Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]>CCO.C1COCC1.[Pd]>[NH2:9][C:5]1[C:6]([OH:8])=[CH:7][C:2]([F:1])=[C:3]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)c1cc(N)c(O)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-fluoro-4-hydroxy-5-nitro-phenyl)-ethanone (3 g, 15.7 mmol) in EtOH (30 mL) and THF (6 mL) was added Pd/C (10%, 1.5 g, 1.4 mmol) and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give 1-(5-amino-2-fluoro-4-hydroxy-phenyl)-ethanone as a black solid (2.5 g, crude), which was used in the next step directly without further purification. 1H-NMR (DMSO-d6, 400 MHz): δ 7.01 (d, J=8.0 Hz, 1H), 6.48 (d, J=12.4 Hz, 1H), 2.39 (d, J=4.8 Hz, 3H).
Reaction SMILES: CS(O[CH:6]([C:19]1[CH:20]=[N:21][C:22]([NH:51][C:52]2[CH:53]=[N:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)=[C:23]([C:25]2[N:30]=[C:29]([N:31]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[N:28]=[C:27]([CH3:50])[N:26]=2)[CH:24]=1)[C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)(=O)=O.[NH3:60]>C(Cl)Cl.O1CCOCC1>[NH2:60][CH:6]([C:19]1[CH:20]=[N:21][C:22]([NH:51][C:52]2[CH:53]=[N:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)=[C:23]([C:25]2[N:30]=[C:29]([N:31]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)[CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[N:28]=[C:27]([CH3:50])[N:26]=2)[CH:24]=1)[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:14]([CH3:15])[CH3:16])(=[O:18])=[O:17])=[CH:9][CH:8]=1
Reactant: N
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(OS(C)(=O)=O)c4ccc(S(=O)(=O)N(C)C)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(N)c4ccc(S(=O)(=O)N(C)C)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(4-(N,N-dimethylsulfamoyl)phenyl)methyl methanesulfonate (14.22 mg, 0.017 mmol) in DCM (0.1 mL) was treated with 0.5 M NH3 in dioxane (2 mL). The mixture was allowed to stand overnight, after which time partial conversion to the amine was observed by LCMS. The mixture was then sealed and heated and 80° C. for 2 h, after which time the starting material was consumed. The mixture was concentrated and taken on directly to the next step.
Reaction SMILES: [C:1]([N:4]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18](Cl)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:1]([N:4]1[C:11]2[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[N:17]=[C:18]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[C:19]([F:21])=[CH:20][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccc(Cl)cc21
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2cc(Cl)ccc2C=C3)cn1

Procedure:
The title compound was prepared from 6D and 2A by a route analogous to that used for the preparation of 2B. HPLC Rt=3.412 min; LCMS Found: (M+H)+=410.
Reaction SMILES: BrC[CH:3]1[CH:12]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:5]([C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4]1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[C:26](=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[C:7]1([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:6]2[CH:5]3[CH2:4][CH2:3][CH:12]([C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CN1CCNCC1
Reactant: BrCC1CC2c3ccccc3C1c1ccccc12
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1CCN(Cc2cccc3c2C2CCC3c3ccccc32)CC1
Temperature: 90 °C

Procedure:
11-Bromomethyl-9,10-dihydro-9,10-ethanoanthracene (0.51 gm), 1-methylpiperazine (1.9 ml) and potassium carbonate (0.20 gm) were combined in hexamethylphosphoramide (5 ml) in a sealed tube and heated to 90° C. for 48 hours. The mixture was extracted between water (25 ml) and ether (50 ml). The ether solution was washed with water (25 ml), then extracted with 3.6 N sulfuric acid (3×25 ml). The combined acid solutions were made basic with the addition of concentrated aqueous ammonia and the resulting mixture was extracted with ether (3×25 ml). The combined ether solutions were dried over magnesium sulfate and the ether removed on a rotary evaporator. The residue was dissolved in anhydrous ether (15 ml) and treated with 3.5% hydrochloric acid in isopropyl alcohol (0.79 ml). The resulting precipitate was filtered, washed with ether (25 ml), and air dried to give the product as a white solid. Analytical data are reported in Table I.
Reaction SMILES: [OH-].C[N+](C)(C)C.C[Si](OCC)(OCC)[O:9][CH2:10]C.CS(C(C)O[Si]([C:29]1[CH:34]=[CH:33]C=CC=1)(OC)OC)(=O)=O.Cl.[C:37]([O:40]CC)(=[O:39])[CH3:38]>O.CC(C)=O>[C:37]([O:40][CH:34]([CH3:29])[CH2:33][O:9][CH3:10])(=[O:39])[CH3:38]
Reactant: CCO[Si](C)(OCC)OCC
Reactant: CO[Si](OC)(OC(C)S(C)(=O)=O)c1ccccc1
Reactant: CCOC(C)=O
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COCC(C)OC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 200 mL flask equipped with a stirrer, a thermometer, and a condenser tube, 4.07 g of a 35% by weight tetramethylammonium hydroxide aqueous solution and 28.94 g of acetone were charged to prepare a reaction solvent. A mixture solution of 6.02 g (70 mol % in all silanes) of methyl triethoxysilane, 4.18 g (30 mol % in all silanes) of methylsulfonyl methylphenyl trimethoxysilane, and 4.18 g of acetone was prepared. While the reaction solvent was stirred with a magnetic stirrer, the mixture solution was added dropwise into the reaction solvent at room temperature. After the completion of the addition, while maintaining the temperature of the resultant reaction mixture at 40° C. using an oil bath, the reaction was progressed for 240 minutes and then the reaction mixture was cooled down to room temperature, followed by adding 2 mol % hydrochloric acid to the reaction mixture to neutralize the reaction mixture. To the reaction liquid, 70 mL of ethyl acetate and 70 mL of water were added and the resultant reaction mixture was shaken, followed by subjecting the reaction mixture to phase separation into two phases. Further, the organic phase was washed with 70 mL of water three times. To the resultant organic phase, 12 g of propylene glycol monomethyl ether acetate was added and from the organic phase, methanol and ethanol as reaction by-products and water were distilled off under reduced pressure. The resultant reaction mixture was concentrated to obtain a hydrolysis-condensation product (polymer) propylene glycol monomethyl ether acetate solution. To the obtained solution, propylene glycol monoethyl ether was added to adjust the resultant solution to contain a solid residue in a proportion of 20% by weight at 160° C. The obtained polymer (corresponding to Formula (F-4)) had a weight-average molecular weight measured by GPC of Mw 6,200 in terms of polystyrene.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>O1CCCC1>[F:12][C:2]([F:1])([F:13])[C:3]1[C:8]([C:9]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])=[O:11])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: NC(CO)CO
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C(NC(CO)CO)c1cnccc1C(F)(F)F
Reaction time: 4 h

Procedure:
3.9 g (20 mmol) of 4-trifluoromethylnicotinic acid and 3.2 g (20 mmol) of carbonyl diimidazole in 100 ml of dry tetrahydrofuran were stirred at 40-50° C. for 6 hours. After cooling, 1.8 g (20 mmol) of serinol were added, and stirring was continued at 50-60° C. for another 4 hours. The crude product obtained after removal of the solvent under reduced pressure was purified by silica gel chromatography. This gave 2.9 g of product (55.3% of theory) of melting point 155-156° C.
Reaction SMILES: C[Mg]Br.[CH:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([CH3:16])=[CH:12]2)([CH3:6])[CH3:5].[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].[NH4+].[Cl-]>CCOCC.C1COCC1>[CH:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([CH3:16])=[C:12]2[C:20]([C:19]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:18]=1[Cl:17])=[O:21])([CH3:6])[CH3:5]
Reactant: Cc1cc2cccc(C(C)C)c2[nH]1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1[nH]c2c(C(C)C)cccc2c1C(=O)c1cccc(Cl)c1Cl
Temperature: -30 °C
Reaction time: 1 h

Procedure:
120 ml of anhydrous THF are cooled to −5° C. and 36 ml of 3M methylmagnesium bromide in ether are added. The mixture is cooled to −30° C. and then 15 g of 7-isopropyl-2-methyl-1H-indole are added dropwise. The mixture is left stirring for 1 hour between −20° C. and −30° C. and then 30.9 g of 2,3-dichlorobenzoyl chloride, dissolved in 120 ml of THF, are added dropwise. The medium is left to return to AT and is then poured onto 300 ml of a saturated NH4Cl solution. Separation is carried out by settling, the organic layer is evaporated and then the residue is taken up in DCM. The organic phase is washed with a saturated NaCl solution and then it is dried and evaporated. The residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (3/7, v/v) mixture.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=4[O:32][CH3:33])[C:16]=3[CH:15]=[CH:14]2)[CH2:4]1.[Cl:34][C:35]1[C:36]([C:51]([F:54])([F:53])[F:52])=[CH:37][C:38]2[N:42]=[C:41]([CH2:43][CH2:44][CH:45]3[CH2:48][C:47](=O)[CH2:46]3)[NH:40][C:39]=2[CH:50]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:34][C:35]1[C:36]([C:51]([F:54])([F:52])[F:53])=[CH:37][C:38]2[N:42]=[C:41]([CH2:43][CH2:44][CH:45]3[CH2:46][CH:47]([NH:1][CH2:2][C@@H:3]4[C@H:7]5[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]5[C@H:5]([N:13]5[C:17]6[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]7[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=7[O:32][CH3:33])[C:16]=6[CH:15]=[CH:14]5)[CH2:4]4)[CH2:48]3)[NH:40][C:39]=2[CH:50]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: O=C1CC(CCc2nc3cc(C(F)(F)F)c(Cl)cc3[nH]2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CNC3CC(CCc4nc5cc(C(F)(F)F)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A solution of 7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80 mg, 0.18 mmol) and 3-(2-(6-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutanone (45 mg, 0.14 mmol) in 1,2-dichloroethane (2.4 mL) was treated dropwise with acetic acid (10 uL, 0.18 mmol). The solution was treated with sodium triacetoxyborohydride (53 mg, 0.25 mmol) in one portion and allowed to stir at room temperature till complete by HPLC. After 4 h, the reaction mixture was diluted with 10 mL CH2Cl2 and washed with 10 mL sat NaHCO3. The aqueous phase was washed with 10 mL CH2Cl2 and the combined organic phase was dried over Na2SO4. The solution was filtered and concentrated to yield a light tan glass/stiff foam. The crude material was purified by flash chromatography (25 g silica gel; 5% 7N NH3 in CH3OH/CHCl3) to yield the title compound (76 mg, 71%) as a colorless glass/stiff foam: MS (ESI+) for C38H43ClF3N7O4 m/z 754.3 (M+H)+; MS (ESI−) for C38H43ClF3N7O4 m/z 752.3 (M−H)−; HPLC purity 90.5% (ret. time, 3.24 min).
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[CH2:8][CH:7](O)[C:6]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:16]([C:3]1([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:17]
Reactant: CCC1(CC)CC(O)c2cc(C#N)ccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCC1(CC)C=Cc2cc(C#N)ccc2O1
Yield: 69.9 %

Procedure:
A mixture of 2,2-diethyl-3,4-dihydro-4-hydroxy-2H-1-benzopyran-6-carbonitrile (2.28 g) and p-toluenesulfonic acid hydrate (0.19 g) in toluene was refluxed for an hour and 20 minutes with azeotropic removal of the formed water. The reaction mixture was diluted with ethyl acetate, and then washed with water and brine successively. The extract was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified with silica gel column chromatography using a mixture of methylene chloride and n-hexane (1:5) as an eluent to give 2,2-diethyl-2H-1-benzopyran-6-carbonitrile (1.47 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:25])[CH2:16]P(OCC)(OCC)=O)[CH3:13].[H-].[Na+].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:16][C:15]([O:14][CH2:12][CH3:13])=[O:25])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
To a solution of 3-nitrobenzaldehyde (49 g, 295 mmol) and (diethoxy-phosphoryl)-acetic acid ethyl ester (72.74 g, 325 mmol) in DMF (300 ml) at 0° C. was added NaH (14.2 g, 354 mmol) portionwise and stirred for 1.5 hrs at r.t. The reaction mixture was poured into water to give colorless crystals, which were collected by filtration and washed with water and hexane to give the product ethyl 3-(3-nitrophenyl)acrylate (63 g, yield 96.6%). 1H NMR MeOD 400 MHz. δ 8.42-7.62 (m, 4H), 7.74-7.70 (d, 1H), 6.68-6.64 (d, 1H), 4.28-4.22 (m, 2H), 1.34-1.30 (m, 3H).
Reaction SMILES: O[CH2:2][CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:18][CH2:2][CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(=CCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=CCBr)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 15.292 g (67.277 mM) of tert-butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate and 24.5 g (74.0 mM) of carbon tetrabromide in 150 ml of acetonitrile was added 19.4 g (74.0 mM) of triphenylphosphine at −78° C. Then, at room temperature, the mixture was stirred for 2 hours. This reaction mixture was distilled under reduced pressure to remove the solvent. To the residue was added diethyl ether, followed by stirring, and the resulting precipitate was filtered off and washed with diethyl ether. The filtrate and washes were pooled and the solvent was distilled under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1 to 9/1) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:12]([N:14](CC)CC)C.ClC(OC(Cl)(Cl)Cl)=O.CN>ClCCl.CCO>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:14][CH3:12])=[O:5]
Reactant: CCN(CC)CC
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: CN
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: CNC(=O)c1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-amino-5-bromonicotinic acid (Combi-Blocks, San Diego, USA, 1.355 mmol) and triethylamine (0.378 ml) in dichloromethane (10 ml) cooled with an ice-bath was added a solution of trichloromethyl chloroformate (Acros, Basel, Switzerland, 0.677 mmol) in dichloromethane (10 ml). After 40 min stirring at 0° C., was added a solution 8 M of methylamine in EtOH (1.7 ml). The RM was stirred for 30 min at rt then was diluted with dichloromethane, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in DMF and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a white solid. (HPLC: tR 1.69 min (Method A); M+H=230, 232 MS-ES)
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:5]([CH3:16])=[CH:4][CH:3]=1.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:7]([C:8]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]2[CH2:24][NH:25][C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)=[O:10])=[C:6]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:5]([CH3:16])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: Cc1ccc(F)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described in Example A318, using 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-chloro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 477 (M+H).
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[OH:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[C:6]([CH3:7])=[C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:18]#[N:19])[C:3]([CH3:17])=[N:4]2)=[CH:9][CH:10]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Product: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1cccc(C#N)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 3-cyanobenzeneboronic acid: MS (EI) m/z 317 [M]+, 1H-NMR (CDCl3) δ 7.63-7.34 (8H, m), 3.92 (2H, t, J=6.6 Hz), 2.94 (2H, t, J=6.6 Hz), 2.32 (3H, s), 2.29 (3H, s).
Reaction SMILES: [H-].[Na+].OC1C=C([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)C=CC=1.Br[CH:19]1[CH2:22][CH2:21][CH2:20]1.CN([CH:26]=[O:27])C>>[CH:19]1([O:27][C:26]2[CH:11]=[C:12]([C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[CH2:11][NH2:10])[CH:17]=[CH:16][CH:15]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: BrC1CCC1
Reactant: Oc1cccc(NCc2cccnc2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: NCc1cnccc1-c1cccc(OC2CCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.072 g, 1.8 mmol) was suspended in DMF at 0° C. To the dispersion was added dropwise N-(3-hydroxyphenyl)pyrid-3-ylmethylamine (0.250 g, 1.24 mmol) as a solution in DMF. The reaction mixture was stirred at room temperature for 30 min. Then bromocyclobutane (0.25 g, 1.84 mmol) was added as a solution in DMF. The reaction was concentrated and the residue was diluted with water, extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica-gel chromatography to give N-(4-(3-Cyclobutyloxyphenyl)pyrid-3-ylmethylamine. 1H NMR:, 8.61 (d,1H,J=2.3 Hz), 8.51 (q,1H,J=1.6, 3.13), 7.68 (m,1H), 7.25 (m,1H), 7.04 (t,1H,1.7 Hz), 6.18-6.24 (m,2H), 6.09 (t,1H,J=2.3 Hz), 4.6 (quint,1H,J=6.7 Hz), 2.33-2.42 (m,2H,), 2.06-2.18 (m,2H), 1.76-1.88 (m,1H), 1.57-1.70 (m,1H). MS calcd. 254.1; MS (M+1) 255.1.
Reaction SMILES: O=[C:2]1[C@@H:7]2[CH2:8][C@@H:4]([CH2:5][N:6]2[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:3]1.[NH2:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[O-]S([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.C(Cl)Cl>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([N:6]2[CH2:5][C@H:4]3[CH2:8][C@@H:7]2[C@@H:2]([NH:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:3]3)=[CH:10][CH:11]=1)#[N:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Reactant: N#Cc1ccc(N2C[C@H]3CC(=O)[C@@H]2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N[C@H]1C[C@@H]2C[C@H]1N(c1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a round bottom flask under argon was added 4-((1S,4R)-6-oxo-2-azabicyclo[2.2.1]heptan-2-yl)benzonitrile (272 mg, 1.282 mmol), tert-butyl (1R,2R)-2-aminocyclohexylcarbamate (330 mg, 1.538 mmol), CH2Cl2 (6.4 ml), solid anhydrous Na2SO4 (1 gm) and HOAc (1 drop). Argon was bubbled through the reaction mixture for 1 min and then the reaction was stirred under argon at rt for 1 hr. After this time, sodium triacetoxy borohydride (815 mg, 3.84 mmol) was added to the reaction which was then stirred at rt overnight. The reaction mixture was then diluted with CH2Cl2. The resulting solution was wash with saturated aqueous NaHCO3, water and saturated aqueous NaCl. The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex. The fractions containing the desired product were concentrated to give tert-butyl (1R,2R)-2-((1R,4R,6S)-2-(4-cyanophenyl)-2-azabicyclo[2.2.1]heptan-6-ylamino)cyclohexylcarbamate (466 mg, 1.135 mmol, 89% yield). Anal. Calcd. for C24H34N4O2 m/z 410.5, found: 411.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.45 (2 H, d, J=8.8 Hz), 6.55 (2 H, d, J=8.8 Hz), 4.26 (1 H, s), 3.65 (1 H, br. s.), 3.47-3.41 (1 H, m), 3.30 (1 H, dt, J=8.8, 3.0 Hz), 3.15 (1 H, d, J=8.8 Hz), 2.98 (1 H, d, J=8.2 Hz), 2.64 (1 H, s), 2.29-2.19 (2 H, m), 2.10-2.02 (1 H, m), 2.01-1.93 (1 H, m), 1.74-1.59 (4 H, m), 1.45-1.37 (1 H, m), 1.35 (9 H, s), 1.30-1.18 (2 H, m), 1.09- -0.93 (2 H, m), 0.90 (1 H, ddd, J=12.9, 3.8, 3.6 Hz).
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[Cl:18][C:19]1[N:24]=[C:23]([C:25](=O)[CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][CH:20]=1>C(O)C>[Cl:18][C:19]1[N:24]=[C:23]([C:25]2[C:26]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[CH:29][CH:28]=3)=[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]3[N:2]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: N[n+]1ccccc1
Reactant: O=C(Cc1ccnc2ccccc12)c1cccc(Cl)n1
Agent: [I-]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Temperature: 110 °C
Yield: 18.8 %

Procedure:
Add 1-aminopyridinium iodide (780 mg, 3.53 mmol), N,N-diisopropylethylamine (0.62 mL, 3.53 mmol), 1-(6-chloro-pyridin-2-yl)-2-quinolin-4-yl-ethanone (500 mg, 1.77 mmol), and ethanol (8 mL) to a sealed tube apparatus. The sealed vessel is heated at 110° C. for 5 hours. After cooling, the crude is concentrated in vacuo. Purification by flash column chromatography (Silica Gel, 25-40% acetone/hexanes) provides the title compound 119 mg (19%) as an orange solid.