Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.[CH3:13][C:14]([OH:18])([C:16]#[CH:17])[CH3:15].CCN(CC)CC>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:17]#[C:16][C:14]([CH3:15])([OH:18])[CH3:13])[CH:8]=[N:7]2
Reactant: C#CC(C)(C)O
Reactant: Clc1cnc2cccc(Br)c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cnc2cccc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A microwave tube is charged with 200 mg (0.821 mmol) of 8-Bromo-2-chloro-quinoxaline, 159 μl (1.64 mmol) of 2-Methyl-but-3-yn-2-ol, 231 μl (1.64 mmol) of Et3N, 6.26 mg (0.0329 mmol) of CuI and 11.8 mg (0.0164 mmol) of Pd(PPh3)2Cl2. After several cycles of vacuum/purge with argon, 5 ml of n-BuOH are added. The reaction mixture is then stirred at RT for 30 min. The reaction mixture is poured onto a solution of NaHCO3 and diluted with EtOAc and the phases are separated. The organic phase is washed several times with de-ionized water and the aqueous layer re-extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is dissolved in CH2Cl2 and purified by chromatography (silicagel, hexane:EtOAc=1:1) to afford the title compound as a brown oil, Rt=1.026 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 291 (M+1, 79Br)+.
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.[CH3:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)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][CH2:28][CH2:27][O:26][CH3:25])[N:17]=[C:18]([CH3:20])[N:19]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nc(C)nc(N2CCC(c3ccc(F)cc3)CC2)c1[N+](=O)[O-]

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 7) was treated with 2-bromoethyl methyl ether and potassium carbonate in N,N-dimethylformamide at 50° C. to yield the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-methoxy-ethoxy)-2-methyl-5-nitro-pyrimidine as a yellow oil; MS: [M+H]30 =391; and the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-3-(2-methoxy-ethyl)-2-methyl-5-nitro-3H-pyrimidin-4-one as a yellow solid; m.p. 45-48° C.; MS: [M+H]+=391.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1.[CH:20]1([CH2:26][N:27]=[C:28]=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][NH:27][C:28](=[O:29])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)CN(Cc2ccccn2)c2ccc(O)cc21
Reactant: O=C=NCC1CCCCC1
Product: CC1(C)CN(Cc2ccccn2)c2ccc(OC(=O)NCC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-(2-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylmethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (16.5 mg, 53%) having the following characteristics.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.[C:15]([O:19][C:20]([NH:22][O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:15]([O:19][C:20]([N:22]([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12](=[O:14])[CH2:11][CH2:10][S:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: COc1ccc(SCCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(SCCC(=O)N(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
To a solution of the compound prepared in Example 8(11) (106 mg) in DMF (5 ml), N-t-butoxycarbonyl-N-t-butoxycarbonyloxyamine (120 mg), EDC hydrochloride (106 mg) and 4-(dimethylamino)pyridine (6 mg) were added at 0° C. The mixture was stirred for 16 hours at room temperature. To the reaction solution, water was added and it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (211 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Cl[C:33]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][N:34]=1>>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:24]3[CH2:25][CH2:26][N:27]([C:33]4[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][N:34]=4)[CH2:28][CH:29]=3)[NH:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: FC(F)(F)c1ccc(-c2nc(C3=CCNCC3)[nH]c2-c2ccc(C(F)(F)F)cc2)cc1
Product: FC(F)(F)c1ccc(-c2nc(C3=CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
4-[4,5-Bis-(4-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-1,2,3,6-tetrahydropyridine from step (b) above reacted with 2-chloro-3-trifluoromethyl-pyridine (352 mg, 1.95 mmol, TCI America) under the condition of Example 22(d) to give the title compound as a light-yellow solid. MS (ESI, positive ion) m/z: 583 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:29][C:30]1[CH:31]=[C:32]([NH2:38])[CH:33]=[C:34]([Cl:37])[C:35]=1[F:36]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[O:12])[NH:38][C:32]1[CH:31]=[C:30]([Cl:29])[C:35]([F:36])=[C:34]([Cl:37])[CH:33]=1)[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(Cl)c(F)c(Cl)c1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)c(F)c(Cl)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−20° C.) solution of (R)-2-tert-butoxycarbonylamino-propionic acid (57.2 g, 302 mmol) in anhydrous THF (582 mL) was added N-methyl-morpholine (34.9 mL, 317 mmol) at a rate to keep the internal temperature at −15° C. Isobutyl chloroformate (42.0 mL, 317 mmol) was then added over a 20 min period and the resulting mixture was stirred for 30 min. A solution of 3,5-dichloro-4-fluoro-phenylamine (54.4 g, 302 mmol) in THF (160 mL) was then added over 40 min. The reaction mixture was warmed to 20° C. and stirred for 20 h. The reaction mixture was filtered and concentrated in vacuo. To the resulting oil was added MeOH (200 mL) and the solution was concentrated to provide the title compound as a tan colored solid, m/z 295.3 [M-t-Bu]+. This material was used without further purification.
Reaction SMILES: C(N[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)C.CC1N=C([O:37][CH2:38][CH2:39][CH3:40])N=C(C(O)=O)C=1>>[CH3:28][C:17]1[CH:16]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[C:6]([CH3:29])[N:5]=[C:4]([O:37][CH2:38][CH2:39][CH3:40])[N:9]=3)[O:14][N:13]=2)[CH:26]=[C:25]([CH3:27])[C:18]=1[O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Reactant: CCCOc1nc(C)cc(C(=O)O)n1
Product: CCCOc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1

Procedure:
rac-3-{2,6-Dimethyl-4-[5-(6-methyl-2-propoxy-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 6-methyl-2-propoxy-pyrimidine-4-carboxylic acid; LC-MS: tR=0.87 min*; [M+H]+=415.08.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].C(O)C>O>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1
Reactant: CCCCCCc1ccc2nc(-c3ccc(OC(C)=O)cc3)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCc1ccc2nc(-c3ccc(O)cc3)sc2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97.3 %

Procedure:
To 0.7 g (2.0 mM) of 2-(p-acetoxyphenyl)-6hexylbenzothiazole, 0.25 g (6.0 mM) of sodium hydroxide and 50 ml of ethanol, followed by stirring for 10 hours at room temperature. After the reaction, the reaction mixture was poured into water, and 2 ml of concentrated hydrochloric was added thereto to precipitate a crystal. The crystal was recovered by filtration and sufficiently washed with water, followed by drying to obtain 0.6 g of 2-(p-hydroxyphenyl)-6-hexylbenzothiazole (Yield: 96.5%).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[N:8]2)=[CH:3][CH:2]=1.[H][H]>CCOC(C)=O.[Pd]>[C:1]1([CH3:22])[CH:2]=[CH:3][C:4]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[N:8]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(-n2nc(-c3ccc([N+](=O)[O-])cc3)cc2N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(-c3ccc(N)cc3)cc2N)cc1

Procedure:
To a solution of 1-(4-tolyl)-3-(4-nitrophenyl)-5-aminopyrazole (0.48 g, 1.6 mmol) in EtOAc (50 mL) at room temperature was added 10% Pd-C (0.1 g). The mixture was treated with hydrogen gas at 30 psi for 30 min. on a Parr shaker. The mixture was filtered through Celite and the solvent removed by rotary evaporation to yield 1-(4-tolyl)-3-(4-aminophenyl)-5-aminopyrazole as an oil, which was used without further purification.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C-]#N.[K+].[CH2:21]([OH:24])[CH:22]=[CH2:23]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:24][CH2:21][CH:22]=[CH2:23])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C=CCO
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Agent: [C-]#N
Agent: [K+]
Product: C=CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1.99 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile, 0.59 g of potassium cyanide and 20 ml of allyl alcohol is stirred at room temperature for 20 hours and thereafter the allyl alcohol is distilled off. The residue is poured onto ice/water and extracted with methylene chloride, and the combined extracts are washed with water, dried over anhydrous sodium sulphate and evaporated. After flash chromatography on silica gel (eluent: ethyl acetate) there is obtained pure allyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil.
Reaction SMILES: [CH:1]1([CH:4]([OH:7])[CH:5]=[CH2:6])[CH2:3][CH2:2]1.N#N.CCN(CC)CC.[Si:17](OS(C(F)(F)F)(=O)=O)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(Cl)Cl>[Si:17]([O:7][C@@H:4]([CH:1]1[CH2:3][CH2:2]1)[CH:5]=[CH2:6])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CC(O)C1CC1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C[C@@H](O[Si](C)(C)C(C)(C)C)C1CC1
Reaction time: 1 h
Yield: 76.9 %

Procedure:
R)-3-Cyclopropyl-3-hydroxy-1-propene (150 mg, 1.53 mmole) was dissolved in anhydrous CH2Cl2 (5 ml) and the mixture was stirred at 0° C./N2. Then Et3N (248 mg, 341 μL, 2.45 mmole) and t-butyl(dimethyl)silyl-trifluoromethane-sulfonate (525 mg, 456 mL, 1.99 mmol) were added. After 1 h 10% aq. KHCO3 (5 mL) was added and the mixture was stirred at room temp. for 1 h. CH2Cl2 (5 mL) was added, the phases were separated, the organic phase was washed with 10% aq. KHCO3 solution (3×8 mL). The combined organic phases were dried over anhydrous K2CO3, filtered and concentrated in vacuo. The crude product was purified on the column with silica gel (230-400 mesh, 10 g, hexane). After drying the product under vacuum (0° C., 10 mm Hg), (3R)-3-t-butyl(dimethyl)silyloxy-3-cyclopropyl-1-propene as a colourless oil (250 mg, 77%) was obtained; C12H24OSi; E1 MS m/z 212 (M+, 3%); [α]D=+8.0° (20° C., c=1, CHCl3); 1H-NMR (200 MHz, CDCl3) δ 5.89 (1H, ddd: 16.9, 10.4, 5.6 Hz), 5.16 (1H, ddd: 17.2,2.0, 1.2 Hz), 5.02 (1H, ddd: 10.4, 1.8, 1.2 Hz), 3.65 (1H, bt: 6.3 Hz), 0.90 (9H, s), 0.89 (1H, m), 0.43 (2H, m), 0.30 (1H, m), 0.26 (1H, m), 0.05 (3H, s), 0.03 (3H, s) ppm.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:19]=[C:18]([NH:20]/[C:21](/[NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:22]\[C:23](=[O:34])[C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[NH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:36]([NH:35]/[C:21](/[NH:20][C:18]1[NH:17][N:16]=[C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[CH:19]=1)=[N:22]/[C:23](=[O:34])[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: [H][H]
Reactant: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2cccc(OCc3ccccc3)c2)n[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)N/C(=N/C(=O)c1ccc(C(F)(F)F)cc1)Nc1cc(-c2cccc(O)c2)n[nH]1
Yield: 54.5 %

Procedure:
(Z)—N-(((3-(3-(Benzyloxy)phenyl)-1H-pyrazol-5-yl)amino)(tert-butylamino)methylene)-4-(trifluoromethyl)benzamide (170 mg) was dissolved in methanol (10 mL) and the solution was degassed with nitrogen. To the solution was added 10% palladium on carbon (34 mg, 0.1 equiv). The mixture was then subjected to hydrogen gas at 30 psi pressure in a Parr shaker. The reaction was checked periodically for completion. Upon completion, the reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to provide the crude product, which was purified by silica chromatography (9:1 to 55:45 hexanes:EtOAc) to provide the title compound (77 mg, 54% yield). 1HNMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 12.79 (s, 1H), 9.63 (s, 1H), 9.02 (s, 1H), 8.28 (d, 2H), 7.82 (d, 2H), 7.23 (m, 1H), 7.18 (m, 1H), 7.09 (m, 1H), 6.79 (m, 1H), 6.49 (s, 1H), 3.98 (m, 1H), 1.95 (s, 1H), 1.56 (s, 9H), 1.12 (m, 1H), 0.82 (m, 1H); MS (EI+) m/z: 445.94, 467.97; HPLC (Method B): 6.08 min.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])=[CH:6][CH:5]=1)#[N:3].[Br:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[Br:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:17][CH:16]=3)[C:10](=[O:15])[CH2:11]2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(CN2CCNCC2=O)cc1
Reactant: O=S(=O)(Cl)c1cccc(CBr)c1
Agent: Cl
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)c3cccc(CBr)c3)CC2=O)cc1

Procedure:
A solution of 4-[3-(bromomethyl)benzenesulfonyl]-1-(4-cyanobenzyl)-2-piperazinone (1.21 g) obtained from 1-(4-cyanobenzyl)-2-piperazinone hydrochloride and 3-(bromomethyl)benzenesulfonyl chloride according to a method described in Reference Example 6 and imidazole (613 mg) in DMF (20 ml) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate: methanol containing 10% ammonia solution=85: 15) to give pale yellow amorphous of 1-(4-cyanobenzyl)-4-[3-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-2-piperazinone (734 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:3]=1[C:16]#[N:17].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:17][C:16]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][C:4]=2[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:1]=[C:19]([CH3:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: COc1cccc(-c2cccc(N)c2C#N)c1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(-c3cccc(OC)c3)c2c1N

Procedure:
Prepared as in Example 2a from 3-amino-3′-methoxy-[1,1′-biphenyl]-2-carbonitrile (Example 114b) and ethyl 3-oxobutanoate as a pale yellow solid (55%). MS 337 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)[CH3:22]
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc2ccccc2n1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
59.5 g benzotriazole (0.50 mol) was dissolved in 700 ml dimethylformamide. 160 g Sodium carbonate (1.5 mol) was added and then dropwise 73.5 g ethyl chloroacetate (0.60 mol). The stirred mixture was slowly heated to 40° C., and kept at that temperature for 17 h. The solvent was evaporated and the residue was extracted with ethyl acetate. GC showed one major and one minor product. The minor product ethyl-2-(2-benzotriazolyl)acetate was isolated by fractional crystallization from cold mixtures of ethanol and ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N:18]([CH:21]([CH:27]([CH3:29])[CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]=[O:20]>>[CH2:25]([O:24][C:22]([CH:21]([NH:18][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20])[CH:27]([CH3:28])[CH3:29])=[O:23])[CH3:26]
Reactant: CCOC(=O)C(N=C=O)C(C)C
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCOC(=O)C(NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1)C(C)C
Yield: 95.3 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 14.56 mg (0.0852 mMol) ethyl 2-isocyanato-3-methylbutyrate, 25.0 mg (95%) of the title compound were recovered.
Reaction SMILES: CN[C:3](=[O:10])[C@H:4]([C:6]([CH3:9])([CH3:8])[CH3:7])[NH2:5].Cl.CC(O)=[O:14]>>[NH2:5][C@H:4]([C:3]([OH:10])=[O:14])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(=O)O
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Product: CC(C)(C)[C@H](N)C(=O)O
Yield: 41 %

Procedure:
A solution of (S)-N-methyl-tert-leucinamide in 100 ml of a 6N solution of HCl/CH3COOH (1:1) was heated under reflux for 14 days. Then, the mixture was evaporated, the residue was chromatographic over AMBERLITE. Evaporation and drying gave 750 mg (41%) of (S)-tert-leucine, [α]=+6.2 (c=1.62, 5N HCl), 97% e.e.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:25][CH:24]=1>>[N+:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:36])=[CH:27][CH:28]=1)([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3ccccc3c2[N+](=O)[O-])cc1
Yield: 81 %

Procedure:
1-Nitronaphthalen-2-yl triflate (2.50 g, 7.78 mmol) and tert-butyl 4-aminophenylcarbamate (1.62 g, 7.78 mmol) were used in a process similar to Example 1(1) to give the titled compound (2.39 g, yield 81%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([Cl:26])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:26][C:22]1[CH:21]=[C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:25]=[CH:24][CH:23]=1
Reactant: Clc1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 3-bromochlorobenzene (1.76 mL, 15 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.06 g (91%) of the product 4-(3-chloro-phenyl)-1H-indole as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Mg].[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27].Cl>O1CCCC1>[CH2:18]([O:17][C:3]1[CH:4]=[C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:7][C:2]=1[CH2:27][CH2:26][C:28](=[O:29])[CH3:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CC(C)=O
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OCc2ccccc2)c1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
A solution of 3.89 g. (0.010 mol.) of 1-bromo-2-benzyloxy-4-(1,1-dimethylheptyl)benzene in 15 ml. of tetrahydrofuran is slowly added to 0.36 g. (0.015 mol.) of 70-80 mesh magnesium metal. The resultant mixture is refluxed for 20 minutes and is then cooled to -10° C. Cuprous iodide (0.115 g., 0.006 mol.) is added and stirring continued for 10 minutes. To the resultant mixture is slowly added a solution of 0.701 g. (0.010 mol.) of methyl vinyl ketone in 5 ml. of tetrahydrofuran at such a rate that the reaction temperature could be maintained below 0° C. The reaction mixture is stirred for 30 minutes longer (t<0° C.) and is then added to 100 ml. of 1N hydrochloric acid and 100 g. of ice. The quenched reaction is extracted three times with 150 ml. portions of ether. The combined ether extract is washed twice with 100 ml. portions of water, twice with 100 ml. portions of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil was purified via column chromatography on 180 g. of silica gel eluted with 20% ether-cyclohexane to yield 1.07 g. (28%) of the title compound as an oil.