Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[C:15]([C:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[N:16][N:17]([CH3:19])[CH:18]=3)=[O:12])=[C:4]2[N:3]=1.[NH3:28]>C(O)C>[Cl:27][C:21]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:15]1[C:14]([NH:13][C:11]([C:10]2[CH:9]=[N:8][N:5]3[CH:6]=[CH:7][C:2]([NH2:28])=[N:3][C:4]=23)=[O:12])=[CH:18][N:17]([CH3:19])[N:16]=1
Reactant: Cn1cc(NC(=O)c2cnn3ccc(Cl)nc23)c(-c2cc(Cl)ccc2Cl)n1
Reactant: N
Solvent: CCO
Product: Cn1cc(NC(=O)c2cnn3ccc(N)nc23)c(-c2cc(Cl)ccc2Cl)n1
Yield: 77 %

Procedure:
A solution of 5-chloro-N-(3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (110 mg, 0.26 mmol) in ethanol saturated with ammonia (4 mL) was heated at 95° C. for 30 minutes with microwave irradiation. The mixture was concentrated. Purification by flash column chromatography afforded 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(2,5-dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-amide as a solid (80 mg, 77% yield). 1H NMR (400 MHz, DMSO-d6): 9.37 (s, 1H), 8.63 (d, J=7.6 Hz, 1H), 8.14-8.16 (m, 2H), 7.70 (m, 1H), 7.52-7.55 (m, 2H), 6.39 (d, J=8.0 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: FC1C=CC([C:8]2[C:17]3[C:12](=[CH:13][C:14](CN4CC(C(F)(F)F)NC[C@@H]4C)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:30]#[N:31])[CH:9]=2)=CC=1.Cl.C(=O)([O-])[O-:34].[K+].[K+]>>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[C:30]([NH2:31])=[O:34]
Reactant: O=C([O-])[O-]
Reactant: C[C@H]1CNC(C(F)(F)F)CN1Cc1ccc2c(-c3ccc(F)cc3)cc(C#N)nc2c1
Agent: Cl
Agent: [K+]
Product: NC(=O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(4-fluorophenyl)-7-(((2S)-2-methyl-5-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carbonitrile (275 mg, 0.642 mmol) was dissolved in conc HCl (2636 μl, 32.1 mmol) and then stirred at ambient temperature for 4 hours. The yellow solution was slowly poured into aq potassium carbonate (12.8 ml, 5M, 64 mmol) at 0° C. The resulting mixture was extracted with chloroform. The organic portion was dried over MgSO4 and concentrated. The residue was purified by preparative HPLC Chiralpak AD, 5 cm×500 cm, 50 ml/min eluting with 20% IPA/hexanes+0.1% Et□NH, to provide isomers A and B of 4-(4-fluorophenyl)-7-(((2S)-2-methyl-5(R or S)-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carboxamide as colorless foams. Isomer A, LRMS m/z (M+H)+ 447.3 found, 447.4 required 1H NMR (500 MHz, CDCl3): 8.22 (1H, s), 8.10 (2H, d, J=12.11 Hz), 7.91 (1H, d, J=8.69 Hz), 7.65 (1H, dd, J=8.72, 1.66 Hz), 7.52 (2H, dd, J=8.44, 5.36 Hz), 5.64 (1H, s), 3.89 (1H, d, J=13.93 Hz), 3.77 (1H, d, J=13.94 Hz), 3.39-3.34 (1H, m), 3.08-3.04 (1H, m), 2.94-2.87 (2H, m), 2.73 (1H, dd, J=11.54, 8.93 Hz), 2.60 (1H, dd, J=11.55, 3.62 Hz), 1.17 (3H, d, J=6.41 Hz).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[S:11][C:12]([Cl:19])=[CH:13][C:14]=1[S:15](Cl)(=[O:17])=[O:16]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:14]1[CH:13]=[C:12]([Cl:19])[S:11][C:10]=1[Cl:9])(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cc(Cl)sc2Cl)c1Br
Yield: 47 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dichlorothiophene-3-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 2,5-dichlorothiophene-3-sulphonyl chloride in 47% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 135°-138° C.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[Na+].[C:5]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:26]3[NH:30][CH2:29][CH2:28][S:27]3)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[C:5]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:26]3[N:30]([C:2]([NH2:1])=[O:3])[CH2:29][CH2:28][S:27]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: [N-]=C=O
Reactant: c1ccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution of 1.07 g of sodium isocyanate in 20 ml of water is added to a solution of 3.03 g of 2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine in 40 ml of ethanol, and 2.46 g of acetic acid are added thereto. The mixture is stirred at room temperature for 2 hours. 200 ml of water are added to the mixture, and the aqueous mixture is made alkaline with potassium carbonate. The aqueous mixture is extracted with ethyl acetate and chloroform, successively. The extracts are combined, washed with water, dried and then concentrated under reduced pressure to remove solvent. The residue is recrystallized from ethyl acetate. 2.78 g of 2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide are obtained. Yield: 82.2%.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:13])(=O)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl.O>[F:14][C:15]1[CH:16]=[C:17]([F:21])[CH:18]=[CH:19][C:20]=1[C:5]([C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)=[O:13]
Reactant: Fc1cccc(F)c1
Reactant: O=C(O)c1ccncc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: O=C(c1ccncc1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
219 ml (3.00 mole) of thionyl chloride were added to a solution of 246.2 g (2.00 mole) of isonicotinic acid in 500 ml of 1,2-dichloroethane and the mixture was refluxed for 4 hours. The excess thionyl chloride and the solvent were removed by evaporation at reduced pressure and 392 ml (4.00 mole) of 1,3-difluorobenzene and then, portionwise, 533 g (4.00 mole) of aluminium trichloride were added over the solid residue. Once the exothermal reaction has ended, the mixture was refluxed for 5 hours. it was cooled and poured over a mixture of 3 kg of ice and 1 kg of water, was stirred for 0.5 hours and the phases were separated. The aqueous phase was washed with 1L of methylene chloride, was than basified with 2L of 40% NaOH and extracted with Ch2Cl2 (2 x 1L). The combined organic extracts were dried (MgSO4) and evaporated at reduced pressure to give 179.4 g (41% yield) of the title compound in the form of an ochre coloured oil.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH:14](=[N+:21]([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:22][N:21]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]1[N:1]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:2]=[CH:3][CH:4]=1)[CH3:23]
Reactant: C[N+](C)=Cc1ccccc1
Reactant: Nc1ccccc1-n1cccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1cccn1-c1ccccc1N

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-pyrrol-1-yl-phenylamine and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:38][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:23])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: NC1CCCCC1
Product: O=C(NC1CCCCC1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with cyclohexylamine as in General Procedure 10 to give the title compound. LCMS: m/z=529.01 (M+H+); retention time=0.96 minutes.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:30]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:22]([NH:26][NH2:27])([CH3:25])([CH3:24])[CH3:23]>C(O)C>[C:22]([N:26]1[C:11]([NH2:12])=[CH:10][C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:27]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: N#CCC(=O)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)n1nc(Cc2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 115.6 %

Procedure:
A solution of 4-(4-chloro-phenyl)-3-oxo-butyronitrile (500 mg, 2 mmol, 1.0 equiv), triethylamine (1.16 mL, 8.3 mmol, 3.2 equiv), and tert-butylhydrazine hydrochloride (1.03 g, 8.3 mmol, 3.2 equiv) in 10 mL of ethanol was heated at 100° C. in a sealed tube. After 4 d, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via automated flash chromatography (40 g SiO2, gradient from hexanes to ethyl acetate) to afford the product as a yellow oil (610 mg, 70%).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].O=[C:10]1[CH2:18][CH2:17][CH2:16][C:15]2[NH:14][CH:13]=[CH:12][C:11]1=2>O.C(O)C>[N:7](=[C:10]1[CH2:18][CH2:17][CH2:16][C:15]2[NH:14][CH:13]=[CH:12][C:11]1=2)[OH:8]
Reactant: NO
Reactant: O=C1CCCc2[nH]ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCCc2[nH]ccc21

Procedure:
A solution of 6.08 g of sodium acetate, 5.15 g of hydroxylamine hydrochloride, and 5.25 g of 4-keto-4,5,6,7-tetrahydro indole in 12 mL of water and 36 mL of ethanol was heated at 50° C. for 3 hr, quenched in water, extracted with ethyl acetate and dried over magnesium sulfate. The solvents were removed in vacuo to give a mixture of oxime isomers which was characterized by NMR and Mass spectroscopy.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:12][C:13](=[O:24])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][C:16]=1[F:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC>[CH2:5]([O:12][C:13](=[O:24])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][Br:2])=[CH:17][C:16]=1[F:23])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccc(CO)cc1F)OCc1ccccc1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: O=C(Nc1ccc(CBr)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Phosphorous tribromide (20.9 mL, 218 mmol) was added to diethylether (700 mL) at 0° C. To the PBr3 solution was added dropwise (2-fluoro-4-hydroxymethyl-phenyl)-carbamic acid benzyl ester (36.5 g, 133 mmol) in Et2O (400 mL) at 0° C. over 1 h. The reaction mixture was stirred at room temperature for 45 min and was carefully quenched at 0° C. with MeOH (100 mL). The reaction mixture was diluted with aq. NaHCO3 solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated to provide the title compound as a yellow foam: TLC (cyclohexane-EtOAc 1:1) Rf=0.88; HPLC RtI=1.16 min; 1H NMR (360 MHz, CDCl3): δ 8.13 (t, 1H), 7.48-0.37 (m, 5H), 7.21-7.14 (m, 2H), 6.78 (s broad, 1H), 5.25 (s, 2H), 4.47 (s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[F:11][C:12]1[CH:13]=[CH:14][C:15]([OH:32])=[C:16]([CH:31]=1)[O:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30]>C(#N)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:32][CH:8]([CH3:10])[CH3:9])=[C:16]([CH:31]=1)[O:17][CH2:18][CH2:19][N:20]1[C:21](=[O:30])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]1=[O:29]
Reactant: CC(C)I
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1ccc(F)cc1OCCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
7.71 g of potassium carbonate (56 mmol) and 7 ml of 2-iodopropane (70 mmol) are added to a solution of 14 g of 2-[2-(5-fluoro-2-hydroxyphenoxy)ethyl]isoindole-1,3-dione (6) (47 mmol) in 250 ml of acetonitrile. The mixture is stirred for 16 hours at 80° C. and the solvent is then evaporated off under reduced pressure and the residue is taken up in diethyl ether. The organic phase is washed with normal aqueous sodium hydroxide solution and then with saturated aqueous sodium chloride solution. It is dried over magnesium sulfate and filtered, and the solvent is evaporated off under vacuum. The title product is isolated by chromatography on a column of silica (eluent: 82/18 cyclohexane/ethyl acetate). 12.2 g of a white solid are isolated.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH:16]=[CH2:17])[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([O:5][C:6](=[O:7])[C:8]([CH2:13][OH:12])([CH2:9][OH:10])[CH:16]=[CH2:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC1(C(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C=CC(CO)(CO)C(=O)OC(C)(C)C
Yield: 81.6 %

Procedure:
A solution of 2,2-dimethyl-5-vinyl-[1,3]dioxane-5-carboxylic acid tert-butyl ester (969 mg, 4 mmol) and 4-toluenesulfonic acid hydrate (76 mg, 0.4 mmol) in methanol (10 mL) was stirred at room temperature for 30 min. The solvent was evaporated and the residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 4:1 to 1:1 to afford the title compound (660 mg, 82%) as a white solid. 1H NMR (300 MHz, d6-DMSO): δ 1.38 (s, 9H), 3.54-3.68 (m, 4H), 4.56 (t, J=5.4 Hz, 2H), 5.12 (d, J=10.5 Hz, 1H), 5.14 (d, J=18.3 Hz, 1H), 5.80 (dd, J=18.3, 10.5 Hz, 1H). LCMS (m/z) 225.2 [M+Na], Tr=1.47 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=[O:9].[OH-].[K+].Cl>CO.O>[OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cccc(OC)c1C#CCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(C(=O)O)c1C#CCCO
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Methyl 2-(4-hydroxybut-1-yn-1-yl)-3-(methyloxy)benzoate (0.056 g, 0.24 mmol) was dissolved in methanol (2 ml), and a solution of potassium hydroxide (0.027 g, 0.48 mmol) in water (0.5 ml) was added. The reaction mixture was stirred at 60° C. for 1 h, cooled to room temperature, and 1.5M hydrochloric acid was added to pH 4. The aqueous mixture was extracted with ethyl acetate, and the organic layer was washed with brine then dried over sodium sulfate. The mixture was then filtered and concentrated to give 2-(4-hydroxybut-1-yn-1-yl)-3-(methyloxy)benzoic acid (0.052 g, 99% yield). MS (EI) for C12H12O4: 219 (M−H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=2)=[CH:9][CH:8]=1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:33])[F:34])=[CH:16][N:15]=2)=[CH:9][CH:8]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCCN3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.1 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-piperidin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (8) (0.023 g, 0.048 mmol) in anhydrous methanol (1.5 mL) were added a 37% aq. solution of formaldehyde (0.014 mL, 0.19 mmol) and sodium triacetoxyborohydride (0.050 g, 0.24 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 2.5 hours, the volatiles were removed in vacuo and the residue was diluted with EtOAc (15 mL) and sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (10 mL), the combined organic layers were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice after which the sample was further dried on high-vacuum to give the title compound (9) (0.022 g, 91% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.17 (s, 1H), 8.66 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.43 (s, 1H), 7.27-7.13 (m, 6H), 6.92 (s, 1H), 3.49 (s, 2H), 3.15-2.98 (m, 4H), 2.97-2.90 (m, 1H), 2.75-2.69 (m, 1H), 2.07-1.97 (m, 1H), 1.90 (s, 3H), 1.73 (d, J=12.8 Hz, 1H), 1.66-1.54 (m, 3H), 1.50-1.38 (m, 1H), 1.36-1.27 (m, 1H). LCMS Method C: rt 4.88 min; m/z 498.3 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1)[C@@H:10]([OH:29])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:45]([Si:49]([CH3:52])([CH3:51])Cl)([CH3:48])([CH3:47])[CH3:46].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:36]=1)[C@@H:10]([O:29][Si:49]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:52])[CH3:51])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H](O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.19 g (5.4 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-[(4-biphenylyl)methyl]hexanoic acid in 55 ml of DMF are silylated, at RT for 20 h and under a protective gas, with 3.71 g (24.6 mmol) of tert-butyldimethylchlorosilane and 3.0 g (44 mmol) of imidazole. The reaction mixture is evaporated and the residue is taken up in ethyl acetate; this solution is then washed with sat. NaHCO3 solution, water and saline. The aqueous phases are extracted 2× with ethyl acetate and the organic phases are dried with Na2SO4 and evaporated. The residue is dissolved in 64 ml of methanol and 15 ml of THF, and this solution is treated with 4.5 g of potassium carbonate and 15 ml of water and stirred at RT for 1 h. Working up in analogy with Example 88c), and medium pressure chromatography (gradient: 0-10% methanol in methylene chloride), results in the title compound: TLC Rf (B)=0.7; tRet (II)=22.7 min.
Reaction SMILES: C(OCC)(=O)C.C(OC([NH:17][C:18]([NH:30][CH2:31]/[CH:32]=[CH:33]/[C:34]1[CH:94]=[CH:93][C:37]([CH2:38][C:39]2[C:40]([CH3:92])=[CH:41][C:42]([O:84]CC3C=CC=CC=3)=[C:43]([C@@H:45]3[O:74][C@H:73]([CH2:75][O:76]CC4C=CC=CC=4)[C@@H:64]([O:65]CC4C=CC=CC=4)[C@H:55]([O:56]CC4C=CC=CC=4)[C@H:46]3[O:47]CC3C=CC=CC=3)[CH:44]=2)=[CH:36][CH:35]=1)=[N:19]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH2:19][C:18]([NH:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:94]=[CH:93][C:37]([CH2:38][C:39]2[C:40]([CH3:92])=[CH:41][C:42]([OH:84])=[C:43]([C@@H:45]3[O:74][C@H:73]([CH2:75][OH:76])[C@@H:64]([OH:65])[C@H:55]([OH:56])[C@H:46]3[OH:47])[CH:44]=2)=[CH:36][CH:35]=1)=[NH:17]
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(O)c([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(CCCNC(=N)N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a methanol (2.6 mL)-ethyl acetate (1.3 mL) mixture solution of (1S)-1-[5-[4-[(1E)-3-[[benzyloxy carbonyl amino(benzyloxycarbonylimino)methyl]amino]prop-1-en-1-yl]benzyl]-2-(benzyloxy)-4-methylphenyl]-1,5-anhydro-2,3,4,6-tetra-O-benzyl-D-glucitol (154 mg, 0.131 mmol) was added 20% palladium hydroxide (160 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through celite, and evaporated under reduced pressure to obtain a residue. Thus obtained residue was dissolved in methanol (1.5 mL). And 20% palladium hydroxide (63 mg) was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 days. The reaction solution was filtered through celite, and evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified with silica gel column chromatography (ethyl acetate:ethanol:water=10:2:1 then 5:2:1, and then ethanol:water=10:1) to obtain the title compound (38 mg, 63%) as a colorless powder. NMR data and MS data of the compound are shown in Table 1.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12](OCC)=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][OH:13])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nc(-c2ccccc2)cs1
Reaction time: 1 h
Yield: 109.4 %

Procedure:
To ethyl 4-phenylthiazole-2-carboxylate (1 g, 4.3 mmol) in anhydrous THF was added LiAlH4 and the mixture was stirred for 1 hour. The reaction was quenched with water, extracted with EtOAc and dried over anhydrous sodium sulfate. The solution was concentrated under vacuum to afford (4-phenylthiazol-2-yl)methanol as a white solid (0.9 g). MS (ESI) m/z 191 (M+H+).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCNCC1
Product: NCCSC(=O)N1CCCCC1

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (300 mg) and piperidine (184 μl) were subjected to similar reations to those described in References 2 and 4 to give 2-piperidinocarbonylthioethylamine (crude formate: 137 mg). The product was dissolved in anhydrous methanol (3 ml). To the solution were added triethylamine (432 μl) and mitomycin A (151 mg: 0.7 molar equivalent). The solution was treated in a similar manner to that described in Example 1 to obtain Compound 42 (0.21 mg) in the form of grayish blue powders with a yield of 74%.