Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:18]=2)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:6][N:5]=[C:4]2[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:3]=12.[I:30]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCCl.O.ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:18]=2)[C:13]([N:15]([CH3:16])[CH3:17])=[O:14])=[CH:6][N:5]=[C:4]2[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[CH:20]=[C:21]([I:30])[C:3]=12
Reactant: O=C1CCC(=O)N1I
Reactant: CN(C)C(=O)c1cncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)c2Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CN(C)C(=O)c1cncc(-c2cnc3c(c(I)cn3COCC[Si](C)(C)C)c2Cl)c1
Temperature: 25 °C

Procedure:
1.117 g (2.59 mmol) of 5-[4-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide was dissolved in 19 ml of anhydrous 1,2-dichloroethane. 1.506 g (6.69 mmol) of N-iodosuccinimide was added and the mixture irradiated in a microwave reactor to 140° C. for 30 minutes. Saturated aqueous solution of sodium thiosulfate was added and the resulting mixture stirred at ambient temperature, then diluted with water and dichloromethane. The aqueous phase was separated and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The resulting crude was purified by flash chromatography on silica gel using a gradient of 10% v/v methanol in ethyl acetate and hexanes to afford 904.7 mg (62%, 1.625 mmol) of (5-[4-chloro-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide as a brown oil. 1H-NMR [500 MHz, d6-DMSO] d 8.75 (m, 1H), 8.69 (m, 1H), 8.39 (m, 1H), 8.12 (s, 1H), 8.02 (m, 1H), 5.64 (s, 2H), 3.54 (t, 2H), 3.02 (s, 3H), 3.00 (s, 3H), 0.84 (t, 2H), 0.09 (s, 9H); MS [MH+] m/z: 557.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10]2)[NH:5][C:4]1=O.[BH4-].[Li+]>C1COCC1.C1(C)C=CC=CC=1>[OH:1][CH2:2][CH:3]1[CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:10]2)[NH:5][CH2:4]1
Reactant: COc1ccc(CC2CCC3NC(=O)C(CO)CC3C2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(CC2CCC3NCC(CO)CC3C2)cc1

Procedure:
In a manner analogous to Example 1, (±)-(3RS,4aRS,6SR,8aSR)-3,4,4a,5,6,7,8,8a-octahydro-3-hydroxymethyl-6-((4-methoxyphenyl)methyl)quinolin-2[1H]-one (prepared according to step a)) was reduced by heating at 100° C. in the presence of lithium borohydride solution in THF/toluene to give the title compound, mg. 282°-4° C. (HCl, hemihydrate salt).
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[C:13]2[O:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[OH-].[K+].Cl>C(O)C>[C:14]([C:11]1[O:12][C:13]2[C:5]([O:4][CH2:3][CH:2]3[O:1][CH2:19]3)=[CH:6][CH:7]=[CH:8][C:9]=2[CH:10]=1)([OH:16])=[O:15]
Reactant: CCOC(=O)c1cc2cccc(OCC3CO3)c2o1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cccc(OCC3CO3)c2o1

Procedure:
There was dissolved 2.6 g (0.01 mole) of 7-(2,3-epoxypropoxy)-2-ethoxycarbonylbenzofuran obtained in Reference Example 9 in 10 ml of ethanol, and thereto 0.9 g (0.012 mole) of potassium hydroxide in 5 ml of ethanol solution was added dropwise with stirred under cooling with ice. After stirring the mixture for 3 hours the reaction was completed to neutralize the reaction mixture by 2N hydrochloric acid. Thereafter, the solvent was distilled away from the reaction mixture under reduced pressure, the resultant residue was extracted from 30 ml of chloroform. After washing the chloroform layer with water the layer was dried with magnesium sulfate, and then chloroform was distilled away under reduced pressure to give the resultant residue.
Reaction SMILES: [OH:1][C:2]1[C:23]([CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[C:22]([O:29][CH2:30][O:31][CH3:32])[CH:21]=[C:20]([O:33][CH2:34][O:35][CH3:36])[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:23]([CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])=[C:22]([O:29][CH2:30][O:31][CH3:32])[CH:21]=[C:20]([O:33][CH2:34][O:35][CH3:36])[C:3]=1[C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1
Reactant: COCOc1ccc(C=CC(=O)c2c(OCOC)cc(OCOC)c(CC=C(C)C)c2O)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(CCC(=O)c2c(OCOC)cc(OCOC)c(CCC(C)C)c2O)cc1OC
Yield: 93.8 %

Procedure:
The so-obtained 2'-hydroxy-3-methoxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone was dissolved in ethyl acetate, and catalytic reduction was carried out by using 3.0 g of 5% palladium/carbon. The reaction liquid was filtered by using Celite and concentrated under a reduced pressure to obtain 12.4 g (yield=93.8%) of 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-isopentylphenyl]-3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone in the form of a syrup.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:15][CH3:16])[S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C(OCC)(=O)C.CO>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:15][CH3:16])[S:11]([CH3:14])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCN(c1cccc(C(C)=O)c1)S(C)(=O)=O
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(C)(=O)=O
Yield: 88.6 %

Procedure:
1.1 g (4.56 mmol) of N-(3-acetyl-phenyl)-N-ethyl-methanesulfonamide were dissolved in 10 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.2 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-methanesulfonamide as a yellowish-white solid were obtained (yield 88.6%)
Reaction SMILES: [CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)[CH3:2].Cl[C:14]1[N:15]=[C:16]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:17]2[N:23]=[C:22]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[CH:21]=[CH:20][C:18]=2[N:19]=1>>[CH2:1]([N:3]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[C:14]1[N:15]=[C:16]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:17]2[N:23]=[C:22]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[CH:21]=[CH:20][C:18]=2[N:19]=1)[CH3:2]
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CCn1[nH]c2ccccc2c1=O
Product: CCn1c(=O)c2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
Following General Procedure C, 2-ethyl-1H-indazol-3(2H)-one and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 104. LCMS (MH+)=532.3. 1H-NMR (DMSO-d6): δ 8.39 (d, 1H), 8.09 (d, 1H), 7.82 (d, 1H), 7.78 (m, 1H), 7.70 (m, 1H), 7.33 (m, 1H), 4.54 (s, 4H), 4.32 (m, 2H), 4.00 (s, 1H), 3.85 (m, 4H), 3.68 (s, 2H), 2.90 (m, 2H), 1.97 (m, 2H), 1.64 (m, 2H), 1.29 (m, 2H), 1.16 (m, 1H), 1.07 (t, 3H), 1.03 (s, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)C>[CH2:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1
Reactant: O=Cc1ccccc1
Solvent: CCOCC
Product: O=C(Nc1ccc(NCc2ccccc2)cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from N-(4-amino-phenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-2-oxo-acetamide (Example 104) and benzaldehyde according to the method described in Example 82. Melting Point: 145-148° C. (diethylether)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:16][C:17]1([C:26]#[N:27])[CH:22]2[CH2:23][CH2:24][CH2:25][CH:18]1[CH2:19][CH2:20][CH2:21]2.C(Cl)Cl.O>O.C1COCC1>[C:26]([C:17]1([NH:16][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:18]2[CH2:19][CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25]2)#[N:27]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#CC1(N)C2CCCC1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(NC(=O)c2ccccc2)C2CCCC1CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add a solution of 2.37 g (17.17 mmol) of potassium carbonate in 30 mL of water, then 1.37 mL (11.8 mmol) of benzoyl chloride, to a solution of 1.88 g (11.45 mmol) of 9-aminobicyclo[3.3.1]nonane-9-carbonitrile in 20 mL of THF. Stir the reaction mixture for 1 h at RT, then distribute in 100 mL of a 1:1 mixture of DCM/water. Wash the organic phase with 50 mL of water, dry over Na2SO4 and concentrate under reduced pressure. Solidify the residue obtained in 100 mL of pentane giving, after filtration and washing with pentane, 2.81 g of N-(9-cyanobicyclo[3.3.1]non-9-yl)benzamide in the form of white powder.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][NH2:19])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:20]([O-])(O)=[O:21].[Na+].C(Cl)(Cl)=O>C(Cl)Cl.O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]3[O:17][C:20](=[O:21])[NH:19][N:18]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]nc(OCC2c3ccccc3-c3ccccc32)o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A suspension of N-[(9H-fluoren-9-ylmethoxy)carbonyl]hydrazine (141) (1.49 g, 5.78 mmol), CH2Cl2 (60 ml) and saturated NaHCO3 solution (60 ml) was stirred vigorously at 0° C. for 5 minutes, and the solution was then left for 5 minutes without stirring. Phosgene (1.89 M in toluene, 7.95 ml, 15.0 mmol) was then carefully added to the lower, organic phase using a syringe, and stirring of the reaction mixture was begun again immediately after the addition. After 10 minutes, water (20 ml) and CH2Cl2 (20 ml) were added to the reaction mixture. The phases were then separated rapidly, the aqueous phase was extracted with CH2Cl2 (50 ml), and the combined organic phases were dried over Na2SO4. Removal of the solvent under reduced pressure and drying gave a colourless solid (1.35 g, 4.82 mmol, 83%).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][C:7]1([C:17](OCC)=[O:18])[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH3:15])[C:8]1=[O:16])([O-])=O>[C].[Pd].C(O)C>[O:16]=[C:8]1[C:7]2([CH2:6][C:5]3[C:4](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:1][C:17]2=[O:18])[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][CH3:15]
Reactant: CCCN1CCCC(Cc2ccccc2[N+](=O)[O-])(C(=O)OCC)C1=O
Agent: [Pd]
Solvent: CCO
Product: CCCN1CCCC2(Cc3ccccc3NC2=O)C1=O
Reaction time: 6 h
Yield: 70.4 %

Procedure:
10% Palladium- carbon (0.2 g) was added to an ethanol solution (20 ml) of ethyl 3-(2-nitrobenzyl)-2-oxo-1-propyl-3-piperidinecarboxylate (1.00 g), and catalytic hydrogenation was conducted at room temperature under one atmospheric pressure for 6 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was dissolved in toluene (20 ml), which was heated under reflux for 12 hours. The reaction mixture was concentrated, and the obtained crude crystals were recrystallized from ethyl acetate-hexane to give the entitled compound (0.55 g).
Reaction SMILES: [C:1]([NH:13][NH2:14])(=[O:12])[C:2]1[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:4](NN)=[O:5].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]1[N:33]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]2[N:27]=[C:28]([C:31]#[N:32])[N:29]=[CH:30][C:25]=2[CH:24]=1>CN(C=O)C>[CH3:36][C:35]([CH3:38])([CH3:37])[CH2:34][N:33]1[C:26]2[N:27]=[C:28]([C:31]#[N:32])[N:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[CH2:22][N:14]1[NH:13][C:1](=[O:12])[C:2]2[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:4]1=[O:5]
Reactant: NNC(=O)c1ccccc1C(=O)NN
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(Cn2[nH]c(=O)c3ccccc3c2=O)cc2cnc(C#N)nc21
Reaction time: 18 h
Yield: 81.6 %

Procedure:
To a solution of 338 mg (1.3 mmoles) of phthalhydrazide in 20 ml of DMF, 252 mg (1.83 mmoles) of K2CO3 and 400 mg (1.30 mmoles) of 6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:2) give 412 mg of desired 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 70% yield. The obtained product is treated with MeJ under the same conditionto give N-methylated compound. To a solution of 295 mg (0.76 mmoles) of 7-(2,2-dimethyl-propyl)-6-(1,4-dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 20 ml of DMF, 0.066 ml (1.06 mmoles) of MeJ and 168 mg (1.22 mmoles) of K2CO3 are added successively and the mixture is stireed for 18 hours at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over MgSO4. Chromatography on silica gel (eluent: n-Hexane:AcOEt=1:4) give 238 mg of 7-(2,2-Dimethyl-propyl)-6-(3-methyl-1,4dioxo-3,4-dihydro-1H-phthalazin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 78% yield.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH:9]([O:11][CH3:12])=[CH2:10].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:12][O:11][CH:9]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH3:10]
Reactant: C=COC
Reactant: Oc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(C)Oc1ccccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
110 parts by weight of pyrocatechol is suspended in 100 parts by weight of toluene. At +5° C., 64 parts by weight of vinylmethyl ether at -40° C. is introduced all at once into the suspension and a drop of concentrated hydrochloric acid is then added. The mixture is heated, with stirring, to about +20° C., whereupon the reaction is initiated and the temperature in the flask rises to about 65° C. If necessary, ice water may be used for external cooling. The mixture is kept for 30 minutes at 65° C. and 5 parts by weight of 2N NaOH is then added. After the mixture has been cooled and dried with Na2SO4 the solvent is evaporated in a rotary evaporator and distillation carried out in vacuo.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[F:9][CH:10]([F:21])[O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>>[F:9][CH:10]([F:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]2)=[O:17])=[CH:19][CH:20]=1
Reactant: NC1CCC(O)CC1
Reactant: O=C(Cl)c1ccc(OC(F)F)cc1
Product: O=C(NC1CCC(O)CC1)c1ccc(OC(F)F)cc1

Procedure:
4-(4-DIFLUOROMETHOXYBENZAMIDO)CYCLOHEXANOL is prepared following the procedure described in Example A-1 using corresponding molar equivalent quantities of 4-aminocyclohexanol and 4-difluoromethoxybenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]([Cl:11])[C:3]=1[Cl:12].[NH2:13][CH2:14][CH2:15][CH2:16][Si:17](OCC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[NH2:13][CH2:14][CH2:15][CH2:16][Si:17]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[O:8][C:7]1[C:2]([Cl:1])=[C:3]([Cl:12])[C:4]([Cl:11])=[C:5]([Cl:10])[C:6]=1[Cl:9]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCO[Si](CCCN)(OCC)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reaction time: 0.17 h

Procedure:
In a 250 ml three-necked flask equipped with magnetic stirrer, reflux condenser and dropping funnel, 26.6 g of pentachlorophenol is placed for dissolving in 70 ml of chloroform and 50 ml of triethylamine. Over a period of 10 minutes, 22.1 g of 3-aminopropyltriethoxysilane is added, drop by drop, with refluxing and stirring. After three hours of boiling and stirring, the clear solution is concentrated by distilling out the chloroform, the ethanol that is formed, and most of the triethylamine, and the product is carefully precipitated with 130 ml of pentane, with stirring. It is washed thrice with pentane and decanted, then dried in a high vacuum at about 60° C. 41 g of a finely divided 3-aminopropyldiethoxypentachlorophenoxysilane is obtained having a melting point of 122° C.
Reaction SMILES: C([O:4][C@H:5]1[CH:9]=[CH:8][C@@H:7]([OH:10])[CH2:6]1)(=O)C.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:19]([Si:16]([CH3:18])([CH3:17])[O:4][C@H:5]1[CH2:6][C@@H:7]([OH:10])[CH:8]=[CH:9]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C=C[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-(+)-4-cyclopentene-1,3-diol 1-acetate (1.0 g, 7.03 mmol) (Aldrich) and imidazole (960 mg, 14.06 mmol) (Aldrich) in tetrahydrofuran (35 mL) was added tert-butyldimethylsilyl chloride (1.27 g, 8.44 mmol) (Aldrich). The mixture was allowed to warm slowly to room temperature, stirred overnight and then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was dissolved in methanol (45 mL). To this solution was added potassium carbonate (1.17 g, 8.44 mmol) and the mixture stirred overnight. The next morning the reaction mixture was partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was purified by silica gel column chromatography with a 0–30% diethyl ether in hexanes gradient to give (−)-(1R,4S)-4-(tert-butyl-dimethyl-silanyloxy)-cyclopent-2-enol as a colorless oil. (Yield 1.29 g, 85%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: OB(O)c1ccc(Cl)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(Cl)nc2)c1

Procedure:
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 6-chloro-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=33%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:34][C@@H:35]([CH2:65][C:66]#[N:67])[C:36]([NH:38][C@@H:39]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=1)[C:40]([NH:42][C@@H:43]([CH2:50][C:51]1[CH2:55][CH2:54][CH2:53][CH:52]=1)[C:44]([C@@:46]1([CH3:49])[CH2:48][O:47]1)=[O:45])=[O:41])=[O:37].[O:68]1[CH2:73][CH2:72][N:71]([CH2:74][C:75](O)=[O:76])[CH2:70][CH2:69]1>CN(C=O)C.O.CCOC(C)=O>[C:66]([CH2:65][C@H:35]([NH:34][C:75](=[O:76])[CH2:74][N:71]1[CH2:72][CH2:73][O:68][CH2:69][CH2:70]1)[C:36]([NH:38][C@@H:39]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=1)[C:40]([NH:42][C@@H:43]([CH2:50][C:51]1[CH2:55][CH2:54][CH2:53][CH:52]=1)[C:44]([C@@:46]1([CH3:49])[CH2:48][O:47]1)=[O:45])=[O:41])=[O:37])#[N:67]
Reactant: O=C(O)CN1CCOCC1
Reactant: COc1ccc(C[C@H](NC(=O)[C@@H](N)CC#N)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(C[C@H](NC(=O)[C@H](CC#N)NC(=O)CN2CCOCC2)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
Sequentially HATU (0.61 g, 1.6 mmol) and DIEA (1.35 mL, 7.8 mmol) were added to a 0° C. solution of (S)-2-amino-3-cyano-N-((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)propanamide (1 mmol) and 2-morpholinoacetic acid (160 mg, 1.10 mmol) in DMF (20 mL) with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added. The two layers were separated and the aqueous phase was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:2) to afford (S)-3-cyano-N-((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)-2-(2-morpholinoacetamido)propanamide (210 mg, 35% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.44 (d, J=6.6 Hz, 1H), 8.16 (d, J=7.5 Hz, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 5.40 (s, 1H), 4.60-4.35 (m, 3H), 3.70 (s, 3H), 3.62-3.57 (m, 4H), 3.18 (m, 1H), 3.05-2.80 (m, 3H), 2.65 (m, 1H), 2.50-2.10 (m, 10H), 1.90-1.70 (m, 2H), 1.37 (s, 3H). MS(EI) for C31H41N5O7, found 596.3 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([C@H:29]4[CH2:33][O:32]C5(CCCCC5)[O:30]4)[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].O.Cl>C(O)C>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([C@H:29]([OH:30])[CH2:33][OH:32])[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)CO)ns1
Yield: 82.6 %

Procedure:
(S)—N-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.600 g, 1.09 mmol) was dissolved in ethanol (25 ml) and water (600 mg) and concentrated HCl (600 mg) were added. The mixture was heated to reflux for 2 hours, concentrated in vacuo, dissolved and concentrated with EtOH (2×50 mL). The material was triturated from acetonitrile to afford (S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol (0.420 g, 0.90 mmol, 82%) as a solid. Mass Spectrum (apci) m/z=469.1 (M+H−HCl).