Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.[ClH:20]>CO.O1CCOCC1>[ClH:20].[ClH:20].[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:10]1[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1CCN(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
tert-Butyl(1-pyridin-2-ylpyrrolidin-3-yl)carbamate (2.5 g) was dissolved in methanol (4 mL) and was treated with 4M hydrogen chloride in 1,4-dioxane (8 mL). The mixture was stirred overnight at RT. The solvents were evaporated under reduced pressure. The residue was washed with ether and dried to give the desired product (2.1 g, 92%). LCMS: (M+H)=164.1.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([Br:12])=[CH:7][C:6]=1[F:13])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[Br:12][C:8]1[C:9]([F:11])=[CH:10][C:5]([CH2:4][NH2:1])=[C:6]([F:13])[CH:7]=1
Reactant: [N-]=[N+]=NCc1cc(F)c(Br)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(F)c(Br)cc1F
Temperature: 55 °C

Procedure:
To a mixture of the crude azide (110 mg, 0.44 mmol) in THF (3 mL) were added polymer-supported Ph3P (3.0 eq.) and water (1.5 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 07: tR=0.40 min; [M+CH3CN+H]+=263.14.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([CH2:14][CH2:15][C:16](Cl)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C(C)C(O)=O)C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:8]1([CH2:14][CH2:15][C:16]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)CCc1ccccc1
Agent: CC(C(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CCc1ccccc1)N1CCC(O)CC1
Reaction time: 24 h
Yield: 38.9 %

Procedure:
This amine was synthesized in accordance with the method of Scheme 37. To 4 g (40 mmol) of 4-hydroxypiperidine in 20 mL of toluene was added phenylpropionyl chloride (derived from 6 g (40 mmol) of phenylpropionic acid in excess thionyl chloride). To the mixture was added excess 2N aqueous NaOH. After stirring 24 hours, the toluene layer was discarded and the aqueous phase was extracted with CH2Cl2, dried, and evaporated under vacuum to give 3.63 g (39%) of 1-(3-phenylpropionyl)-4-hydroxypiperidine (134). GC/MS indicated 100% purity with a molecular ion of 233.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:21]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22]>O1CCOCC1>[C:21]([C:24]1[CH:25]=[C:26]([S:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22]
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)O)c2)cc1
Reaction time: 8 h

Procedure:
2.1 g (0.01 mol) of 3-(4-aminobenzenesulfonyl) acrylonitrile are dissolved in 100 ml dioxane, and 2 ml of pyridine are added thereto. A solution of 2.21 g (0.01 mol) of 3-carboxybenzenesulfonyl chloride in 50 ml dioxane is added portionwise at room temperature and the reaction mixture is held overnight. After filtering and mixing the filtrate with about 4 volumes of water the mixture is left at room temperature for 5 days. White flocs separate which are recovered by filtration and dried, giving 3-[4-(3-carboxybenzenesulfonamido)-benzenesulfonyl]acrylonitrile: ##SPC30##
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH:16]1([S:19](Cl)(=[O:21])=[O:20])[CH2:18][CH2:17]1.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[CH:16]1([S:19]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:30]([C:29]4[CH:31]=[CH:32][C:26]([O:25][C:24]([F:23])([F:33])[F:34])=[CH:27][CH:28]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:21])=[O:20])[CH2:18][CH2:17]1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)C1CC1)CC2

Procedure:
White solid. MS (ESI): 419.12 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), cyclopropanesulfonyl chloride, 4-(trifluoromethoxy)-aniline.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:26][CH2:25][CH2:24][CH2:23][N:20]3[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:2]4[C:11]5[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)[CH2:22][CH2:21]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(NCCCN3CCN(CCCNc4ccnc5cc(Cl)ccc45)CC3)ccnc2c1

Procedure:
A solution of 4,7-dichloroquinoline (1.58 g, 8.0 mmol) and 1,4-bis(3-aminopropyl)piperazine (0.33 mL, 1.6 mmol) in DMF (5 mL) is refluxed (160° C.) for 18 h in the presence of K2CO3 (1.77 g, 12.8 mmol). After evaporation, the media is diluted with HCl 1M, and washed with ethyl acetate. Aqueous layer is alcalinised with NaHCO3, extracted with CH2Cl2, and dried over MgSO4. Crude compound is purified by precipitation in ethyl acetate.
Reaction SMILES: C1(C)C=CC=CC=1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([CH:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>O>[O:13]1[C:17]2([CH2:18][CH2:19][CH:20]([CH:23]3[CH2:28][CH2:27][C:26]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)=[CH:25][CH2:24]3)[CH2:21][CH2:22]2)[O:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)CCC(C2CCC3(CC2)OCCO3)C1
Temperature: 25 °C

Procedure:
Toluene (200 ml) and pyrrolidine (90 ml) were added to 4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone (100 g) in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 3 hours while the water formed was removed by a Dean-Stark apparatus. After the reaction mixture had been cooled to a room temperature, it was washed with brine, and dried over anhydrous magnesium sulfate. The toluene was distilled off to give 1-(4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohex-1-enyl)pyrrolidine (105.8 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O>>[CH3:19][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: OB(O)c1cccs1
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccs4)nc23)CCCCC1

Procedure:
(1-Methyl-cyclohexyl)-(2-thiophen-2-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and thiophene-2-boronic acid following general procedures described in these Examples. MP 224-225° C., M+H=326.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[N:9][C:10]=1[CH3:11])([CH3:3])[CH3:2].[Li+].[OH-].O.CCOC(C)=O>C1COCC1.O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[N:9][C:10]=1[CH3:11])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC(C)C)c(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
Methyl 5-isopropoxy-6-methylpicolinate (1.3 g, 6.22 mmol) was dissolved in THF/water 2:1 (9 mL). LiOH*H2O (0.26 g, 6.22 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into a mixture of water and EtOAc and the layers were separated. The aqueous layer was acidified to pH 4 with 2 N HCl and was extracted with EtOAc (2×). The combined organics were dried (Na2SO4) and concentrated to give 5-isopropoxy-6-methylpicolinic acid (860 mg, 74%) as a beige solid. 1H-NMR (300 MHz, DMSO) 1.31 (d, 6H), 4.73 (m, 1H), 7.44 (d, 1H), 7.86 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH:7]([P:18](=[O:27])([O:23][CH2:24][CH:25]=[CH2:26])[O:19][CH2:20][CH:21]=[CH2:22])[P:8](=[O:17])([O:13][CH2:14][CH:15]=[CH2:16])[O:9][CH2:10][CH:11]=[CH2:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:36][CH2:37][C:38](Br)=[O:39]>C(Cl)Cl>[Br:36][CH2:37][C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([P:18](=[O:27])([O:23][CH2:24][CH:25]=[CH2:26])[O:19][CH2:20][CH:21]=[CH2:22])[P:8](=[O:17])([O:13][CH2:14][CH:15]=[CH2:16])[O:9][CH2:10][CH:11]=[CH2:12])=[CH:28][CH:29]=1)=[O:39]
Reactant: C=CCOP(=O)(OCC=C)C(Cc1ccc(N)cc1)P(=O)(OCC=C)OCC=C
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOP(=O)(OCC=C)C(Cc1ccc(NC(=O)CBr)cc1)P(=O)(OCC=C)OCC=C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 75.9 %

Procedure:
To a solution of aminobenzyl bisphosphonate 27 (180 mg, 0.41 mmol) in CH2Cl2 (5 mL) at 0° C. was added pyridine (49 μL, 0.61 mmol) followed by bromoacetylbromide (35 μL, 0.41 mmol). The reaction mixture was stirred at 0° C. for 30 min and at room temperature for another 2.5 h. The reaction mixture was diluted with CH2Cl2, washed with aqueous 1N HCl solution, saturated NaHCO3 solution, and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using a gradient of 0-10% MeOH in CH2Cl2 as eluant to provide bromide 28 as a clear yellow oil (175 mg, 3.11×10−4 mol, 76%). 1H NMR (400 MHz, CDCl3) δ 2.72 (tt, J=23.9, 6.2 Hz, 1H), 3.26 (dt, J=16.3, 6.1 Hz, 2H), 4.02 (s, 2H), 4.48-4.62 (m, 8H), 5.20-5.24 (m, 4H), 5.29-5.35 (m, 4H), 5.83-5.94 (m, 4H), 7.25-7.28 (m, 2H), 7.42-7.46 (m, 2H), 8.11 (bs, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[F:17][CH:18]([F:22])[CH2:19][O:20][NH2:21]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([NH:21][O:20][CH2:19][CH:18]([F:22])[F:17])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: NOCC(F)F
Agent: Cl
Product: CCCNc1nc(NCCC)nc(NOCC(F)F)n1
Yield: 59 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) was reacted with O-(2,2-difluoro-ethyl)-hydroxylamine hydrochloride as described in Example 13, affording C in 59% yield. 400 MHz 1H NMR (DMSO-d6, ppm) 9.91-9.56 (1H, m), 7.00-6.90 (1H, m), 6.89-6.67 (1H, m), 6.48-6.13 (1H, m, 4.12-3.98 (2H, m), 3.20-3.09 (4H, m), 1.53-1.41 (4H, m), 0.88-0.80 (6H, m). ESI-MS (m/z) 291 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:3]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)C(=O)[CH2:4]1)[CH3:2].[CH3:18][O-:19].[Na+].[CH3:21][OH:22]>CO>[F:14][C:13]([F:15])([F:16])[C:10]1[CH:9]=[CH:8][C:7]([NH:6][C@H:3]([CH2:1][CH3:2])[CH2:4][C:18]([O:22][CH3:21])=[O:19])=[CH:12][CH:11]=1
Reactant: C[O-]
Reactant: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Reactant: CO
Agent: [Na+]
Product: CC[C@H](CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
420 mg (1.73 mmol) of (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone produced in Example 6 was dissolved in methanol (7.0 mL) and further mixed with 668 mg (3.46 mmol) of 28 wt % sodium methoxide/methanol solution at room temperature. After stirring at the same temperature for further 1 hour, the solvent was removed by distillation under reduced pressure and 1 N hydrochloric acid (5.0 mL) was added and extraction with ethyl acetate was carried out. The organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, and the product was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to obtain methyl (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoate as a colorless oil (459 mg, crude yield: 97%).
Reaction SMILES: [C:1]([N:4]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=[O:28])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1.O>[C:1]([N:4]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[CH2:24][CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([OH:29])=[O:28])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCN(C)c1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)CCC(C)(C)C(=O)O)cc2)c2ccccc21
Temperature: 40 °C

Procedure:
Methyl 4-[(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)(methyl)amino]-2,2-dimethylbutanoate was dissolved in methanol/tetrahydrofuran/water (2/1/1) then sodium hydroxide (3 equivalents) was added and reaction mixture heated to 40° C. for 2 h. The mixture was concentrated, the residue acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-[(4-{[(2S,4R)-4-[Acetyl-(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)(methyl)amino]-2,2-dimethylbutanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][C:8]2=O.C[Si]([C:24]#[N:25])(C)C.[Cl-].[Al+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:24]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)#[N:25]
Reactant: C[Si](C)(C)C#N
Reactant: COc1cccc2c1CC(c1ccccc1)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC(c1ccccc1)C=C2C#N
Temperature: 60 °C

Procedure:
To a suspension of 8.8 g (35 mmol) of 5-methoxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone, the product of Example 1, is added 7.5 g (75.6 mmol) of trimethylsilyl cyanide (commercially available from Aldrich Chemical Company) and approximately 50 mg of anhydrous aluminum chloride (AlCl3). The reaction mixture is heated at 60° C. for 3 h then cooled to ambient temperature and diluted with 150 mL of toluene. The volume of the reaction mixture is reduced in vacuo to approximately 50 mL. The resultant trimethylsilyl adduct is dehydrated by treatment with 15 mL of trifluroacetic acid and 100 mg of p-toluenesulfonic acid in 200 mL of toluene at reflux temperature for 1 h. The reaction mixture is cooled to ambient temperature, the layers separated and the organic layer washed with water, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound.
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.O.C(OC([NH:20][CH2:21][CH:22]([N:31]([CH3:41])[C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])[CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=O)(C)(C)C>C(O)C.CCOCC>[NH2:20][CH2:21][CH:22]([N:31]([CH3:41])[C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])=[O:33])[CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CN(C(=O)OCC[Si](C)(C)C)C(CNC(=O)OC(C)(C)C)CC1(O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CN(C(=O)OCC[Si](C)(C)C)C(CN)CC1(O)CCCCC1
Temperature: 62.5 °C
Yield: 108.4 %

Procedure:
A solution of p-TsOH.H2O (25 mg) in ethanol (0.5 mL) was added to 1-(3-(t-butoxy-carbonylamino)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)cyclohexanol (50 mg, 0.12 mmol) dissolved in ether (12 mL). The transfer was completed with additional ether (2 mL). The resulting solution was evaporated under reduced pressure at rt to remove Et2O and heated at 60-65° C. for 20 min under reduced pressure to remove ethanol. The residue was dissolved in MeOH and aqueous K2CO3 was added. The mixture was evaporated and extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4, filtered and evaporated to give 1-(3-amino-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propyl)cyclohexanol (43 mg, 89%). MS m/z 453 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.Cl[C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:20]
Reactant: COC(=O)Cl
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 53.5 %

Procedure:
To a mixture of 6.0 mg (0.026 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.0 mg (0.07 mMol) polyvinylpyridine in 3.0 mL dichloromethane were added 2.4 mg (0.0273 mMol) methyl chloroformate. The reaction mixture was mixed for 2 days at ambient temperature. To this mixture were then added 90 mg (0.073 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 4.0 mg (53%) of the title compound.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:15]=[CH:14][C:11](OC)=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C[O:19][CH2:18][CH2:17]1.C([Li])CCC.C1[O:28][CH2:27]1>CCCCCC.O.C(O)(=O)C>[OH:19][CH2:18][CH2:17][C:9]1[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:15][CH:14]=[CH:11][C:10]=1[O:28][CH3:27]
Reactant: COc1ccc(NC(=O)C(C)(C)C)cc1
Reactant: C1CCOC1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: COc1cccc(NC(=O)C(C)(C)C)c1CCO
Temperature: 0 °C
Yield: 69 %

Procedure:
To N-pivaloylanisidine (4.14 g, 0.02 mole) in freshly distilled THF (60 ml) under nitrogen is added 2.3 N butyllithium in hexane (23 ml) at 0° C. and the resultant solution is stirred at 0° C. for 2 hours. Ethylene oxide (liquid, 1.6 ml) is added and the reaction mixture is stirred for an hour at 0° C. and then an additional hour at ambient temperature. Acetic acid (2 ml) and water (30 ml) are added to quench the reaction. The THF is evaporated in vacuo and the aqueous mixture is extracted with ether (2×30 ml). The extracts are combined, washed with 5% sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to 5.42 g of crystalline material. Recrystallization from n-butyl chloride (13 ml) gives 3.46 g (69%) of 2-(2-hydroxyethyl)-3-pivalamidoanisole, m.p. 118°-119.5° C.
Reaction SMILES: [CH3:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3].C1CCCCC1.[F:17][C:18]([F:34])([F:33])[C:19](=[O:32])[CH2:20][C:21]([C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH3:31])([CH3:23])[CH3:22].C1COCC1>>[F:34][C:18]([F:17])([F:33])[C@@:19]([CH2:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3])([OH:32])[CH2:20][C:21]([C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH3:31])([CH3:23])[CH3:22].[F:34][C:18]([F:17])([F:33])[C@:19]([CH2:1][S@:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:3])([OH:32])[CH2:20][C:21]([C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH3:31])([CH3:23])[CH3:22]
Reactant: Cc1ccc([S@@](C)=O)cc1
Reactant: Cc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc([S@](=O)C[C@@](O)(CC(C)(C)c2cc(F)ccc2C)C(F)(F)F)cc1
Product: Cc1ccc([S@](=O)C[C@](O)(CC(C)(C)c2cc(F)ccc2C)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 58 %
Yield: 27 %

Procedure:
To a suspension of (R)-(+)-methyl p-tolylsulfoxide (1.00 g, 6.48 mmol) in 10 mL of anhydrous THF at −78° C. was added LDA mono(tetrahydrofuran), 1.5 M solution in cyclohexane (4.32 mL, 6.48 mmol) over 5 minutes. The resulting clear yellow solution was stirred for an additional 15 minutes. 1,1,1-Trifluoro-4-(5-fluoro-2-methylphenyl)-4-methylpentan-2-one (1.55 g, 5.90 mmol) was then added via cannula with the aid of 4 mL of THF over 5 minutes. After 1 hour at −78° C., the reaction mixture was quenched with 50 mL of water and extracted with three 50 mL portions of EtOAc. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 15%-25% EtOAc/hexanes) afforded sequentially (S)-1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (1.42 g, 58%) and (R)-1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (665 mg, 27%). The diastereomeric excess was determined to be >99% for both isomers (HPLC peak area).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[N:9]=[C:10]([OH:27])[C:11]2[CH2:17][CH:16]([CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:15][NH:14][C:12]=2[N:13]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C1COCC1.O>[C:1]([C:5]([NH:7][C:8]1[N:9]=[C:10]([OH:27])[C:11]2[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15][NH:14][C:12]=2[N:13]=1)=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2c(n1)NCC(CO[Si](C)(C)C(C)(C)C)C2
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)Nc1nc(O)c2c(n1)NCC(CO)C2
Temperature: 22 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a mixture of 5.0 g of 2-t-butylcarbonylamino-4-hydroxy-6-[t-butyl(dimethyl)silyloxymethyl]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine in 50 ml of THF and 50 ml of water were added 150 ml of glacial acetic acid. The mixture was stirred 18 hours at 22° C. and then evaporated to a viscous oil. Water was added and the resulting white precipitate collected by filtration to give 3.1 g of the title compound: mp 236°-238° C.; Anal. Calcd for C19H34N4O3Si: C, 55.70; H, 7.19; N, 19.99. Found: C, 55.96; H, 7.25; N, 19.69.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][S:22][CH2:23]Cl.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:21][S:22][CH3:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2C1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (13 g) in dirnethylformamide (100 ml) was added 60% sodium hydride (2.5 g) under an argon atmosphere, and the mixture was stirred at room temperature for 30 minutes. Then, chloromethyl methyl sulfide (5.2 ml) was dropwise added with ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=20:1-10:1) and dried under reduced pressure to give the title compound (9.6 g).