added a solution of BBr3 (1M in dichloromethane, 1.23 ml) over one minute. The reacture was warmed to room temperature and stirred for 2 h and then poured onto ice/1M hydrochloric acid (10 ml). After stirring for 15 min the mixture was extracted with ethyl acetate (1×50 ml, 2×20 ml), dried (MgSO4) and evaporated in vacuo to give 5-fluoro-6-hydroxy-1-methanesulphonylindole (70 mg)
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@H:13]([C:17]([OH:19])=[O:18])[C@H:14]([CH3:16])[OH:15].C([O-])(O)=O.[Na+]>O>[C:9]([NH:12][C@H:13]([C:17]([OH:19])=[O:18])[C@H:14]([CH3:16])[OH:15])([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: C[C@H](O)[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 60.2 %

Procedure:
Benzylchloroformate (0.35 ml; 2.3 mmol) was added to a mixture of L-allothreonine (0.25 g; 2.1 mmol) and NaHCO3 (435 mg; 5.18 mmol) in 2.5 ml of H2O at RT. After 3 h, the reaction mixture was partitioned between Et2O and H2O. The aqueous layer was washed with Et2O, acidified to pH <2 with 6N HCl, and extracted with CH2 Cl2. The organic layer was dried (MgSO4) and concentrated to afford 320 mg (63%) of Cbz-L-allothreonine.
Reaction SMILES: CCCCCCCCCCCCC/C=[CH:15]/[C@@H:16]([OH:21])[C@@H:17](N)[CH2:18][OH:19].N1C=CC=CC=1.C([O:31][C:32](=[O:34])[CH3:33])(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:15][C:16]([CH2:17][C:18]([CH2:33][C:32]([OH:31])=[O:34])=[O:19])=[O:21]
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 38.1 mg (0.127 mmol) of D-erythro-sphingosine 1 in 3.0 mL of dichloromethane was added 61.5 μL (0.762 mmol) of pyridine, 72.0 μL (0.762 mmol) of acetic anhydride and 0.78 mg (6.4 μmol) of 4-dimethylaminopyridine. The solution was warmed to 25° C., stirred for 2 h and poured in 30 mL of dichloromethane. The mixture was washed with 40 mL each of saturated aqueous sodium bicarbonate, saturated aqueous cupric sulfate, brine and dried over anhydrous sodium sulfate. Concentration in vacuo yielded 52.3 mg (97%) of nearly pure triacetate as an off-white solid. Recrystallization from hexanes afforded 48.2 mg (89%) of pure triacetate as feathery white crystals, mp 102-103° C. A second recrystallization from diethyl ether:hexanes gave an analytical sample as feathery white crystals, mp 103.0-103.5° C.
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]=[CH:5][CH:6]=[CH2:7].[CH:10]([O:15][CH3:16])([O:13][CH3:14])OC.C([O-])(O)=O.[Na+]>ClCCl.[Cl-].[Cl-].[Zn+2]>[CH3:16][O:15][CH:10]([O:13][CH3:14])[CH2:7][CH:6]=[CH:5][CH:4]=[O:3]
Reactant: C=CC=CO[Si](C)(C)C
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(CC=CC=O)OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 1-trimethylsilyloxy-1,3-butadiene (14.57 g, 0.1 mol) and trimethyl orthoformate (10 855 g, 0.1 mol) stirring in dichloromethane (500 ml) was added ZnCl2 (1.75 g, 10% mol), and the mixture stirred vigorously at 25° C. for 18 h. The reaction mixture was then poured into saturated aq. NaHCO3 (100 ml), and the organic layer collected. The aqueous layer was reextracted with dichloromethane (100 ml), the combined organic extracts dried over MgSO4, and the solvents removed in vacuo. The resulting brown oil was taken up in hexane/ethyl acetate (1:1) and filtered through a pad of flash silica gel, washing through with a further 400 ml of the solvent mixture. The solvents were removed in vacuo and the crude product Kugelrohr distilled slowly (~0.4 MM Hg/100° C.) to provide the pure enal (7.065 g, 49%)
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:10][C@@H:11]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[C@@H:15]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[S:14][CH:12]1[OH:13])(=[O:9])[CH3:8].C(=O)(O)[O-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:12]1([S:14][C@H:15]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@@H:16]([O:22][C:23](=[O:25])[CH3:24])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:11]1[O:10][C:7](=[O:9])[CH3:8])[OH:13]
Reactant: C1=COCCC1
Reactant: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1SC(O)(C2CCCCO2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
3,4-Dihydro-2H-pyran (1.5 mL, 16.5 mmol) and p-toluenesulfonic acid monohydrate (104 mg, 0.549 mmol) were added to a chloroform (40 mL) solution of 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.0 g, 5.49 mmol) and stirred at room temperature for one hour. The reaction mixture was added with a saturated sodium bicarbonate aqueous solution and extracted with chloroform, and after the organic layer was washed with brine, it was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain pale yellow amorphous tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.56 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[C:23]([Cl:25])[CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(O)C.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([C:33]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=4)=[N:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(Cl)c3)nc2)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)c(Cl)c3)nc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a sealed tube were added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(5,6-dichloropyridin-3-yl)acetamide 184-5 (65 mg, 0.16 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 183-2 (42 mg, 0.19 mmol), Pd(PPh3)4 (9 mg, 0.08 mmol), Na2CO3 (84 mg, 0.79 mmol), DME (0.5 mL), H2O (0.5 mL) and ethanol (0.1 mL). The reaction mixture was stirred at 100° C. overnight. After cooling to room temperature, the solvents were removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2-(2-methylpyridin-4-yl)pyrimidin-5-yl)acetamide 184. MS m/z 465.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.52 (d, 2H), 8.46 (d, 1H), 7.98-7.95 (m, 2H), 7.87 (d, 1H), 7.53 (s, 1H), 7.49-7.46 (m, 1 Hz), 7.36 (dd, 1H), 3.81 (s, 2H), 3.67 (t, 2H), 3.62 (t, 2H), 3.13 (t, 2H), 3.08 (t, 2H), 2.56 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:7]([OH:9])=O)(=[O:3])[CH3:2].[CH2:18]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH2:30][CH2:31][CH3:32])[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH2:30][CH2:31][CH3:32])[NH:28][C:7](=[O:9])[CH:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCC[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(=O)SCC(C(=O)O)C(C)c1ccccc1
Product: CCCC[C@H](NC(=O)C(CSC(C)=O)C(C)c1ccccc1)C(=O)OCc1ccccc1
Yield: 75 %

Procedure:
Using the procedure described in Example 60, but starting with 2-acetylthiomethyl-3-phenylbutanoic acid and norleucine benzyl ester, and after purifying by chromatography, eluting with a hexane/ethyl acetate (75:25 by volume) mixture, N-(2-acetylthiomethyl-1-oxo-3-phenylbutyl)norleucine benzyl ester is obtained in a 75% yield in the form of an oil, having the following characteristics: Rf =0.46 [hexane/ethyl acetate(6.5:3.5 by volume)].