Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:20][N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[O:26][CH2:27][CH3:28])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@H:9]1[O:17][C@H:14]([CH2:15]O)[C@@H:12]([OH:13])[C@H:10]1[OH:11].S(Cl)([Cl:31])=O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][N:21]2[CH2:25][CH2:24][CH2:23][CH:22]2[O:26][CH2:27][CH3:28])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@H:9]1[O:17][C@H:14]([CH2:15][Cl:31])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: CCOC1CCCN1Nc1nc(Cl)nc2c1ncn2[C@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC1CCCN1Nc1nc(Cl)nc2c1ncn2[C@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
The title compound was prepared according to general method C. (S)-2-Chloro-N-[2-(methylmethoxy)-1-pyrrolidinyl]adenosine [Knutsen, L. J. S., Lau, J., Sheardown, M. J., Thomsen, C.; Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666](0.35 g, 0.8 mmol) was dissolved in acetonitrile (5 ml) and cooled on an ice-water bath. Under a nitrogen atmosphere, thionyl chloride (0.34 g, 0.2 ml, 2.4 mmol) (see Borchardt, R. T., Huber, J. A. and Wu, Y. S., Journal of Organic Chemistry, 1976, 41, 565-567) was added and a precipitate appeared which dissolved over the following 15 min. Pyridine (0.13 ml, 0.13 g, 1.6 mmol) was introduced gradually, the reaction mixture became yellow in colour and was allowed to reach room temperature gradually. After stirring the mixture overnight, ice was added and the reaction mixture was neutralised to pH 7 with aqueous sodium bicarbonate prior to extraction with ethyl acetate (2×10 ml). The combined extracts were dried (MgSO4) and evaporated to provide the intermediate 2,3-O-sulphinyl derivative (0.35 g), to which was added methanol (5 ml), water (1 ml) and 25% aqueous ammonia solution (0.25 ml) and this mixture was stirred for 16 h. The solution was evaporated in vacuo, and the resultant residue was purified by flash chromatography on silica gel eluting with a mixture of dichloromethane and 10% ammonia in ethanol (17:3), to provide the title (S)-2,5'-dichloro-5'-deoxy-N-[2-(methylmethoxy)-1-pyrrolidinyl]adenosine (0.12 g, 34%) as a foam, 1H-NMR (400 MHz, DMSO-d6) δ1.50-1.60 (1H, br, pyrrolidine C--H), 1.78 (2H, br q, pyrrolidine C--H), 1.92-2.03 (1H, br, pyrrolidine C--H), 3.85, 3.95 (2H, ABX, H-5'a and H-5'b), 4.09 (1H, br dd, H-4'), 4.17 (1H, dd, H-3'), 4.67 (1H, dd, H-2'), 5.49, 5.62 (2H, 2d, 2'- and 3'-OH), 5.87 (1H, d, H-1'), 8.38 (1H, s, H-8), 9.34 (1H, br s, --NH). HPLC retention time 9.65 min. (gradient elution over 30 min.; 20-80% acetonitrile/0.1% TFA in water, 99% purity at 250 nm). C16H22Cl2N6O4.0.25 H2O requires C, 43.9; H, 5.2; N, 19.2. Found: C, 43.7; H, 5.4; N, 19.4%.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][C:7]([C:11]([OH:13])=O)=[CH:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](CC[NH-])=[CH:15]1>>[CH2:15]([NH:14][C:11]([C:7]1[CH2:8][CH2:9][C:10]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]=2[CH:6]=1)=[O:13])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [NH-]CCc1c[nH]c2ccccc12
Reactant: O=C(O)C1=Cc2ccncc2CC1
Product: O=C(NCCc1ccccc1)C1=Cc2ccncc2CC1

Procedure:
Compound #68 7,8-Dihydro-isoquinoline-6-carboxylic acid [2-(1H-indol-3-yl)-ethyl-amide
Reaction SMILES: [CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:4])[OH:3].[N+](=[CH2:31])=[N-]>CCOCC>[CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:3])[O:4][CH3:31]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])P(C)(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COP(C)(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
The phosphinic acid of Example 20 is reacted with an excess of diazomethane in ether to give methyl P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinate.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCc2ccccc2C1
Product: c1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 200 °C

Procedure:
A mixture of 14.6 g. of 2-tetralone, 20 g. of phenylmagnesium bromide, and 200 ml. of diethyl ester is stirred for four hours and then refluxed for one hour. The mixture is acidified with the addition of 200 ml. of 1 N hydrochloric acid, filtered, and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, filtered, dried and evaporated; unchanged 2-tetralone is removed by distillation. The residue, containing 2-phenyl-3,4-dihydronaphthalene is mixed with 25 g. of 5 percent palladium-on-charcoal catalyst; the resulting mixture is heated to 200° C for six hours, cooled, diluted with 250 ml. of chloroform, filtered, and evaporated to give 2-phenylnaphthalene.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:2]#[CH:3].Br[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:18]/[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:34])[CH:22]=2)=[CH:13][CH:12]=1>C(N(CC)CC)C.C1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:41][C:38]1[CH:37]=[CH:36][C:35](/[C:17](/[C:14]2[CH:13]=[CH:12][C:11]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[CH:16][CH:15]=2)=[CH:18]\[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:34])[CH:22]=2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)C(C)c1ccc(OC/C=C(\c2ccc(Cl)cc2)c2ccc(Br)cc2)cc1C
Reactant: C#CCN1CCOCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)c1ccc(OC/C=C(\c2ccc(Cl)cc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C

Procedure:
Under nitrogen atmosphere, 4-propargylmorpholine (550 mg, 4.4 mmol) bis(triphenylphosphine)palladium(II) dichloride (40 mg, 0.057 mmol) and copper(II) acetate (7 mg, 0.038 mmol) were added to a degassed solution of the above ester (280 mg, 0.55 mmol) in triethylamine (30 mL). The reaction mixture was refluxed for 8 h, diluted with benzene (100 mL), filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform/methanol 9:1) yielding ethyl (Z)-[4-[3-(4-chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]propionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[CH3:16][N:17]([CH3:19])[CH:18]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: CCOC(OCC)N(C)C
Reactant: COc1ccc(CC(C)=O)cc1
Product: COc1ccc(C(=CN(C)C)C(C)=O)cc1

Procedure:
A stirred mixture of 1-(4-methoxyphenyl)-2-propanone (8.2 g) and dimethylformamide diethyl acetal (9.5 ml) was heated on an oil bath at 95°-100° C. for 30 minutes. Volatile material was removed under vacuum and the residue was crystallised from ether-petroleum spirit (40°-60° C.) to give the title compound (mp 56°-58° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)[C:5]([F:24])=[CH:4][N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][O:31][CH2:32][CH2:33][O:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[F:24][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([NH:39][C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:33][CH2:32][O:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:41][CH:40]=2)=[N:3][CH:4]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COCCOCOCCOc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COCCOCOCCOc1ccc(Nc2ncc(F)c(Nc3cccc(N(C)C(=O)OC(C)(C)C)c3)n2)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 57.5 %

Procedure:
In a 25 ml 3-Neck RBF, tert-butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)(methyl)carbamate (0.88 g), 4-(2-((2-methoxyethoxy)methoxy)ethoxy)aniline (0.901 g), Cs2CO3 (1.21 g) and Xantphose (0.144 g) were added in degassed 1,4-dioxane (10 mL) and the reaction mixture was degassed under argon for 30 minutes. Palladium(II)acetate (0.055 g) was added to reaction mixture and again it was degassed for 30 minutes. The reaction mixture was heated to 80° C. and stirred for 3.5 h. The reaction was monitored on TLC using CHCl3:methanol (9.5:0.5) as mobile phase. After completion of the reaction, reaction mixture was allowed to cool at room temperature. The reaction mixture was poured into water and product was extracted with ethyl acetate (3×25 ml). Ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by using Combiflash chromatography. Product was eluted with 2% methanol in CHCl3 to give 0.8 g of tert-butyl (3-((5-fluoro-2-((4-(2-((2-methoxyethoxy)methoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)(methyl)carbamate. M+1=557.9.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:7]
Reactant: NCCCCC(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCCCNC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Yield: 72.1 %

Procedure:
A mixture of 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (50 mg, 0.14 mmol) (prepared according to WO 2004108681), 5-aminovaleric acid (830 mg, 7.08 mmol) and NaOMe (11 mL, 5.31 mmol, 0.5 M in MeOH) was refluxed for 3 days. Solvent was evaporated, and the residue was partitioned between EtOAc and water. 1 M HCl was added with stirring until pH was ˜1. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 40 mg of the title compound. MS: (+) m/z 397.11 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][CH2:20][CH:19]=[N:18]2)[CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[OH:24]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[C:6]([Cl:16])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1
Reactant: O=C1NCC=NN1c1cc(Cl)c(Cc2ccc(Cl)cc2)c(Cl)c1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: O=c1cnn(-c2cc(Cl)c(Cc3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reaction time: 3 h
Yield: 85 %

Procedure:
In 2 ml of acetic acid were dissolved 0.2 g of 2-[3,5-dichloro-4-(4-chlorobenzyl)phenyl]-4,5-dihydro-1,2,4-triazine-3(2H)-one and 0.2 ml of hydrogenperoxide (30%). The reaction was allowed to proceed for 3 hours at temperatures ranging from 100 to 110° C. To the reaction mixture was added 20 ml of water to cause precipitation of the titled compound as crystalline product. The product was collected by filtration. The yield was 85%. m.p. 175-176° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([CH2:18][OH:19])=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.C(O)C.[C].[Pd]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1C(CO)=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1C(CO)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 55.3 %

Procedure:
A suspension of 10% palladium carbon (16 g) in acetic acid (50 ml) was added to a solution of t-butyl 7-(2-phenylacetamido)-3-hydroxymethyl-2-cephem-4-carboxylate (9.0 g) in ethanol (300 ml.), and the mixture was subjected to catalytic reduction at 65° C. in the presence of hydrogen at 20 atm. for 9 hours. After removing the insoluble substance by filtration, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (150 ml.) and adjusted to pH 7.5 with aqueous solution of sodium bicarbonate. The organic layer was separated, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with petroleum ether and collected by filtration to give t-butyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (5.0 g.).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:14])[NH:6][CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5](=[O:14])[NH:6][CH:7]=[C:8]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:9]=1
Reactant: CC(C)(C)c1c[nH]c(=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1c[nH]c(=O)c(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
3-Nitro-5-tert-butyl-1H-pyridin-2-one (360 mg, 1.83 mmol) was dissolved in methanol/ethyl acetate (2:1, 3 mL) and placed in a Parr hydrogenation vessel. Pd (10% on carbon, 36 mg) was added and the reaction was placed under a hydrogen atmosphere (50 psi) and shaken at room temperature for 2 h. The solution was then filtered through diatomaceous earth and concentrated in vacuo. The residue was redissolved in diethyl ether and extracted (3×) with 1.0 M HCl. The pH of the combined aqueous layers was adjusted to 10 with NaHCO3 and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide 3-amino-5-tert-butyl-1H-pyridin-2-one (195 mg, 64%) as a pale green solid: ESI MS m/z 166 [C9H14N2O+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[C:3]=1[CH3:25].[C:26](OC(C)=O)([CH3:29])([CH3:28])[CH3:27].C([O-])(O)=O.[Na+]>Cl(O)(=O)(=O)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([CH:19]([O:24][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH3:23])=[O:21])[C:3]=1[CH3:25]
Reactant: COC(=O)C(O)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Reaction time: 4.5 h

Procedure:
Methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate (298 mg, 0.71 mmol) was dissolved in t-BuOAc (18.0 mL, 134 mmol) and 7 drops of perchloric acid were added. The reaction was monitored by HPLC and TLC for progress. After 4.5 hours, the mixture was added to icy saturated NaHCO3 and stirred for 10-15 minutes. This mixture was extracted with EtOAc, extracts dried with sodium sulfate and concentrated in vacuo. Purification on silica gel using EtOAc in hexanes gave desired product as well as some starting material. 1H-NMR: (400 MHz, CDCl3): δ 8.39 (d, J=8.8 Hz, 1H); 7.57-7.48 (m, 3H); 7.45-7.42 (m, 1H); 7.35-7.31 (m, 1H); 7.28-7.18 (m, 2H); 5.20 (s, 1H); 3.70 (s, 3H); 2.72 (s, 3H); 0.99 (s, 9H).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:21](=[O:41])[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([C@@H:21]([OH:41])[C@H:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:12]([CH3:14])[CH3:13])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)N1CCC(O)(c2ccc(C(F)(F)F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)[Si](Oc1ccc([C@@H](O)[C@@H](C)N2CCC(O)(c3ccc(C(F)(F)F)cc3)CC2)cc1F)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 45.2 %

Procedure:
A mixture of sodium borohydride (0.049 g, 1.30 mmol) and ethanol (5 mL) was stirred 10 min and then 1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-(4-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (0.738 g, 1.30 mmol in 10 mL of ethanol) was added with a 5 mL ethanol rinse. The reaction was stirred at ambient temperature overnight. The white precipitate which formed was collected by filtration to afford 0.335 g (45%) of (1R*,2R*)-1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-(4-trifluoromethylphenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol which had: NMR δ 7.63 (s, 4 H), 7.07 (dd, J=2, 11.5 Hz, 1 H), 6.98-6.84 (m, 2 H), 5.13 (s, 1 H), 4.20 (d, J=9.5 Hz, 1 H), 3.06 (sym m, 1 H), 2.81-2.71 (m, 1 H), 2.70-2.50 (m, 3 H), 2.15 (sym m, 2 H), 1.81 (distorted d, J=14 Hz, 2 H), 1.59 (s, 1 H), 1.33-1.19 (m, 3 H), 1.08 (d, J=7 Hz, 18 H), 0.81 (d, J=6.5 Hz, 3 H). The product also contained about 7% of the erythro diastereomer but was suitable for use without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1cccc(N)c1
Product: CCOC(=O)C(=CNc1cccc(OC)c1)C(=O)OCC
Reaction time: 3 h

Procedure:
According to Scheme A, ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (VIII) is obtained in four steps from commercially available synthetically accessible m-anisidine (II). m-Anisidine is combined with diethyl ethoxymethylenemalonate at temperatures ranging from 100° C. to about 125° C., preferably 125° C. for a period of 1 to 5 h, preferably about 3 h to provide diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate. Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) is obtained by heating Dowtherm™ at a temperature of 257° C. and diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate for a period of 15 minutes to 2 h. Compound (IV) ethyl 7-methoxyquinoline-3-carboxylate is commercially available or synthetically accessible from ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) in two steps. Chlorination of compound (III) under conditions known to one skilled in the art, for example, but not limited to, oxalyl chloride, thionyl chloride, or phosphorus oxychloride, with or without a catalytic amount of DMF, in the presence or absence of a solvent such as DCM or CHCl3, at temperatures ranging from 50° C. to about 70° C., for a period ranging from 2 to 4 h, preferably 2.5 h, provides ethyl 4-chloro-7-methoxyquinoline-3-carboxylate. Subsequent reduction of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate, employing Pd/C under hydrogenation conditions, in a solvent such as MeOH or EtOH, in the presence or absence of an acid such as acetic or formic acid, provides ethyl 7-methoxyquinoline-3-carboxylate (IV). Commercially available or synthetically accessible ethyl 7-methoxyquinoline-3-carboxylate (IV) is reacted under demethylation conditions, for example, HBr in H2O or HOAc, at temperatures ranging from 80° C. to about 110° C., preferably 105° C. for a period of 0.5 h to 24 h, preferably about 2 h, to provide 7-hydroxyquinoline-3-carboxylic acid. Ethyl 7-hydroxyquinoline-3-carboxylate (V), where R3 is H, is obtained by esterification of 7-hydroxyquinoline-3-carboxylic acid, employing methods known to one skilled in the art, for example, but not limited to, reaction of 7-hydroxyquinoline-3-carboxylic acid with an acid such as H2SO4, and the like, in a solvent such as EtOH, at temperatures ranging from 60° C. to about 80° C., preferably 75° C. for a period of about 12 to 24 h, preferably 20 h.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[OH:28][CH2:29][CH:30]([CH2:32]O)[OH:31].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:32][CH:30]([OH:31])[CH2:29][OH:28])=[O:24])=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: OCC(O)CO
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
A solution of 11.8 g. of 4-(16-bromohexadecylamino)benzoic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2,3-dihydroxypropyl 4-(16-bromohexadecylamino)benzoate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[CH:8]1[O:10][CH2:9]1.[CH:11]([NH2:14])([CH3:13])[CH3:12]>C(O)(C)C>[CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[CH:8]([OH:10])[CH2:9][NH:14][CH:11]([CH3:13])[CH3:12]
Reactant: Cc1csc(C2CO2)c1C
Reactant: CC(C)N
Solvent: CC(C)O
Product: Cc1csc(C(O)CNC(C)C)c1C
Yield: 153.5 %

Procedure:
To 5.7 g of 3-methyl-4-methylthiophenylethylene oxide in 30 cc of isopropanol, 7.6 g of isopropylamine are added. The solution is refluxed overnight. The solvent and excess of amine are evaporated under vacuum. The oil obtained crystallises a little moment later. 12.1 g of 1-(3-methyl-4-methylthiophenyl)-2-isopropylaminoethanol are obtained (yield of 61 %) which are recrystallised from cyclohexane. Melting point: 89.5°-90.5°. The hydrochloride is recrystallised from a methanol-ether mixture; melting point: 154°-155.5°C.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[N:10]1([C:16]2[C:17]3[C:24]([C:25]4[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=4)[C:28]#[N:29])=[CH:23][N:22]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C(O)C.O>[OH:3][N:2]=[C:28]([C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([C:24]2[C:17]3[C:16]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[N:21][CH:20]=[N:19][C:18]=3[N:22]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:23]=2)[CH:26]=1)[NH2:29]
Reactant: NO
Reactant: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2cccc(C(N)=NO)c2)c2c(N3CCOCC3)ncnc21

Procedure:
Hydroxylamine hydrochloride (278 mg, 4.00 mmol) and sodium carbonate (318 mg, 3.00 mmol) were added to a stirred solution of 3-[4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (C34) (436 mg, 1.00 mmol) in ethanol (10 mL) and water (5 mL). The reaction mixture was heated at reflux for 2 hours, then concentrated in vacuo, poured into water (25 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (25 mL), dried over sodium sulfate, filtered, and concentrated, affording the product as a white solid. Yield: 280 mg, 0.60 mmol, 60%. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.43 (s, 1H), 7.89 (br s, 1H), 7.72 (s, 1H), 7.64 (br d, J=7.8 Hz, 1H), 7.53 (br d, J=7.8 Hz, 1H), 7.46 (dd, J=7.6, 7.6 Hz, 1H), 5.89 (br s, ˜1.6H), 5.61 (s, 2H), 3.53-3.61 (m, 2H), 3.39-3.47 (m, 4H), 3.13-3.21 (m, 4H), 0.81-0.88 (m, 2H), −0.09 (s, 9H).