Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([CH2:18][S:19][CH2:20][CH2:21]O)([CH2:13][S:14][CH2:15][CH2:16]O)[CH2:8][S:9][CH2:10][CH2:11]O)([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.ClCCl>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:23])[C:7]([CH2:18][S:19][CH2:20][CH2:21][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])([CH2:13][S:14][CH2:15][CH2:16][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])[CH2:8][S:9][CH2:10][CH2:11][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C(CSCCO)(CSCCO)CSCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CCSCC(CSCCS(=O)(=O)c2ccc(C)cc2)(CSCCS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)cc1
Reaction time: 15 h

Procedure:
A solution of t-butyl-tris[(2-hydroxyethyl)thiomethyl]acetate (11.2 g, 0.029 mol) in 50 mL of pyridine is cooled to 0° C. and p-toluenesulfonyl chloride (18.3 g, 0.096 mol) is added in portions over 1 hr. The mixture is kept at 0° C. for 15 hrs. Then dichloromethane (200 mL) is added and the solution is washed four times with 100 mL of 10% hydrochloric acid, once with 100 mL of saturated sodium bicarbonate and once with 100 mL of water. The organic layer is dried over anhydrous sodium sulfate and evaporated to give t-butyl-tris[(2-tosylethyl)-thiomethyl]acetate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]2=[O:17])=[CH:6][N:5]=[C:4]([CH3:18])[N:3]=1.C1C(=O)N([Br:26])C(=O)C1>C(O)(=O)C>[NH2:1][C:2]1[C:7]([CH2:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[C:11]([Br:26])[C:10]2=[O:17])=[CH:6][N:5]=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1ncc(Cn2c(C)cc(O)cc2=O)c(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Cc1ncc(Cn2c(C)cc(O)c(Br)c2=O)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A mixture of 1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-hydroxy-6-methylpyridin-2(1H)-one (0.5 g, 0.002 mol), and NBS (0.4 g, 0.002 mol)in glacial acetic acid (5.0 ml) was stirred at room temperature for 1 h under argon atmosphere. Acetic acid was removed in vacuo, residue was triturated with EtOAc containing 10% EtOH, and filtered. The pale yellow precipitate was washed with EtOAc containing 10% EtOH and dried in vacuo to afford the title compound (0.47 g, 725) as a pale yellow powder:
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+].Cl>CO.O>[C:1]([C:3]1[C:4]([CH:19]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CCN(C)C)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)CCC(c1ccc(Cl)c(Cl)c1)c1c(C(=O)O)sc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
To a solution of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (29.0 mg, 0.0584 mmol) in methanol (0.500 mL) was added 1.030 M of sodium hydroxide in water (284 uL, 0.284 mmol). The reaction was stirred at rt over 2 days. The mixture was neutralized with 1.00 M of hydrochloric acid in water (0.292 mL), diluted with 5 mL of water and extracted with 10% MeOH/CHCl3 (×5). The combined organic layer was dried and concentrated, and the resulting white syrup/solid was lyophilized to provide 4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylic acid as a white solid (26 mg, 95% yield). LCMS: (AA) ES+ 468, 470, 472; 1H NMR (400 MHz, DMSO) δ 7.63-7.52 (d, J=8.4 Hz, 1H), 7.44-7.37 (s, 1H), 7.15-7.02 (d, J=8.1 Hz, 1H), 5.49-5.34 (d, J=9.4 Hz, 1H), 3.73-3.63 (t, J=4.8 Hz, 4H), 3.38-3.31 (dd, J=6.2, 4.0 Hz, 4H), 3.13-2.97 (s, 1H), 2.85-2.73 (s, 1H), 2.72-2.60 (s, 6H), 2.56-2.52 (m, 1H).
Reaction SMILES: [Br:1][C:2]([Br:9])([Br:8])[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:12])=O>CN(C)C=O>[Br:1][C:2]([Br:9])([Br:8])[CH2:3][CH2:4][C:5]([Cl:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC(Br)(Br)Br
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(Br)(Br)Br
Reaction time: 3 h
Yield: 95 %

Procedure:
324.8 g (1.0 mol) of 4,4,4-tribromobutyric acid are warmed with 600 g of thionyl chloride and 1 ml of dimethylformamide, first for 2 hours at 40° C. and then for 3 hours at 75° C. The excess thionyl chloride is then distilled off and the residue is rectified under a high vacuum. 326.0 g (95% of theory) of 4,4,4-tribromobutyric acid chloride with a boiling point of 71° to 73° C./0.05 mm Hg are obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([OH:18])=[O:17])[CH:2]=[CH2:3].[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].ClCCl.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[CH:15]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:16]([O:18][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(C)(C)C)cc1C(C(=O)O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOc1ccc(C(C)(C)C)cc1C(C(=O)OCCCCCCCCCCCCCCCCCC)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 69.3 %

Procedure:
A solution of 3.24 g (10.0 mmol) of 2-(2-allyloxy-5-tert-butylphenyl)-2-phenylacetic acid (compound (105), Example 2) and 2.70 g (10.0 mmol) of stearyl alcohol (1-octadecanol) in 25 mol of dichloromethane is treated with 100 mg (0.82 mmol) of 4-dimethylaminopyridine and 2.20 g (10.7 mmol) of N,N'-dicyclohexylcarbodiimide, and the mixture is stirred for 60 hours at room temperature. The reaction mixture is filtered and concentrated on a vacuum rotary evaporator. Chromatography of the residue from silica gel using the diluent system dichloromethane/hexane=1:1 yields 4.0 g (69%) of stearyl 2-(2-allyloxy-5-tert-butylphenyl)-2-phenylacetate (compound (106), Table 1) as an oil.
Reaction SMILES: [C:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH2:5]1)#[C:2][CH3:3].Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]([OH:31])([CH3:30])[C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:29][C:26]([F:27])([F:28])[C:25]([C:22]1[CH:23]=[N:24][C:19]([N:9]2[CH2:8][CH2:7][N:6]([S:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)(=[O:12])=[O:11])[CH2:5][CH:4]2[C:1]#[C:2][CH3:3])=[N:20][CH:21]=1)([OH:31])[CH3:30]
Reactant: CC#CC1CN(S(=O)(=O)c2cccs2)CCN1
Reactant: CC(O)(c1cnc(Cl)nc1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC#CC1CN(S(=O)(=O)c2cccs2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 3 h
Yield: 19.3 %

Procedure:
A mixture of 3-(1-propyn-1-yl)-1-(2-thiophenylsulfonyl)piperazine (55 mg, 0.203 mmol), 2-(2-chloro-5-pyrimidinyl)-1,1,1-trifluoro-2-propanol (100 mg, 0.441 mmol, Intermediate E), Hünig's base (100 μL, 0.573 mmol), and dioxane (2 mL) was heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 1 h and then at 160° C. for 3 h. The resulting red mixture was purified via silica gel chromatography (10-50% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(2-(2-(1-propyn-1-yl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (18 mg) as a mixture of 4 isomers.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([CH3:16])=[C:11]([CH2:17][CH3:18])[N:10]=1.[CH3:19][CH:20]1[C:25]2[S:26][CH:27]=[CH:28][C:24]=2[CH2:23][CH2:22][NH:21]1>CN(C)C=O>[CH3:16][C:12]1[C:13]([N:21]2[CH2:22][CH2:23][C:24]3[CH:28]=[CH:27][S:26][C:25]=3[CH:20]2[CH3:19])=[N:14][C:9]([Cl:8])=[N:10][C:11]=1[CH2:17][CH3:18]
Reactant: CC1NCCc2ccsc21
Reactant: CCc1nc(Cl)nc(Cl)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nc(Cl)nc(N2CCc3ccsc3C2C)c1C
Yield: 51.4 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that triethylamine(2.2 ml), N,N-dimethyl formamide(20 ml), 2,4-dichloro-5-methyl-6-ethylpyrimidine (2.7 g, 14.1 mmol) prepared in Preparation 4 and 7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine(2.4 g, 15.7 mmol) prepared in Preparation 1 were used as starting materials, 2.23 g of the titled compound was prepared. (Yield: 51.3%)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11](=O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH2:20][CH3:21])[C:4]([CH2:23][CH2:24][CH3:25])=[N:3]1.OO.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:1][N:2]1[C:6]2[C:7](=[O:8])[NH:9][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:10][C:5]=2[C:4]([CH2:23][CH2:24][CH3:25])=[N:3]1
Reactant: CCCOc1ccccc1C(=O)Nc1c(CCC)nn(C)c1C(N)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 58.8 %

Procedure:
1-Methyl-4-(2-n-propoxybenzamido)-3-n-propylpyrazole-5-carboxamide (0.34 g, 0.99 mmol) was added to a stirred mixture of 30% hydrogen peroxide solution (1.0 ml), potassium carbonate (0.54 g, 3.92 mmol), water (10 ml) and ethanol (5 ml). The mixture was heated under reflux for 38 hours and then evaporated under vacuum. The residue was suspended in water (20 ml), then the mixture acidified with 2N hydrochloric acid and extracted with dichloromethane (3×20 ml). The extracts are combined, dried (Na2SO4) and evaporated under vacuum. The resulting residue was chromatographed on silica gel (6 g), using a methanol in dichloromethane elution gradient (0.0-1.0%), to give an oil, successive trituration of which with ether gave the required product as a white solid (0.19 g, 59%), m.p. 111-114° C. Found: C, 66.26; H, 6.92; N, 17.15. C18H22N4O2 requires C, 66.23; H, 6.80; N, 17.17%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27](C(OCC4C=CC=CC=4)=O)[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cn2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cn2)c2ccccc21
Yield: 94.1 %

Procedure:
5.08 g of 4-[5-(4-(benzyloxycarbonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are placed in 240 ml of ethanol in a Parr bottle. 2 g of 10% Pd/C (50% in water) are added. The reaction medium is stirred at 35° C. under 45 psi hydrogen for 3.5 h. It is filtered on a Whatman filter under an inert atmosphere and then the filter residue is washed many times with methanol. The methanol is evaporated under reduced pressure. 3.57 g of 4-(5-(piperazin-1-yl)pyridin-2-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH3:18])[C:6]([OH:8])=O)#[N:2].O[N:20]=[C:21]([C:23]1[CH:31]=[CH:30][C:26]2[NH:27][CH:28]=[N:29][C:25]=2[CH:24]=1)[NH2:22]>>[NH:27]1[C:26]2[CH:30]=[CH:31][C:23]([C:21]3[N:20]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([N:12]5[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]5[CH3:18])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:22]=3)=[CH:24][C:25]=2[N:29]=[CH:28]1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C#N
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cc1C#N

Procedure:
Title compound was prepared following general procedure 1 starting from Intermediate 12 (122 mg; 0.50 mmol) and Intermediate 1 (88 mg; 0.50 mmol). Reaction mixture was filtered over a SPE-NH2 column, washed with THF followed by evaporation of the solvent under reduced pressure. Reaction mixture was extracted with ethyl acetate and combined organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oily residue. Purification by silica column chromatography (DCM/MeOH, 98/2 then 95/5) afforded the title compound as an off-white solid. 1H NMR (DMSO, d6): δ 12.78 (s, 1H), 8.39-8.37 (m, 2H), 8.31 (s, 1H), 8.24 (dd, J=8.8, 2.2 Hz, 1H), 7.95-7.92 (m, 1H), 7.78-7.75 (m, 1H), 7.32 (d, J=8.8 Hz, 1H), 4.23-4.22 (m, 1H), 3.38-3.35 (m, 2H), 1.82-1.57 (m, 6H), 1.17 (d, 6.6 Hz, 3H). HPLC (Method A) Rt 3.65 min (Purity: 95.1%). LC/MS (method B): 358.3 (M+H)+.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15]O>C1COCC1.O.[O-2].[O-2].[Mn+4]>[CH:4]1[CH:3]=[CH:2][C:1]([C@H:7]2[O:15][C@@H:8]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: OO
Reactant: C(=C/c1ccccc1)\c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
In a 25 mL scintillation vial equipped with a magnetic stirrer, trans-stilbene (1.80 g, 10 mmol) was placed followed by addition of 2.8 mL THF.6 To this solution was added BTSP (2.8 g, 15 mmol). The vial was immersed into ice/water bath. After 5 minutes Re2O7 (24 mg, 0.05 mmol) was added dropwise as a solution in 1.2 mL THF.7 The reaction turned yellow and was allowed to warm up to room temperature and stirred for 10 h. Upon completion, water (3 drops) was added followed by manganese dioxide (ca. 5 mg) in order to decompose the remaining H2O2. The destruction of H2O2 was evident by the disappearance of yellow color. The mixture was then dried over Na2SO4. Concentration afforded trans-stilbene oxide (1.88 g, 96% yield) of as an off-yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:17]([S:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:16][C:15](F)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N:31]1[C:35](=O)[CH2:34][CH2:33][CH2:32]1>O>[CH2:3]([N:10]1[C:18]2[C:17]([S:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:16][C:15]([NH:10][C:3]3[CH:32]=[CH:33][C:34]([C:35]#[N:31])=[CH:5][CH:4]=3)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCCC1=O
Reactant: Cc1cc(C)c(Sc2nc(F)nc3ccn(Cc4ccccc4)c23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a stirred suspension of NaH (30 mg, 1.25 mmol) in dry NMP (1.5 mL) was added 4-aminobenzylnitrile (87.4 mg, 0.74 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2-fluoro-4-(mesitylthio)-5H-pyrrolo[3,2-d]pyrimidine (93 mg, 0.25 mmol) in dry NMP (1 mL) and stirred at room temperature for 2 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc×3. The combined organic layers were washed with water, NH4Cl, water×2, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with Hexanes:Ethyl acetate (1.5:1) afforded the product as a tan solid (12.6 mg, 11%).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1
Product: O=S(=O)(Nc1ccc(N2CCN3CCC2CC3)cc1)c1ccccc1

Procedure:
Was prepared by Method G from 4-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-phenylamine and phenylsulfonyl chloride. Mp. 267° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([C:22]([OH:24])=O)[N:16]=[N:15]2)=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C1C=C[C:28]2N(O)N=[N:31][C:29]=2[CH:30]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH2:1]([NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]([C:22]([NH:31][CH:29]3[CH2:30][CH2:28]3)=[O:24])[N:16]=[N:15]2)=[CH:12][CH:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CCCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.8 %

Procedure:
1-{4-[(Butylamino)carbonyl]phenyl}-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (504 mg, 1.53 mmol) obtained in Example 56b), HOBt (208 mg, 1.53 mmol, 1.0 eq.) and cyclopropylamine (0.142 ml, 1.98 mmol, 1.3 eq.) were dissolved in acetonitrile (4 ml) and DMF (4 ml), WSC (358 mg, 1.83 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (535 mg, 1.45 mmol, 94.9%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:10]=[C:9]1[CH2:23]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:25][CH2:26][CH3:27].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:10]=[C:9]1[CH2:23][O:25][CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[O-]
Reactant: CCOC(=O)c1nc(CBr)n(Cc2ccccc2)c1C(=O)OCC
Agent: [Na+]
Solvent: CCO
Product: CCOCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccccc1
Reaction time: 13 h

Procedure:
A solution of 1.80 g of diethyl 1-benzyl-2-bromomethylimidazole-4,5-dicarboxylate [prepared as described in Preparation42(ii)] in 50 ml of ethanol was added dropwise to a solution of sodium ethoxide in ethanol (prepared from 0.18 g of sodium and 50 ml of ethanol), and the resulting mixture was left at room temperature for 13 hours. At the end of this time, a procedure similar to that described in preparation42(iii) was repeated, and the residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.14 g of the title compound as a syrup.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:7][C:8]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH3:32])[C:15]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9])[C:4](O)=[O:5].[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:35][N:36]([CH3:37])[C:4]([C@@H:3]([NH:7][C:8]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH3:32])[C:15]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9])[CH2:2][OH:1])=[O:5]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)N[C@@H](CO)C(=O)O)ccc21
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@H](CO)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((S)-1-dimethylcarbamoyl-2-hydroxy-ethyl)-amide (68 mg) was prepared by following General Procedure F starting from (S)-3-hydroxy-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid (50 mg), dimethylamine (56 uL, 2 M in THF), HBTU (46 mg), and DIEA (27 uL). LC/MS: m/z 524.0.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][CH2:13][C@@H:14]1[CH2:18][C@H:17](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][N:15]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)C.CN(C)C=O>[N:1]([C@H:17]1[CH2:16][N:15]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[C@H:14]([CH2:13][O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:18]1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](COCc3ccccc3)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@H]1COCc1ccccc1
Temperature: 80 °C
Yield: 99 %

Procedure:
Sodium azide (0.32 g) was added to a solution of tert-Butyl (2S,4S)-2-[(benzyloxy)methyl]-4-[(4-methylphenyl)sulfonyl]oxypyrrolidine-1-carboxylate (1.15 g) [see Preparation 32] in ethanol (20 ml) and dimethylformamide (5 ml). The reaction mixture was heated to 80° C. for 4 hours, after which time the cooled mixture was partitioned between diethyl ether and water. The organic layer was separated and the aqueous extracted twice with diethyl ether, the combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was azeotroped with dichloromethane to afford tert-butyl (2S,4R)-4-azido-2-[(benzyloxy)methyl]pyrrolidine-1-carboxylate (820 mg) as an oil.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:21]1([CH3:38])[CH:26]=[CH:25][C:24](S(OCC2CCCCC2)(=O)=O)=[CH:23][CH:22]=1>>[CH:21]1([CH2:38][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCC2)cc1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CC2CCCCC2)c1
Yield: 54.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and (cyclohexyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (210 mg, yield: 54.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([NH:37][C@@H:38]([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35]>>[O:20]1[CH2:21][CH2:22][NH:23][C:24]2[N:25]=[CH:26][C:17]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[C:29]([S:34]([NH:37][C@@H:38]([CH3:41])[CH2:39][OH:40])(=[O:35])=[O:36])=[CH:28][CH:33]=[CH:32][CH:31]=4)=[CH:7][C:2]=3[F:1])=[CH:18][C:19]1=2
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Reactant: C[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Product: C[C@@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and (S)-2-bromo-N-(1-hydroxypropan-2-yl)benzenesulfonamide. MS (ESI): mass calcd. for C22H22FN3O4S, 443.13; m/z found, 444.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.15-8.12 (m, 1H), 7.80 (m, 1H), 7.72 (d, J=1.3, 1H), 7.69-7.64 (m, 1H), 7.62-7.52 (m, 2H), 7.40-7.33 (m, 3H), 4.37 (t, J=4.6, 2H), 3.76-3.69 (m, 2H), 3.43-3.36 (m, 1H), 3.30-3.26 (m, 1H), 3.24-3.16 (m, 1H), 1.04-1.01 (m, 3H).