Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1.CO.[H][H]>[C].[Pd].O1CCCC1>[O:11]=[C:10]1[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[C:6]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[C:7]=2[CH2:8][CH2:9]1
Reactant: CCOC(=O)/C=C/c1c(Oc2ccc([N+](=O)[O-])cc2)ccnc1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc3c2CCC(=O)N3)cc1
Yield: 16.8 %

Procedure:
Ethyl (E)-3-[2-amino-4-(4-nitrophenoxy)-3-pyridyl]-2-propenoate (330 mg), palladium-carbon (10%, aqueous, 100 mg), methanol (5 ml) and tetrahydrofuran (5 ml) were stirred overnight at under a hydrogen atomsphere at 1 atmosphere. The palladium-carbon was filtered off, the filtrate was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography (ethyl acetate, followed by ethyl acetate:methanol=5:1) to obtain 43 mg of a white solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:9][C:6]=1[C:7]#[N:8])[CH3:3].C([O-])(=O)C.[Na+].[Br:23]Br>C(O)(=O)C>[Br:23][C:15]1[S:14][C:13]([C:10]2[CH:11]=[CH:12][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:17][CH:16]=1
Reactant: CC(C)Oc1ccc(-c2nccs2)cc1C#N
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1C#N
Temperature: 20 °C

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-5-(1,3-thiazol-2-yl)benzonitrile (D64) (215 mg) and sodium acetate (144 mg) in acetic acid (8 mL) stirred at room temperature was added a solution of Br2 (0.045 mL) in acetic acid (1 mL) dropwise. The reaction mixture was stirred at 20° C. until start material was consumed completely. The reaction mixture was basified with 2M NaOH, then diluted with ethyl acetate. The mixture was washed with water and brine. The organic phase was dried over anhydrous sodium sulphate. After concentration, the crude product 5-(5-bromo-1,3-thiazol-2-yl)-2-[(1-methylethyl)oxy]benzonitrile (D65) (320 mg) was used for next step without further purification. δH (CDCl3, 600 MHz): 1.36 (6H, d), 4.65 (1H, m), 6.95 (1H, d), 7.64 (1H, s), 7.92 (1H, d), 7.97 (1H, dd).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=O)C.[Li+].[BH4-].O>C1COCC1>[F:17][C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][CH:6]2[CH2:4][OH:3])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CCOC(=O)C1CC1c1ccc(OC)c(F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2CC2CO)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid-ethyl ester (0.71 g, 2.98 mmol) was dissolved in anhydrous THF (10 mL), LiBH4-2.0M THF solution (3 mL, 5.96 mmol) was added thereto, and the mixture was stirred at 50° C. for 2 hours. After the termination of the reaction, the reactant was cooled to room temperature, added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and then concentrated under reduced pressure to obtain the title compound (0.519 g, 88%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:4][CH2:3]1.[CH:23](=O)[CH2:24][CH2:25][CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][C:2]1([CH3:22])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17]2)=[CH:4][CH2:3]1
Reactant: COc1ccc(C2=CCC(C)(C)CC2)c(N2CCNCC2)c1
Reactant: CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCN1CCN(c2cc(OC)ccc2C2=CCC(C)(C)CC2)CC1
Reaction time: 3 h
Yield: 102.4 %

Procedure:
To a solution of 1-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine (90 mg, 0.29 mmol) prepared in Example (1e) in tetrahydrofuran (10 mL) were added valeraldehyde (31 mg, 0.36 mmol), sodium triacetoxyborohydride (95 mg, 0.59 mmol) and acetic acid (35 mg, 0.59 mmol) in that order, and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off and then the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 110 mg of 1-[2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenyl]-4-pentylpiperazine as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:16][CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>CC(C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20](/[CH:19]=[CH:18]/[CH2:17][OH:16])[CH:21]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: OC/C=C/c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(/C=C/CO)c1
Reaction time: 20 h
Yield: 97.2 %

Procedure:
A solution of tert-butyl bromoacetate (0.60 mL, 4.03 mmol) and potassium carbonate (1.12 g, 8.06 mmol) was added to a solution of trans-3-(3-hydroxypropenyl)phenol (0.58 g, 3.84 mmol) in acetone (15 mL) at room temperature under a nitrogen atmosphere and stirred for about 20 hours. The mixture was filtered, and the filtrate was concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate, gave pure trans-[3-(3-hydroxypropenyl)phenoxy]acetic acid tert-butyl ester as a clear oil (0.987 g, 97%).
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:37])=O>>[Cl:37][C:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)=[O:2]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: O=S(Cl)Cl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1-(4-carboxybenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (240 mg) and thionyl chloride (1 mL) was stirred at room temperature for 12 h and the excess thionyl chloride was removed under reduced pressure to give desired 1-[4-(chloroformyl)benzyl]-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl{aminomethyl]piperidine. The acid chloride was used without further purification.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]3[C:15]4[C:20]([CH2:21][CH2:22][C:11]=23)=[CH:19][C:18]([OH:23])=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)[CH2:2][CH3:3].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[F:40][C:41]([F:56])([S:52](F)(=[O:54])=[O:53])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]>ClCCl>[F:56][C:41]([F:40])([S:52]([O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[C:12]1=[N:13][O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)=[C:11]1[CH2:22][CH2:21]2)(=[O:54])=[O:53])[C:42]([F:50])([F:51])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(O)ccc2-3)cc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1ccc(-c2onc3c2CCc2cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 72.1 %

Procedure:
To a solution of 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (Example 9, 115 mg, 0.377 mmol), dimethylaminopyridine (4.60 mg, 0.038 mmol), and triethylamine (0.262 mL, 1.883 mmol) in anhydrous dichloromethane (2 mL) was added perfluoro-1-butanesulfonyl fluoride (0.102 mL, 0.565 mmol) dropwise at room temperature under nitrogen. The mixture was stirred at room temperature for 4.5 hr and allowed to stand in the freezer overnight and quenched by the addition of saturated aqueous sodium bicarbonate solution (3 mL). The dichloromethane layer was separated and the aqueous layer was re-extracted with dichloromethane (2 mL). The combined organic solutions were dried over sodium sulfate, filtered through a silica gel pad and concentrated under reduced pressure to give 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (160 mg, 0.272 mmol, 72.3% yield) as a white solid. LC/MS M+1=588
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2.Br[CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]([F:40])[C:35]([F:39])=[C:36]([F:38])[CH:37]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][N:18]([CH2:29][CH2:30][O:31][C:32]3[CH:33]=[C:34]([F:40])[C:35]([F:39])=[C:36]([F:38])[CH:37]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2
Reactant: Fc1cc(OCCBr)cc(F)c1F
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCOc2cc(F)c(F)c(F)c2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
A mixture of 0.62 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.505 g of 5-(2-bromoethoxy)-1,2,3-trifluorobenzene, 0.34 g of potassium iodide and 1.14 g of potassium carbonate in 80 cm3 of acetonitrile was stirred under an inert atmosphere for 18 hours at a temperature in the region of 70° C. After cooling to about 20° C., the suspension was filtered and the insoluble material was washed with 3 times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height 21 cm), eluting with ethyl acetate and collecting 40-cm3 fractions. Fractions 9 to 24 were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.8 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,4,5-trifluorophenoxy)ethyl]piperidine-4-carboxylate was obtained in the form of a pale yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:4]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:33])=O>ClCCl>[Cl:33][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc(OC2CCN(C)CC2)c2c(=O)[nH]cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 7-methoxy-5-((1-methylpiperidin-4-yl)oxy)quinazolin-4(3H)-one (3.00 g, 10.4 mmol) and diisopropyl ethylamine (5 ml) in dichloromethane (300 ml) was stirred at ambient temperature under an atmosphere of nitrogen. Phosphoryl chloride (10 ml) was added, and the resultant orange solution was heated at reflux for 20 hours. The reaction mixture was then cooled to ambient temperature and concentrated in vacuo. Residual phosphoryl chloride was then removed by azeotrope with toluene to give the crude product as an orange oil. Purification by chromatography on silica gel, eluting with 5% triethylamine in dichloromethane, gave an orange solid, which was further purified by trituration under acetonitrile, and then dried in vacuo to yield 4-chloro-5-(N-methylpiperidin-4-yloxy)-7-methoxyquinazoline (2.4 g, 75% yield) as a pale yellow amorphous solid:
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].CCN(CC)CC.Cl.[CH:13]1([CH:18]([NH2:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[CH:13]1([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[NH:25][C:1](=[O:2])[CH3:3])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CC(=O)Cl
Reactant: NC(c1ccccn1)C1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(c1ccccn1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
AcCl (0.10 g, 1.25 mmol) was added to a stirred suspension of Et3N (0.35 mL, 0.25 g, 2.5 mmol, 2.2 eq.) and (rac)-1-cyclopentyl-1-(2-pyridinyl)methylamine HCl salt (0.25 g, 1.14 mmol) in CH2Cl2 (5 mL). The resulting mixture was stirred at rt for 2 h. The reaction mixture was washed with H2O (10%, 3×3 mL) and was dried over Na2SO4 and was concentrated under reduced pressure yielding the crude product (0.20 g) as a clear yellow oil which quickly crystallized. 1H NMR (300 MHz, CDCl3) δ ppm 8.53 (d, J=5.0 Hz, 1H), 7.62 (dt, J=1.5, 7.5 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.16 (d, J=5.0 Hz, 1H), 6.72 (br d, J=7.0 Hz, 1H), 4.93 (t, J=9.0 Hz, 1H), 2.37-2.20 (m, 1H), 2.00 (s, 3H), 1.80-1.10 (m, 8H); HPLC: Daicel Chiralpak AD-H, 80:20 v/v heptane-EtOH (+0.2% Et2NH), 1.0 mL min−1, 210 nm, Rt=9.5 min, Rt=19.2 min.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13]N=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].Br[C:19]1C=CC(N2CCC(O)CC2)=CC=1>>[C:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:19]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCN(c2ccc(Br)cn2)CC1
Reactant: OC1CCN(c2ccc(Br)cc2)CC1
Product: CC(=O)OC1CCN(c2ccc(Br)cc2)CC1
Yield: 92 %

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(5-bromopyridin-2-yl)piperidin-4-yl acetate, except substituting 1-(4-bromophenyl)piperidin-4-ol (606 mg, 2.37 mmol). Crude product was purified by flash chromatography using EtOAc/hexanes as eluent (1:9 to 1:4) to give the title compound as a white solid (648 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 4.92-4.89 (m, 1H), 3.47-3.41 (m, 2H), 3.06-3.00 (m, 2H), 2.08 (s, 3H), 2.04-1.99 (m, 2H), 1.84-1.76 (m, 2H); MS ESI 297.9 [M+H]+, calcd for [C13H16BrNO2+H]+ 298.04.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]=2[N:6]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:1][C:2]1[S:3][C:4]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]=2[N:6]=1
Reactant: Cc1nc2c(ccc3ccccc32)s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2c(ccc3ccccc32)s1
Reaction time: 6 h
Yield: 63 %

Procedure:
To 3.98 g of 2-methylnaphtho[1,2-d]thiazole dissolved in carbon tetrachloride (40 ml) was added 3.56 g of N-bromosuccinimide and 0.20 g of benzoyl peroxide, followed by 6 hours of heating under reflux. After cooling the reaction solution, insoluble matter was removed by filtration, and the solvent was evaporated. The residue was subjected to silica gel column chromatography eluted with hexane-chloroform (5:1) to obtain 3.50 g (63%) of 2-bromomethylnaphtho[1,2-d]thiazole.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:18][CH2:17]3)[C:14]3[C:19]([C:23](OC)=[O:24])=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1[C:27]#[N:28].N[C@H](C1N(C2CC2)C2C(C([NH:46][C:47]([CH3:50])([CH3:49])[CH3:48])=O)=CC=CC=2N=1)C>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:15]([CH:16]3[CH2:18][CH2:17]3)[C:14]3[C:19]([C:23]([NH:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:24])=[CH:20][CH:21]=[CH:22][C:13]=3[N:12]=2)[CH3:10])[C:3]=1[C:27]#[N:28]
Reactant: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(C3CC3)c12
Reactant: C[C@H](N)c1nc2cccc(C(=O)NC(C)(C)C)c2n1C1CC1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)NC(C)(C)C)c2n1C1CC1

Procedure:
Using the general synthetic procedure for (S)-methyl 2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate in example 47, 2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-N-tert-butyl-1-cyclopropyl-1H-benzimidazole-7-carboxamidewas prepared using (S)-2-(1-amino ethyl)-N-tert-butyl-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxamide: 1H NMR (400 MHz, MeOH-d4) δ 8.03 (1H, s), 7.68 (1H, d, J=8.0 Hz), 7.38 (1H, d, J=8.0 Hz), 7.27 (1H, t, J=8.0 Hz), 6.04 (1H, q, J=8.0 Hz), 3.55-3.43 (1H, m), 3.03-2.96 (1H, m), 1.73 (3H, d, J=4.0 Hz), 1.53 (9H, s), 1.40-1.30 (1H, m), 1.30-1.15 (2H, m), 1.10-0.93 (1H, m); LC-MS (ESI) m/z 419.2 [M+H]+.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.CCOC(/N=N/C(OCC)=O)=O.[OH:32][C:33]1[CH:34]=[C:35]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]#[N:49])[CH:46]=3)[N:41](C3CCCCO3)[N:40]=2)[CH:36]=[CH:37][CH:38]=1.OC1C=C(C2C3[C:66](=CC=C(C#N)C=3)[N:65]([CH:74]3CCCCO3)N=2)C=CC=1.Cl>O1CCCC1>[CH3:66][N:65]([CH3:74])[CH2:2][CH2:1][CH2:6][O:32][C:33]1[CH:34]=[C:35]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]#[N:49])[CH:46]=3)[NH:41][N:40]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(O)c1)nn2C1CCCCO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCCOc1cccc(-c2n[nH]c3ccc(C#N)cc23)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 56.2 %

Procedure:
Triphenylphosphine (1.31 g, 5.00 mmol), tetrahydrofuran (4.00 mL), 3-N,N-dimethylaminopropanol (0.592 mL, 5.00 mmol) and diethylazodicarboxylate (0.788 mL, 5.00 mmol) were added to 3-(3-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile 3-(3-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.400 g, 1.25 mmol). The mixture was stirred at ambient temperature for 15.5 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ethyl acetate (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. Purification by flash chromatography on silica gel pretreated with 2% triethylamine/hexanes followed by 0–20% ethyl acetate/hexanes elution, sonication of the product in ethyl acetate (3 mL), addition of hexanes (20 mL) and filtration gave the title compound (0.225 g, 56% yield). ES-MS (m/z) 321 [M+1]+
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33][C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:49]=[CH:48][C:47]([CH2:50]O)=[CH:46][CH:45]=1)=[O:35]>>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:50][C:47]2[CH:46]=[CH:45][C:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH2:37][NH:36][C:34]([NH:33][CH3:32])=[O:35])=[CH:49][CH:48]=2)[C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)cc1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC[C@@H](C)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step C) and 2'-[[(methylamino)carbonyl]amino]methyl-1,1'-biphenyl-4-methanol, methanesulfonate ester (Example 48, Step I) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CD3OD): δ 1.10 (s, 3H), 1.12 (s, 3H), 1.18 (d, 6 Hz, 3H), 1.95 (m, 1H), 2.12-2.39 (m, 3H), 2.40-2.63 (m, 3H), 2.63 (s, 3H), 3.70 (m, 1H), 4.13 (s, 2H), 4.42 (dd; 12, 8 Hz; 1H), 4.46 (d, 12 Hz, 1H), 4.59 (d, 12 Hz, 1H), 4.93 (d, 15 Hz, 1H), 5.23 (d, 15 Hz, 1H), 7.02-7.40 (m, 17H). FAB-MS: calculated for C41H49N5O4 675; found 676 (M+H, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:19](=[O:21])[CH3:20])[N:10]=2)[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1nc2ccc(Br)cn2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc2ccc(Br)cn2n1
Temperature: 20 °C

Procedure:
To a solution of 6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3) (7.10 g, 33.3 mmol) in dry acetonitrile (150 mL) at 5° C. was added triethylamine (11.6 mL, 83.3 mmol) followed by acetyl chloride (2.35 mL 83.3 mmol). The reaction mixture was then allowed to warm to room temperature (20° C.) and stirred until all starting material was consumed (if required, further triethylamine (4.64 mL, 33.3 mmol) and acetyl chloride (33.3 mmol) were added to ensure complete reaction). After this time the solvent was removed in vacuo and to the resultant residue was added 7 N (Methanolic ammonia solution (50 mL)). The reaction mixture was stirred at room temperature (20° C.) to hydrolyze any bis-acylated material. After 16 h evaporation in vacuo and trituration from diethyl ether (50 mL) afforded the title compound which was collected by filtration, washed with water (2×50 mL), acetone (50 mL) and diethyl ether (50 mL) and then dried in vacuo.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]=1.[Li:18]CCCC>CCCCCC>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([Li:18])[CH:4]=1
Reactant: CN(C1=CCc2ccccc21)c1ccccc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]C1C=C(N(C)c2ccccc2)c2ccccc21
Reaction time: 8 h
Yield: 89 %

Procedure:
N-Methyl-N-phenyl-1H-inden-3-amine(6.8g, 30.7 mmol) was dissolved in 100 mL of hexane and 10 12.3 mL of 2.5 M n-BuLi (0.936 eq) was added dropwise via syringe over a 15 minute period. The solution developed a yellow precipitate upon the addition of n-BuLi and the slurry was allowed to stir overnight. After this time the solid was filtered, washed with 50 mL of hexane and allowed to dry in Vacuo overnight to afford the desired anion as a yellow-orange solid (5.83 g, 25.6 mmol) in 89 percent yield based upon the lithio reagent.