Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=[CH2:2].[NH2:22][NH2:23]>C(O)C>[CH2:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:22][NH2:23])=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: C=Cc1ccc(CN2CCN(CC(=O)OCC)CC2)cc1
Reactant: NN
Solvent: CCO
Product: CCc1ccc(CN2CCN(CC(=O)NN)CC2)cc1

Procedure:
Synthesized according to General Procedure C: 9 (3.23 g, 11.2 mmol, 1 equiv.), anhydrous hydrazine (1.1 mL, 33.6 mmol, 3 equiv.), ethanol (22.6 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{28} (1.92 g, 62%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.14 (br s, 1H), 7.20 (d, 2H, J=8.0 Hz), 7.14 (d, 2H, J=8.0 Hz), 3.84 (d, 2H, J=4.0 Hz), 3.47 (s, 2H), 3.06 (s, 2H), 2.63 (q, 2H, J=7.5 Hz), 2.53 (br s, 4H), 2.45 (br s, 4H), 1.22 (t, 3H, J=7.5 Hz). 13C-NMR (125 MHz, CDCl3): δ 170.5, 143.1, 134.9, 129.1, 127.7, 62.6, 60.5, 53.6, 52.9, 28.5, 15.5.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([F:43])[CH:34]=1.N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:40])=[O:41])=[C:35]([F:43])[CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(Cl)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 4-chloro-2-fluorobenzenesulfonyl chloride (16 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 26 mg of the target compound, 4-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-2-fluorobenzenesulfonamide (percentage yield: 91%), was obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][OH:6].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:6][CH2:5][CH2:4][CH:3]([C:2]([F:11])([F:12])[F:1])[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CCCCC(CCO)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 92 %

Procedure:
0.48 g of 3-trifluoromethyl-1-heptanol was dissolved in 0.79 g of pyridine, and the solution was cooled with ice, followed by addition of 0.5 g of p-toluenesulfonyl chloride, stirring for 2 hours under cooling with ice and stirring for 2 hours at room temperature. After the reaction, the product was acidified with 2N-hydrochloric acid and extracted with methylene chloride. The resultant methylene chloride solution was washed with water and dried with magnesium sulfate, and the solvent was distilled off, whereby 3-trifluoromethylheptyl p-toluenesulfonate was obtained in an amount of 0.82 g (yield: 92%) and showed: [α]D23 +0.5, [α]43523 +2.2 (c 2, methylene chloride).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([NH:9][CH3:10])=[O:8])=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([C:7](=[O:8])[NH:9][CH3:10])=[N:4][N:5]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CNC(=O)c1n[nH]cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Yield: 41.8 %

Procedure:
4-bromo-N-methyl-1H-pyrazole-3-carboxamide (550 mg), potassium carbonate (579 mg) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (1081 mg) in acetonitrile (20 mL) were stirred at 90° C. overnight. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, brine dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 40 to 70% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-bromo-3-(methylcarbamoyl)pyrazol-1-yl]piperidine-1-carboxylate (436 mg) as a off-white solid. The product gave the following characterizing data: NMR Spectrum: (DMSOd6) 1.42 (s, 9H), 1.79 (dd, 1H), 1.84 (dd, 1H), 1.97-2.05 (m, 2H), 2.71 (d, 3H), 2.91 (bs, 2H), 3.97-4.13 (m, 2H), 4.33-4.43 (m, 1H), 8.05 (q, 1H), 8.15 (s, 1H); Mass spectrum: M+H+ 386-388.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:30]1[C:35]([C:36]([OH:38])=[O:37])=[CH:34][C:33]2[C:39]([O:41][C:42](=O)[C:32]=2[CH:31]=1)=[O:40]>>[CH2:24]([NH:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:39](=[O:40])[C:33]3[C:32](=[CH:31][CH:30]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[C:42]2=[O:41])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCCCCNc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Product: CCCCCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-hexylaminophenyl)-5-phenylbenzoxazole (237 mg, 0.61 mmol) and 1,2,4-benzenetricarboxylic anhydride (117 mg, 0.61 mmol) the title compound was obtained (129 mg, 38%). 1H NMR (DMSO) δ 8.46(m, 2H), 8.30(m, 1H), 8.08(m, 2H), 7.80(m, 4H), 7.49(m, 3H), 7.40(m, 1H), 7.02(m, 1H), 3.40(m, 2H), 1.75(m, 2H), 1.41(m, 6H), 0.91(m, 3H). MS 560 m/z (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][N:14]=1)[C:9](O)=O)[CH2:2][CH2:3][CH3:4].S(O)(O)(=O)=O.[NH2:20][NH:21][C:22]([NH2:24])=[NH:23].[OH-].[Na+]>O>[NH2:24][C:22]1[N:23]=[C:9]([C:8]2[CH:12]=[CH:13][N:14]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=2)[NH:20][N:21]=1
Reactant: N=C(N)NN
Reactant: CCCCNc1cc(C(=O)O)ccn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNc1cc(-c2nc(N)n[nH]2)ccn1
Temperature: 200 °C
Yield: 18.6 %

Procedure:
A mixture consisting of 2.5 g. (0.0108 mole) of 2-[N-mono(n-butyl)-amino]isonicotinic acid and 2.7 g. (0.0219 mole) of aminoguanidine sulfate was placed in a suitable reaction flask and heated at 200° C. for a period of three hours while under a nitrogen atmosphere. The melt was then cooled to room temperature (~25° C.), diluted with water and the pH of the resulting mixture adjusted to pH 8.0 with 1 N aqueous sodium hydroxide. The basified aqueous mixture was next filtered and the clear aqueous filtrate so obtained was subsequently concentrated in vacuo to afford a brown oil, which was thereafter triturated with methanol. After removal of the resultant solid by means of suction filtration, ethyl acetate was added to the filtrate and the latter solution was subsequently concentrated on a steam bath, followed by cooling to room temperature. In this way, there were ultimately isolated 1.04 g. of crude product (m.p. 218°-220° C.) in the form of a beige-colored precipitate. Recrystallization of the latter material from ethyl acetate/methanol then gave 467 mg (18%) of pure 3-amino-5-{2-[N-mono(n-butyl)amino]-4-pyridyl}-1,2,4-triazole, m.p. 268°-270° C. The final product was subsequently characterized by means of nuclear magnetic resonance data.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][N:21]([C@@H:28]2[CH2:30][C@H:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)C(=O)C(F)(F)F)[CH2:16][CH2:15]1)[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[K+:38]>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][C@@H:28]2[CH2:30][C@H:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:16][CH2:15]1)[C:6]([O-:8])=[O:7])#[N:2].[K+:38]
Reactant: COC(=O)c1ccc(CN2CCC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)CC2)c(C#N)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1cc(C(=O)[O-])ccc1CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a stirred solution of methyl 3-cyano-4-((4-((2,2,2-trifluoro-N-((trans)-2-phenylcyclopropyl)acetamido)methyl)piperidin-1-yl)methyl)benzoate (1.2 g, 2.402 mmol) in a mixture of methanol (15 mL) and water (2 mL) was added KOH (0.404 g, 7.21 mmol) at RT. Then the reaction mixture was stirred at 65° C. for 3 h. The reaction mixture was concentrated to afford (crude) potassium 3-cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (1 g, 107% yield). This was used as such in the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[C:19]([CH3:28])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[C:33]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:33])[S:24]([CH3:27])(=[O:26])=[O:25])=[C:19]([CH3:28])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: CCC(CC)(c1ccc(NS(C)(=O)=O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(N(C)S(C)(=O)=O)c(C)c1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of N-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-methanesulfonamide (230 mg, 0.5 mmol), triphenyl phosphine (197 mg, 0.75 mmol), MeOH (0.03 mL, 0.75 mmol), and THF (10 mL) is added diethylazodicarboxylate (0.12 mL, 0.75 mmol) and stirred overnight. The reaction is concentrated and chromatographed (0% to 25% EtOAc/Hex) to give the title compound (180 mg, 76%).
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([CH:16]=[CH2:17])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=O)C1C=CC=CC=1.[Na].N>O1CCCC1>[C:22]([O:21][C:19]([NH:18][C@H:13]1[C@@H:14]([CH:16]=[CH2:17])[CH2:15][NH:11][CH2:12]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: C=C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: C=C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-vinylpyrrolidine (275 mg, 0.794 mmol) in tetrahydrofuran (5 mL) and sodium (300 mg, 13.0 mmol) were sequentially added to liquid ammonia (80 mL) at −78° C., and the mixture was stirred at the same temperature for 0.5 hours. The solvent was removed, followed by dilution with chloroform (80 mL). The resultant mixture was washed sequentially by 1 mol/L sodium hydroxide (30 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, to thereby yield the title compound as a colorless oily substance (168 mg, 100%).
Reaction SMILES: C([O:3][C:4](=[O:57])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([S:27]([C:30]3[CH:34]=[C:33]([C:35]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[NH:36])[S:32][C:31]=3[S:45][CH3:46])(=[O:29])=[O:28])[CH:22]=2)=[C:16]([NH:47][C:48](=[O:56])[CH2:49][CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:15]=1)=[O:12])C.[Li+].[OH-]>CO.O>[C:41]([O:40][C:38]([NH:37][C:35](=[NH:36])[C:33]1[S:32][C:31]([S:45][CH3:46])=[C:30]([S:27]([C:23]2[CH:22]=[C:21]([C:17]3[C:18]([CH3:20])=[CH:19][C:14]([NH:13][C:11](=[O:12])[NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:57])=[O:3])=[CH:15][C:16]=3[NH:47][C:48](=[O:56])[CH2:49][CH2:50][CH2:51][S:52]([CH3:55])(=[O:53])=[O:54])[CH:26]=[CH:25][CH:24]=2)(=[O:28])=[O:29])[CH:34]=1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(NC(=O)CCCS(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)NCCCCCC(=O)O)cc2NC(=O)CCCS(C)(=O)=O)c1

Procedure:
The procedure as in Example 278: step e was followed using 6-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methanesulfonyl-butyrylamino)-6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester (48 mg, 54.3 μmol, Example 279: step a) in a MeOH/H2O (2:1) solution and 4N LiOH (54.3 μL, 0.217 mmol). The crude was taken on directly to the next step. ESI-MS (m/z): Calcd. for C36H47N5O10S4: 838.2 (M+1); found: 837.8.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10]([NH:12][C@@H:13]([C@H:15]([C:18]1[O:19][CH:20]=[C:21]([C:23]([OH:25])=O)[N:22]=1)[CH2:16][CH3:17])[CH3:14])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1C=CC2N(O)N=[N:32]C=2C=1>ClCCl>[C:5]([O:9][C:10](=[O:11])[NH:12][C@@H:13]([C@H:15]([C:18]1[O:19][CH:20]=[C:21]([C:23](=[O:25])[NH2:32])[N:22]=1)[CH2:16][CH3:17])[CH3:14])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC[C@@H](c1nc(C(=O)O)co1)[C@@H](C)NC(=O)OC(C)(C)C
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC[C@@H](c1nc(C(N)=O)co1)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
1N aqueous sodium hydroxide (5.69 ml, 5.69 mmol) was added in one portion to a solution of methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylate (100 mg, 0.32 mmol) in anhydrous THF (1.11 ml). The reaction mixture was allowed to stir at room temperature for 3.5 hours before evaporating the organic in vacuo. The remaining aqueous portion was cooled to 0° C. and acidified to pH 4 using 1N HCl. The aqueous phase was then extracted with ethyl acetate (3×3 mL). The aqueous pH was re-checked and judged to be ˜pH 6-7. A small amount of 1N HCl was added to re-acidify the aqueous layer which was once again extracted with an additional portion of ethyl acetate (1×3 mL). The combined organics were dried (MgSO4) and evaporated in vacuo to give crude 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylic acid (95 mg, 0.32 mmol, 100% yield) as a white solid which was used immediately in the next reaction. EDC (86 mg, 0.45 mmol) was added in one portion to a mixture of 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylic acid (95 mg, 0.32 mmol) and HOBT (69 mg, 0.45 mmol) in anhydrous dichloromethane (5.0 ml) and the reaction allowed to stir at room temperature under a nitrogen atmosphere for 30 minutes. Ammonia was then bubbled through for approximately 5 minutes and the resulting white suspension allowed to stir at room temperature overnight. The reaction was then evaporated in vacuo and the residue partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was then dried (MgSO4) and evaporated in vacuo to give tert-butyl((2R,3R)-3-(4-carbamoyloxazol-2-yl)pentan-2-yl)carbamate (95 mg, 0.32 mmol, 100% yield) which was used immediately in the next step. LC/MS: M+H+436.11, ret. time=1.89 min. Column: Phenomenex, 2.0×30 mm, 2.5-μm particles; Mobile Phase A: 10:90 methanol:water with 0.05% TFA; Mobile Phase B: 90:10 methanol:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min. HPLC: ret. time=2.73 min. Column: YMC CombiScreen ODS-A, 4.6×50 mm; Mobile Phase A: 10:90 methanol:water with 0.2% H3PO4; Mobile Phase B: 90:10 methanol:water with 0.2% H3PO4; Temperature: 50° C.; Gradient: 0-100% B over 4 minutes, then a 0.75-minute hold at 100% B; Flow: 4 mL/min.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH3:20])[N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>C(Cl)Cl.FC(C(O)=O)(F)F>[CH3:20][C:17]1[N:16]=[C:15]([C:14]2[C:9]([OH:8])=[N:10][CH:11]=[CH:12][CH:13]=2)[O:19][N:18]=1
Reactant: Cc1noc(-c2cccnc2OCc2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(-c2cccnc2O)n1

Procedure:
A solution of 2-(benzyloxy)-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine in CH2Cl2-TFA (0.25M) was stirred 15 min at 20° C. and then concentrated. The residue was diluted with EtOAc and aqueous NaHCO3. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to afforded the title compound.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[CH2:9]([C:14]1[CH:15]=[CH:16][C:17]([C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])=[CH:18][CH:19]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCc1ccccc1
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCc1ccc(C(=O)CCCC(=O)O)cc1
Temperature: 0 °C

Procedure:
Glutaric anhydride (10 g; 0.1mole) is reacted with pentylbenzene (100 ml) and aluminum chloride (29 g; 0.22 mole) at room temperature for 4 hours. The reaction mixture is poured into a mixture of ice-water (500 ml) and concentrated hydrochloric acid (50 ml) with vigorous stirring. The crude product is collected by filtration and recrystallized from aqueous ethanol to give 4-(4-n-pentylbenzoyl)butanoic acid (16.2 g) as colorless crystals, m.p. 104°-106° C.
Reaction SMILES: C(OC([NH:8][CH:9]([CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]([CH:14]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(Sc1cccc(OC)c1)c1cccc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(N)C(Sc1cccc(OC)c1)c1cccc(OC)c1

Procedure:
A solution of 0.110 g (0.25 mmol) of (R,S; R,S)-2-tert-butoxycarbonylamino-3-(3-methoxyphenyl)-3-(3-methoxyphenyl-sulfanyl) propionic acid, methyl ester of Example 31 and 0.75 mL of trifluoroacetic acid in 2 mL of methylene chloride is stirred at room temperature for 30 minutes. The solvent is evaporated ant the residue is dissolved in 100 mL of ethyl acetate. The solution is washed with 2×80 mL of 1N sodium hydroxide and 80 mL of brine and then dried (magnesium sulfate) and evaporated to give the product as a mixture of diastereomers which is used in the next step without further purification; wt 0.084 g (94%); tlc (ethyl acetate/silica gel) one spot Rf 0.4;
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH2:25]([NH:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=1[O:45][CH3:46])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:25]([NH:33][C:34](=[O:35])[C:36]1[CH:41]=[CH:40][C:39]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)=[CH:38][C:37]=1[O:45][CH3:46])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B(O)O)ccc1C(=O)NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)NCCc1ccccc1

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (154 mg, 0.349 mmol), 4-[(phenethylamino)carbonyl]-3-methoxyphenylboronic acid (115 mg, 0.384 mmol), palladium tetrakistriphenyphosphine (24 mg, 0.021 mmol) and sodium carbonate (89 mg, 0.839 mmol) were mixed with ethylene glycol dimethyl ether (4 mL) and water (2 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give cis-N1-phenethyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (64 mg, 32%). 1H NMR (CDCl3-d) δ 1.62 (m, 4H), 2.16 (m, 16H), 2.87 (m, 2H), 3.57 (m, 2H), 3.90 (s, 3H), 4.83 (m, 1H), 7.31 (m, 7H), 7.95 (m, 1H), 8.22 (m, 2H); LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =569.3, Rt=2.50 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15](C3C=CC(Br)=CC=3C)=[N:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[S:9][CH:10]([CH3:12])[CH3:11])#[N:2].[Br-].[CH2:27]([O:29][C:30](=[O:34])[CH2:31][CH2:32][Zn+])[CH3:28]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][CH2:15][N:16]([C:8]3[CH:7]=[CH:6][C:5]([CH2:32][CH2:31][C:30]([O:29][CH2:27][CH3:28])=[O:34])=[CH:4][C:3]=3[CH3:1])[N:17]=2)[CH:6]=[CH:7][C:8]=1[S:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CCOC(=O)CC[Zn+]
Reactant: Cc1cc(Br)ccc1-c1nnc(-c2ccc(SC(C)C)c(C#N)c2)s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Product: CCOC(=O)CCc1ccc(N2CSC(c3ccc(SC(C)C)c(C#N)c3)=N2)c(C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Bis(tri-tert-butylphosphine)palladium (0) (5 mg) was added to a solution of 2-(3-cyano-4-isopropylthiophenyl)-5-(4-bromo-2-methyphenyl)-1,3,4-thiadiazole (0.15 mmol, 0.066 g, from Step C) in 3-ethoxy-3-oxopropylzinc bromide (0.5M in TI-IF) (0.31 mmol, 0.61 mL) which had been degassed with argon. The reaction mixture was stirred under an atmosphere of argon at rt for 5 h after which it was concentrated in vacuo. Silica gel chromatography eluting with 20% EtOAc/hexane yielded the desired product. ESI-MS (m/z) 452.3; HPLC A: 2.85 min.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.N1C=CC=CC=1>O>[C:1]1([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COc1ccc(C2=CCCCCCC2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(C2=CCCCCCC2)cc1
Temperature: 180 °C

Procedure:
80 Grams of p-(1-cyclooctenyl)-anisol and 175 g of pyridine-hydrochloride are thoroughly mixed and heated for 4 hours under nitrogen to 180° C. The mixture is cooled, treated with water and extracted with benzene. The benzene extracts are shaken with 3×100 ml of N-sodium hydroxide solution. The alkaline phase is acidified with 2N hydrochloric acid and extracted with ether. The ether solution is dried over sodium sulphate and evaporated. The residue is recrystallised from benzene-petroleum ether to yield the p-(1-cyclooctenyl)-phenol (m.p. 95°-97° C).