Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.[C:6]([CH2:8][C:9]([OH:11])=O)#[N:7].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]C(O)=O)=[CH:15][CH:14]=1.C1N=CN(C(N2C=NC=C2)=O)C=1>O1CCCC1.C(O)(=O)C.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:9](=[O:11])[CH2:8][C:6]#[N:7])=[CH:15][CH:14]=1
Reactant: N#CCC(=O)O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CC(C)[Mg]Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CCC(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
Isopropylmagnesium chloride (24.6 mL, 2 M solution in THF, 50 mmol, 5 equiv) was added to a −78° C. solution of cyanoacetic acid (2.52 g, 29.6 mmol, 2.96 equiv) in 80 mL of anhydrous tetrahydrofuran. After 1 h, a solution of 4-chlorophenylacetic acid (1.7 g, 10 mmol, 1.0 equiv) and N,N-carbonyldiimidazole (1.93 g, 11.9 mmol, 1.19 equiv) in 20 mL of anhydrous tetrahydrofuran was added to the reaction mixture, and the reaction mixture was warmed to ambient temperature. After 16 h, the reaction mixture was poured into 300 mL of water. The mixture was adjusted to pH 4 with glacial acetic acid. Gas evolution was evident during addition of the acetic acid. The mixture was extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via automated flash chromatography (80 g SiO2, gradient from hexanes to ethyl acetate) to afford the product as a white solid (1.17 g, 57%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=O.[C:13]([NH2:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:13]2[O:20][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=3)[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1ccccc1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Product: N#Cc1ccc(-c2coc(-c3ccccc3)n2)cc1
Temperature: 135 °C
Yield: 66 %

Procedure:
The mixture of the 2-bromo-1-(4-cyanophenyl)ethanone (4 g, 17.85 mmol) and benzamide (5.41 g, 44.6 mmol) was heated to 135° C. for 3 hours. Then the reaction mixture was cooled, and partitioned between diethyl ether and water. The aqueous layer was extracted with ether twice, and the combined organic layers were washed with 1N NaOH, 1N HCl, water, and brine, dried over MgSO4. After concentration, the solid residue was dissolved in CHCl3. The insoluable solid was filtered through a flits funnel and discarded. The CHCl3 solution was filtered through a pad of silica and evaporate to dryness to give 2.9 g (66% yield) of 4-(2-phenyl-1,3-oxazol-4-yl)benzonitrile. LCMS: m/z 247.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:15][N:16]([CH3:21])[C:17](=[O:20])[CH:18]=[CH2:19].Cl>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][N:11]([CH2:19][CH2:18][C:17]([N:16]([CH3:21])[CH3:15])=[O:20])[CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: C=CC(=O)N(C)C
Agent: Cl
Product: CC1=C2CCN(CCC(=O)N(C)C)CC2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and N,N-dimethyl acrylamide are reacted in accordance with the process described in Example 6. Reaction period 7 hours. M.P. of the hydrochloride of the title compound 219°-221° from ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13]O)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.F[P-](F)(F)(F)(F)F.[C:39]([C:43]1[CH:44]=[C:45]([NH2:50])[C:46]([NH2:49])=[CH:47][CH:48]=1)([CH3:42])([CH3:41])[CH3:40]>CN(C)C=O.O>[C:39]([C:43]1[CH:48]=[CH:47][C:46]2[NH:49][C:13]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][OH:12])=[N:50][C:45]=2[CH:44]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CO)c1nc2cc(C(C)(C)C)ccc2[nH]1
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
(S)-2-((tert-Butoxycarbonyl)amino)-3-hydroxypropanoic acid (226 mg, 1.10 mmol) was dissolved in N,N-dimethylformamide (5 mL) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid-hexafluorophosphate (440 mg, 1.10 mmol) was added. The reaction was stirred for 10 minutes then 4-(tert-butyl)benzene-1,2-diamine (164 mg, 1.00 mmol) was added and the reaction mixture stirred for 18 hours. The reaction mixture was diluted with water and extracted twice with ethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo. The residue was dissolved in 1,2-dichloroethane and anhydrous magnesium sulfate was added. The reaction was stirred at 65° C. for 18 hours to complete the dehydration. The reaction mixture was filtered and loaded directly onto a 4 g silica gel column for purification. The column was eluted with 0-10% methanol in dichloromethane to afford 73 mg of product as a white solid.
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[H-].[Na+].C([C:13]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23]Br)=[CH:20][CH:21]=2)[C:16](CC)=[C:15]([C:27](P(=O)([O-])[O-])([F:29])[F:28])[C:14]=1[Br:34])C>C1(C)C=CC=CC=1>[Br:34][C:14]1[CH:13]=[C:22]2[C:17](=[CH:16][C:15]=1[C:27]([P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])([F:28])[F:29])[CH:18]=[C:19]([CH2:23][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH:20]=[CH:21]2
Reactant: CCc1c(Br)c(C(F)(F)P(=O)([O-])[O-])c(CC)c2cc(CBr)ccc12
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc2cc(Br)c(C(F)(F)P(=O)(OCC)OCC)cc2c1)OCC
Reaction time: 1 h

Procedure:
To a solution of diethylphosphite (0.22 mL) in toluene (5 mL) at 0° C. was added NaH (60% in mineral oil, 20 mg). The reaction mixture was stirred for 1 hour and then a solution of diethyl[3-bromo-7-(bromomethyl)-2-naphthyl](difluoro)methylphosphonate (220 mg) in toluene (2 mL) was added dropwise. The reaction was stirred for 1 h at 0° C., quenched with a solution of saturated NH4Cl, extracted with EtOAc and dried over Na2SO4. The organic extracts were evaporated to dryness and the residue was purified by flash chromatography eluting with 50% EtOAc/hexanes to afford the titled compound.
Reaction SMILES: CC(C)(OC([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH:19][CH:20]([CH3:22])[CH3:21])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=O)C.FC(F)(F)C(O)=O.O.[OH-].[Na+]>C(Cl)Cl>[CH3:22][CH:20]([NH:19][C:18]1[C:13]([N:10]2[CH2:9][CH2:8][NH:7][CH2:12][CH2:11]2)=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:21]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)Nc1cccnc1N1CCNCC1

Procedure:
1-[1,1-Dimethylethoxycarbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine (PREPARATION 3) is dissolved in methylene chloride (56 ml) and cooled to 0°. Then trifluoroacetic acid is added dropwise. The reaction is warmed to 20-25° and additional trifluoroacetic acid is added (26.6 g). When the reaction is complete by TLC, it is poured into 200 ml of water and ice, basified to pH 12 with 2N aqueous sodium hydroxide, and extracted with 10% tetrahydrofuranchloroform (21) followed by 10% methanol/chloroform (II). The organic layers are dried over anhydrous sodium sulfate, concentrated in vacuo, and used without further purification, NMR (300 MHz, CDCl3) 7.65, 6.85, 6.76, 4. 16, 3.50, 2.98 and 1.20 δ.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:40]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:41])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H](Cc1ccccc1)CN1CC=C(c2cc(F)ccc2OC)CC1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)N2CCOCC2)CC1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
Under a N2 atmosphere, a solution of of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl]-ethyl}-methyl-amine (0.17 g, 0.48 mmole described as intermediate 12 above) and triethylamine (0.15 mL, 1.0 mmole) in dichloromethane (10 mL) was cooled to 0° C. 4-Morpholinecarbonyl chloride (0.06 mL, 0.51 mmole) was added and the resulting mixture was stirred at 0° C. to room temperature (ice melt) overnight. The solvent was evaporated to give a brown residue. Flash chromatography (elution with 7:3 EtOAc-hexane) gave 0.17 g (74% yield) of morpholine-4-carboxylic acid {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydro-4H-pyridin-1-yl]-ethyl}-methyl-amide. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:15]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.Cl.C[O:44][C:45](=[O:52])[C@H:46]([CH2:48][CH2:49][S:50][CH3:51])[NH2:47].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CCOC(C)=O.O>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:47][C@H:46]([C:45]([OH:44])=[O:52])[CH2:48][CH2:49][S:50][CH3:51])=[O:19])=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:15]=2)=[N:11][N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1-c1cc(Cc2nnnn2Cc2ccccc2)ccc1C(=O)O
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CSCC[C@H](NC(=O)c1ccc(Cc2nnnn2Cc2ccccc2)cc1-c1ccccc1C)C(=O)O

Procedure:
A 50 mL round-bottom flasks was charged with 4-(1-benzyltetrazol-5-ylmethyl)-2-(2-methylphenyl)benzoic acid (205.1 mg, 0.52 mmol), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDAC) (110.1 mg, 0.0.572 mmol), L-methionine methyl ester hydrochloride (135.0 mg, 0.676 mmol), 1-hydroxybenzotriazole (78.6 mg, 0.572 mmol) and dmf (3 mL). The reagents were stirred until completely dissolved and then triethylamine (0.14 mL, 0.936mmol) was added. The reaction was stirred about 48 h until no starting material was present. Water (2 mL) and EtOAc (2 mL) were added to dissolve the precipitate. The mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with 2 M Na2CO3 (10 mL), water (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum. Yield: 273.0 mg , yellow solid. 1H NMR (δ, CDCl3): 8.0 (2H), 7.0-7.4 (10H), 5.85 (1H), 5.7 (2H), 4.6 (1H), 4.3 (2H), 3.65 (3H), 1.95-2.2 (6H), 1.5-1.9 (4H).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:38][CH3:39])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH2:19][N:20]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[C:21]#[N:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:40]O.[OH-].[K+].O>C(O)C>[F:33][C:30]([F:31])([F:32])[C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:27]=1)[CH2:23][N:20]([CH2:19][C:9]1[CH:10]=[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH3:18])[C:12]2=[N:13][C:8]=1[N:7]([CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:38][CH3:39])[C:21]([NH2:22])=[O:40]
Reactant: OO
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CN(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c(C)nn2C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(N)=O)c(C)nn2C
Temperature: 25 °C
Yield: 60 %

Procedure:
To a stirred solution of [6-(cyclopentylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-ylmethyl-(3,5-bis-trifluoromethyl-benzyl)-cyanamide (0.50 g, 0.880 mmol) in ethanol (15 mL) were added H2O2 (1.5 mL) and a saturated aqueous solution of KOH (0.70 g, 11.97 mmol) at 0° C. This mixture was slowly heated to reflux. After 2 h the reaction mixture was cooled to RT, water (10 mL) was added, and the product was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over sodium sulfate and evaporated to yield the crude residue. The crude was purified by column chromatography over 100-200 mesh silica gel using 10% ethyl acetate and petroleum ether to yield the title compound as a sticky oil (yield: 60%).
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:9])[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Cl.[N:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=1.C1CCCCC1>CN(C=O)C>[N:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C:3]2=[O:9])=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: O=C1CCC(=O)N1Cc1ccncc1
Reaction time: 48 h

Procedure:
A suspension of sodium hydride (17.6 g, 0.44 mol) in DMF (500 mL) was stirred with ice bath cooling as succinimide (29.73 g, 0.3 mol) was cautiously added. 4-Picolyl chloride hydrochloride (32.81 g, 0.2 mol) was then added cautiously with vigorous stirring. The mixture was stirred at room temperature for 1 day and then at 100° C. for 2 days. The mixture was then cooled and filtered. The filtrate was concentrated in vacuo to give a black oil. This dark crude product was stirred four times with boiling cyclohexane (150 mL), each time decanting the boiling cyclohexane from the dark residue. Upon cooling the cyclohexane extracts, the desired product crystallized as colorless needles (23.05 g, 60.9%) which were filtered and air dried.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][N:4]=1)=O.Cl.[CH:24]([C@H:27]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1)([CH3:26])[CH3:25].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:24]([C@H:27]1[CH2:32][CH2:31][C@H:30]([NH:33][CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:5][N:4]=2)[CH2:29][CH2:28]1)([CH3:26])[CH3:25]
Reactant: CC(C)[C@H]1CC[C@H](N)CC1
Reactant: NC(=O)c1ccc(Oc2cnc(C=O)c3ccccc23)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)[C@H]1CC[C@H](NCc2ncc(Oc3ccc(C(N)=O)cn3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 6-(1-formylisoquinolin-4-yloxy)nicotinamide (Preparation 20) (150 mg, 0.51 mmol) and trans-4-isopropylcyclohexylamine hydrochloride (Preparation 9) (273 mg, 1.53 mmol) in 1,2-dichloroethane (10 mL) under argon was added acetic acid (30 μL, 0.51 mmol) followed by NaBH(OAc)3 (325 mg, 1.53 mmol). The mixture was stirred at rt for 16 h then the reaction solvent was removed in vacuo. The residue was partitioned between EtOAc (50 mL) and NaHCO3 (30 mL), and the organic phase washed with NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (SiO2, NH4OH:MeOH:DCM 0.5:5:95) to give the title compound: RT=2.85 min; m/z (ES+)=419.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(CC)CC>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
4-Nitrobenzyl chloride (0.086 g, 0.501 mmol) is dissolved in THF (1 mL), and to this solution, is added piperidine (0.059 mL, 0.601 mmol) followed by Et3N (0.210, 1.50 mmol). After stirring the mixture at 50° C. for 5 h, the resulting solution is filtered, and then the solvent is removed via high vacuum to afford the product (0.090 g, 82%); 1H NMR (DMSO-d6) δ 1.25-1.35 (m, 2H), 1.40-1.48 (m, 4H), 2.23-2.32 (m, 4H), 3.47 (s, 2H), 7.50 (d, J=8.8 Hz, 2H), 8.11 (d, J=8.8 Hz, 2H); mass spectrum [(+) ESI], m/z 221 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(Br)cc1F
Yield: 46.5 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-fluoro-benzene (100 g, 373 mmol) in DMF (190 mL) and water (10 mL) was added sodium cyanide (22 g, 448 mmol). The reaction was heated to 70 degrees Celsius for 3 hours, concentrated to a volume of 100 mL, and then the solution was diluted with 100 mL of ethyl acetate. After the solids were removed by filtration, water (250 mL) was added and the layers were separated. The organic layer was further washed with 3×100 mL of water. The organic layer was dried over MgSO4, filtered to remove solids, and then concentrated. Purification by distillation gave the desired product (37.124 g, 46%). B.P.=72–75 degrees Celsius.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][NH:6][C:7](=[O:9])[OH:8].C(N(CC)[CH:14]([CH3:16])[CH3:15])(C)C.[C:19](=O)(O)[O-].[Na+]>CC#N.C(O)(C(F)(F)F)=O>[C:14]([O:9][C:7](=[O:8])[NH:6][CH2:5]/[CH:4]=[CH:3]\[CH2:2][Cl:1])([CH3:16])([CH3:19])[CH3:15]
Reactant: O=C([O-])O
Reactant: O=C(O)NC/C=C\CCl
Reactant: CCN(C(C)C)C(C)C
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NC/C=C\CCl
Temperature: 60 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
Following the General Procedure for N-alkylation: To a solution of (1H-N-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (200 mg, 0.53 mmol) and ((Z)-4-chloro-but-2-enyl)-carbamic acid Cert-butyl ester (130 mg, 0.64 mmol) in CH3CN (3 mL) were added N,N-diisopropylethylamine (138 μL, 0.80 mmol) and KI (4.4 mg, 0.027 mmol) and the reaction stirred at 60° C. for 18 h. The crude material was taken up in neat TFA (1 mL) and stirred 3 h. Saturated aqueous sodium bicarbonate (5 mL) was cautiously added, and the resulting mixture was extracted with CH2Cl2 (3×10 mL) then the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude material by radial chromatography (1 mm plate, 50:1:1 CH2Cl2—MeOH—NH4OH) afforded the title compound (57 mg, 31%) as a white solid. 1H NMR (CDCl3) δ 1.68-1.72 (m, 1H), 1.84-2.05 (m, 2H), 2.15-2.22 (m, 1H), 2.71 (dt, 1H, J=17, 5 Hz), 2.84 (ddd, 1H, J=16, 10, 5 Hz), 3.15-3.26 (m, 3H), 3.38 (dd, 1H, J=14, 7 Hz), 3.97-4.12 (m, 3H), 5.46-5.54 (m, 2H), 7.13 (dd, 1H, J=8, 5 Hz), 7.16-7.21 (m, 2H), 7.40 (dd, 1H, J=7, 1 Hz), 7.57 (br s, 2H), 8.57 (dd, 1H, J=5, 1 Hz); 13C NMR (CDCl3) δ 21.0, 22.9, 28.9, 37.4, 46.4, 48.6, 60.5, 115.0, 121.8, 122.2, 130.7, 131.6, 134.6, 137.4, 146.6, 154.2, 156.8. ES-MS m/z 348 (M+H). Anal. Calcd. for C21H25N5.0.1CHCl3.0.8CH4O: C, 68.32; H, 7.41; N, 18.19. Found: C, 68.60; 14, 7.05; N, 17.82.
Reaction SMILES: [CH2:1]([C:6](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:22]([Br:25])[CH:23]=[CH2:24]>C(O)(=O)C>[Br-:25].[CH2:1]([C:6](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH2:7][N+:8]1([CH2:24][CH:23]=[CH2:22])[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C=CCBr
Reactant: CCCCCC(=Cc1ccc(Cl)cc1Cl)CN1CCCC1
Solvent: CC(=O)O
Product: C=CC[N+]1(CC(=Cc2ccc(Cl)cc2Cl)CCCCC)CCCC1
Product: [Br-]
Yield: 53.8 %

Procedure:
19 g of (IV) and 14.5 g of allyl bromide in 200 ml of glacial acetic acid were refluxed for 5 hours, the mixture was cooled, and the liquid product which separated out was triturated with ethyl acetate. The product which crystallized out was filtered off under suction, washed with ethyl acetate and dried under reduced pressure. 14 g of (V) of melting point 109° C. were obtained (compound No. 3a).
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[C:9]=1[C:42]#[N:43].[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55].O>>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)[C:9]=1[C:42]#[N:43].[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2C#N)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reaction time: 0.17 h

Procedure:
Tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-cyano-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (190 mg) was treated with TFA/water (95:5, 3 ml) with stirring for 10 minutes. The reaction mixture was concentrated and lyophilized to yield the title compound as TFA salt.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][CH:49]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][CH:49]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:78])[CH3:79])=[CH:71][CH:70]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCC(Oc3ccccc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCC(Oc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 26.4 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-phenoxypiperidin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.20 mL), ethanol (1.00 mL), 1M Na2S2O4 (3 eq, 0.58 mmol, 0.58 mL) and tert-butyl N-(4-formylbenzyl)carbamate (1.1 eq, 0.21 mmol, 49 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (29 mg, 20%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.41 (s, 9H, C(CH3)3), 1.84-1.90 (m, 2H, 2× piperidine CHAHB), 2.16-2.19 (m, 2H, 2× piperidine CHAHB), 3.59-3.64 (m, 2H, 2× piperidine NCHAHA), 3.87-3.91 (m, 2H, 2× piperidine NCHAHA), 4.19 (d, J=5.9 Hz, 2H, CH2NH), 4.70 (septet, J=3.9 Hz, 1H, piperidine CH), 6.94 (t, J=7.3 Hz, 1H, phenyl H-4), 7.04 (d, J=7.8 Hz, 2H, phenyl H-3′ & H-5′), 7.31 (dd, J=8.6, 7.4 Hz, 2H, phenyl H-3 & H-5), 7.40 (d, J=8.3 Hz, 2H, phenyl H-2 & H-6), 8.13 (d, J=8.1 Hz, 2H, phenyl H-2′ & H-6′), 8.24 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.45 (s, br, 1H, imidazo[4,5-b]pyridine NH);