Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.[Br:22]Br.O>C(O)(=O)C>[Br:22][C:15]1[NH:14][C:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][C:4]=2[Cl:12])=[N:17][C:16]=1[C:18]([F:21])([F:19])[F:20]
Reactant: BrBr
Reactant: FC(F)(F)c1cc(Cl)c(-c2nc(C(F)(F)F)c[nH]2)c(Cl)c1
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Cl)c(-c2nc(C(F)(F)F)c(Br)[nH]2)c(Cl)c1
Yield: 70.1 %

Procedure:
A solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylimidazole (0.7 g, 0.002 mol) and bromine (0.32 g, 0.1 ml, 0.002 mol) in glacial acetic acid (5 ml) was stirred and heated at reflux for 2 hours. The cooled suspension was poured into cold water (50 ml) and the solid was filtered and washed with water. The solid was dissolved in glacial acetic acid (5 ml) and bromine (0.32 g, 0.1 ml, 0.002 mol) was added. The mixture was stirred and heated at reflux for 2 hours, cooled and poured into cold water (50 ml). The solid was filtered and washed thoroughly with water to give 5-bromo-2-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylimidazole (0.6 g) as a white solid, m.p. 295° C. with decomposition.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17](=[O:40])[NH:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[CH2:41]([O:43][C:44]1[C:45](=O)[C:46](=[O:51])[C:47]=1[O:48]CC)[CH3:42]>C(Cl)Cl>[CH2:41]([O:43][C:44]1[C:47](=[O:48])[C:46](=[O:51])[C:45]=1[NH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17](=[O:40])[NH:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH3:42]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)CNCCCOCCOCCOCCCN
Solvent: ClCCl
Product: CCOc1c(NCCCOCCOCCOCCCNCC(=O)NCCCOCCOCCOCCCNC(=O)OC(C)(C)C)c(=O)c1=O

Procedure:
0.25 g of tert-butyl 30-amino-15-oxo-4,7,10,21,24,27-hexaoxa-14,17-diazatriacont-1-ylcarbamate is dissolved in 1.5 ml of CH2Cl2. 57.5 μl of 3,4-diethoxy-3-cyclobutene-1,2-dione are added.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14].Cl>C1COCC1.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
A solution of 6-bromo-1H-indole (2.34 g, 11.9 mmol) in dry THF (25 mL) was cooled in an ice bath. Sodium hydride (1.12 g of 60% dispersion in oil, 28.0 mmol) was added. The mixture was stirred for 30 minutes under nitrogen at room temperature, then cooled in an ice bath. Iodomethane (1.6 mL, 26 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature, poured into excess water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using hexane as an eluant to yield 6-bromo-1-methyl-1H-indole 2.04 g (81.6%, 9.71 mmol) as a yellow oil. 1HNMR (200 MHz, DMSO-d6): δ 7.7 (s, 1H), 7.5 (d, 1H, J=8.6 Hz), 7.35 (d, 1H, J=2.1 Hz), 7.15 (d, 1H, 7.3 Hz), 6.4 (d, 1H, J=1.3 Hz), and 3.75 ppm (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43]12([NH2:53])[CH2:52][CH:47]3[CH2:48][CH:49]([CH2:51][CH:45]([CH2:46]3)[CH2:44]1)[CH2:50]2>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:53][C:43]34[CH2:44][CH:45]5[CH2:51][CH:49]([CH2:48][CH:47]([CH2:46]5)[CH2:52]3)[CH2:50]4)=[O:22])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NC34CC5CC(CC(C5)C3)C4)(CC1)CC2
Yield: 74.3 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and adamantanamine (17.1 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-adamantylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (38.2 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[O:14]([NH2:16])[CH3:15]>>[CH3:15][O:14][N:16]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CON
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Product: CON=Cc1ccc(C(=O)OC)cc1
Yield: 96 %

Procedure:
Reaction of methyl 4-formylbenzoate with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether (96% yield) as a white solid (mixture of E- and Z-isomers). The E-isomer was obtained as white crystals from hexane; mp 66-67° C. (Lit. mp 65-66° C., Cooks, R. G.; Varvoglis, A. G. Org. Mass Spectrum., 5, 1971, 687). 1HNMR 400 MHz (DMSO-d6) δ (ppm): (E-isomer) 3.86 (3H, s, OCH3), 3.93 (3H, s, OCH3), 7.75 (2H, d, aromatics), 7.98 (2H, d, aromatics), 8.32 (1H, s, CH).
Reaction SMILES: [CH2:1]([SiH:6]1[CH2:11][CH2:10][CH:9](Br)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].[F:14][CH:15]1[C:20]([F:24])(OCC)[CH:19]=[CH:18][C:17]([CH:25]2[CH2:30][CH2:29][CH:28](Br)[CH2:27][CH2:26]2)=[CH:16]1.[CH2:32]1COC[CH2:33]1>>[F:14][C:15]1[CH:16]=[C:17]([CH2:25][CH2:30][C@H:29]2[CH2:28][CH2:27][C@H:26]([C@H:9]3[CH2:10][CH2:11][Si@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)[CH2:33][CH2:32]2)[CH:18]=[CH:19][C:20]=1[F:24]
Reactant: CCCCC[SiH]1CCC(Br)CC1
Reactant: CCOC1(F)C=CC(C2CCC(Br)CC2)=CC1F
Reactant: C1CCOC1
Agent: [Mg]
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
5.0 g (20 mmol) of 1-n-pentyl-4-bromo-1-silacyclohexane was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.1 g (20 mmol) of 4-(3,4-difluorophenetyl)-1-bromocyclohexane. The products obtained were separated by means of chromatography to obtain 6.5 g (yield 80%) of trans-4-(trans-4-(2-(3,4-difluorophenyl) ethyl) cyclohexyl)-1-n-pentyl-1-silacyclohexane.
Reaction SMILES: C(#N)C.[Br:4][CH2:5][C:6]([CH3:10])=[CH:7][CH:8]=[O:9].Br[Si:12]([CH3:15])([CH3:14])[CH3:13]>CCCCC.C(N(CC)CC)C>[Br:4][CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][O:9][Si:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(=CC=O)CBr
Reactant: C[Si](C)(C)Br
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C=CO[Si](C)(C)C)=CBr
Temperature: 20 °C
Reaction time: 48 h
Yield: 25.8 %

Procedure:
Pentane (120 cc), acetonitrile (120 cc), 4-bromo-3-methyl-2-butenal (9 g, 107 mmol) and triethylamine (13 g) are introduced under an argon atmosphere into a 500-cc three-necked round-bottomed flask. The temperature is kept at 0° C. and bromotrimethylsilane (19.6 g) is then added over 20 minutes. The mixture is stirred for 2 days at a temperature in the region of 20° C. The pentane solution is sampled with a syringe and is then replaced with an equivalent quantity of pentane. The operation is repeated 4 times. The various pentane solutions are combined and the pentane is removed, any entry of air being excluded. The residue obtained is purified by distillation. 1-Bromo-2-methyl-4-trimethylsilyloxybutadiene (6.5 g) is thus obtained (B.P.0.25 =59° C.).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH3:18])=[N:15]2)=[CH:10][CH:9]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:6])[C:3](=[S:4])[O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH3:18])=[N:15]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc2ccc(O)cc2n1
Reactant: CN(C)C(=S)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc2ccc(OC(=S)N(C)C)cc2n1
Reaction time: 24 h
Yield: 147.9 %

Procedure:
Referring now to FIG. 22, under nitrogen, dimethylthio-carbamoyl chloride (1.35 g, 10.95 mmol) and DMAP (1.33 g, 10.95 mmol) were added to a suspension of 4 (300.0 mg, 0.628 mmol) in CH2Cl2 (6 mL). The dark brown solution was stirred for 24 h before it was diluted with chloroform and purified by column chromatography (4:6 to 1:1 EtOAc/hexane) to provide 16 (299 mg, 0.929 mmol, 64%) as an off-white solid: 1H NMR (CDCl3) δ 8.05, (1H, d, J=8.4 Hz), 7.78 (1H, d, J=8.8 Hz), 7.67 (1H, d, J=2.4 Hz), 7.29 (1H, dd, J=8.0, 2.8 Hz), 7.27, (1H, dd, J=8.4, 3.6 Hz), 3.48 (3H, s), 3.40 (3H, s), 2.73 (3H, s); 13C NMR (CDCl3) δ 187.6, 159.9, 154.7, 148.6, 136.2, 128.3, 124.8, 122.7, 122.1, 120.9, 43.5, 39.1, 25.6; FTIR (neat) 3379, 2940, 1624, 1603, 1531, 1504, 1393, 1283, 1206, 1169, 1130, 843, 748 cm−1; MS (ESI) m/z calculated for (C13H14N2OS+H)+ 247, found 247; HRMS (ESI) m/z calculated for (C13H14N2OS+H)+ 247.0905, found 201.0900.
Reaction SMILES: C1O[C:4]2([CH2:21][C@H:20]([CH3:22])[C@@:19]3([CH2:23][OH:24])[C:6]([CH2:7][CH2:8][C@@H:9]4[C@@H:18]3[CH2:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][CH2:12][C@@H:13]3[OH:25])=[CH:5]2)SC1>[Ni].CO>[CH3:22][C@@H:20]1[C@@:19]2([CH2:23][OH:24])[C:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[OH:25])=[CH:5][CH2:4][CH2:21]1
Reactant: C[C@H]1CC2(C=C3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31CO)OCCS2
Agent: [Ni]
Solvent: CO
Product: C[C@H]1CCC=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO

Procedure:
Raney nickel is added to a solution of 17β,19-dihydroxy-1α-methyl-4-androsten-3-one 3-ethylenethioketal in methanol and the resulting suspension is refluxed for four hours with rapid stirring. The suspension is cooled, filtered and the solvent evaporated. The remaining residue is chromatographed on silica gel and eluted with methylenechloride. Recrystallization from acetone-hexane yields the compound 1α-methyl-4-androstene-17β,19-diol.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:41]=[CH:40][C:11]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[N:25]=[C:24]([N:26]4[C:30]([C:31]([F:34])([F:33])[F:32])=[C:29]([C:35]([O:37]CC)=[O:36])[CH:28]=[N:27]4)[CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-:42].[Li+].Cl.[O:45]1CCOCC1>>[C:30]([OH:45])([C:31]([F:34])([F:33])[F:32])=[O:42].[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[N:25]=[C:24]([N:26]4[C:30]([C:31]([F:34])([F:33])[F:32])=[C:29]([C:35]([OH:37])=[O:36])[CH:28]=[N:27]4)[CH:23]=[CH:22][CH:21]=3)=[CH:40][CH:41]=2)[CH2:4][CH2:3]1
Reactant: C1COCCO1
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCC(=O)CC4)cc3)n2)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Product: O=C(O)C(F)(F)F
Product: O=C1CCC(c2ccc(COc3ccccc3-c3cccc(-n4ncc(C(=O)O)c4C(F)(F)F)n3)cc2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title compound from Example 10 Step E (20.0 mg, 0.035 mmol) in 1,4-dioxane (1.0 mL) was added lithium hydroxide (0.500 mL, 2.0 M in water, 1.00 mmol), and the resulting mixture was stirred at 50° C. After 30 min, the reaction mixture was rendered acidic by addition of aqueous hydrochloric acid, then was diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (40 to 95% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 536.0 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.30 (s, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.11 (t, J=7.5 Hz, 1H), 7.73-7.70 (m, 2H), 7.43 (t, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.29-7.26 (m, 3H), 7.09 (t, J=7.5 Hz, 1H), 5.21 (s, 2H), 3.07-3.02 (m, 1H), 2.57 (td, J=14.0, 5.5 Hz, 2 H), 2.26-2.24 (m, 2H), 2.05-2.03 (m, 2H), 1.90-1.82 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=[O:4])=[O:3]>CN(C=O)C.[Pd]>[CH3:1][S:2]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]([C:24]([F:27])([F:26])[F:25])=[CH:7][N:6]=1)(=[O:3])=[O:4]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
Methyl 2-(2-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate (I14) (1.50 g, 3.76 mmol) was taken up in DMF (30 mL) then 10% Pd/C (750 mg) was added. The resulting suspension was stirred under H2 (1 atm) for 16 hours at room temperature. The crude reaction mixture was filtered through Celite, washing with MeOH. The filtrate was evaporated under reduced pressure to give a yellow liquid which was adsorbing onto silica. The silica adsorbed material was chromatographed on silica gel (0-100% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I15) (1.38 g, 91%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 9.07 (d, J=0.7 Hz, 1H), 7.30-7.12 (m, 4H), 3.72 (s, 2H), 3.68 (s, 3H), 3.41-3.35 (m, 2H), 3.35 (s, 3H), 3.20 (dd, J=9.6, 6.3 Hz, 2H). LCMS Method C: rt 5.92 min; m/z 425.1 (M+Na), 403.1 (M+1), 401.1 (M−1), 371.1 (M—OMe), 343.1 (M—COOMe).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]([F:36])([F:35])[C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:37])[CH:8]=1)[CH3:2].O1CCCC1.O.[OH-].[Li+].Cl>O.C(O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:37])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][C:29]([F:35])([F:36])[C:30]([OH:32])=[O:31])=[CH:26][CH:27]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CC(F)(F)C(=O)OCC)cc3)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CC(F)(F)C(=O)O)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of ethyl 3-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)phenyl]-2,2-difluoropropanoate (665 mg, 1.30 mmol), tetrahydrofuran (15 mL), ethanol (10 mL), water (10 mL) and lithium hydroxide monohydrate (162 mg, 3.89 mmol) was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (20%-100% ethyl acetate/hexane), and the residue was recrystallized from ethyl acetate-hexane to give the title compound (415 mg, yield 66%) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:16]=[N+:17]=[N-:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[CH2:9]([N:16]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:18]=[N:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#Cc1ccccc1
Reactant: [N-]=[N+]=NCc1ccccc1
Solvent: ClCCl
Product: c1ccc(Cn2cc(-c3ccccc3)nn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
Phenylacetylene (103 mg, 1.0 mmol, 1.0 eq.) and benzyl azide (133 mg, 1.0 mmol, 1.0 eq.) were dissolved in an air-tight lockable vial with a septum in 10 mL dry dichloromethane. The Cu complex (catalytic or stoichiometric amounts) was added, the vial sealed and the reaction stirred at room temperature for 2 days. For the removal of the catalyst complex the reaction mixture was put in 50 mL methanol and stirred for 20 min. The complex was removed by filtering and the filtrate was concentrated. Removal of the solvent and drying of the product in high vacuum resulted in the compound 1-benzyl-4-phenyl-1H-1,2,3-triazole as light yellow solid with 95% yield (245 mg, 0.95 mmol). The identity of the product was proven by NMR-spectroscopy, infrared spectroscopy and high-resolution mass spectroscopy.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:8]([NH2:9])=[C:7](Cl)[N:6]=[CH:5][N:4]=1>CO>[Cl:2][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH2:1])[C:8]=1[NH2:9]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: N
Solvent: CO
Product: Nc1ncnc(Cl)c1N
Temperature: 100 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
To a 7 N solution of ammonia in MeOH (40 mL) was added 4,6-dichloro-pyrimidin-5-ylamine (8.7 g, 53 mmol) and the solution was heated to 100° C. in a sealed tube. After 12 h, the resulting solution was cooled to rt and allowed to stand for 2 h. The colorless crystalline material that resulted was collected by filtration and washed with ice cold MeOH (10 mL) to give the title compound (5.4 g, 71%). MS (ESI): mass calcd. for C4H5ClN4, 144.0; m/z found, 145.0 [M+H]+. 1H NMR ((CD3)2SO): 7.64 (s, 1H), 6.70 (s, 2H), 4.93 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14](=[O:18])[C:15]([OH:17])=[CH:16][C:9]=2[C:8](=[O:19])[CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].CN(C)C=O.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:11]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8](=[O:19])[C:9]2[CH:16]=[C:15]([OH:17])[C:14](=[O:18])[CH:13]=[CH:12][C:10]1=2)[CH3:33]
Reactant: CCOC(=O)c1cc(=O)c2cc(O)c(=O)ccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(C(=O)OCC)cc(=O)c2cc(O)c(=O)ccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4,7-Dihydro-4,7-dioxo-6-hydroxy-1H-cyclohepta[b]pyridine-2-carboxylic acid ethyl ester (12.0 g, described in Example 3) is added to a stirring mixture of sodium hydride (57%, 2.8 g) and dimethylformamide (400 ml) at room temperature. Ethyl bromoacetate (15.8 g) is added. The mixture is stirred at room temperature for 20 hr and poured on ice. Water is added and the mixture is extracted with chloroform. The organic extract is dried over sodium sulfate and evaporated. The residue is crystallized from ethyl acetate to give the title compound, mp 186°-188° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([CH3:20])=[CH:22][CH:23]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Cc1ccc(N)cc1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 4-methyl-aniline (Aldrich) according to the method described in Example 94. Melting Point: 125-126° C. (diethylether
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([C:32](Cl)=[O:33])[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([C:32](=[O:33])[NH:15][C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:14]=[CH:13][N:12]=2)[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: COc1ccccc1-c1cc(N)ncn1
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cc(NC(=O)[C@H]2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (7.80 g, 39.1 mmol) in 90 ml of dichloromethane was added 4-dimethylaminopyridine (5.70 g, 47.0 mmol) followed by dropwise addition of N—(S)-3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXXIII) (11.0 g, 39.1 mmol) at room temperature. The reaction mixture was stirred for 2 hours and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated. The obtained crude residue was passed through a pad of silica gel eluting with 25% ethyl acetate in hexane to provide (S)-3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXXIV) (9.4 g, 54%).
Reaction SMILES: [C:1]([N:5]1[CH2:11][CH:10]([N:12]2[C:16]3[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].C(N(CC)C(C)C)(C)C.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([N:8]1[CH2:9][CH:10]([N:12]2[C:16]3[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:11][N:5]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:6][CH2:7]1)(=[O:43])[CH3:42]
Reactant: C=CC(=O)N1CCNCC(n2c(NC(=O)c3ccnc(C)c3)nc3cccc(Cl)c32)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CCN(C(C)=O)CC(n2c(NC(=O)c3ccnc(C)c3)nc3cccc(Cl)c32)C1
Reaction time: 0.08 h

Procedure:
A solution of Example 13 (30 mg, 0.068 mmol), N,N-dimethylaminopyridine (17 mg, 0.137 mmol), and N,N-diisopropylethylamine (0.024 mL, 0.137 mmol) in CH2Cl2 (0.75 mL) was treated at room temperature with acetic anhydride (0.01 mL, 0.103 mmol) and stirred for 5 min. The reaction was then added directly to a RediSep dry loader cartridge and purified by column chromatography (9:1:0.175 M CH2Cl2/MeOH/NH3 in CH2Cl2, 0-50%) to afford the title compound (Example 14). 1H NMR (400 MHz, MeOD) δ 8.53-8.41 (m, 1H), 7.96-7.88 (m, 1H), 7.88-7.77 (m, 1H), 7.50-7.36 (m, 1H), 7.31-7.13 (m, 2H), 6.91-6.60 (m, 1H), 6.30-6.08 (m, 1H), 5.87-5.72 (m, 1H), 5.72-5.65 (m, 1H), 4.43-4.24 (m, 4H), 4.24-3.94 (m, 2H), 3.64-3.48 (m, 2H), 2.55 (s, 3H), 2.12-1.99 (m, 3H); MS calculated for C24H26ClN6O3 (M+H+) 481.17. found 481.2.
Reaction SMILES: O[C:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[N:9][CH:10]=1)([CH3:4])[CH3:3]>C(C(O)=O)(F)(F)F>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[N:9][CH:10]=1)([CH3:4])=[CH2:3]
Reactant: CC(C)(O)c1ccc(S(N)(=O)=O)nc1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)c1ccc(S(N)(=O)=O)nc1

Procedure:
A solution of 0.1 g of (5-(1-hydroxy-1-methyl-ethyl))-pyridine-2-sulfonic acid amide in CF3CO2H (2 ml) was refluxed for 20 h. The solvent was then removed in vacuo to give 5-isopropenyl-pyridine-2-sulfonic acid amide as a white solid which was essentially pure. El mass spectrum, m/e 198 (M calculated for C8H10N2O2S: 198).