Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.O.CCOCC>C1COCC1>[Br:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Br)cnc21
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Fc1c(Br)cnc2[nH]ccc12
Reaction time: 0.33 h
Yield: 71.9 %

Procedure:
3H2O (80.8 mL, 80.8 mmol; 1.0M solution in THF) was added to 5-bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (30.0 g, 80.8 mmol) in THF (200 mL) at room temperature. The reaction was stirred for 20 minutes, and then water (200 mL) and ether (500 mL) were added. The aqueous phase was extracted with ether. The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The solid was crystallized from EtOAc to provide 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (12.5 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ 11.06 (br s, 1H), 8.39 (d, 1H), 7.35 (dd, 1H), 6.60 (dd, 1H); LCMS (APCI+) m/z 214.9, 216.9 (M+H)+, Retention time=2.75 minutes (Method 1).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH2:13]([CH2:15][NH2:16])[OH:14].Cl>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:16][CH2:15][CH2:13][OH:14])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCO
Agent: Cl
Solvent: O
Product: Nc1ccccc1C(=O)NCCO
Yield: 71.4 %

Procedure:
A round-bottomed flask was charged with isatoic anhydride (5.0 g, 0.030 mol) and 40 mL water. Ethanolamine (2.21 mL, 0.036 mol) was added slowly to the reaction mixture. The reaction mixture was acidified with 1N HCl and extracted with EtOAc. The aqueous layer was basified with 6N NaOH and extracted with EtOAc. The EtOac layer was dried over Na2SO4, filtered, and concentrated to dryness to afford 2-amino-N-(2-hydroxyethyl)benzamide (3.86 g, 70%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[N:7][CH:8]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>>[CH:21]([C:18]1[CH:19]=[CH:20][C:13]([O:9][C:5]2[CH:6]=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=2)=[C:14]([CH:17]=1)[C:15]#[N:16])=[O:22]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cncc(C(F)(F)F)c1
Product: N#Cc1cc(C=O)ccc1Oc1cncc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 5-(trifluoromethyl)pyridin-3-ol and 2-fluoro-5-formylbenzonitrile.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C@H:7]1[CH2:12][O:11][CH2:10][CH2:9][N:8]1C(OC(C)(C)C)=O)[CH2:4][CH3:5])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)[Cl:28]>>[ClH:28].[CH2:1]([N:3]([CH2:6][C@H:7]1[CH2:12][O:11][CH2:10][CH2:9][NH:8]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)C[C@H]1COCCN1C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C[C@H]1COCCN1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
(S)-tert-butyl 3-((diethylamino)methyl)morpholine-4-carboxylate (INTERMEDIATE 86, STEP 1) was dissolved with TFA/DCM, (10 ml, 1:1 v/v) and the resulting mixture was stirred for 1 hour at room temperature. The volatiles were removed under reduced pressure and the concentrate was treated with 4N HCl in dioxane (5 ml), stirred for 10 minutes and the volatiles were removed under reduced pressure. The resulting semi solid was triturated with diethyl ether (2×30 ml), filtered and dried to give the title product (0.65 g, yield: 67%).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1.C(NCC)C.[F:23][C:24]([F:31])([F:30])[C:25]([F:29])=[C:26](F)F.CN(C)C=[O:35]>>[F:29][CH:25]([C:24]([F:31])([F:30])[F:23])[C:26]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH:5]=[C:4]([CH3:17])[S:3]1)=[O:35]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CN(C)C=O
Solvent: CCNCC
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 77 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.29 g, 5.0 mmol) and diethylamine (0.51 g, 7.0 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with hexafluoropropene in the flask atmosphere, which was supplied from a balloon to the flask, with vigorous stirring at room temperature for 3.5 hours. After completion of the reaction, the reaction mixture was subjected to a similar post-treatment as described above, which afforded 2-(2,3,3,3-tetrafluoropropanoylimino)-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.48 g, 3.8 mmol, yield 77%).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24].O>O1CCCC1>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:23](=[O:24])[CH2:22][Cl:21])([CH3:13])[CH3:12]
Reactant: O=C(Cl)CCl
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Reaction time: 10 h

Procedure:
Part A. A solution of 2,6-diisopropylaniline (10.0 mL, 53.0 mmol) and triethylamine (10.0 mL, 71.7 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C., and treated dropwise with a solution of chloroacetyl chloride (5.00 mL, 62.8 mmol) in tetrahydrofuran (20 mL). After being stirred for 10 hours, the solution was poured into water (200 mL) and extracted with methylene chloride (2×200 mL). The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford the product, N-(2,6-diisopropylphenyl)-2-chloroacetamide, as a solid. The solid was purified by trituration in boiling ether, filtration and drying; mp 157°-158° C. (10.7 g, 42.0 mmol, 79%). 1HNMR (CDCl3): δ 7.81 (1H, br s); 7.32 (1H, t, J=8.1 Hz); 7.19 (2H, d, J=8 Hz); 4.26 (2H, s); 3.02 (2H, heptet, J=6.6 Hz); 1.21 (12H, d, J=6.6 Hz). Mass spectrum (NH3 -CI/DDIP): m/z 271 (100%); 256 (11%); 255 (6%); 254 (30%); 219 (1%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.[CH2:17](B(O)O)[CH3:18].C(Cl)Cl.[F-].[Cs+]>CN(C=O)C.O1CCOCC1>[CH2:17]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1)[CH3:18]
Reactant: Brc1cccc2c1CCOC2C1=NCCN1
Reactant: CCB(O)O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1cccc2c1CCOC2C1=NCCN1
Temperature: 150 °C

Procedure:
To a mixture of 2-(5-bromoisochroman-1-yl)-4,5-dihydro-1H-imidazole (100 mg), ethylboronic acid (56.2 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II), complex with CH2Cl2 (1:1) (13 mg) and CsF (108 mg) was added dioxane (4 ml) and DMF (1 ml). The mixture was degassed with N2 and heated in a microwave oven for 30 min at 100° C. and 30 min at 150° C. The title compound was purified by separation methods J and G. (Yield 6.1 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19]1(=O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1.Cl>C(OCC)C>[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:20]1
Reactant: O=C1CCc2ccccc21
Reactant: c1ccc(Cc2ccccn2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C1=C(c2ccccc2Cc2ccccn2)c2ccccc2C1
Temperature: -20 °C
Yield: 33.5 %

Procedure:
A mixture of 3.23 ml (0.02 mol) of 2-benzylpyridine in 15 ml of diethyl ether was cooled to −20° C. and 13 ml of n-butyllithium (1.6M in hexane, 0.02 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature, stirred for another one hour and subsequently cooled to −60° C. A solution of 2.8 g (0.021 mol) of 1-indanone in 10 ml of diethyl ether was subsequently added while maintaining the temperature. The mixture was allowed to warm to room temperature, stirred for a further 3.5 hours and hydrolyzed with 40 ml of dilute hydrochloric acid. The solid which had precipitated was filtered off, the organic phase was separated off and the aqueous phase was extracted twice with ethyl acetate. The aqueous phase was then neutralized with aqueous ammonia solution and extracted three times with 30 ml each time of methylene chloride. The organic phases were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. Recrystallization of the residue obtained in this way from hexane gave 1.9 g (34%) of [2-(1H-inden-3-yl)(phenyl)methyl]pyridine.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C:2]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]2[CH2:16][CH2:17][C@H:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1)=[O:7]
Reactant: COC(=O)C(=O)Cl
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl chlorooxoacetate (670 mg, 5.45 mmol) in DCM (3 mL) was added in one portion to a solution of trans-ethyl 2-[4-(4-aminophenyl)cyclohexyl]propanoate (1.0 g, 3.63 mmol) and pyridine (0.59 mL, 7.26 mmol) in DCM (22 mL) at 5° C. and the mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo and EtOAc (30 mL) was added. The layers were separated and the organic layer was washed with water (25 mL) and brine (25 mL). The organic layer was dried and concentrated in vacuo to give the title compound (1.3 g, 99%) as a solid; 1H NMR δ (CDCl3) 1.0-1.1.25 (2H, m), 1.1 (3H, d), 1.2 (3H, t), 1.3-1.47 (2H, m), 1.48-1.55 (2H, m), 1.68-1.79 (1H, m), 1.8-1.95 (2H, m), 2.18-2.28 (1H, m), 2.35-2.5 (1H, m), 3.9 (3H, t), 4.08 (2H, q), 7.12 (2H, d), 7.47 (2H, d); MS m/e (M−H)− 360.
Reaction SMILES: [OH:1][CH:2]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:7]([CH2:26][CH2:27][CH3:28])[N:6]2[N:29]=[C:30]([CH3:32])[N:31]=[C:5]12.N1C(C)=CC=CC=1C.O1CCCC1.FC(F)(F)S(O[Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])(=O)=O>C(OCC)(=O)C>[Si:56]([O:1][CH:2]([C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)=[C:7]([CH2:26][CH2:27][CH3:28])[N:6]2[N:29]=[C:30]([CH3:32])[N:31]=[C:5]12)([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)C(C)(C)C)c2nc(C)nn12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a mixture of 4′-{[4-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.9 g), 2,6-lutidine (0.32 mL) and tetrahydrofuran (20 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.64 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.9 g, 81%).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:37][OH:38])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[N:16][CH:17]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH2:27][CH:28]([N:37]([OH:38])[CH:5]=[O:7])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:26])=[O:25])[CH2:22][CH2:23]2)=[N:16][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(NO)c1ccc(Cl)c(Cl)c1)N1CCN(c2ccc(Cl)cn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CN(O)C(CS(=O)(=O)N1CCN(c2ccc(Cl)cn2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (0.63 ml) was added directly to formic acid (2.48 ml). The solution was stirred at room temperature for 30 minutes and then added a solution of N-[2-{[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]hydroxylamine (0.6 g) in tetrahydrofuran (10 ml). The solution was stirred at room temperature for 3 hours and then diluted with ethyl acetate, neutralised the pH with saturated aqueous sodium hydrogen carbonate solution The ethyl acetate layer was separated, dried (Na2SO4), and evaporated to dryness. The residue was purified by chromatography using a 10 g silica isolute eluting with 10% ethyl acetate/heaxane—80% ethyl acetate/hexane and then evaporated to dryness. The resulting white solid was filtered from diethyl ether to give N-[2-{[4-(5-chloropyridin-2-yl)piperazino]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide (0.43 1 g), 211-212° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([C:8]2([C:24](Cl)=[O:25])[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C.[CH2:29]([OH:31])[CH3:30]>>[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([C:8]2([C:24]([O:31][CH2:29][CH3:30])=[O:25])[CH2:9][CH2:10][N:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(C(=O)Cl)(c3cccc(Cl)c3C)CC2)cc1
Reactant: CCO
Product: CCOC(=O)C1(c2cccc(Cl)c2C)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A mixture of 36.5 parts of 4-(3-chloro-2-methylphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonyl chloride and 240 parts of ethanol is stirred and refluxed overnight. The reaction mixture is treated with activated charcoal while hot. The latter is filtered off and the product is allowed to crystallize from the filtrate by cooling spontaneously to room temperature. The product is filtered off and dried, yielding 33 parts (89.1%) of ethyl 4-(3-chloro-2-methylphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarboxylate; mp. 134° C.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(OCC)(=O)C.CO>CC#N>[C:18]([C:4]1[CH:3]=[N:2][NH:1][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: C1=Cc2ccccc2NN=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)C1=Cc2ccccc2NN=C1
Temperature: 18.5 °C
Yield: 95 %

Procedure:
To a suspension of benzodiazapine (92.0 g, 0.62 mole) and K2CO3 (90.2 g, 0.65 mole, −325 mesh) in CH3CN (1000 ml) was added acetic anhydride (63.4 g, 58.6 ml, 0.62 mole) in 0.5 h (reaction mixture was cooled in ice water to maintain the reaction mixture temperature between 15-22° C.). The suspension was stirred for 0.5 h at room temperature (check TLC after 30 min, eluent ethyl acetate:MeOH 9:1). The reaction mixture was evaporated and to the residue water (400 ml) was added. The suspension was cooled in ice, filtered, washed with cold water (50 ml×2). Dried under vacuum to give 109.7 g of 4-acetylbenzodiazepine as a white solid, yield 93%).
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[C:15]([N:17]3[CH:21]=[N:20][C:19]([NH:22][C:23]4[CH:31]=[CH:30][C:26](C(O)=O)=[CH:25][CH:24]=4)=[N:18]3)[CH:14]=[CH:13][N:12]=2)[CH2:6][CH:5]1[CH3:32])(=[O:3])[CH3:2].CC[N:35](C(C)C)C(C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[CH3:59][N:60]([CH:62]=[O:63])[CH3:61]>C(Cl)Cl.CO>[C:1]([N:4]1[CH:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[C:15]([N:17]3[CH:21]=[N:20][C:19]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([NH:35][C:62](=[O:63])[N:60]([CH3:61])[CH3:59])=[CH:25][CH:24]=4)=[N:18]3)[CH:14]=[CH:13][N:12]=2)[CH2:6][CH:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(C(=O)O)cc4)n3)ccn2)CC1C
Reactant: CN(C)C=O
Reactant: CCN(C(C)C)C(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(NC(=O)N(C)C)cc4)n3)ccn2)CC1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
To a solution of 50 mg of 4-{1-[2-(4-Acetyl-3,5-dimethyl-piperazin-1-yl)-pyridin-4-yl]-1H-[1,2,4]triazol-3-ylamino}-benzoic acid (0.11 mMol, 1.0 equiv) in 10 mL of CH2Cl2 and 5 mL of DMF was added 500 μL of Hunig's base followed by 50 mg of DPPA (0.18 mMol, 1.6 equiv). The reaction was stirred for 30 min at 25° C. and then diluted with 10 mL of MeOH and warmed to 80° C. for 12 hr. The reaction was concentrated and purified by flash chromatography (10:1 CH2Cl2:MeOH) to yield 7 mg of 3-(4-{1-[2-(4-Acetyl-3,5-dimethyl-piperazin-1-yl)-pyridin-4-yl]-1H-[1,2,4]triazol-3-ylamino}-phenyl)-1,1-dimethyl-urea (0.015 mMol, 13% yield). 1H NMR (500 MHz, CDCl3) ∂ 8.31 (1H, s), 8.13 (1H, d), 7.40 (2H, d), 7.30 (2H, d), 6.95 (1H, s), 6.82 (1H, d), 6.70 (1H, s), 6.18 (1H, s), 4.15 (2H, m), 3.10 (2H, m), 2.99 (6H, s), 2.90 (2H, m), 2.10 (3H, s), 1.35 (6H, d) ppm. LC/MS: 1.92 min/478.1 (M+1)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[O:15]1[C:19]([CH:20]=O)=[CH:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2.[BH4-].[Na+].[OH2:28]>C(O)C>[O:28]1[C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[CH:18]=[C:19]1[CH2:20][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:20][C:19]2[O:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[CH:18]=2)[CH2:10][CH2:9]1
Reactant: O=Cc1cc2ccccc2o1
Reactant: O
Reactant: NCCCN1CCN(CCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc2oc(CNCCCN3CCN(CCCNCc4cc5ccccc5o4)CC3)cc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and benzo[b]furan-2-carboxaldehyde (565 mg, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×36 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: [C:1]([N-:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])C.[C:11]12([NH2:21])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.[C:22](OI(C1C=CC=CC=1)OC(=O)C)(=[O:24])[CH3:23]>C(#N)C>[C:22]([N:8]1[CH2:9][CH2:10][CH:5]([NH:4][C:1]([NH:21][C:11]23[CH2:18][CH:17]4[CH2:16][CH:15]([CH2:14][CH:13]([CH2:19]4)[CH2:12]2)[CH2:20]3)=[O:3])[CH2:6][CH2:7]1)(=[O:24])[CH3:23]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: CC(=O)[N-]C1CCNCC1
Solvent: CC#N
Product: CC(=O)N1CCC(NC(=O)NC23CC4CC(CC(C4)C2)C3)CC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A reactor was charged with 100 mole-equivalents of N-acetyl piperid-4-yl amide, 0.87 mole-equivalents of 1-adamantyl amine, and 49.7 mole-equivalent of acetonitrile, and the resulting mixture was heated to 75° C. internal under a nitrogen atmosphere. (Diacetoxyiodo)benzene was added, the reaction mixture was cooled to 25° C. internal, and approximately 24 mole-equivalents of solvent was distilled out under vacuum while maintaining internal temperature below 40° C. The reaction mixture was cooled with agitation to 0-5° C. internal and stirred for an additional 2 hours. The technical product was collected by filtration and washed with acetonitrile. The crude product was dried to constant weight in a vacuum oven under a nitrogen bleed maintaining an internal temperature of ≦50° C. The dried, crude product was slurried with water maintaining an internal temperature of 20±5° C. internal for 4 hours and then collected by filtration. The filter cake was washed with heptane under a nitrogen atmosphere then dried to constant weight in a vacuum oven under a nitrogen bleed maintaining an internal temperature of ≦70° C. to afford product as a white solid in 72% yield based on 1-adamantyl amine. 1H NMR(DMSO-d6) δ: 5.65-5.70 (bd, 1H), 5.41 (s, 1H), 4.02-4.10 (m, 1H), 3.61-5.70, (m, 1H), 3.46-3.58 (m, 1H), 3.04-3.23 (m, 1H), 2.70-2.78 (m, 1H), 1.98 (s, 3H), 1.84 (s, 6H), 1.64-1.82 (m, 2H), 1.59 (s, 6H), 1.13-1.25 (m, 1H), 1.00-1.12 (m, 1H); MS: 320 [M+H]+; m.p. 202-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH2:11]OC2C=CC=CC=2)=[CH:5][CH:4]=1.[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH2:11][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:28])=[CH:7][CH:8]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1ccc(/C=C/COc2ccccc2)cc1
Product: COc1ccc(/C=C/Cc2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.6 %

Procedure:
Following the general procedure using (E)-1-methoxy-4-(3-phenoxyprop-1-enyl)benzene (60 mg, 0.25 mmol), o-tolylboronic acid (51 mg, 0.38 mmol) and PdCl2(DPEphos) (0.015 mmol, 11 mg), the reaction was stirred for 6 h at rt. Column chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded the product as a colorless liquid (51 mg, 84%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[Cl:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1>O>[Cl:14][C:15]1[C:16]([C:17]2[N:2]([CH3:1])[C:3]3=[N:4][CH:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:8]3[N:9]=2)=[CH:20][CH:21]=[CH:22][N:23]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: O=C(O)c1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(-c2cccnc2Cl)nc2cc(C(F)(F)F)cnc21
Temperature: 120 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A mixture of 0.96 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.95 g of 2-chloronicotinic acid, 0.85 g of EDCI hydrochloride and 10 ml of pyridine was heated and stirred at 120° C. for 3 hours. Water was poured to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 1.02 g of 2-(2-chloropyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine. 2-(2-Chloropyridin-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine