Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrBr
Reactant: CCCCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
6-Amino-9-benzyl-2-pentylaminopurine (70 mg, 0.23 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (80 mg, yield 91%).
Reaction SMILES: C(OC(N([C@@H](C1C=CC=CC=1)C)C(=O)[CH:9]([CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=O)(C)C.[CH3:28][O-:29].[Na+].C1C[O:34][CH2:33]C1>>[CH2:13]([CH:12]([CH2:11][CH2:10][CH2:9][CH2:16][CH2:17][CH3:18])[C:28]([O:34][CH3:33])=[O:29])[CH:14]=[CH2:15]
Reactant: C1CCOC1
Reactant: C[O-]
Reactant: C=CCC(CCCCCC)C(=O)N(C(=O)OC(C)C)[C@H](C)c1ccccc1
Agent: [Na+]
Product: C=CCC(CCCCCC)C(=O)OC
Reaction time: 1 h

Procedure:
A solution of 0.374 g (1.0 mmol) of N-isopropyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine ((1R,2S):(1R,2R)=77.6:22.4) in 5 ml of THF was cooled to 0° C., 0.386 g (2.0 mmol) of NaOMe (28% solution in methanol) was added, and the mixture was stirred for 1 hour. The reaction was terminated by addition of 2 ml of 1 N hydrochloric acid, and the product was extracted with ethyl acetate (30 ml×2). The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was quantitated by GC. Thus was obtained 0.165 g (83%, 55.3% ee) of the title compound.
Reaction SMILES: [CH:1]1(/[CH:4]=[N:5]/[S:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[CH2:3][CH2:2]1.[CH:12]1([Mg]Br)[CH2:14][CH2:13]1.[NH4+].[Cl-]>C(Cl)Cl>[CH:1]1([CH:4]([CH:12]2[CH2:14][CH2:13]2)[NH:5][S:6]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[CH2:2][CH2:3]1
Reactant: CC(C)(C)S(=O)/N=C/C1CC1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC(C1CC1)C1CC1
Temperature: 25 °C

Procedure:
To a stirred solution of N-[(1E)-cyclopropylmethylene]-2-methylpropane-2-sulfinamide (35 g, 202 mmol) in DCM (800 mL) was added cyclopropylmagnesium bromide (1 M in THF, 404 mL, 404 mmol) at −78° C. The reaction mixture was allowed to warm to room temperature as the bath did (2 h). The mixture was treated with sat'd NH4Cl solution, and extracted with EtOAc. The organic layer was washed with brine, dried (sodium sulfate), concentrated, and purified by flash chromatography to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1>>[O:31]1[CH2:32][CH2:33][N:28]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=5)(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:38]3[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: O=S(=O)(c1cccc(F)c1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)c5cccc(F)c5)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-[4-(3-fluoro-benzenesulfonyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid via General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 284. NMR (DMSO): 2.55-2.58 (4H, m), 2.98-3.03 (4H, m), 3.73-3.77 (4H, m), 3.88 (2H, s), 3.90-3.94 (4H, m), 7.06 (2H, br. s), 7.32 (1H, s), 7.55-7.65 (2H, m), 7.70-7.75 (1H, m), 9.10 (2H, s). MS (ESI+): MH+ 571.20 (100%)
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:15]C1C=CC(CBr)=CC=1.COP(OC)OC>>[CH3:15][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Agent: COP(OC)OC
Product: COP(=O)(Cc1ccc(C)cc1)OC

Procedure:
Following the procedure of Compound 11, 4-methylbenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: Clc1nc2ccccc2o1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNc2nc3ccccc3o2)C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (150 mg) and 2-chlorobenzoxazole (0.0573 ml) in DMF (1.4 mL) was added ethyldiisopropylamine (0.183 ml), and the mixture was stirred at 60° C. for 4 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (175 mg).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.Cl[C:32]([F:37])([F:36])C([O-])=O.[Na+].CN(C=O)C>C(#N)C.C(OCC)(=O)C>[F:36][CH:32]([F:37])[O:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1
Reactant: O=c1c2cc(Cc3ccc(O)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2cc(Cc3ccc(OC(F)F)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Temperature: 100 °C

Procedure:
To a solution of 6-[(6-hydroxypyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 29, 0.025 g, 0.062 mmol) in 1 mL of acetonitrile was added sodium chlorodifluoroacetate (0.010 g, 0.068 mmol). The reaction was heated to reflux under an atmosphere of nitrogen for 4 h, and then DMF (0.310 mL) was added. The mixture was heated to 100° C. for 1 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed 3× with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 454.1573 for [M+H]+ [Calc'd for C24H22F2N3O4, [M+H]+=454.1573]: 1H NMR (400 MHz, CDCl6) δ 8.90-8.88 (m, 1H), 8.26 (s, 1H), 8.03 (s, 1H), 7.77-7.75 (m, 2H), 7.65-7.59 (m, 2H), 7.43-7.40 (m, 1H), 7.37 (t, J=73.2 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.84-4.77 (m, 1H), 4.25 (s, 2H), 4.22-4.06 (m, 3H), 3.59-3.53 (m, 1H), 3.45 (br s, 1H), 3.35-3.30 (m, 1H), 2.21-1.96 (m, 1H), 2.00-1.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([OH:21])=O)[N:13]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[NH:26]([C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)[NH2:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([NH:27][NH:26][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)=[O:21])[N:13]=2)=[CH:4][C:3]=1[C:22]([F:24])([F:25])[F:23]
Reactant: NNc1cnccn1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c2)n1)NNc1cnccn1
Temperature: -70 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
In a 50-mL, 3-necked, round-bottomed flask charged with a solution of (Z)-3-(3-(4-chloro-3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.8 g) in 1:1 EtOAc:THF (20 mL). The solution was cooled to −70° C. and treated sequentially with 2-hydrazinopyrazine (0.275 g, 1.2 eq.), T3P (50% in EtOAc; 2.5 mL, 2.0 eq.) and DIPEA (1.44 mL, 4.0 eq.), added dropwise. The clear reaction mixture was stirred at −60° C. for 1 h before being concentrated under reduced pressure (25° C., 20 mm Hg) to afford crude compound. Purification by column chromatography using (60/120 mesh SiO2, elution with 3-4% MeOH in CH2Cl2) afforded 0.30 g (yield: 30%) (Z)-3-(3-(4-chloro-3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyrazin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) 8=10.53 (s, 1H), 9.58 (s, 1H), 9.11 (s, 1H), 8.47 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.52-7.55 (d, J=10.4 Hz, 1H), 6.08-6.11 (d, J=10.4 Hz, 1H); LCMS for C17H11ClF6N7O [M+H]+ 478.76 found 478.1 (RT 2.64 min, purity: 100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH2:25][OH:26])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:25]=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21
Reactant: COc1ccc(N2CCCCn3c2nc2c(Cl)ccc(CO)c23)c(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
To a stirred suspension of [10-chloro-1-(2-chloro-4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-yl]methanol (313 mg, 0.798 mmol) in acetonitrile (8 mL) was added Dess-Martin reagent (406 mg, 0.958 mmol) at room temperature. After 15 min, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a pale brown solid (267 mg, 0.684 mmol, 85%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([C@@H:15]2[CH2:17][C@H:16]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26][CH2:25]1>CN1C(=O)CCC1.CS(C)=O.CO>[C:31]([NH:30][CH:27]1[CH2:28][CH2:29][N:24]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([C@@H:15]3[CH2:17][C@H:16]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:25][CH2:26]1)(=[O:33])[CH3:32]
Reactant: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccccc3)cc(Cl)n2n1
Reactant: CC(=O)NC1CCNCC1
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(=O)NC1CCN(c2cc(NC(=O)[C@@H]3C[C@H]3c3ccccc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
The title compound was prepared by combining (1R,2R)—N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-phenylcyclopropane carboxamide (8D, 0.1 g, 0.306 mmol) and the N-(piperidin-4-yl)acetamide (0.087 g, 0.612 mmol) in NMP (Volume: 1.020 ml) and heating the mixture at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by 45-65% preparatory HPLC (MeCN/MeOH)/H2O+0.01% TFA). Lyophilization of the combined fractions gave 87 mg (66%) of the titled compound as a white solid. Melting point (190.2-231.1° C.). 1H NMR (DMSO-d6) δ: 10.95 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.23-7.37 (m, 3H), 7.12-7.24 (m, 3H), 6.08 (s, 1H), 4.30 (d, J=12.9 Hz, 2H), 3.88 (br. s., 1H), 3.16 (dd, J=24.3, 11.6 Hz, 2H), 2.39-2.47 (m, 1H), 2.25-2.38 (m, 4H), 1.89 (d, J=13.6 Hz, 2H), 1.82 (s, 3H), 1.46-1.62 (m, 3H), 1.40 (ddd, J=8.2, 6.4, 4.0 Hz, 1H); [α]D20=+218° (C=0.6917, MeOH). ESI-MS: m/z 433.0 (M+H)+. Melting point (190.2-231.1° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)=[N:6][C:5]2=[C:14]([C:16]([OH:18])=O)[CH:15]=1.Cl.Cl.[NH2:21][C@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:24]12[CH2:29][CH2:28][CH:27]([CH2:26][CH2:25]1)[C@H:22]([NH:21][C:16]([C:14]1[CH:15]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:13]=[CH:12][S:11][CH:10]=4)=[N:6][C:5]=13)=[O:18])[CH2:23]2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccsc3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc(Cl)cc2oc(-c3ccsc3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 17.5 %

Procedure:
A mixture of 6-chloro-2-(thiophen-3-yl)benzo[d]oxazole-4-carboxylic acid (70 mg, 0.25 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (50 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol) in DMF (2 mL) was stirred at room temperature for 5 min, then triethylamine (0.13 mL, 1.0 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×20 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) followed by recrystallization from acetonitrile to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-thiophen-3-ylbenzoxazole-4-carboxamide (17 mg, 18%) as a colorless crystal: 1H NMR (500 MHz, CDCl3) δ 9.41 (d, J=7.5 Hz, 1H), 8.23 (dd, J=3.0, 1.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.73 (dd, J=5.0, 1.0 Hz, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.52 (dd, J=5.0, 3.0 Hz, 1H), 4.29-4.25 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.10-2.83 (m, 4H), 2.77 (dd, J=14.0, 4.5 Hz, 1H), 2.15-2.11 (m, 1H), 2.04-1.98 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z 388 (M+H); HPLC>99% (AUC), tR=12.45 min.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[F:55][C:56]([F:66])([F:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[OH:64].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:62]1[CH:61]=[CH:60][C:59]([OH:64])=[C:58]([CH2:57][C:56]([F:65])([F:66])[F:55])[CH:63]=1
Reactant: Oc1ccccc1CC(F)(F)F
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)cc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 187.3 %

Procedure:
Tetrabutylammonium tribromide (6.56 g) was dissolved in chloroform (50 ml) and added dropwise to a solution of 2-(2,2,2-trifluoroethyl)phenol (2.4 g) in chloroform (50 ml). The reaction mixture was stirred at room temperature for 2 hrs, after which time 5% sodium thiosulfate solution (100 ml) was added and the resultant stirred for 30 mins. The mixture was then partitioned between dichloromethane (100 ml) and 1N HCl (200 ml). The organics were separated and dried over magnesium sulfate. The solvent was then removed in vacuuo, the crude residue was then purified by column chromatography on silica gel eluting with 90:10 hexanes:ethl acetate to afford the title compound as a yellow oil (3.24 g). 1H NMR (CDCl3): δ 3.50 (q, J=21.48 Hz 2H), 6.70 (d, J=2.54 Hz, 1H), 7.32 (d, J=2.54 Hz, 1H), 7.45 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.Cl.[F:19][C:20]1[CH:21]=[N:22][C:23]([C@@H:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[NH:11][N:10]=2)=[N:7][C:2]([NH:28][C@H:26]([C:23]2[N:24]=[CH:25][C:20]([F:19])=[CH:21][N:22]=2)[CH3:27])=[N:3][CH:4]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: CN(C)c1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(N(C)C)[nH]n2)n1)c1ncc(F)cn1
Temperature: 160 °C

Procedure:
A microwave reaction vessel was charged with N3-(2,5-dichloropyrimidin-4-yl)-N5,N5-dimethyl-1H-pyrazole-3,5-diamine (Method 36, 50 mg, 0.2 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 50 mg, 0.23 mmol), and DIPEA (0.15 ml, 0.86 mmol) in n-BuOH (1 ml) was heated in a microwave reactor at 160° C. for 2 hours. Solvent was removed. The residue was purified by silica gel chromatography (by ISCO Combiflash with gradient 0-5% methanol in DCM with 1% NH4OH) to afford the title compound as a white solid. 1H NMR (CD3OD, 400 MHz) δ 8.77 (s, 2H), 8.26 (br, 1H), 5.35 (br, 1H), 3.49 (q, 1H), 3.11 (s, 6H), 1.72 (d, 3H); m/z 378.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[C:10]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1ccccc1C=O

Procedure:
A mixture of 2-bromobenzaldehyde (10.05 mmoles), 1-dodecyne (12.03 mmoles), cuprous iodide (0.11 mmoles) and bis(triphenylphosphine) palladium chloride (0.20 mmoles) in freshly distilled triethylamine (30 ml.) was heated for one hour at reflux producing a white precipitate. The reaction mixture was cooled and filtered. The filtrate was evaporated to dryness at reduced pressure and then dissolved in diethyl ether (50 ml) and washed with brine (50 ml). After treatment with anhydrous magnesium sulfate and charcoal, the solution was evaporated to afford a dark oil, which was purified by flash chromatography (2% Et2O/hexane) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](Cl)=[O:31]>>[CH3:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:31]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)CC(C)(C)C)c4)CC3)cccc2n1
Yield: 62 %

Procedure:
The title compound was prepared in 62% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 3,3-dimethylbutanoyl chloride.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].C1C=CC=CC=1>C(OCC)(=O)C.[OH-].[Na+]>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:28](=[O:30])[CH3:29])=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 8.5 g (0.03 mole) of the base of 4-[4-(phenylmethyl)-1-piperazinyl)benzeneamine and 16.0 g (0.16 mole) of triethylamine in 450 ml of ethyl acetate was added, dropwise, a solution of 2.5 g (0.035 mole) of acetyl chloride in 50 ml of ethyl acetate. The mixture was magnetically stirred for 3 hr and then heated at reflux for 1 hr. The excess acetyl chloride was co-distilled with benzene and the resulting oil was shaken in 400 ml of 10% sodium hydroxide solution. The suspended tan solid was collected by filtration, washed thrice with 100 ml portions of water, and air dried to give 9.7 g (99%) of crude product. A one gram portion was recrystallized from benzene/petroleum ether to give 100 ml of cream colored solid, m.p. 159°-161° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[O:31]([C:33]#[N:34])[K]>C(O)(=O)C>[C:33]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[N:11]([CH2:19][C:20]3[CH:24]=[C:23]([C:25]4[S:26][C:27]([Cl:30])=[CH:28][CH:29]=4)[O:22][N:21]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1)(=[O:31])[NH2:34]
Reactant: N#CO[K]
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2n1Cc1cc(-c2ccc(Cl)s2)on1
Solvent: CC(=O)O
Product: NC(=O)N1CCC(NC(=O)c2cc3ccccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
To a solution of 50 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2-carboxylic acid piperidin-4-ylamide in 2 ml acetic acid, 14 mg KOCN were added at RT and stirred over night. After removal of the solvent under reduced pressure the residue directly purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization the product was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
Periodinane (26.9 g, 63.5 mmol) was added to 4-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (10.5 g, 48.8 mmol) in CH2Cl2 (200 mL) and stirred for 90 min. Diethyl ether (560 mL) was added and precipitates were removed by extraction with 10% Na2S2O3/saturated NaHCO3 (1:1, 300 mL). The organic layer was washed with 0.5 M NaOH solution and brine. The organic phase was dried and concentrated under reduced pressure. Purification using flash chromatography (hexane/EtOAc, 8:2) gave 4-Formyl-piperidine-1-carboxylic acid tert-butyl ester (8.5 g, 81%).