Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:9]=2[CH3:26])[CH:5]=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:12]([CH3:13])[N:11]=[C:10]([C:14]([N:16]4[CH2:20][CH2:19][CH:18]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH2:17]4)=[O:15])[C:9]=3[CH3:26])[CH:3]=2)[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(-c4ccc(Cl)c(Cl)c4)c3)c2C)C1
Yield: 55 %

Procedure:
In analogy to the procedure described in example 14C], [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and 3,4-dichlorophenylboronic acid gave [5-(3′,4′-dichloro-biphenyl-3-yl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone in 55% yield as light brown foam. MS: 485.2 (MH+, 2 Cl).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].[H][H]>[Ni]>[CH2:20]([OH:21])[CH2:19][CH:17]([CH2:16][CH2:15][CH2:14][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[CH3:13])[CH3:18]
Reactant: [H][H]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Ni]
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO

Procedure:
Hydrogenation of phytol can also be accomplished using Raney nickel and hydrogen to yield phytanol as referenced in Bendavid, A., Burns, C. J., Leslie, D. F., Hashimoto, K., Ridley, D. D., Sandanayake, S., and Wieczorek L., J. Org. Chem. (2001), 66, 3709-3716; Kim, T., Chan, K. C, and Crooks, R. M., J. Am. Chem. Soc. (1997) 119, 189; and Jellum, E., Eldjarn, L., and Try, K., Acta Chem. Scand. (1966), 20, 2335.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:7]([CH2:8][Cl:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OCc1cccnc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: ClCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a solution of the compound (18.5 g) obtained in step 1 in a mixture of chloroform (95 mL) and DMF (0.63 mL) was added thionyl chloride (14.0 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was poured into a mixture of water and ethyl acetate. The solution was neutralized with sodium hydrogen carbonate, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine, and concentrated to give 2-chloro-3-(chloromethyl)pyridine (20.5 g, 89%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:21]([CH2:30]Cl)=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[O:40]([NH2:42])[CH3:41]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:21]([CH2:30][NH:42][O:40][CH3:41])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc(CCl)n2CC1CCOCC1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CONCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Temperature: 50 °C
Reaction time: 40 h
Yield: 36.1 %

Procedure:
7-(Benzyloxy)-2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.3 g, 5.26 mmol) and triethylamine (1.6 g, 15.78 mmol) were added to a solution of methoxylamine hydrochloride (0.88 g, 10.52 mmol) in N,N-dimethylformamide (DMF) (11 mL). The reaction was heated with stirring for 40 hours at 50° C., allowed to cool to ambient temperature, and partitioned between dichloromethane (50 mL) and water (50 mL). The aqueous layer was extracted with another portion of dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography using a HORIZON HPFC system equipped with a FLASH 40+M silica cartridge eluting with dichloromethane:methanol in a gradient from 100:0 to 90:10. The resulting product (1.0 g) was recrystallized from acetonitrile, and the crystals were isolated by filtration, washed with acetonitrile, and dried overnight in a vacuum oven at 65° C. to provide 0.85 g of 7-(benzyloxy)-2-[(methoxyamino)methyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a yellow, crystalline solid, mp 190-193° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[F:12].ClC1C=C2C(C=C[N+]([O-:24])=C2)=CC=1F>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-:24])=[CH:9]2)=[CH:4][C:3]=1[F:12]
Reactant: Fc1cc2ccncc2cc1Br
Reactant: [O-][n+]1ccc2cc(F)c(Cl)cc2c1
Product: [O-][n+]1ccc2cc(F)c(Br)cc2c1

Procedure:
Starting from 7-bromo-6-fluoro-isoquinoline (15), the title compound was prepared following the method described for 7-chloro-6-fluoro-isoquinoline 2-oxide (5). Rt=0.93 min (Method C). Detected mass: 242.2/244.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][CH:3]=1.Cl.Cl.[CH2:23]([O:25][C:26]([C@H:28]1[C@H:33]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:35])[CH2:32][CH2:31][NH:30][CH2:29]1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:23]([O:25][C:26]([C@H:28]1[C@H:33]([N:34]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:35])[CH2:32][CH2:31][N:30]([CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:29]1)=[O:27])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Reactant: CCOC(=O)[C@@H]1CNCC[C@H]1N(C)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CN(CCc2ccc(F)cc2)CC[C@H]1N(C)Cc1ccccc1
Yield: 65.3 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(4-fluorophenyl)-ethyl ester (containing 10% by weight of 2-(4-fluorophenyl)ethanol; 206 mg, 630 μmol), trans-4-(benzyl-methyl-amino)-piperidine-3-carboxylic acid ethyl ester dihydrochloride (220 mg, 630 μmol) and potassium carbonate (261 mg, 1.9 mmol) in acetonitrile (6 mL) was heated at reflux for 17 hours. The mixture was cooled and filtered, the solid was washed with acetonitrile, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 20%, then 30% ethyl acetate in hexane, to provide an oil (164 mg, 65%). 1H NMR (300 MHz, CDCl3) δ7.28 (m, 5H), 7.16 (m, 2H), 6.98 (t, J=9 Hz, 2H), 4.20 (m, 2H), 3.75 (d, J=13 Hz, 1H), 3.48 (d, J=13 Hz, 1H), 3.14 (m, 2H), 2.88 (m, 2H), 2.80 (m, 2H), 2.62 (m, 2H), 2.29 (m, 1H), 2.20 (s, 3H), 1.87 (m, 1H), 1.70 (m, 2H), 1.28 (t, J=7 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)[C:5]=2[CH3:24])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([O:36][CH:37]([F:39])[F:38])=[CH:31][C:30]=1[F:40].O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH2:28][C:29]3[C:30]([F:40])=[CH:31][C:32]([O:36][CH:37]([F:38])[F:39])=[CH:33][C:34]=3[F:35])[N:7]=[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)[C:5]=2[CH3:24])[CH2:3][CH2:2]1
Reactant: COc1cnc(-c2n[nH]c(C3CC3)c2C)nc1Nc1ccncc1
Reactant: Fc1cc(OC(F)F)cc(F)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cnc(-c2nn(Cc3c(F)cc(OC(F)F)cc3F)c(C3CC3)c2C)nc1Nc1ccncc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
70 mg 2-(5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine 1-16-1 (0-217 mmol, 1.0 eq) were dissolved in 0.52 mL THF and cooled to 0° C. 10.4 mg sodiumhydride (60%, 0.261 mmol, 1.2 eq) were added. The mixture stirred for 5 minutes, then the ice bath was removed and 65.2 mg 2-(bromomethyl)-5-(difluoromethoxy)-1,3-difluorobenzene (0.239 mmol, 1.1 eq) were added. The reaction stirred at rt for 4 days. Again 5 mg sodiumhydride (60%, 0.130 mmol, 0.6 eq) and 33 mg 2-(bromomethyl)-5-(difluoromethoxy)-1,3-difluorobenzene (0.120 mmol, 0.55 eq) were added. The reaction stirred at rt for 2 hours. Water was added and the aqueous layer was extracted by ethylacetate twice. The collected organic layers were washed with brine, dried with a silicon filter and concentrated in vacuo The crude product was purified by flashcromatography and HPLC to provide 10 mg (0.02 mmol, 8%) of the analytically pure target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27]([OH:29])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@H:10]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic acid (Example 41) (500 mg, 1.156 mmol) in 10% MeOH in DCM (10 mL) was added (trimethylsilyl)diazomethane (2.0 M in diethyl ether) (1 mL). The yellow colored reaction mixture was stirred at room temperature for 30 min. The reaction was concentrated under reduced pressure and was purified by flash chromatography on silica gel (eluent: 0 to 50% EtOAc in hexanes) to give the title compound as a clear oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:17]=[CH:16][O:15][CH:14]=1)[OH:6].[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1.O>C1COCC1>[Cl:20][C:21]1[CH:26]=[C:25]([O:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:17]=[CH:16][O:15][CH:14]=2)[C:4]([F:3])([F:18])[F:19])[N:24]=[CH:23][N:22]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OC(c1ccccc1-c1ccoc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1-c1ccoc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
Sixty percent NaH (12 mg, 0.3 mmol) was added to a solution of 2,2,2-trifluoro-1-(2-furan-3-yl-phenyl)-ethanol (54 mg, 0.2 mmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, after which 4,6-dichloro-pyrimidine (30 mg, 0.2 mmol) was added. The mixture was then heated at 70° C. until the reaction was complete. After cooling, 5 ml of water was added to quench the reaction, and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give of 67 mg 4-chloro-6-[2,2,2-trifluoro-1-(2-furan-3-yl-phenyl)-ethoxy]-pyrimidine (yield: 94%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:28][C:29]1[C:30]([Cl:44])=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][C:40]([OH:42])=O)[C:33]=2[CH:43]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:28][C:29]1[C:30]([Cl:44])=[CH:31][C:32]2[O:37][CH2:36][C:35](=[O:38])[N:34]([CH2:39][C:40]([N:2]([CH3:1])[C@H:3]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:42])[C:33]=2[CH:43]=1
Reactant: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Reactant: CCOC(=O)c1ccc(-c2ccc([C@H](CN3CCOCC3)NC)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc([C@H](CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Temperature: 0 °C
Yield: 69.5 %

Procedure:
Ethyl 4′-[(1R)-1-(methylamino)-2-(4-morpholinyl)ethyl]-4-biphenylcarboxylate (crude, 26.5 g) was dissolved in 500 mL of DMF at room temperature with magnetic stirring. The resulting solution was treated with (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (28.8 g, 80.4 mmol, with 23 wt % LiCl) and cooled to 0° C. To this solution was added triethylamine (20.5 mL, 147.4 mmol) and BOP (35.5 g, 80.4 mmol). The reaction mixture was maintained at room temperature overnight. The reaction mixture was filtered. The filtrate was slowly added to 2500 mL of H2O with vigorous stirring. The resulting precipitate was collected by filtration and partitioned between 300 mL of brine solution and 1000 mL of DCM. The organic layer was dried over MgSO4, filtered, and concentrated. The brown residue was purified by column chromatography (250 g silica gel 60, 230-400 mesh, 2% MeOH and 0.5% NEt3 in CH2Cl2 as eluent) to give the title compound as a brown solid (31.3 g, 75% yield). MS (ES) m/e 626 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=[CH:12][C:3]1=2.O.NN>[Pd].C(O)C>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:3]1=2
Reactant: CN1CCCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1CCCCc2cc(N)ccc21
Temperature: 60 °C
Yield: 94.6 %

Procedure:
1-Methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (135 mg, 0.66 mmol) in a solution of ethanol (4 mL) and hydrazine hydrate (1 mL) was treated with 10% palladium on carbon (40 mg) and heated at 60° C. for 2 h. The mixture was cooled to room temperature, filtered and concentrated to give 1-Methyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (110 mgs, 96%) as a grayish oil. 1H-NMR (CDCl3) δ 6.78-6.72 (m, 1H), 6.51 (s, 2H), 3.38 (br s, 2H), 2.82-2.74 (m, 7H), 2.21-2.15 (m, 2H), 1.75-1.68 (m, 2H), 1.57-1.52 (m, 2H); LC/MS (ESI+): 177.16 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([OH:17])[C:9]=2[C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:17][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[C:2]([CH3:1])[N:3]2[CH2:18][CH2:19][CH3:20])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(-c2ccncc2)c2c(O)cccc21
Product: CCCn1c(C)c(-c2ccncc2)c2c(OC(C)(C)C(=O)OCC)cccc21

Procedure:
The above compound was prepared from 2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-4-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:44]=[CH:43][C:8]([CH2:9][N:10]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:11](=[O:34])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:32])([F:31])[F:30])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[NH:4].CCN(C(C)C)C(C)C.[CH3:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][C:64]([C:67](Cl)=O)=[CH:63][CH:62]=2)=[CH:57][CH:56]=1>O1CCOCC1.C([O-])(O)=O.[Na+]>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]([N:10]([CH2:35][C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]4[N:4]=[C:54]([C:55]5[CH:60]=[CH:59][C:58]([C:61]6[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=6)=[CH:57][CH:56]=5)[O:1][N:2]=4)=[CH:44][CH:43]=3)=[O:34])=[CH:13][CH:14]=2)=[O:33])=[C:22]([C:29]([F:31])([F:30])[F:32])[CH:23]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=N)NO)cc3)cc2)c(C(F)(F)F)c1
Reactant: Cc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Prepared using General Procedure 20: To a stirring solution of tert-butyl 2-(N-(4-(N-hydroxycarbamimidoyl)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-33 (104 mg, 0.169 mmol) and DIEA (47.0 μL, 0.254 mmol) in dioxane (4 mL) was added 4′-methyl-[1,1′-biphenyl]-4-carbonyl chloride (39.0 mg, 0.169 mmol) in dioxane (1 mL). After stirring at room temperature for 30 min, the reaction mixture was heated to 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature then diluted with NaHCO3 (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (EA/isohexanes) to yield 54 mg (40%) of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-34. LCMS-ESI (m/z) calculated for C45H41F3N4O6: 791; no m/z observed, tR=1.70 min (Method 10).
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH2:10]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([O:17]C1C=CC(C(=O)C)=CC=1)([CH3:16])[CH3:15]>CCOC(C)=O>[CH:14]([O:17][C:4]1[CH:3]=[CH:2][C:1]([C:7](=[O:13])[CH2:8][C:9](=[O:12])[CH3:10])=[CH:6][CH:5]=1)([CH3:16])[CH3:15]
Reactant: CC(=O)c1ccc(OC(C)C)cc1
Reactant: CCC(=O)CC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)c1ccc(OC(C)C)cc1

Procedure:
The title compound was prepared (as described above for Intermediate 16) from 2.42 g of 4′-isopropoxyacetophenone and 2.65 mL of EtOAc to yield 2.25 grams of Intermediate 29: TLC analysis: Rf=0.73 (2/1, hexanes/EtOAc); 1H NMR (400 MHz, CDCl3, enol form) δ7.84 (d, 2H, J=8.9), 6.9 (d, 2H, J=9.0), 6.1 (s, 1H), 4.62 (hept, 1H, J=6.0), 2.16 (s, 3H), 1.36 (d, 6H, J=6.0).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)OC(=O)c2ccccc2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Benzoyl chloride (0.295 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 17 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.308 g, 91%). 1H NMR (Acetone d6, 400 MHz) δ 8.21-8.14 (m, 2 H), 8.03 (d, J=9 Hz, 2 H), 7.96 (d, J=9 Hz, 1 H), 7.81 (t, J=8 Hz, 1 H), 7.65-7.59 (m, 2 H), 7.55-7.49 (m, 2 H), 7.01 (d, J=9 Hz, 1 H), 5.94-5.85 (m, 1 H), 5.64 (dd, J=9 and 6 Hz, 1H), 5.48 (dd, J=5 and 8 Hz, 1H), 2.34 (s, 3 H), 1.62 (d, J=6 Hz, 3 H).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([Cl:30])=[N:28][CH:29]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CO>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:23][C:24]3[CH:25]=[C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([Cl:30])=[N:28][CH:29]=3)=[N:3][CH:4]=[C:5]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:6]=2)[N:9]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 77.3 %

Procedure:
To a stirred solution of 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.0602 g, 0.198 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330, step 2, 0.0494 g, 0.223 mmol) in DMF (1 mL) in a 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 0.80 mL, 0.80 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 45 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (20 mL). The aq phase was acidified to a pH of about 3 to 4 then extracted with 25% isopropanol in chloroform (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown residue. Upon addition of MeOH to the residue, a tan precipitate came out. The solid was collected via filtration and washed with MeOH to afford N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-(morpholinomethyl)pyridin-2-ylamino)-2-chloropyridin-3-yl)methanesulfonamide (0.0774 g, 77% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.26 (s, 1H) 9.66 (br. s., 1H) 8.76 (s, 1H) 8.67 (t, J=2.45 Hz, 2H) 8.31 (d, J=1.56 Hz, 1H) 7.74-8.01 (m, 2H) 3.43-3.66 (m, 6H) 3.14 (s, 3H) 2.38-2.48 (m, 7H). m/z (ESI, pos. ion): 505.9 (M+H)+.
Reaction SMILES: [Br:1]Br.[CH2:3]([N:5]([CH2:12][CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:4]>C(O)(=O)C>[CH2:12]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([Br:1])=[CH:8][CH:7]=1)[CH2:3][CH3:4])[CH3:13]
Reactant: CCN(CC)c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
93 g of bromine were added dropwise to a solution of 86 g of N,N-diethylaniline in 400 ml of acetic acid and the mixture was poured into an ice-water mixture. The mixture was extracted with methylene chloride and the organic phase was washed with aqueous sodium bicarbonate solution, dried and evaporated to dryness to obtain 125 g of 4-(N,N-diethylamino)-bromobenzene boiling at 97° C. at 0.6 mm Hg.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>O1CCCC1>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:13](=[O:14])[CH2:12][C:11](=[O:15])[CH3:10])[CH2:6][CH2:5]1
Reactant: OCCN1CCNCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCN(CCO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A solution of 32.5 g (0.25 mol) 1-(2-hydroxyethyl)piperazine in 100 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml of tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 36.10 g (0.17 mol, 71% yield) of a colorless oil.