Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][CH2:8][N:9]2[CH2:16][CH2:15][CH2:14][C@@:10]2([CH3:17])[C:11](O)=[O:12])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:12][CH2:11][C@:10]1([CH3:17])[CH2:14][CH2:15][CH2:16][N:9]1[CH2:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=1
Reactant: COc1ccc(CCN2CCC[C@@]2(C)C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCC[C@@]2(C)CO)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 46 %

Procedure:
(S)-1-(4-Methoxyphenethyl)-2-methylproline (see Preparation 12) (895 mg) was added portionwise to a stirred suspension of lithium aluminium hydride (380 mg) in tetrahydrofuran (60 ml) and the mixture stirred at room temperature for 22 hours. The reaction was quenched by the cautious, dropwise, sequential addition of water (0.4 ml), 5M aqueous sodium hydroxide solution (0.4 ml) and water (1.2 ml), and then the resulting mixture filtered. The filtrate was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a colourless oil, (390 mg, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[OH:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:17][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:19][CH:20]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccc(Br)cc2C=O)cc1
Temperature: 170 °C
Yield: 95.5 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (4.04 g, 20 mmol) (Alfa) in N,N-dimethylacetamide (30 mL) was added anhydrous K2CO3 (2.76 g, 20 mmol), and methyl 4-hydroxybenzoate (3.1 g, 20 mmol, Aldrich). The reaction mixture was heated at 170° C. for 1 h. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, brine. The organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc: hexanes=1:8 then 1:4) to give 4-(4-bromo-2-formyl-phenoxy)-benzoic acid methyl ester as a white solid (Yield 6.4 g, 95%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH2:10]([O:12][C:13](=[O:16])[NH:14][NH2:15])[CH3:11]>C(O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[N:15][NH:14][C:13]([O:12][CH2:10][CH3:11])=[O:16])[CH3:2]
Reactant: CC(=O)c1ccccn1
Reactant: CCOC(=O)NN
Solvent: CCO
Product: CCOC(=O)NN=C(C)c1ccccn1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A mixture of 6.06 gm (0.05 mole) of 2-acetylpyridine, 5.21 gm (0.05 mole) of ethylcarbazate and 100 ml of absolute ethanol is refluxed 2 hr. The hot solution is filtered. The filtrate is cooled to room temperature and then chilled in the refrigerator. The product is collected, washed with Skellysolve B and dried to yield 3.8 gm (37%) of the title compound having a melting point of 113.2° C.
Reaction SMILES: [NH:1]1C2=NC=CC=C2C=N1.[C:10]([C:13]1[C:21]2[C:16](=CN=[C:19]([CH3:22])[CH:20]=2)[N:15]([CH2:23][C:24]([OH:26])=[O:25])[N:14]=1)(=[O:12])[NH2:11]>>[C:10]([C:13]1[C:21]2[C:16](=[N:1][CH:22]=[CH:19][CH:20]=2)[N:15]([CH2:23][C:24]([OH:26])=[O:25])[N:14]=1)(=[O:12])[NH2:11]
Reactant: c1cnc2[nH]ncc2c1
Reactant: Cc1cc2c(C(N)=O)nn(CC(=O)O)c2cn1
Product: NC(=O)c1nn(CC(=O)O)c2ncccc12

Procedure:
was prepared from 1H-pyrazolo[3,4-b]pyridine [271-73-8] by using the same procedures as described for the preparation of (3-carbamoyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid (Scheme A27). MS (LC-MS): 221 [M+H]+, tR (HPLC conditions k): 0.87 min.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:15](OCC)[CH2:16][NH2:17])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[NH4+]>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:9][CH:15]=[CH:16][N:17]=2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(CN)OCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: O=[N+]([O-])c1ccc(-c2ncco2)cc1
Temperature: 100 °C
Yield: 26.6 %

Procedure:
A mixture of p-nitro benzaldehyde (3 g, 19.8 mmol) and 2,2-diethoxy-ethylamine (2.64 g, 19.8 mmol) was heated at 100° C. for 2 hrs. The reaction mixture was cooled to room temperature and sulphuric acid (20 ml) was added. The resultant solution was added slowly to a mixture of phosphorus pentoxide (10 g) and sulphuric acid (3 ml) at 180° C. and the temperature was maintained for 30 min. The reaction mixture was cooled to room temperature and basified with saturated ammonium hydroxide solution. The resultant solid was filtered and recrystallised with ether to give 2-(4-nitro-phenyl)-oxazole (1 g, 26%).
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)C>O1CCCC1>[O:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH:5]=[O:4])=[CH:9][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(COc1ccc(Oc2ccccc2)cc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCOc1ccc(Oc2ccccc2)cc1
Temperature: 45 °C
Reaction time: 21 h

Procedure:
280 ml of 1N HCl are added to a solution of 170 g of the acetal obtained in step (a) in 2000 ml of tetrahydrofuran, and the batch is stirred, under nitrogen, for 21 hours at 45° C. Subsequently, the tetrahydrofuran is distilled off in vacuo, the residue is taken up in diethyl ether and the resultant solution is washed repeatedly with saturated sodium bicarbonate solution and finally with water. The ethereal phase is dried over sodium sulfate and the solvent is distilled off entirely. The crude aldehyde is purified by chromatography over silica gel (eluant: a 1:1 mixture of diethyl ether and hexane), affording pure 4-phenoxyphenoxyacetaldehyde with a melting point of 79°-81° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH:8]=1)(=O)=O.[CH:19]([O:22][C:23]1[C:24]([N+:39]([O-:41])=[O:40])=[CH:25][C:26]([CH3:38])=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)([CH3:21])[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.CCCCCC.CCOC(C)=O>C1COCC1.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>[CH:19]([O:22][C:23]1[C:24]([N+:39]([O-:41])=[O:40])=[CH:25][C:26]([CH3:38])=[C:27]([C:7]2[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH:8]=2)[CH:28]=1)([CH3:21])[CH3:20]
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCC2(CC1)OCCO2
Temperature: 80 °C

Procedure:
A stirred solution of the 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (0.03 mmol) and 2-(5-isopropoxy-2-methyl-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 5, 0.04 mmol) in THF (3 mL), containing [Pd(PPh3)4] (0.013 mmol) and K3PO4.H2O (0.045 mmol), is heated to 80° C. under argon for 16 hours. After workup and silica flash chromatography (hexane/EtOAc 4:1), 8-(5-isopropoxy-2-methyl-4-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene is obtained. 1H NMR (CDCl3, 400 MHz) δ 7.62 (s, 1H), 6.82 (s, 1H), 5.74 (m, 1H), 4.65 (m, 1H), 4.04 (m, 4H), 2.47 (m, 4H), 2.27 (s, 3H), 1.89 (t, 2H), 1.29 (d, 6H). MS (ES+): 334.16 (M+1)+.
Reaction SMILES: CC(NC(=O)C1C=CC=C(C(F)(F)F)C=1[Cl:17])C#C.N1N2C=CC=NC2=NN=1.[Cl:28][C:29]1[CH:37]=[C:36](F)[CH:35]=[CH:34][C:30]=1[C:31]([Cl:33])=[O:32].C(Br)C=C.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.[Cu]I.CCOC(C)=O>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:17])[CH:35]=[CH:34][C:30]=1[C:31]([Cl:33])=[O:32]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: C#CC(C)NC(=O)c1cccc(C(F)(F)F)c1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C=CCBr
Product: O=C(Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To the suspension of Intermediate 233 (138 mg, 0.5 mmol, 1.0 equiv), tetrazolo[1,5-a]pyrimidine (Intermediate 234) (67 mg, 0.55 mmol, 1.1 equiv.), allyl bromide (73 mg, 0.6 mmol, 1.2 equiv.) and Cs2CO3(0.49 g, 1.5 mmol, 3.0 equiv.) in THF (2 mL), CuI (48 mg, 0.25 mmol, 0.5 equiv.) was added at room temperature in one portion under N2. The reaction mixture was then stirred at room temperature under N2 for 16 hours. Celite and EtOAc (5 mL) were added and the suspension was stirred for 20 minutes. The insoluble solid was filtered off and washed with EtOAc. The filtrate solution was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography with EtOAc/hexanes as eluents to afford compound Intermediate 235 (146 mg, 0.34 mmol, 67% yield) as a white solid. Byproducts Intermediate 236 (30 mg, 0.075 mmol, 15% yield) and Intermediate 237 (2% yield) were also isolated.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[F:12][C:13]1[CH:40]=[CH:39][C:16]([C:17]([CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[NH:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=O)=[O:18])=[CH:15][CH:14]=1>O>[F:12][C:13]1[CH:40]=[CH:39][C:16]([CH:17]([OH:18])[CH2:19][CH2:20][CH2:21][N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[NH:31][C:30]3=[O:38])[CH2:25][CH2:24]2)=[CH:15][CH:14]=1
Reactant: O=C(CCC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCC(O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 2.0 g of lithium aluminum hydride and 180 ml of tetrahydrofuran at room temperature, was added 4.6 g of 1-[1-(β-p-fluorobenzoylpropionyl)-4-piperidyl]-2-oxobenzimidazoline portionwise over a period of about 10 minutes. The mixture was further stirred at room temperature for one hour, then gradually heated to 60°C over a period of one hour, stirred for additional 4 hours at 60° - 65°C, and then cooled in ice. To the reaction mixture was carefully added 20 milliliters of cold water, and the precipitate formed was filtered off. The filtrate was added with 6 ml of acetic acid, and the tetrahydrofuran was removed by distillation under reduced pressure. The residue was made slightly alkaline by adding a 14% aqueous ammonia, and the solid precipitated was collected by filtration, dried, and recrystallized from toluene to obtain a white crystalline powder of 1-(p-fluorophenyl)-4-[4-(2-oxo-1-benzimidazolinyl)-piperidino]-1-butanol, melting at 160° - 161° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[N:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:64]O>O1CCCC1>[CH3:1][C:2]1[N:3]([CH2:64][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][N:58]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OCc1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCc1nc(C)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (7 g), 1,1′-(azodicarbonyl)dipiperidine (9.9 g), tributylphosphine (12.2 mL), pyridin-2-ylmethanol (2.8 mL) and tetrahydrofuran (350 mL) was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (2.6 g, 31%).
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21]([S:25][CH2:26][CH2:27][CH:28]=[O:29])[CH:22]=[CH:23][CH:24]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:29][CH:28]([CH2:27][CH2:26][S:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:30])([F:17])[F:31])[CH:20]=1)[CH2:2][C:3](=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: O=CCCSc1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)CC(O)CCSc1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 96.7 %

Procedure:
7.54 Grams of methyl acetoacetate were dissolved in 10 ml of water, and 9.07 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 35° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.5 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.41 g of sodium acetate and 1.61 g of tetrabutylammonium bromide were added thereto and then 29.4 g of a toluene solution containing 33.8% of 3-(3-trifluoromethylphenylthio)propanal were added thereto. The mixture was stirred at 45°-50° C. for 6 hours. After the mixture had been neutralized with a concentrated aqueous hydrochloric acid solution, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 14.92 g of crude 4-hydroxy-6-(3-trifluoromethylphenylthio)-2-hexanone (purity: 80.2%, yield: 96.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[C:32]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)#[CH:33].C(NCC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:33]#[C:32][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#Cc3cccnc3)c21
Reaction time: 48 h
Yield: 86 %

Procedure:
A flame-dried flask under an atmosphere of nitrogen gas containing N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Preparation # 15) (0.28 g) is treated with copper (I) iodide (0.01 g), dichlorobis(triphenylphosphine)palladium (II) (0.03 g) and 3-ethynylpyridine (0.10 g). The solids are treated with dimethylformamide (DMF) (3 mL) and diethylamine (3 mL). The resulting suspension is stirred for 2 days and is then concentrated under reduced pressure. The residue is flash column chromatographed on silica eluting with 2% to 4% methanol in dichloromethane. The product-containing fractions are combined and concentrated under reduced pressure. The resulting material is crystallized from methanol:acetonitrile to afford the title compound (0.23 g) as a tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[CH3:18][C@@:19]1([C:33]([O:35][CH3:36])=[O:34])[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][N:20]1C(OC(C)(C)C)=O.ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[NH:13][N:14]=2)[N:3]=[C:2]([N:20]2[CH2:21][C:22]([CH3:24])([CH3:25])[CH2:23][C@@:19]2([CH3:18])[C:33]([O:35][CH3:36])=[O:34])[N:7]=1
Reactant: COC(=O)[C@]1(C)CC(C)(C)CN1C(=O)OC(C)(C)C
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: COC(=O)[C@]1(C)CC(C)(C)CN1c1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)n1

Procedure:
Compound 106E was prepared from 1A and 106D as described for 1C: LC/MS [M+H]+: 406/408; Ret time (Method F): 3.55 min.
Reaction SMILES: [OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].B>C1COCC1>[NH2:5][CH2:4][CH2:3][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:1]
Reactant: N#CC[C@H](O)c1ccccc1
Agent: B
Solvent: C1CCOC1
Product: NCC[C@H](O)c1ccccc1
Yield: 97.2 %

Procedure:
To 10 ml of a THF solution of 1.47 g (10.0 mmol) of the (S)-3-hydroxy-3-phenylpropanenitrile obtained in Example 1, slowly added was 1.23 ml (13.0 mmol) of borane.dimethylsulfide complex. After removing the dimethylsulfide by reducing the pressure, the reaction mixture was refluxed for 2.5 hours. The reaction was stopped by the addition of a methanol/hydrochloric acid solution, and the methanol was distilled off under vacuum. After neutralizing with a 5N aqueous solution of sodium hydroxide, the solvent was distilled off, a further aqueous solution of sodium hydroxide was added to make the reaction solution basic, and this was then extracted with methylene chloride. This methylene chloride solution was dried with anhydrous sodium sulfate, and the solvent was then distilled off under vacuum to give 1.47 g of (S)-3-amino-1-phenylpropanol. The amino group of (S)-3-amino-1-phenylpropanol was monobenzoylated by reaction with benzoyl chloride, and when it was analyzed using a CHIRALCEL OB column (manufactured by Daicel Chemical Industries, Ltd., eluant; n-hexane:2-propanol=90:10) it was found that the optical purity was 98% ee.
Reaction SMILES: [CH3:1][N:2]1S[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=2[C:3]1=[O:4].[S:11]([S:14]([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH3:1][NH:2][C:3]([C:5]1[CH2:10][CH2:9][CH2:8][C:6]=1[S:11][S:14][C:6]1[CH2:8][CH2:9][CH2:10][C:5]=1[C:3]([NH:2][CH3:1])=[O:4])=[O:4]
Reactant: O=S([O-])S(=O)[O-]
Reactant: Cn1sc2c(c1=O)CCC2
Agent: [Na+]
Solvent: O
Product: CNC(=O)C1=C(SSC2=C(C(=O)NC)CCC2)CCC1

Procedure:
2-methyl-4,5-trimethylene-4-isothiazolin-3-one (1 part) was stirred in distilled water (25 parts) at 20°-25° C. Sodium hydrosulphite (2×0.2 parts) was added in two portions over 30 minutes. Analysis by HPLC indicated the formation of two products.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)CC1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 168) (598 mg, 1.18 mmol) and N-methylpiperazine (120 mg, 1.18 mmol) as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)c1ccc(I)cc1
Product: COC(=O)c1ccc(Sc2ccccc2)cc1

Procedure:
The general procedure was used to convert Methyl-4-iodobenzoate and thiophenol to the title product. Purification by flash chromatography (hexane/ethyl acetate [6:1] as the eluent) gave the analytically pure product as a white solid (411 mg, 84% yield). 1H NMR (300 MHz, CDCl3) δ 7.88 (dt, J=8.67, 2H; Hb, Hb′), 7.51–7.47 (m, 2H; Hc, Hc′), 7.39–7.37 (m, 3H; Hd, Hd′, He), 7.21 (dt, J=8.67, 2H; Ha, Ha′), 3.89 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 166.60 (C13), 144.33 (C1), 133.63 (C4), 132.29 (C8, C12), 130.03 (C7), 129.58 (C9, C11), 128.60 (C3, C5), 127.47 (C10), 127.39 (C2, C6), 52.02 (C14). Anal. Calcd. for C14H12O2S: C, 68.83; H, 4.95; S, 13.13; Found C, 68.87; H, 4.95; S, 12.96. mp found: 70–71° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26]([Cl:28])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([N:34]3[CH:38]=[C:37]([C:39](C4C=CC=CC=4)(C4C=CC=CC=4)[O:40][SiH2]C(C)(C)C)[CH:36]=[N:35]3)[C@@H:31]([OH:58])[C@H:30]2[OH:59])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:18][C:19]2[N:27]=[C:26]([Cl:28])[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:29]2[CH2:33][C@H:32]([N:34]3[CH:38]=[C:37]([CH2:39][OH:40])[CH:36]=[N:35]3)[C@@H:31]([OH:58])[C@H:30]2[OH:59])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](n3cc(C(O[SiH2]C(C)(C)C)(c4ccccc4)c4ccccc4)cn3)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(Nc2nc(Cl)nc3c2ncn3[C@@H]2C[C@H](n3cc(CO)cn3)[C@@H](O)[C@H]2O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1R,2S,3R,5S)-3-(6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-2-chloro-purin-9-yl)-5-[4-(tert-butyl-diphenyl-silanyloxymethyl)-pyrazol-1-yl]-cyclopentane-1,2-diol (step 1) (0.2 g, 0.24 mmol) is placed in a flask with THF (0.5 mL). Tetrabutylammonium fluoride (1M in THF, 0.26 mL, 0.26 mmol) is added and the reaction mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, dichloromethane/methanol 25:1). MS (ES+) m/e 592 (MH+).
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][N:3]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:2]12.N1C=CC=CC=1.[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>ClCCl>[C:27]1([CH3:28])[CH:29]=[CH:30][C:24]([S:21]([O:10][CH2:9][CH2:8][CH2:7][N:6]2[CH2:5][CH2:4][N:3]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:2]3[CH2:1]2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: OCCCN1CCN2CCCCC2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCN2CCN3CCCCC3C2)cc1

Procedure:
A solution of 4.5 g of the compound obtained in Step B, 2.5 ml of pyridine, and 4.8 g of tosyl chloride in 100 ml of dichloromethane is stirred for 24 hours at room temperature, and then washed with 100 ml of water and finally purified over a silica gel chromatography column, eluted with a mixture of CH2Cl2/MeOH (95/5), enabling the expected product to be isolated.