Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[C:22]3[CH3:32])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:32][C:22]1[N:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][CH:19]=2)[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-{4-[(1-t-butoxycarbonyl-4-piperidinyl)oxy]phenyl}-2-methyl-4(3H)-quinazolinone (1.1 g, 2.53 mmol) was dissolved in chloroform (10 mL), trifluoroacetic acid (10 mL) was added and the mixture stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, ethyl acetate and 2N sodium hydroxide aqueous solution were added, the mixture was extracted with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated and dried to obtain the target substance (0.83 g, 98%) as a lavender-colored solid.
Reaction SMILES: C[Si](C)(C)CCOC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([CH:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(OC4CCN(C(=O)OCC[Si](C)(C)C)CC4)sc3c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 117.8 %

Procedure:
To a solution of tert-butyl 4-(2-((1-((2-(trimethylsilyl)ethoxy)carbonyl)-piperidin-4-yl)oxy)benzo[d]thiazol-6-yl)piperidine-1-carboxylate (385 mg, 0.685 mmol) in THF (5 mL) was added a solution of TBAF (1 M in THF, 3.4 mL, 3.4 mmol). The mixture was stirred at rt for 4 h. The mixture was diluted with EtOAc (8 mL), washed with aq. NaOH (1 N, 5 mL), then brine. The organic layer was dried (Na2SO4), filtered, and concentrated to afford tert-butyl 4-(2-(piperidin-4-yloxy)benzo[d]thiazol-6-yl)piperidine-1-carboxylate (337 mg, 0.807 mmol, 84% purity, 100% yield). The product was used without further purification. LCMS (m/z)=418 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:14]([Zn]C#N)#[N:15]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:6]1[CH:5]=[CH:4][C:3]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:2]([F:1])[CH:7]=1)#[N:15]
Reactant: CS(=O)(=O)Nc1ccc(I)cc1F
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(C#N)cc1F
Yield: 167.1 %

Procedure:
A mixture of Example 10A (5.0 g, 16 mmol), dicyanozinc (1.12 g, 9.5 mmol), and Pd(PPh3)4 (0.92 g, 0.79 mmol) in DMF (15 mL) was heated at 80° C. overnight. The mixture was concentrated in vacuo then diluted with EtOAc (400 mL) and washed with brine (3×100 mL). The organic extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (SiO2, 25-50% Hexanes/EtOAc gradient) to afford the title compound (3.4 g, 99% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.92 (dd, J=10.7, 1.8 Hz, 1H), 7.73-7.56 (m, 2H), 3.31 (s, 3H). MS (ESI; M−H) m/z 213.
Reaction SMILES: Br[CH2:2][C:3]([F:15])=[CH:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]([CH3:7])([CH3:6])[CH:4]=[C:3]([F:15])[CH2:2][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[C:24]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:25]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C=C(F)CBr)c1ccc(Cl)cc1
Reactant: OB(O)c1ccc(F)c(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C=C(F)Cc1ccc(F)c(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-bromo-4-(p-chlorophenyl)-2-fluoro-4-methyl-2-pentene, (Z)—(320.8 mg, 1.1 mmol), bis(dibenzylideneacetone)palladium(O) (Pd(dba)2, 31.6 mg, 0.055 mmol) in toluene (8 mL) is treated with potassium carbonate (608 mg, 4.4 mmol), degassed, treated with a solution of 4-fluoro-3-phenoxybenzeneboronic acid (331.8 mg, 1.43 mmol) in ethanol (2 mL), refluxed for 45 minutes, cooled to room temperature, and filtered through diatomaceous earth. The filtrate is diluted with ethyl acetate, and the resultant solution is washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as a colorless liquid (401 mg, 91% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].NC([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)CNC(=O)OC(C)(C)C.N1CCC[C@@H]1CNC(C1SC=CC=1NC1C=CN=C2NC=CC=12)=O>>[NH2:1][CH2:2][CH:3]([NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc(F)c1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Agent: O=C(NC[C@H]1CCCN1)c1sccc1Nc1ccnc2[nH]ccc12
Product: NCC(NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1cccc(F)c1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using tert-butyl [2-amino-2-(3-fluorophenyl)ethyl]carbamate instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 496 (M+H) followed by deprotection in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid ((R)-1-pyrrolidin-2-ylmethyl)-amide. LCMS (ESI) 396 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (1H, br. s.) 10.87 (1H, s) 9.24 (1H, d, J=8.59 Hz) 8.20 (1H, br. s.) 8.01 (1H, d, J=6.78 Hz) 7.95 (1H, d, J=5.22 Hz) 7.41 (1H, dd, J=3.51, 2.59 Hz) 7.32 (1H, d, J=5.22 Hz) 7.18-7.27 (1H, m) 7.13-7.17 (1H, m) 7.10 (1H, dd, J=12.89, 1.61 Hz) 7.04 (1H, td, J=8.90, 3.29 Hz) 6.94 (1H, br. s.) 6.58 (1H, d, J=6.93 Hz) 5.32 (1H, dd, J=18.28, 4.32 Hz) 3.18 (1H, dd, J=11.86, 5.12 Hz)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:25])=[C:4]([CH3:26])[CH:3]=1.[Cu][C:28]#[N:29]>CN(C)C=O>[C:28]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=3)[C:9]2=[O:25])=[C:4]([CH3:26])[CH:3]=1)#[N:29]
Reactant: COC(=O)CCc1ccc(N2CCN(c3ccc(Br)cc3C)C2=O)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(N2CCN(c3ccc(C#N)cc3C)C2=O)cc1

Procedure:
3.0 g of 1-(4-bromo-2-methyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one and 1.3 g of copper(I)cyanide were heated in 10 ml of dimethylformamide for 10 hours at a bath temperature of 175° C. The dimethylformamide was evaporated off in vacuo, the residue was digested with chloroform and filtered off. The chloroform solution was washed with water and saturated saline solution and concentrated by evaporation. The residue was purified by column chromatography (silica gel; methylene chloride/ethyl acetate=100:2)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:18]5[C:13](=[N:14][CH:15]=[N:16][C:17]=5[NH2:19])[N:12]([CH3:20])[N:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)cc(F)c2)c2c(N)ncnc21
Yield: 72.1 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.495 mmol), (3,5-difluorophenyl)acetic acid (85 mg, 0.495 mmol), HATU (188 mg, 0.495 mmol), DIEA (0.346 mL, 1.982 mmol) was stirred at room temperature over the weekend. At this time, LCMS analysis indicated complete conversion, so the reaction mixture was poured into water (10 mL), whereupon a beige precipitate formed. The precipitate was filtered, suspended in DCM-methanol and dry-loaded onto silica, then purified by flash chromatography (0-10% methanol in DCM) to afford 3-{1-[(3,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.357 mmol, 72.0% yield) as a white solid. LC-MS (ES) m/z=421 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.27 (m, 2H), 3.94 (s, 3H), 3.97 (s, 2H), 4.18-4.32 (m, 2H), 7.02-7.09 (m, 2H), 7.11-7.20 (m, 1H), 7.41-7.47 (m, 1H), 7.50-7.55 (m, 1H), 8.12-8.22 (m, 1H), 8.25 (s, 1H). Note: NH's are not observed as individual peaks.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([O:10][C:11]2[C:20]3[C:15](=[C:16]([O:21][C:22](=[O:32])[C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=4)[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C=O)C.[Pd]>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([O:21][C:16]2[C:15]3[C:20](=[C:11]([O:10][C:8](=[O:9])[C:7]4[CH:33]=[CH:34][C:4]([NH2:1])=[CH:5][CH:6]=4)[CH:12]=[CH:13][CH:14]=3)[CH:19]=[CH:18][CH:17]=2)=[O:32])=[CH:28][CH:27]=1
Reactant: O=C(Oc1cccc2c(OC(=O)c3ccc([N+](=O)[O-])cc3)cccc12)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)Oc2cccc3c(OC(=O)c4ccc(N)cc4)cccc23)cc1
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
22.2 g of 5-[(4-nitrobenzoyl)oxy]-1-naphthyl 4-nitrobenzoate (48.4 mM) were suspended in 400 ml of DMF and 2.5 g of palladium on charcoal (10%) were added. The resulting mixture was hydrogenated at atmospheric pressure until the theoretical amount of hydrogen was consumed. The mixture was then filtered, the cake was washed with DMF and the filtrate was poured onto 4 L of water. The resulting suspension was stirred for 10 min. and the solids ware filtered off, washed with water and dried to give 16.0 g (40.2 mM, 83.0%) of 5-[(4-aminobenzoyl)oxy]-1-naphthyl 4-aminobenzoate as beige crystals.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[F:27][C:28]([F:40])([F:39])[S:29]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]>>[F:40][C:28]([F:39])([F:27])[S:29]([C:32]1[CH:33]=[C:34]([NH:38][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:31]
Reactant: Nc1cccc(S(=O)(=O)C(F)(F)F)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)C(F)(F)F)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-trifluoromethanesulfonyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 583.3 [(M+H)+]; mp 207° C.
Reaction SMILES: [F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].C(N(CC)CC)C.COC(C)(C)C.[CH2:25]([O:27][C:28](Cl)=[O:29])[CH3:26]>O>[C:28](=[O:29])([O:4][CH2:3][C:2]([F:11])([F:1])[CH:5]([F:10])[C:6]([F:9])([F:7])[F:8])[O:27][CH2:25][CH3:26]
Reactant: OCC(F)(F)C(F)C(F)(F)F
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCOC(=O)OCC(F)(F)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 2,2,3,4,4,4-hexafluorobutyl carbonate was prepared by combining 2,2,3,4,4,4-hexafluorobutan-1-ol (184 g, 1.012 moles, available from Lancaster Synthesis Ltd., Ward Hill, Mass.), triethylamine (102 g, 1.008 moles) and methyl-t-butyl ether (350 mL) in a 1-L round bottom flask that was maintained at a temperature between 5° C. and 15° C. with a CO2/water bath. To the stirred mix, ethylchloroformate (100 g, 0.92 moles) was added from a jacketed addition funnel that was maintained between 5° C. and 15° C. The ethylchloroformate was added over a period of 4 h. Once addition was complete, the reaction mixture was stirred for an additional 16 h and was allowed to warm to room temperature. Then 100 mL of distilled water was added to the reaction mixture. The organic phase was collected. The water phase was extracted twice with 100 mL portions of methyl t-butyl ether and all of the organic phases were combined. The organic phase was washed with a 100 mL portion of distilled water and a 100 mL portion of 1N HCl. The ether was removed by rotary evaporation. The remaining sample was purified by fractional distillation, using a concentric tube column. The product was analyzed by GC/MS.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1C=CC=CC=1.C(OCC)C>[CH3:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1cccc(CBr)c1
Reactant: C1CNCCN1
Solvent: c1ccccc1
Solvent: CCOCC
Product: Cc1cccc(CN2CCNCC2)c1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
α-Bromo-m-xylene (10 ml, 74 mmole) was added to a solution of 75 g (11.8 equiv.) of anhydrous piperazine in 500 ml of benzene and the reaction was heated to reflux for two hours. After cooling to room temperature, the reaction was diluted with 300 ml of diethyl ether and washed with 500 ml of 0.2 M sodium hydroxide followed by two 500 ml portions of water. The organic solution was dried over sodium sulfate and the solvent removed to give 11.0 g (78%) of crude 1-(3-methylbenzyl)piperazine as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].[H][H]>[Ni].C(O)C>[CH3:5][CH:4]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][CH2:2][OH:1]
Reactant: [H][H]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCO
Reaction time: 144 h
Yield: 88 %

Procedure:
Under nitrogen in a 1 liter 3-neck flask equipped with mechanical stirring, Raney Nickel (Raney 2800, Aldrich, 30% slurry in water, 20.4 g) was suspended in ethanol (400 mL). A solution of farnesol (mixture of cis and trans isomers, 25.0 g), in ethanol (75 mL) was added dropwise with a gentle sweep of hydrogen through the reaction mixture, and the mixture was stirred under hydrogen for 144 hours. Hydrogen was then replaced by nitrogen, and under a positive pressure of nitrogen the suspension was filtered through a filter stick. The catalyst was suspended in a small volume of ethanol and the filtration was repeated. Finally the catalyst was suspended in water and the suspension was rejected. The ethanol filtrate was filtered again through celite and the filtrate was concentrated. After extractive work-up using toluene, the residue was distilled under vacuum. The desired product, by 112-115° C., was obtained as a colorless liquid, 22.76 g (88% yield). Mass spec: m/z 226 (M−2)+. Anal. Calcd for C15H32O: C, 78.88%; H, 14.12%. Found: C, 77.90%; H, 14.32%. No hydrocarbon was detected in the fore-run (0.28 g) or distillation residue (0.9 g). The alcohol product was converted to the corresponding bromide, without additional purification.
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][CH:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)(=O)=O)=CC=1>>[CH:30]1([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)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc32)cc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: O=C(N[C@H]1CCN(CC2CCc3ccccc32)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide and (2,3-dihydroinden-1-yl)methyl p-toluenesulfonate were reacted under the same conditions as in Example 6 to give (S)-N-(1-((2,3-dihydroinden-1-yl)methyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([O:8][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)Oc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
Resorcinol monoacetate (6.10 g, 40 mmol) in DMF (10 mL) was added dropwise to the mixture of NaH (95%, 0.92 g, 40 mmol) in DMF (50 mL). The mixture was stirred at room temperature for 10 min. Benzyl bromide (6.85 g, 40 mmol) in DMF (10 mL) was then added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched slowly with water (100 mL) and then extracted with ethyl acetate (3×100 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a white solid (5.30 g, 55%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:26])=[C:4]([C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:27](B1OC2C=CC=CC=2O1)[CH2:28][CH3:29]>C1COCC1.[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([O:21][C:19]([NH:18][C:15]1[C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[C:3]([CH3:26])[C:2]([CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)OCc1ccccc1
Reactant: CCCB1Oc2ccccc2O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccc(NC(=O)OC(C)(C)C)c(C(=O)OCc2ccccc2)c1C
Temperature: 90 °C
Reaction time: 72 h
Yield: 79.3 %

Procedure:
A mixture of Example 126A (0.52 g, 1.25 mmol), 2-propyl-1,3,2-benzodioxaborole (0.50 g, 3.0 mmol), Pd(dppf)Cl2 (24 mg, 0.03 mmol) and Tl2CO3 (0.75 g, 1.6 mmol) in THF (15 mL) in a scintillation vial was purged with argon, sealed, and shaken at 90° C. for 72 hours. The mixture was treated with brine (25 mL) and extracted with ethyl acetate. The extract was dried (Mg2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% ethyl acetate/hexanes to provide the desired product (0.38 g, 80.0%). 1H NMR (CDCl3) δ 0.94 (t, 3H), 1.48 (s, 9H), 1.55 (m, 2H), 2.24 (s, 3H), 2.54 (t, 2H), 5.38 (s, 2H), 7.15 (d, 1H), 7.36-7.46 (m, 5H), 7.77 (d, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)=[N:2]1.CN(C=O)C.Br[CH2:36][CH3:37].O.[OH-].[Cs+]>>[CH2:28]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][CH:20]=2)=[O:18])[N:7]([CH2:6][C:3]2[CH:4]=[CH:5][N:1]([CH2:36][CH3:37])[N:2]=2)[N:8]=1)[CH3:29]
Reactant: CCBr
Reactant: CCc1nn(Cc2cc[nH]n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To N-(1-((1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (40 mg, 0.10 mmol; prepared as in Example 39, Step H) in dry DMF (519 μL, 0.10 mmol) was added bromoethane (11 mg, 0.10 mmol), cesium hydroxide hydrate (17 mg, 0.10 mmol) and 4 angstrom molecular sieves. The reaction mixture was stirred for one hour, filtered through an Acrodisk, rinsed with DCM and MeOH, and concentrated under a nitrogen stream to a residue. Preparative thin layer chromatography eluting with 10% MeOH, 0.5% NH4OH in CHCl3 provided the final product (10 mg). MS (ES+APCI) m/z=414 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16](OCC)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:16](=[O:17])[CH2:15][CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:22][CH2:21][C:5]1=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)NCc2ccccc2)CCN(C)C1
Temperature: 100 °C
Yield: 29.16 %

Procedure:
Ethyl 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate (200 mg, 0.66 mmol) was added to benzylamine (2.0 ml, excess) and the reaction mixture was heated at 100° C. for 14 h. After completion of the reaction (monitored by LCMS) it was concentrated and basified with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was concentrated to dryness and the crude obtained was purified by silica gel chromatography (Eluent: 10% MeOH in dichloromethane) to get 70 mg (yield: 29.16%) of N-benzyl-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanamide as a free base. To the free base (40 mg, 0.11 mmol) dissolved in THF (5.0 ml), oxalic acid (13 mg, 0.10 mmol) in THF (5.0 ml) was added slowly, the mixture was stirred at RT for 20 minutes and the solid obtained was filtered, washed with ether and dried to get 35 mg (yield: 71.4%) of N-benzyl-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrid[4,3-b]indol-5-yl)propanamide as oxalate salt. 1H NMR (DMSO) 7.50-7.30 (t, 3H), 7.20-7.10 (m, 3H), 7.0-6.90 (m, 2H), 4.40-4.30 (m, 4H), 4.30-4.20 (t, 2H), 4.0 (s, 2H), 3.10 (m, 2H), 2.90 (s, 3H), 2.60-2.50 (t, 3H), 2.40 (s, 3H).