Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:13][C@@H:14]([OH:29])[C@@H:15]([OH:28])[C@@H:16]1[O:25][C:20]([OH:24])([C:21](=[O:23])[OH:22])[CH2:19][C@H:18]([OH:26])[C@H:17]1[OH:27])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[OH:30][C:31]([C:33]1([O:44][C@@H:43]([C@@H:45]([C@@H:47]([CH2:49][OH:50])[OH:48])[OH:46])[C@H:38]([NH:39][C:40]([CH3:42])=[O:41])[C@@H:36]([OH:37])[CH2:35]1)O)=[O:32].[Mg+2].[Cl-].[Cl-]>C(O)C(N)(CO)CO.Cl>[OH:32][C:31]([C@@:33]1([O:44][C@@H:43]([C@@H:45]([C@@H:47]([CH2:49][OH:50])[OH:48])[OH:46])[C@H:38]([NH:39][C:40]([CH3:42])=[O:41])[C@@H:36]([OH:37])[CH2:35]1)[O:6][C@H:5]1[C@@H:7]([OH:8])[C@@H:9]([CH2:11][OH:12])[O:10][C@@H:2]([O:1][CH2:13][C@@H:14]([OH:29])[C@@H:15]([OH:28])[C@@H:16]2[O:25][C:20]([OH:24])([C:21](=[O:22])[OH:23])[CH2:19][C@H:18]([OH:26])[C@H:17]2[OH:27])[C@@H:3]1[OH:4])=[O:30]
Reactant: O=C(O)C1(O)C[C@H](O)[C@@H](O)[C@H]([C@H](O)[C@H](O)CO[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)O1
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Cl-]
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@@](O[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](OC[C@@H](O)[C@@H](O)[C@@H]3OC(O)(C(=O)O)C[C@H](O)[C@H]3O)[C@@H]2O)(C(=O)O)C[C@@H]1O
Reaction time: 3 h

Procedure:
Neu5Acα2-3Galβ1-9Kdn was prepared first by following the general one-pot two-enzyme α2-3-sialylation system described above from Galβ1-9Kdn (101 mg, 0.22 mmol) in Tris-HCl buffer (100 mM, pH 8.5) containing Neu5Ac (109 mg, 0.33 mmol), CTP (188 mg, 0.33 mmol), MgCl2 (20 mM), NmCSS (0.8 mg), and PmST1 (0.04 mg). The reaction was incubated at 37° C. for 3 h with shaking (120 rpm). The crude product was purified by Bio-Gel P-2 gel filtration to afford the sialoside product Neu5Acα2-3Galβ1-9Kdn (148 mg, 89%). 1H NMR (600 MHz, D2O): δ 4.33 (d, 1H, J=7.8 Hz, H′-1), 4.00 (dd, 1H, J=1.8 and 10.8 Hz), 3.93 (dd, 1H, J=3.6 and 11.2 Hz), 3.82-3.65 (m, 9H), 3.60-3.39 (m, 9H), 2.58 (dd, 1H, J=4.2 and 12.6 Hz, H-3 eq″), 2.01 (dd, 1H, J=4.8 and 13.2 Hz, H-3 eq), 1.85 (s, 3H, CH3), 1.62 (t, 1H, J=12.0 Hz, H-3ax), 1.60 (t, 1H, J=12.0 Hz, H-3ax″). 13C NMR (75 MHz, D2O): δ 176.29, 175.17, 173.95, 103.28, 99.93, 96.35, 75.87, 75.07, 73.02, 71.93, 71.90, 71.86, 71.61, 70.44, 69.64, 69.50, 69.15, 68.48, 68.25, 67.97, 67.67, 62.75, 61.13, 59.50, 51.84, 39.82, 39.14, 22.22. HRMS (ESI) calcd. for C26H41NNaO22 (MNa), 742.2018, found 742.2001.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=1)[N:8]([CH:28]([CH3:30])[CH3:29])[CH2:7][CH2:6]2>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[N:8]([CH:28]([CH3:30])[CH3:29])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN(C(C)C)C2Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CCN(C(C)C)C2Cc1ccc(O)cc1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
A suspension of 6-methoxy-2-(methylethyl)-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.3 g, 0.75 mmol), palladium (10% wt) on activated carbon (0.06 g) and acetic acid (5 drops) in ethyl acetate (10 mL) was stirred under hydrogen overnight. The reaction was filtered and concentrated to provide the title compound (0.212 g, 91% yield): ES-MS (m/z) 312 [M+H]+.
Reaction SMILES: [Cl-].[CH:2]1([CH2:5][NH2+:6][CH2:7][CH2:8]Cl)[CH2:4][CH2:3]1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N:18]=[C:19]=[S:20]>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N:18]=[C:19]1[N:6]([CH2:5][CH:2]2[CH2:3][CH2:4]2)[CH2:7][CH2:8][S:20]1
Reactant: ClCC[NH2+]CC1CC1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: [Cl-]
Product: Clc1cccc(N=C2SCCN2CC2CC2)c1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:36]([CH2:40][OH:41])([F:39])([F:38])[F:37]>>[OH:35][C:8]1([C:5]2[CH:6]=[N:7][C:2]([O:41][CH2:40][C:36]([F:39])([F:38])[F:37])=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)=[O:20])[CH2:17]2)[CH2:10][CH2:9]1
Reactant: OCC(F)(F)F
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(F)nc3)CC2)C1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc(OCC(F)(F)F)nc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-(6-fluoro-pyridin-3-yl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide 6a and CF3CH2OH (Sigma) using the procedure described in Example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH:15](O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.P(Br)(Br)(Br)(Br)[Br:23]>>[Br:23][CH:15]([CH2:14][C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: BrP(Br)(Br)(Br)Br
Reactant: CCOC(=O)C(O)Cc1ccc(C2CCCCC2)c(Cl)c1
Product: CCOC(=O)C(Br)Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
To 15.6 g. (0.0476 moles) of ethyl β-(3-chloro-4-cyclohexylphenyl)lactate there is added slowly with stirring at 40°-50°C 23 g. (0.053 moles) of phosphorus pentabromide. The mixture is stirred at room temperature for 16 hours, then diluted with 70 ml. of petroleum ether, and poured into 125 ml. of ice-cold water. The organic phase is separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to obtain ethyl α-bromo-β-(3-chloro-4-cyclohexylphenyl)propionate.
Reaction SMILES: C1([O:6][C:7]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:10]=2)=[O:8])CCCC1.[OH-].[Na+].Cl>C1COCC1.O>[CH:16]1([N:11]2[C:12](=[O:15])[CH:13]=[CH:14][C:9]([C:7]([OH:8])=[O:6])=[N:10]2)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: O=C(OC1CCCC1)c1ccc(=O)n(C2CCCC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(=O)n(C2CCCC2)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Cyclopentyl-1-cyclopentyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (20 mg, 0.072 mmol) was dissolved in 2 ml THF/water (1/1) and 2 ml NaOH (5M, aq.) was added. The reaction was stirred at 40° C. for 2 h and 5 ml HCl (5M, aq.) was added. The reaction was concentrated and 10 ml of CH2Cl2/MeOH (1/1) was added and the reaction was sonicated for 10 min and filtered. The filtrate was concentrated and used in the next step without further purification. Yield: 11 mg (0.052 mmol, 73%, film, MS m/z: 209(100%, M+1).
Reaction SMILES: [OH:1][N:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][CH:9]=[CH:8]3)[N:5]=[CH:4][CH:3]1[C:16]([O:18]CC)=[O:17].Cl>[OH-].[K+]>[OH:1][N:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][CH:9]=[CH:8]3)[N:5]=[CH:4][CH:3]1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C1C=Nc2c(ccc3ncccc23)N1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C1C=Nc2c(ccc3ncccc23)N1O
Yield: 91 %

Procedure:
A mixture of ethyl 4-hydroxy-pyrazino[2,3-f]quinoline-3-carboxylate(28.8 g) and 10% potassium hydroxide solution(350 ml) was heated under reflux for an hour. The resulting reaction solution was acidified with a concentrated hydrochloric acid. After filtration, the resulting solid was washed with water and acetone, and then dried over phosphorus pentoxide to give 4-hydroxy-pyrazino[2,3-f]quinoline-3-carboxylic acid(23.5 g) as pale yellow crystalline powders, m.p. >300° C.
Reaction SMILES: [C:1]1([CH:11]=[C:12]([CH2:16][C:17](=[O:27])[NH:18]CCC2C=CC=CC=2)[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:28]([OH:31])(=O)[CH3:29]>[Pd]>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][C:1]2[CH:10]=[CH:5][C:4]([O:31][CH2:28][CH3:29])=[CH:3][CH:2]=2)[C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: O=C(CC(=Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Agent: [Pd]
Product: CCOc1ccc(NC(=O)CC(Cc2cccc3ccccc23)C(=O)O)cc1

Procedure:
A solution of 500 mg of 2-(1-naphthylmethylene)-3-(phenethylcarbamoyl)propionic acid in 50 ml of acetic acid was hydrogenated over 250 mg of a 10% palladium/charcoal under a hydrogen atmosphere at room temperature. After filtration of the catalyst, the filtrate was concentrated under reduced pressure, and hexane was added to the residue. The precipitates were collected to obtain 500 mg of (±)-2-(1-naphthylmethyl)-3-(phenetylcarbamoyl)propionic acid as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.O=C1C2C(=CC=CC=2)C(=O)[N:10]1[CH2:19][C:20]1[S:24][C:23]([NH:25][C:26]2[CH:27]=[C:28]([CH:44]=[CH:45][CH:46]=2)[CH2:29][NH:30][C:31]2[C:40]3[C:35](=[C:36]([C:41]([NH2:43])=[O:42])[CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][N:32]=2)=[N:22][CH:21]=1.O.NN>C(O)C>[NH2:10][CH2:19][C:20]1[S:24][C:23]([NH:25][C:26]2[CH:27]=[C:28]([CH:44]=[CH:45][CH:46]=2)[CH2:29][NH:30][C:31]2[C:40]3[C:35](=[C:36]([C:41]([NH2:43])=[O:42])[CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][N:32]=2)=[N:22][CH:21]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(Nc4ncc(CN5C(=O)c6ccccc6C5=O)s4)c3)ncnc12
Agent: NN
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: NCc1cnc(Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
24 mg (0.04 mmol) 4-{3-[5-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-thiazol-2-ylamino]-benzylamino}-quinazoline-8-carboxylic acid amide trifluoroacetic acid salt were dissolved in 1 ml ethanol and treated with 10 μl (0.21 mmol) hydrazine hydrate. The mixture was stirred overnight at 50° C. in a closed vessel. Additional 40 μl hydrazine hydrate were added and the mixture was stirred at 60° C. for 24 h. The reaction mixture was evaporated and the crude product was purified using preparative HPLC. The product was treated with HCl in methanol and concentrated in the SpeedVac.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=[O:9])=[N+:2]=[N-:3].[OH-].[K+]>O.CO>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:2]=[N-:3]
Reactant: COC(=O)CCCCN=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCCCCC(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
Methyl 5-azidovalerate (4.01 g, 25.5 mmol) and KOH (7.58 g, 0.135 mol) were dissolved in a mixture of 70 ml of water and 90 ml of MeOH. The solution was stirred at 0° C. After 2 hrs, the MeOH was removed in vacuo. The aqueous layer was extracted by CHCl3 (50 ml), acidified to pH=1 by 2N aqueous HCl and extracted by Et2O (2×100 ml). The organic layers were combined, washed with water (100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 5-azidovaleric acid (2.85 g, 77.6%) was obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5](=[N:15]S(C2C=CC(C)=CC=2)(=O)=O)[N:6]([CH:8]([CH3:14])[C:9]([CH:11]2[CH2:13][CH2:12]2)=O)[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:15]=2)[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2cnc(Br)cn2C(C)C(=O)C2CC2)cc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1c(C2CC2)nc2cnc(Br)cn12
Temperature: 60 °C
Yield: 80.5 %

Procedure:
To a solution of N-(5-bromo-1-(1-cyclopropyl-1-oxopropan-2-yl)pyrazin-2(1H)-ylidene)-4-methylbenzenesulfonamide (1.24 g) in THF (10 ml) was added trifluoroacetic anhydride (1.23 g) at 0° C., and the mixture was heated at 60° C. for 3 h. The mixture was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with 1 M NaOH and brine successively, dried over MgSO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (593 mg) as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1)(=O)=O>CN(C=O)C>[N:39]1[CH:40]=[CH:41][N:42]=[CH:43][C:38]=1[C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:1][C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=4[C:4]=3[CH:3]=2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: CS(=O)(=O)OCc1ccc(-c2cnccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(-c4cnccn4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
To a mixture of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (20 mg, 0.077 mmol) and cesium carbonate (38 mg, 0.12 mmol) in DMF (1 mL) was added 4-(pyrazin-2-yl)benzyl methanesulfonate (41 mg, 0.15 mmol). The reaction mixture was stirred at room temperature overnight. The solid was filtered, and the filtrate was concentrated. The residue was purified by preparative TLC to give the title compound (15 mg). LCMS m/z=428.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 1.30 (t, J=7.1 Hz, 3H), 2.07-2.14 (m, 1H), 2.50 (dd, J=16.7 and 11.2 Hz, 1H), 2.70-2.87 (m, 4H), 3.50-3.57 (m, 1H), 4.18-4.24 (m, 2H), 5.18 (s, 2H), 6.87 (dd, J=8.8 and 2.4 Hz, 1H), 7.01 (d, J=2.3 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 8.03 (d, J=8.3 Hz, 2H), 8.46 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 8.64 (dd, J=2.3 and 1.6 Hz, 1H), 9.04 (d, J=1.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH3:19][C:20]1([CH3:27])[CH2:25][C:24](=[O:26])[O:23][C:21]1=[O:22]>ClCCl>[CH3:19][C:20]([CH3:27])([CH2:25][C:24]([NH:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1)=[O:26])[C:21]([OH:23])=[O:22]
Reactant: CC1(C)CC(=O)OC1=O
Reactant: CN(C(=O)Oc1ccc(N)cn1)c1ccccc1
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)C(=O)O)cn1)c1ccccc1

Procedure:
A solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.49 g, 2.00 mmol) and 2,2-dimethylsuccinic anhydride (0.26 g, 2.00 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight. Evaporation of the solvent in vacuo yielded the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12].CC1C=C(C)C=C(C)C=1S(O[C:29]1[C:34]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])=[CH:38][C:37]=2[O:54][CH3:55])=[C:33]([CH3:56])[N:32]=[C:31]([NH2:57])[N:30]=1)(=O)=O>C(#N)CC.C(=O)([O-])O.[Na+]>[NH2:57][C:31]1[N:30]=[C:29]([NH:8][C@@H:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][OH:12])[C:34]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:51])([CH3:52])[CH3:53])([CH3:49])[CH3:48])=[CH:38][C:37]=2[O:54][CH3:55])=[C:33]([CH3:56])[N:32]=1
Reactant: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CCC[C@H](N)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCC#N
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(OCCCO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: 120 °C
Yield: 80.7 %

Procedure:
Trifluoroacetic acid (0.154 mL) was added to the mixture of (S)-3-aminohexan-1-ol (586 mg) and the product from step (i) (616 mg) in propionitrile (6 mL). After the mixture was heated at 120° C. for 23 h, the reaction mixture was cooled to RT, diluted with sat. sodium hydrogen carbonate and extracted with EtOAc. The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by flash column chromatography on amino silica gel to afford the sub-title compound (430 mg) as a colorless oil; 1H NMR (CDCl3); 6.83 (1H, d), 6.44 (1H, d), 6.39 (1H, dd), 4.79 (2H, br s), 4.15-4.04 (1H, m), 4.00 (2H, t), 3.85 (3H, s), 3.77 (2H, t), 3.60 (2H, s), 3.50-3.40 (1H, m), 3.33-3.22 (1H, m), 2.36 (3H, s), 2.00-1.88 (2H, m), 1.86-1.71 (1H, m), 1.48-1.32 (1H, m), 1.30-0.95 (4H, m), 0.86 (9H, s), 0.75 (3H, t), 0.01 (6H, s); LC-MS: m/z 534.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[C@H:10]([CH3:36])[CH2:9]2)=[C:4]([C:37]([F:40])([F:39])[F:38])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:36])[CH2:9]2)=[C:4]([C:37]([F:40])([F:38])[F:39])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of tert-butyl 4-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]piperidine-1-carboxylate (540 mg, 0.923 mmol) in DCM (15 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 2 h and washed with aq. Na2CO3. The organic layer was dried over Na2SO4, concentrated and redissolved in Et2O and acidified with 1N HCl in Et2O to give the titled compound as a white solid (427 mg, 89%). HRMS: calcd for C23H27F4N3O2S+H+, 486.18328. found (ESI-FTMS, [M+H]1+), 486.18382.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([S:24][CH2:25][CH2:26][O:27][CH3:28])=[N:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.[O:29]=[S:30]1(=[O:40])[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]O)[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[O:40]=[S:30]1(=[O:29])[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([S:24][CH2:25][CH2:26][O:27][CH3:28])=[N:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH2:32][CH2:31]1
Reactant: O=S1(=O)CCN(CCCO)CC1
Reactant: COCCSc1ncnc2cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCSc1ncnc2cc(OCCCN3CCS(=O)(=O)CC3)ccc12
Reaction time: 4 h
Yield: 41.7 %

Procedure:
Diethyl azodicarboxylate (100 μl; 0.63 mmol) was added dropwise to a solution of 7-hydroxy-4-(2-methoxyethylsulphanyl)quinazoline (100 mg, 0.42 mmol), (prepared as described for the starting material in Example 11), 3-(1,1-dioxothiomorpholino)-1-propanol (99 mg, 0.51 mmol) and triphenylphosphine (167 mg, 0.63 mmol) in methylene chloride (6 ml). After stiring for 4 hours, triphenylphosphine (167 mg, 0.63 mmol) and diethyl azodicarboxylate (100 μl, 0.63 mmol) were added and stirring was continued for 1 hour. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate/methanol (100/0 followed by 92/8). After removal of the solvent by evaporation, the residue was triturated with ether and the solid was collected by filtration and dried under vacuum to give 7-(3-(1,1-dioxothiomorpholino)propoxy)4-(2-methoxyethylsulphanyl)quinazoline (72 mg, 41%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[C:27]1(C)CC(C)OB(C=C)[O:28]1.C[N+]1([O-])CCOCC1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].O.O1CCOCC1.O.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.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([CH:27]=[O:28])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CB1OC(C)CC(C)(C)O1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(Br)cc1-c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of (2-phenyl-4-bromobenzoyl) methionine methyl ester (100 mmol), 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane (100 mmol), tetrakis(triphenylphosphine)palladium (0) (3 mmol) in toluene and 2 M sodium carbonate in water (100 mL) is heated at 80° C. until the starting methyl ester disappears. The resulting mixture is extracted with ether, and washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel. To a solution of the resulting vinyl compound in dioxane/water (4/1) is added osmium tetraoxide (0.03 equivalent), N-methylmorpholine N-oxide (3 equivalents), and the reaction is stirred at 25° C. until TLC analysis shows the reaction to be complete. The reaction mixture is extracted with ether, which is washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue is then purified by column chromatography on silica gel to afford the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[N:12]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[C:30]([O:44][CH3:45])=[C:31]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:32]=[C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:34]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C=O)C.C1COCC1>[C:35]([C:33]1[CH:32]=[C:31]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[C:30]([O:44][CH3:45])=[C:29]([NH:28][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:34]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2cccnc2)nn1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cccnc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 2 h

Procedure:
4-Methyl-3-(4-pyridin-3-yl-1,2,3-triazol-1-yl)-benzoic acid (76.3 mg; 0.272 mmol) was suspended in 5 mL of CH2Cl2, and 1 mL of THF, and 0.04 mL (0.4 mmol) of oxalyl chloride was added. One drop of DMF was then added to the stirring suspension, and the mixture was stirred for 2 h. The resulting cloudy solution was concentrated to dryness and suspended in CH2Cl2. N-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (81 mg; 0.30 mmol) was added, then 0.06 mL (0.5 mmol) of 2,6-lutidine, and the resulting solution was stirred overnight. The mixture was then washed with 1M NaHSO4, saturated NaHCO3, and brine. The organic portion was dried with Na2SO4, filtered, and concentrated. Chromatography (0-6.5% MeOH in CH2Cl2), with careful selection of only the pure fractions, provided 80 mg (0.15 mmol; 55%) of Example 14. ESI MS m/z 535 [C27H30N6O4S+H]+.