Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:26][CH:27]=[CH2:28])[C:22](OC)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].O>C1COCC1.CCOC(C)=O>[CH3:4][O:3][P:2]([CH2:1][C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:26][CH:27]=[CH2:28])([O:5][CH3:6])=[O:7]
Reactant: COP(C)(=O)OC
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)CP(=O)(OC)OC
Reaction time: 0.67 h
Yield: 88.6 %

Procedure:
To a solution of dimethyl methylphosphonate (13.98 mL, 131 mmol) in THF (87 mL) at −78° C. was added n-BuLi (82 mL, 131 mmol) slowly. After completion of addition, the reaction was stirred for 40 min and then a solution of (5)-methyl 2-(tert-butoxycarbonylamino)pent-4-enoate (6.0 g, 26.2 mmol) in THF (30 mL) was added slowly. Stirring was continued for another 40 min at −78° C. The reaction mixture was then quenched by adding H2O (2.357 mL, 131 mmol). The reaction mixture was diluted with EtOAc (100 mL) and the layers were separated. The organic layer was washed with 1M HCl, saturated NaHCO3 solution followed by brine. The organic phase was then dried over MgSO4, filtered and concentrated to give a clear oil. The crude product was finally purified using silica gel chromatography to give the desired product (7.46 g, 89%) as colorless oil. MS (ESI) m/z: 343.9 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 5.63-5.76 (1H, m), 5.08-5.17 (2H, m), 4.33-4.43 (1H, m), 3.80 (3H, d, J=2.20 Hz), 3.77 (3H, d, J=2.20 Hz), 3.28-3.37 (1H, m), 3.05-3.16 (1H, m), 2.58-2.69 (1H, m), 2.42 (1H, dt, J=14.58, 7.29 Hz), 1.43 (9H, s) ppm.
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH:36]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C>[CH:36]1([NH:41][CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]5[S:29][CH:30]=[CH:31][CH:32]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: NC1CCCC1
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCNC4CCCC4)CC3)c[nH]c12
Yield: 44 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide (50 mg, 0.12 mmol) and cyclopentyl amine (54 uL, 0.60 mmol) were allowed to react in the presence of K2CO3 (74 mg, 0.55 mmol) and NaI (Cat. 5 mg) in DMF at 120° C. The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (27.2 mg, 44%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]1[C:17]([OH:19])=O.C1C=CNC=1.S(Cl)([Cl:27])=O>CN(C=O)C.[Pd]>[CH3:8][N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]1[C:17]([Cl:27])=[O:19]
Reactant: O=S(Cl)Cl
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: c1cc[nH]c1
Solvent: CN(C)C=O
Product: Cn1cc([N+](=O)[O-])cc1C(=O)Cl

Procedure:
A solution of 15 g (0.08 mol) monopyrrole nitro ester in 130 mL DMF was reduced over 5% palladium on charcoal (1.5 g) at atmospheric pressure. The solution was filtered through Celite to remove the catalyst and 20 mL triethylamine (0.14 mol) was added. A mixture of 15 g N-methyl-4-nitropyrrole-2-carboxylic acid 22 (0.09 mol) in 20 mL DMF was added with stirring. (N-methyl-4-nitropyrrole-2-carboxylic acid chloride was prepared by reluxing the monopyrrole acid in thionyl chloride until clear (~1 h) and removing excess thionyl chloride under vacuum.) The mixture stirred 12 h, 700 mL ice and water was added and the product was filtered off. After washing with water twice and diethyl ether, the light-green product was dried yielding 24 g (95%) of the dipyrrole nitro ester 20 (Bailer et al., 1978). NMR (DMSO-d6) δ3.75 (s, 3H), 3.85 (s, 3H), 4.0 (s, 3H), 6.9 (d, 1H, J=1.5 Hz), 7.5 (d, 1H, J=1.5 Hz), 7.6 (d, 1H, J=2.0 Hz), 8.2 (d, 1H, J=1.5 Hz), 10.3 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:19]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].IC.CN(C)C=O>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:19]=1
Reactant: O=C1CCN(C2CCCCC2)c2nc(Cl)ncc2N1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCN(C2CCCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.12 g (0.00042 mole) of 2-chloro-9-cyclohexyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.469 g (0.00144 mole) of cesium carbonate, 0.135 g (0.00096 mole) of iodomethane and 1 mL of dimethylformamide was stirred overnight at ambient temperature and then diluted with 5 mL of water. The mixture was stirred for 15 minutes and the solid was collected by filtration to give 2-chloro-9-cyclohexyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20) which was used without further purification.
Reaction SMILES: I[C:2]1[CH:32]=[CH:31][C:5]2[N:6]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[C:13]([O:29][CH3:30])[CH:12]=3)[CH3:10])[CH:7]=[N:8][C:4]=2[CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:32]=[CH:31][C:5]3[N:6]([CH:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]5[CH:20]=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=5)=[C:13]([O:29][CH3:30])[CH:12]=4)[CH3:10])[CH:7]=[N:8][C:4]=3[CH:3]=2)=[CH:36][CH:35]=1
Reactant: COc1cc(C(C)n2cnc3cc(I)ccc32)ccc1OCc1ccc(C(F)(F)F)nc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(C)n2cnc3cc(-c4ccc(F)cc4)ccc32)ccc1OCc1ccc(C(F)(F)F)nc1
Temperature: 75 °C
Reaction time: 0.75 h
Yield: 115.5 %

Procedure:
To a stirred solution of 5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole (0.248 g, 0.45 mmol), (4-fluorophenyl)boronic acid (0.088 g, 0.63 mmol), and potassium phosphate tribasic (0.485 g, 2.24 mmol) in tetrahydrofuran (7 mL)/water (5 mL) was added 2nd generation XPhos precatalyst (0.024 g, 0.031 mmol). The yellow solution was degassed under vacuum/backfilled with nitrogen (×3). The mixture was heated to 75° C. After 45 min, the brown reaction mixture was allowed to cool to room temperature and was diluted with water (30 mL). The mixture was extracted with dichloromethane (2×25 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 0.271 g of a brown oil. Chromatographic purification (CombiFlash, 12 g SiO2 gold column, 1-5% methanol/dichloromethane elute) afforded 0.200 g (86%) of the product as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=2.0 Hz, 1H), 8.08 (s, 1H), 7.99-7.94 (m, 2H), 7.70 (dd, J=8.1, 0.8 Hz, 1H), 7.61-7.52 (m, 2H), 7.40 (dd, J=8.4, 1.7 Hz, 1H), 7.27-7.23 (m, 1H), 7.16-7.09 (m, 2H), 6.88-6.84 (m, 1H), 6.80-6.76 (m, 1H), 6.75-6.73 (m, 1H), 5.60 (q, J=7.0 Hz, 1H), 5.20 (s, 2H), 3.80 (s, 3H), 2.01 (d, J=7.0 Hz, 3H) ppm; (M+1)=522.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:29])[CH3:28])[CH:22]=3)=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14].C(N(CC)CC)C>ClCCl>[C:27]([C:23]1[CH:22]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:11]3[O:12][C:13]([CH3:14])=[C:9]([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:10]=3)=[CH:20][CH:19]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:29])[CH3:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cccc(-c2ccc(-c3nc(CCO)c(C)o3)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(-c2ccc(-c3nc(CCOS(C)(=O)=O)c(C)o3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
Add methanesulfonyl chloride (0.110 g, 0.760 mmol) to a cool (0° C.) solution of 1-{4′-[4-(2-hydroxy-ethyl)-5-methyl-oxazol-2-yl]-biphenyl-3-yl}-ethanone (0.188 g, 0.584 mmol) and triethylamine (0.089 g, 0.88 mmol) in dichloromethane (5 mL). Warm the reaction mixture to room temperature and stir for 1 hour. Add dichloromethane and wash the crude organic layer with saturated sodium chloride solution. Dry the organic extracts over Na2SO4, filter, and concentrate to give crude methanesulfonic acid 2-[2-(3′-acetyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl ester (0.256 g, >100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.C(OCC)(=O)C.[ClH:38]>C(O)C>[ClH:38].[Br:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:22][NH:23][CH3:24])=[CH:12]2)(=[O:9])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(Br)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
tert-Butyl ({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (120 mg) was dissolved in ethanol (3 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 4 hr, the mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a solid (yield 51.3 mg, 49%).
Reaction SMILES: [OH:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:6]1[N:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=[CH:4][CH:5]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1nccc1-c1cccs1
Product: CN(C(=O)On1nccc1-c1cccs1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-5-(2-thienyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (51%, crystals).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[NH2:9].[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:13]=2[O:12][CH2:11]1.N=C=N.OC1C2N=NNC=2C=CC=1.C(O)C(N)(CO)CO>C(#N)C.ClCCl.CN(C=O)C.C(#N)C>[CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:3]1[NH:9][C:19]([C:17]1[CH:16]=[CH:15][C:14]2[O:10][CH2:11][O:12][C:13]=2[CH:18]=1)=[O:20]
Reactant: CC1CCCC(N)C1C
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC1CCCC(NC(=O)c2ccc3c(c2)OCO3)C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3-dimethylcyclohexanamine (20 μmol) and benzo[d][1,3]dioxole-5-carboxylic acid (1.1 eq) were each dissolved in acetonitrile/dichloromethane (200 μL, 2:1). PS-Carbodiimide resin (2 eq) was loaded into a 1.2 mL 96 well Greiner plate, followed by the addition of amine and acid solutions. Hydroxybenzotriazole (1.1 eq) was dissolved in DMF (100 mL) and was added into the reaction well. The reaction was shaken overnight at room temperature. Once the reaction was completed, PS-Trisamine resin (1.5 eq) was added into the reaction mixture and the solution was allowed to shake overnight at room temperature. Acetonitrile (200 mL) was added into the reaction well, and the top clear solution was transferred into a new plate. The solution was evaporated to give N-(2,3-dimethylcyclohexyl)benzo[d][1,3]dioxole-5-carboxamide. MS (M+H, 276.20).
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:34]C)[N:19]2[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][O:29][C:28]([CH3:33])([CH3:32])[CH2:27]2)=[C:15]([NH2:36])[N:14]=1)[CH2:9][CH2:10][CH3:11]>CO>[NH2:36][C:15]1[N:14]=[C:13]([NH:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[NH:17][C:18](=[O:34])[N:19]2[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][O:29][C:28]([CH3:33])([CH3:32])[CH2:27]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCOC(C)(C)C3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCCC3CCOC(C)(C)C3)c2n1
Reaction time: 8 h
Yield: 81.4 %

Procedure:
4M HCl in 1,4-dioxane (3 ml, 12.00 mmol) was added in one portion to a stirred solution of N2-butyl-9-[4-(2,2-dimethyltetrahydro-2H-pyran-4-yl)butyl]-8-(methyloxy)-9H-purine-2,6-diamine (130 mg, 0.321 mmol) in methanol (3 ml) at room temperature and the mixture stirred under nitrogen overnight. The mixture was then concentrated and the residue dissolved in MeOH:DCM (1:15 ml) and loaded onto a 2 g aminopropyl SPE cartridge. The cartridge was washed with MeOH:DCM (1:1, 3 column volumes) and the desired fractions were concentrated in vacuo to give the title compound as a yellow solid (102 mg).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=[C:7]([NH:17][C:18](=[O:29])[NH:19][C:20]2[S:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[N:6]=1.[H-].[Na+].[CH2:34]([O:41][CH2:42]Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH2:34]([O:41][CH2:42][N:17]([C:7]1[N:6]=[C:5]([O:4][CH2:3][C:2]([F:1])([F:30])[F:31])[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=1)[C:18](=[O:29])[NH:19][C:20]1[S:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)Nc1ccc(C(F)(F)F)s1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(F)(F)F)s1)N(COCc1ccccc1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (1) (750 mg, 1.54 mmol) in anhydrous DMF (7.5 mL) at ambient temperature was added NaH (37 mg, 1.54 mmol, 60% dispersion in mineral oil). After stirring for 20 minutes a solution of benzyloxymethylchloride (241 mg, 1.54 mmol) in anhydrous DMF (0.75 mL) was added. After 2 h of stirring at room temperature the reaction was quenched with H2O (5 mL) and diluted with EtOAc. The organic layer was separated and washed with H2O (3×10 mL) and brine (10 mL). The organics were dried (Na2SO4), filtered and evaporated. The crude material was purified by silica gel chromatography (0 to 10% EtOAc in pet ether) to afford 3-(benzyloxymethyl)-3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea as an off white solid (550 mg, 59%), mp 101-104° C.; 1H NMR (400 MHz, Acetone-d6) δ 11.82 (s, 1H), 7.37-6.99 (m, 5H), 6.65 (d, J=4.0 Hz, 1H), 6.17 (s, 1H), 5.71 (s, 2H), 4.97 (q, J=8.5 Hz, 4H), 4.60 (s, 2H); ESIMS m/z 605 ([M+H]+). Also isolated was a by-product 1,3-bis(benzyloxymethyl)-3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (11) as a pale yellow gum (65 mg); 1H NMR (400 MHz, Aceton) δ 7.29-7.05 (m, 10H), 6.87 (d, J=4.0 Hz, 1H), 5.90 (s, 1H), 5.40 (s, 2H), 5.23 (s, 2H), 4.75 (q, J=8.7 Hz, 4H), 4.69 (s, 2H), 4.52 (s, 2H); ESIMS m/z 618 ([M-PhCH2O]+).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[N:15]=[C:14]([CH2:16][C:17]#[N:18])[O:13][N:12]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[CH:25]=[C:26]([C:31]([CH3:33])=[O:32])[C:27]([O:29][CH3:30])=[O:28])([O-:21])=[O:20].N1CCCCC1>C(O)C>[NH2:18][C:17]1[O:32][C:31]([CH3:33])=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]([C:24]2[CH:34]=[CH:35][CH:36]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:16]=1[C:14]1[O:13][N:12]=[C:11]([CH2:10][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:9])[N:15]=1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: CN(Cc1ccccc1)Cc1noc(CC#N)n1
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)C1=C(C)OC(N)=C(c2nc(CN(C)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Yield: 33.4 %

Procedure:
To a stirred mixture of 1.21 g of 3-(N-benzyl-N-methylamino)methyl-5-cyanomethyl-1,2,4-oxadiazole prepared in Example 95 and 1.25 g of methyl 2-(3-nitrobenzylidene)acetoacetate in 10 ml of ethanol was added 0.1 ml of piperidine. The reaction mixture was heated under reflux for 3 hours and then concentrated in vacuo. The residue was triturated with 10 ml of ethyl acetate and the insoluble crystals were collected by filtration. Treatment of a solution of this base in chloroform with etherial hydrogen chloride afforded 820 mg of methyl 2-amino-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-6-methyl-4-(3-nitrophenyl)-4H-pyran-5-carboxylate as pale yellow powder, m.p. 201.5° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][CH2:5]2>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([OH:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2O1
Solvent: C1CCOC1
Product: OC1CCc2cc(Br)ccc2O1
Temperature: 25 °C

Procedure:
To a mixture of 16.4 g (72.2 mmole) 6-bromo-2chromanone and 60 ml dry tetrahydrofuran, under nitrogen at -70° C., was added a cloudy solution of 18.4 g (72.2 mmole) lithium hydrido-tri(t-butoxy)aluminate (commercial) over 30 minutes. The mixture was stirred while allowing it to warm to room temperature over 90 minutes, then poured onto 250 ml ice/water. The resulting mixture was filtered, the cake washed with ethyl ether, then ethyl acetate and the organic phase is separated. The aqueous layer is extracted with ethyl acetate, the organic layers combined, dried (Na2SO4) and solvent evaporated to obtain 9.5 g crude product. An additional 4 g was obtained by reworking the filter cake, above. The combined crude products were purified on a silica gel column, eluting with 9:1 hexane/ethyl acetate, then a 4:1 mixture of the same solvents to obtain the purified product as an oil, 5.6 g.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:29])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][CH2:10][CH2:9]1)=[O:6])[CH3:4].P(=O)(O)(O)[OH:31].[OH-].[Na+].O>C(#N)C>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21]([OH:29])[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@@H:10]([OH:31])[CH2:9]1)=[O:6])[CH3:4]
Reactant: CC[C@H](C)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Reactant: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Reaction time: 0.83 h

Procedure:
Analysis of the starting compactin by HPLC using a Waters column RP-18 (5 m, 2.1×150 mm) with a mobile phase of (a) 0.1% phosphoric acid and the pH adjusted with 25% NaOH and (b) a mixture of distilled water and acetonitrile (1:9). The column was run for 50 min at 40° C. using a detection wavelength of 240 nm. The amount of compactin was determined using a standardized solution of 10 mg of compactin and 10 mg compactin ammonium salt.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(-c2cc(F)cc(F)c2)cc1
Yield: 50.9 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (225 mg, 0.57 mmol, prepared in example 17) and 3,5-difluorophenylboronic acid (108 mg, 0.69 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with methylene chloride to afford 110 mg (51%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[N:22]2)=[CH:17][CH:16]=1>>[N:22]1[C:23]2[C:18](=[CH:17][CH:16]=[C:15]([NH:14][C:11]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=4)=[O:13])[CH:24]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)c1cc2ccc(Br)cc2[nH]1
Product: O=C(Nc1ccc2cccnc2c1)c1cc2ccc(Br)cc2[nH]1

Procedure:
This material was prepared analogous to the procedure described for Example 6(b). 6-Bromo-1H-indole-2-carboxylic acid (208 mg, 0.87 mmol, Asymchem) reacted with 7-amino-quinoline (125 mg, 0.87 mmol, prepared according to the procedure described in WO03099284) to give the title compound as a light-brown amorphous solid. MS (ESI, pos. ion) m/z: 366 (M+1).
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([C:36]([F:39])([F:38])[F:37])([OH:35])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[H][H]>CO.[C].[Pd]>[CH2:1]([C:3]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([C:31]([F:34])([F:32])[F:33])([OH:35])[C:36]([F:38])([F:37])[F:39])=[C:24]([CH3:40])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:17])([CH3:18])[C:14]([CH3:19])([CH3:20])[O:13]2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: [H][H]
Reactant: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Yield: 94 %

Procedure:
10% palladium-carbon (50 mg) was added to a solution of 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-butyn-2-ol (Example 27-(1); 142 mg, 0.249 mmol) in methanol (6 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for five hours. Then, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the target product as a colorless oil (134 mg, 94%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1.O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([N:9]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
140 ml of benzylbromide are added dropwise to a mixture of 61 g of trans-4-amino-cyclohexanol, 350 ml of water, 350 ml of ethanol and 110 g of potassium carbonate. The mixture is then heated to boiling for 1 hour, cooled and the crystalline residue is suction filtered. The residue is taken up in 1.51 of cyclohexane, the mixture is boiled, cooled and suction filtered. Washing with cyclohexane and drying in vacuo yields 108 g (92% of theory) of trans-4-dibenzylamino-cyclohexanol.