Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[N+]=[N-].N#N>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])CC1CCCCC1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CN)CC1CCCCC1
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A solution of (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate (7.2 g, 25.5 mmol) in methanol (250 mL) was added to wetted Pd/C (1.0 g) in a N2-filled Parr bottle. After 3 vac/purge cycles with H2, the vessel was charged to 50 psi and shaken on a Parr apparatus overnight. Theoretical equivalents (36 psi) of H2 were consumed. The reaction mixture was filtered through a pad of Celite and the solvent was removed to give (S)-tert-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate (5.9 g, 90%) as a white solid. 1H NMR (D6-DMSO) δ 0.70-1.30 (m 10H), 1.38 (s, 9H), 1.58 (d, 2H), 1.80 (d, 1H), 2.66 (m, 1H), 2.78 (d, 1H), 3.74 (m, 1H), 6.77 (d, 1H), 8.0 (bs, 2H). MS ESI +ve m/z 157 (M(−BOC)+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[CH2:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH2:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[CH:27][CH:26]=1)[CH3:24]
Reactant: CCc1ccc(C=O)cc1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(CNC2CCN(CCn3c(=O)cnc4ccc(OC)cc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To 10 mL of a chloroform solution containing 500 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 200 mg of 4-ethylbenzaldehyde, 100 mg of acetic acid were added, and stirred at room temperature for 1 hour. To the reaction mixture, 526 mg of sodium triacetoxyborohydride was added, and stirred for 15 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 0.32 g of 1-(2-(4-(4-ethylbenzylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a brown oil.
Reaction SMILES: Br[C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([Br:18])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:25][SH:26]>CN(C=O)C.CCOCC>[Br:18][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([S:26][CH3:25])[C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: CS
Reactant: CCOC(=O)c1ccc(Br)c(OCCOC)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Br)c(OCCOC)c1SC

Procedure:
Ethyl 2,4-dibromo-3-(2-methoxyethoxy)benzoate(32.2 g) was stirred in DMF (80 ml) with potassium carbonate (36 g). To the resultant suspension was added a solution of methane thiol (13 ml) in DMF (20 ml). The resultant mixture was stirred overnight at room temperature. It was then diluted with ether, and the mixture washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was purified by column chromatography on silica eluting with ethyl acetate and cyclohexane (1:20) which yielded ethyl 4-bromo-3-(2-methoxyethoxy)-2-methylsulphenylbenzoate (3.5 g) as an oil which was not further characterized.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:31][C:32]([F:35])([F:34])[F:33])(=O)=O.[Na].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([N+:22]([O-:24])=[O:23])=[C:16]([O:21][CH2:31][C:32]([F:35])([F:34])[F:33])[N:17]=[C:18]([CH3:20])[N:19]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC(C)=O
Product: Cc1nc(OCC(F)(F)F)c([N+](=O)[O-])c(N2CCC(c3ccc(F)cc3)CC2)n1

Procedure:
In analogy to the procedure described in example 9, the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 7) was treated with 2,2,2-trifluoro-ethyl trifluoromethanesulfonate, sodium and potassium carbonate in acetone at room temperature to yield the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-6-(2,2,2-trifluoro-ethoxy)-pyrimidine as a yellow oil; MS: [M+H]+=415; and the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3-(2,2,2-trifluoro-ethyl)-3H-pyrimidin-4-one as yellow solid; m.p. 61-64° C.; MS: [M+H]+=415.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:28][N:27]([CH3:29])[C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:26][CH:25]=1
Reactant: CN(C)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of 1-(tert-butoxycarbonyl)-4-(4-dimethylaminophenyl)piperazine (2.01 g 6.58 mmol) in dichloromethane (20 ml) and the mixture stirred for 30 min at room temperature. The mixture was concentrated in vacuo and saturated aqueous potassium carbonate (100 ml) was cautiously added to the residue. The mixture was extracted with dichloromethane (3×100 ml), the extracts were washed with brine (50 ml), combined and dried (MgSO4). Concentration of the extracts gave 1-(4-dimethylaminophenyl)piperazine (1.14 g, 84%) as a cream solid; δH (DMSO-d6) 2.77 (6H, s, N(CH3)2), 2.79 (4H, m, 2×piperazinyl CH2), 2.86 (4H, m, 2×piperazinyl CH2), 2.86 (4H, m, 2×piperazinyl CH2), 6.68 (2H, m, ArH), and 6.82 (2H, m, ArH).
Reaction SMILES: FC(F)(F)C(O)=O.O[C:9]1([CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>ClCCl>[CH3:26][C:24]1([CH3:25])[CH2:23][CH2:22][C:9]2([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[O:27]1
Reactant: CC(C)(O)CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC2(CCNCC2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxy-3-methylbut-1-yl)-1-piperidinecarboxylate (Description 80, 3.9 g, 13.57 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/MeOH/NH3(Aq.) (90:10:1) to give the title compound (2.04 g, 89%). m/z (ES+) 170 (M+1).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[F:31][C:32]1[CH:37]=[CH:36]C(CCN)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:37]=[CH:36][C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCc1ccc(F)cc1
Product: O=C(NCCc1ccc(F)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(4-fluorophenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 381 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.19 (1H, br. s.) 10.45 (1H, s) 8.21 (1H, t, J=5.76 Hz) 8.07 (1H, d, J=6.64 Hz) 7.86 (1H, d, J=5.27 Hz) 7.42 (1H, dd, J=3.12, 1.76 Hz) 7.36 (1H, d, J=5.27 Hz) 7.18 (2H, dd, J=8.79, 5.66 Hz) 7.00 (2H, t, J=8.98 Hz) 6.73 (1H, d, J=6.44 Hz) 6.63 (1H, d, J=3.32 Hz) 3.39-3.47 (2H, m) 2.75 (2H, t, J=7.22 Hz)
Reaction SMILES: [Br:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[OH-].[Na+].Br[CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:21]=[C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:19][C:18]=2[S:26]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])=[O:27])[CH:14]=[CH:15][CH:16]=1>CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[N:3]([CH2:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:21]=[C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:19][C:18]=3[S:26]([NH:29][C:30]([CH3:32])([CH3:31])[CH3:33])(=[O:27])=[O:28])[CH:14]=[CH:15][CH:16]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Brc1ncc[nH]1
Reactant: CC(C)Cc1cc(-c2cccc(CBr)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Cc1cc(-c2cccc(Cn3ccnc3Br)c2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of 2-bromoimidazole (68.9 mg, 0.469 mmol; see step (a)) in DMSO (1 mL) and NaOH (32.8 mg, 0.82 mmol), that had been stirred for 40 min at ambient temperature, was added a solution of 3-(3-bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (173.6 mg, 0.391 mmol; see Example 1(e)) in DMSO (1 mL) dropwise. The reaction mixture was stirred for 1 h at ambient temperature and then diluted with CH2Cl2 (15 mL). The organic layer was washed with water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (3:97) as eluent to give the sub-title compound in 99% yield as a colourless syrup (197.3 mg, 0.387 mmol).
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][C:16]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:9]([OH:38])[CH:8]=1.[N:39]1[C:46]([Cl:47])=[N:45][C:43](Cl)=[N:42][C:40]=1[Cl:41]>C1COCC1>[CH2:30]([O:29][C:16]1[CH:17]=[C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:15]=1[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:43]2[N:45]=[C:46]([Cl:47])[N:39]=[C:40]([Cl:41])[N:42]=2)=[CH:8][C:9]=1[OH:38])=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(NC(=O)c2ccc(OCc3ccccc3)cc2OCc2ccccc2)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
NaHCO3 (300 mg, 3.58 mmol) was added to a solution of compound 40 (263.8 mg, 598 μmol) in THF (5 mL). Cyanuric chloride (110 mg, 598 μmol) in THF (3 mL) was added to the reaction mixture in an ice water bath. The reaction mixture was stirred from 0° C. to room temperature for 30 minutes. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was directly used in the next step. LC-MS (ESI): m/e=588.2 [M+H]+
Reaction SMILES: [CH:1]1([C:4](=[O:18])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])=[O:7])[CH2:3][CH2:2]1.[CH:19](OCC)(OCC)[O:20][CH2:21][CH3:22]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:18])[C:5](=[CH:19][O:20][CH2:21][CH3:22])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(SC)ccc1C(=O)CC(=O)C1CC1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(SC)cc1OC)C(=O)C1CC1
Yield: 99.4 %

Procedure:
A mixture of 3-cyclopropyl-1-(2-methoxy-4-methylsulphenylphenyl)-propan-1,3-dione (25.4 g) and triethyl orthoformate (39 g) in acetic anhydride was stirred and heated at reflux for 3 hours. After cooling the mixture was evaporated to dryness and the residue was dissolved in toluene and re-evaporated to dryness to give 3-cyclopropyl-2-ethoxymethylene-1-(2-methoxy-4-methylsulphenylphenyl)-propan-1,3-dione (30.6 g) as a red gum which was not further purified.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:2]=1.[CH:17]1([Bi](C2CC2)C2CC2)[CH2:19][CH2:18]1.N1C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCl>[CH:17]1([N:12]2[C:13]3[C:9](=[CH:8][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:15][CH:14]=3)[CH2:10][C:11]2=[O:16])[CH2:19][CH2:18]1
Reactant: C1CC1[Bi](C1CC1)C1CC1
Reactant: O=C1Cc2cc(-c3cccnc3)ccc2N1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(-c3cccnc3)ccc2N1C1CC1
Temperature: 75 °C

Procedure:
To 5-pyridin-3-yl-1,3-dihydro-indol-2-one (CAS#220904-98-3, 63 mg, 0.3 mmol) was added freshly prepared tricyclopropyl-bismuthine [(J. Am. Chem. Soc., 2007, 129, 44-45), CAS#925430-09-7, 250 mg, 0.75 mmol], Cu(OAc)2 (82 mg, 0.45 mmol) and dichloromethane (3 ml). The reaction mixture was degassed by sparging with argon for 5 min. Then pyridine (0.073 ml, 0.9 mmol) was added and the reaction was heated at 75° C. for 1.5 hr. The reaction mixture was cooled to room temperature and then directly loaded on to a silica gel flash chromatography column. The 1-cyclopropyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one was eluted via a gradient of ethyl acetate-heptane (0 to 100%); HRMS: (ESI) m/z 251.1173 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.88-1.01 (m, 2H), 1.07-1.19 (m, 2H), 2.60-2.76 (m, 1H), 3.60 (s, 2H), 7.22-7.31 (m, 1H), 7.49 (s, 1H), 7.55 (d. J=8.5 Hz, 1H), 7.81 (br. s., 1H), 8.36 (d, J=7.7 Hz, 1H), 8.63 (br. s., 1H), 8.92 (br. s., 1H.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)(=O)=O)=CC=1.[ClH:42].Cl.C(O)(C)C>>[ClH:42].[F:38][C:37]([F:39])([F:40])[C:34]1[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:36][CH:35]=1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CC(C)O
Product: O=C(N[C@H]1CCN(CCc2ccc(C(F)(F)F)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.5 g) and 2-(4-trifluoromethylphenyl)ethyl p-toluenesulfonate (0.69 g) were reacted under the same conditions as in Example 1. After the same post-treatment as in Example 1, the obtained compound was converted to hydrochloride with 30% hydrochloric acid-isopropanol to give (S)-N-(1-(2-(4-trifluoromethylphenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide hydrochloride 1/2 hydrate (0.51 g), melting point 214-215° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[CH3:34][OH:35]>>[CH3:34][O:35][C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:19])(=[O:20])[NH:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])=[CH:14][CH:13]=2)=[O:32])[CH:4]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Reactant: CO
Agent: Cl
Product: COC(=N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-[3-(3-Cyanophenyl)-ureido]-N-(2,3,6-trifluorobenzyl)-benzenesulfonamide (230 mg, 0.5 mmol) was dissolved in HCl/MeOH (25 ml, 7 M) at 0° C. under inert atmosphere and stirred overnight at rt. The solution was concentrated and dried in vacuo to yield 99% of 3-{3-[4-(2,3,6-trifluorobenzyl-sulfamoyl)-phenyl]-ureido}-benzimidic acid methyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][NH:43][C:44](=[O:67])[CH2:45][CH2:46][S:47]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:12][C:11]=2[N:10]=1.C([SiH](CC)CC)C>ClCCl>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][O:28][CH2:29][CH3:30])[N:21]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:17]=2[C:16]2[CH:15]=[CH:14][C:13]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][NH:43][C:44](=[O:67])[CH2:45][CH2:46][SH:47])=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCOCCOCCOCCNC(=O)CCSC(c4ccccc4)(c4ccccc4)c4ccccc4)ccc3c2n1CC(C)(C)O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3cc(OCCOCCOCCOCCNC(=O)CCS)ccc3c2n1CC(C)(C)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
Trifluoroacetic acid (8 mL) was added to a 0° C. solution of N-(2-{2-[2-(2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethoxy)ethoxy]ethoxy}ethyl)-3-(tritylthio)propanamide (1.38 g, 1.65 mmol) and triethylsilane (3.16 mL, 19.8 mmol) in dichloromethane (12 mL). The solution was stirred at 0° C. for 2 hours, then was concentrated under reduced pressure. The residue was concentrated under reduced pressure from toluene several times. The crude product was purified twice by HPFC on silica gel (gradient elution with 2-70% CMA in chloroform) to provide 0.55 g of N-(2-{2-[2-(2-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethoxy)ethoxy]ethoxy}ethyl)-3-mercaptopropanamide as a foam. MS (ESI) m/z 594 (M+H)+. Anal. Calcd for C28H43N5O7S: C, 56.64; H, 7.30; N, 11.80; S, 5.40. Found: C, 56.36; H, 7.52; N, 11.53; S, 5.34.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].[OH-].[K+].NN>>[CH3:6][CH:5]([CH3:7])[CH2:4][CH2:3][CH2:2][C:8]1[CH:9]=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=1
Reactant: CC(C)CCC(=O)c1ccc(Br)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Product: CC(C)CCCc1ccc(Br)cc1

Procedure:
Reaction Scheme 5 discloses a specific synthetic route to 4-(4-methylpentyl)-phenylethyne (Compound 28). In accordance with this scheme, bromobenzene (Compound 29) is reacted under Friedel Crafts conditions (AlCl3) with the acid chloride (Compound 30) prepared in situ from 4-methyl valeric acid, to yield 4-(1-oxo-4-methyl-pentyl) bromobenzene (Compound 31). Compound 31 is reduced under Wolff-Kishner conditions (KOH, NH2NH2) to yield 4-(4-methylpentyl) bromobenzene (Compound 32). The bromobenzene derivative 32 is converted to the ethyne derivative 28 through the intermediate trimethylsilyl ethyne derivative 33 in a manner similar to the conversion described in connection with Reaction Scheme 3. ##STR9##
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:23]1[CH:27]=[C:26]([CH2:28][C:29]([NH:31][NH2:32])=[O:30])[N:25]=[CH:24]1.Cl>C(O)C.O1CCOCC1>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[N:32]/[NH:31][C:29](=[O:30])[CH2:28][C:26]2[N:25]=[CH:24][NH:23][CH:27]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NNC(=O)Cc1c[nH]cn1
Reactant: O=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(Cc1c[nH]cn1)N/N=C/c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-formylphenyl 4-(trifluoromethyl)benzenesulfonate (6.5 g, 19.7 mmol) in ethanol (100 ml) is added to a solution of 4-imidazoleacetic acid hydrazide (18 mmol) in ethanol (200 mL). A catalytic amount of HCl in dioxane (3 mL) is added and the mixture is stirred at room temperature overnight. The precipitate that forms is removed by filtration. The filtrate is concentrated and chromatographed on silica eluting with 5% (2M ammonia in methanol)/CH2Cl2 to give 2-((E)-{2-[2-(1H-imidazol-4-yl)acetyl]hydrazono}methyl)phenyl 4-(trifluoromethyl)benzenesulfonate as a white solid. The yield is 3.1 g, 38%. 1H NMR (400 MHz, DMSO) d 11.94 (s, 1H), 11.48 (2s, 1H), 8.02 (m, 6H), 7.21 (m, 5H), 3.64 (2 s, 2H). ESI+ for C19H15F3N4O4S, m/z 453, (M+H)+.
Reaction SMILES: [OH-].[K+].CCOCC.[CH3:8][N:9]([N:16]=O)C(N[N+]([O-])=O)=N.[CH2:18]([O:25][C:26]1[C:27]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:28][N:29]2[CH:34]([C:35](Cl)=[O:36])[CH2:33][N:32]([CH3:38])[C:31](=[O:39])[C:30]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH2:18]([O:25][C:26]1[C:27]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:28][N:29]2[CH:34]([C:35](=[O:36])[CH:8]=[N+:9]=[N-:16])[CH2:33][N:32]([CH3:38])[C:31](=[O:39])[C:30]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)C=[N+]=[N-]
Reaction time: 0.25 h

Procedure:
To a stirring biphasic mixture of 40% aqueous KOH (20 mL) and Et2O (10 mL) at 0° C. was slowly added N-methyl-N-nitroso-N′-nitroguanidine (492 mg, 3.34 mmol). The mixture was stirred for 15 minutes, and the Et2O layer was transferred to a solution of ethyl 3-benzyloxy-7-chlorocarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (262 mg, 0.669 mmol) in CH2Cl2 (10 mL). The reaction was stirred at room temperature for 30 minutes, and the solvent was removed in vacuo to afford the title product. ES MS (M+H)=398.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17]O)([CH3:3])[CH3:2].S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:21][CH2:17][C:5]1[S:6][C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1c(CO)sc2cc(C(F)(F)F)ccc12
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)c1c(CCl)sc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of 3-isopropyl-6-(trifluoromethyl)-benzothiophene-2-methanol (obtained in Example 12(4), 878 mg, 3.20 mmol) in benzene (27 mL) was added dropwise a solution of thionyl chloride (0.28 mL, 3.8 mmol) in benzene (5 mL) under cooling with ice. The mixture was stirred for 3 hours at room temperature. After the solvent was removed under reduced pressure, the residue was purified by chromatography on silica gel (hexane/ethyl acetate, 10:1) to give the titled compound as a pale yellow oil (655 mg, y. 70%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][OH:9].CCN(C(C)C)C(C)C.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[OH:9][CH2:8][C@@H:3]1[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]1[C:25]([C:24]1[CH:28]=[C:20]([CH3:19])[CH:21]=[CH:22][C:23]=1[N:29]1[N:33]=[CH:32][CH:31]=[N:30]1)=[O:26]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CO)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
((2S,3R)-3-Methylpiperidin-2-yl)methanol from the previous step in DMA (0.2M) was added DIPEA (2 equiv.) followed by 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (1.2 eq) and HATU (1.1 equiv.). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMAC. The crude residue was taken up in EtOAc and washed with 1M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hexanes) to give the title compound as a brown oil which crystallized (2.6 g). MS (ESI) 315 (M+H).