Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH3:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:18].[K+].[Mn]([O-])(=O)(=O)=O.[OH2:28]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC>[C:1]1([N:7]2[C:11]([C:12]([OH:18])=[O:28])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(C(F)(F)F)nn1-c1ccccc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 95 °C
Reaction time: 0.13 h

Procedure:
A sample of crude 1-phenyl-3-(trifluoromethyl)-5-methylpyrazole (˜89%, 50.0 g, 0.221 mole) was mixed with water (400 mL) and cetyltrimethylammonium chloride (4.00 g, 0.011 mole). The mixture was heated to 95° C. Potassium permanganate was added in 10 equal portions, spaced at ˜8 minute intervals. The reaction mass was maintained at 95-100° C. during this period. After the last portion was added, the mixture was held for 15 minutes at 95-100° C., whereupon the purple, permanganate color had been discharged. The reaction mass was filtered while hot (˜75° C.) through a 1 cm thick bed of Celite® on a 150 ml, coarse, glass frit. The filter cake was washed with warm (˜50° C.) water (3×100 mL). The combined filtrate and washings were extracted with ether (2×100 mL) to remove a small amount of yellow, water-insoluble material. The aqueous layer was purged with nitrogen to remove residual ether. The clear, colorless alkaline solution was acidified by adding concentrated hydrochloric acid dropwise until the pH reached ˜1.3 (28 g, 0.28 mole). Gas evolution was vigorous during the first two-thirds of the addition. The product was collected via filtration, washed with water (3×40 mL), then dried overnight at 55° C. in vacuo. The product consisted of 11.7 g of a white, crystalline powder, which was essentially pure based upon 1H NMR.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:19][CH2:18][C:17](=O)[CH2:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([NH2:31])[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33]>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([NH:31][CH:17]2[CH2:18][CH2:19][C@H:15]([C:12]3[CH:13]=[CH:14][C:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])=[CH:10][CH:11]=3)[CH2:16]2)[CH3:30])=[CH:25][C:24]=1[O:32][CH3:33]
Reactant: O=C1CC[C@H](c2ccc(C(=O)N3CCOCC3)cc2)C1
Reactant: COc1cc([C@@H](C)N)ccc1F
Agent: Cl
Product: COc1cc([C@@H](C)NC2CC[C@H](c3ccc(C(=O)N4CCOCC4)cc3)C2)ccc1F

Procedure:
General procedure B was followed using (3S)-3-[4-(Morpholine-4-carbonyl)phenyl]-cyclopentanone (preparation 15) as the ketone and (1R)-1-(4-fluoro-3-methoxyphenyl)ethylamine hydrochloride as the amine. 1H NMR (600 MHz, DMSO) δ 7.30-7.27 (m, 2H), 7.23 (d, J=8.2 Hz, 2H), 7.16 (dd, J=8.6, 1.9 Hz, 1H), 7.10 (dd, J=11.5, 8.2 Hz, 1H), 6.89 (ddd, J=8.1, 4.4, 1.9 Hz, 1H), 3.82 (s, 3H), 3.73 (q, J=6.4 Hz, 1H), 3.57 (m, 4H), 3.32 (m, 4H), 3.27-3.19 (m, 1H), 3.06-3.00 (m, 1H), 2.11-1.90 (m, 2H), 1.78-1.72 (m, 1H), 1.65-1.57 (m, 1H), 1.53-1.41 (m, 2H), 1.24 (d, J=6.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.[CH3:28][N:29]1[C@@H:33]2[CH2:34][C@H:35]([OH:37])[CH2:36][C@H:30]1[CH2:31][CH2:32]2.BrC1C=C(CO)C=C2C=1CN(CC1C=CC(OC)=CC=1)C(=O)N2C1C(Cl)=CC=CC=1Cl.[H-].[Na+]>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:4]1[N:3]=[C:2]([O:37][CH:35]2[CH2:34][CH:33]3[N:29]([CH3:28])[CH:30]([CH2:31][CH2:32]3)[CH2:36]2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: CN1[C@@H]2CC[C@H]1C[C@H](O)C2
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Agent: COc1ccc(CN2Cc3c(Br)cc(CO)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Agent: [H-]
Agent: [Na+]
Product: CN1C2CCC1CC(Oc1cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n1)C2

Procedure:
The title compound was prepared from 100 mg of 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2), 147 mg of a ca. 1.4:1 mixture of pseudotropine and tropine (EXAMPLE HHH9, Step A), and 25 mg of NaH by a procedure analogous to that described in COMPOUND HHH6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=S)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([O:17][C:18](=[O:44])[NH:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]1[CH:29]=[C:28]([C:30]([N:32]([CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH:27]=[CH:26][C:25]=1[NH2:43])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[CH3:41][CH:40]([CH3:42])[CH2:39][CH2:38][N:32]([CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[C:30]([C:28]1[CH:27]=[CH:26][C:25]2[N:43]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:18](=[O:44])[O:17][C:13]([CH3:16])([CH3:14])[CH3:15])[C:24]=2[CH:29]=1)=[O:31]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Solvent: C1CCOC1
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc2nc(Nc3ccc([N+](=O)[O-])cc3)n(CCCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 88 %

Procedure:
4-nitrophenyl isothiocyanate (305 mg, 1.5 eq) and N-methylcyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; charge 1.9 mmol/g; 1.75 g, 3 eq) are successively added to a solution of tert-butyl-3-[(2-amino-5-{[bis(3-methylbutyl)amino]carbonyl}phenyl)amino]propylcarbamate prepared according to Example A1 (500 mg, 1 eq) in tetrahydrofuran (30 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and filtered on frit. The filtrate is concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 7:3 to 2:8) produces the expected compound in the form of a yellow solid (584 mg; 88% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:29])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC1(C)CN(Cc2ccccn2)c2ccc(O)cc21
Product: CC1(C)CN(Cc2ccccn2)c2ccc(OC(=O)NCc3ccccc3)cc21

Procedure:
The title compound was synthesized from 1-(2-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with benzylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (15.5 mg, 51%) having the following characteristics.
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:7]/[C:6]/1=[CH:24]\[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)(=O)C.[ClH:31].C(#N)C>C(O)C>[ClH:31].[CH:14]1([C:12](=[O:13])[CH:11]([N:8]2[CH2:9][CH2:10][CH:5]([SH:4])/[C:6](=[CH:24]/[C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)/[CH2:7]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:16][CH2:15]1
Reactant: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1cnccn1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)/C(=C/c2cnccn2)C1
Yield: 60 %

Procedure:
(E)-4-(Acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-[(pyrazin-2-yl)methylidene]piperidine (Example 31, free base, 540 mg) was treated with hydrogen chloride in ethanol in a similar manner to that described in Example 133, and the crude product was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 25/75, v/v) to afford the title compound (295 mg, yield: 60%) as a colourless amorphous solid.
Reaction SMILES: OC(CCCCCC)CCCCCCCCCCC(O)=O.[B:22]([OH:25])([OH:24])[OH:23].O.[OH-].[Li+:28]>>[B:22]([OH:25])([O-:24])[O-:23].[Li+:28].[Li+:28].[B:22]([O-:25])([O-:24])[O-:23].[Li+:28].[Li+:28].[Li+:28]
Reactant: OB(O)O
Agent: CCCCCCC(O)CCCCCCCCCCC(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: [O-]B([O-])O
Product: [O-]B([O-])[O-]

Procedure:
Two additional 5 kg batches of grease were prepared. In each case the same proportion of 12-hydroxy-stearic acid and boric acid as in the grease A but increasing the amount of lithium hydroxide monohydrate so as to form dilithium borate (Grease 2) and trilithium borate (Grease 3) instead of monolithium borate (Grease A).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]=[C:3]1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7]([CH3:8])=[O:24])=[N:5][N:4]=[C:3]1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(-c2ccc3ccccc3c2)n1C
Solvent: ClCCl
Product: Cn1c(-c2ccc3ccccc3c2)nnc1S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, 0° C., solution of 4-methyl-5-methylthio-3-(2-naphthyl)-4H-1,2,4-triazole (4.00 g, 1.57×10-2 mole) and CH2Cl2 (110 ml) was added portionwise m-chloroperoxybenzoic acid (3.38 g, 1.57×10-2 mole). After stirring overnight at room temperature the reaction was diluted with CH2Cl2 (200 ml), washed two times with saturated aqueous NaHCO3 and one time with saturated aqueous NaCl, and dried over anhydrous N2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an off-white solid which was purified by flash chromatography (4% CH3OH/CH2Cl2). Crystallization from toluene afforded small colorless plates: 2.5 g (59%), mp 224°-226° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1C=CC=CC=1.CO>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[OH:1])[C:6]([O:8][CH3:15])=[O:7])([O-:13])=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a stirred solution of 4-hydroxy-3-nitrobenzoic acid (5.18 g, 28.29 mmol) in benzene-MeOH (4:1, v/v, 140 mL) was added TMSCHN2 (14.10 mL, 28.20 mmol, 2 M solution in hexane) at room temp, and the resulting mixture was stirred overnight. The mixture was evaporated and the residue was purified by column chromatography on silica-gel with CHCl3 as eluent to give 4.18 g (75%) methyl 3-nitro-4-hydroxybenzoate as a yellow crystalline solid. 1H-NMR (CDCl3) δ 3.95 (s, 3H), 7.22 (d, 1H, J=8.8 Hz), 8.24 (dd, 1 , J=2.0, 8.8 Hz), 8.83 (d, 1H, J=2.0 Hz), 10.89 (s, 1H).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:10]([OH:18])([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH2:28](O)[CH2:29][CH2:30][CH2:31][OH:32]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2([O:18][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7](=[O:8])[N:9]2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(CN2C(=O)c3ccccc3C2(O)c2ccc(Cl)cc2)cc1
Reactant: OCCCCO
Product: N#Cc1ccc(CN2C(=O)c3ccccc3C2(OCCCCO)c2ccc(Cl)cc2)cc1
Yield: 49.3 %

Procedure:
The named compound was synthesised from 2-(4-(aminomethyl)benzonitrile)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one (513 mg, 1.37 mmol, 1 equiv.) and 1,4-butanediol (616 mg, 6.85 mmol, 5 equiv.) using General Procedure B and obtained as a white solid (302 mg, 67%). 1H NMR (300 MHz, CDCl3): 7.94-7.91 (m, 1H, C(O)═C═CH), 7.55-7.52 (m, 2H, Ar—H), 7.47 and 7.33 (d: A2B2, J=8.4 Hz, 4H, Ar—H), 7.20 (m, 4H, Ar—H), 7.13-7.10 (m, 1H, Ar—H), 4.60 and 4.24 (d: AB, J=15.0 Hz, 2H, NCH2), 3.56 (t, J=5.4 Hz, 2H, HOCH2), 2.80-2.74 (m, 2H, OCH2), 1.53-1.16 (m, 4H, CH2). 13C NMR (75 MHz, CDCl3): 168.18, 145.32, 142.86, 137.20, 134.77, 132.90, 131.86, 131.46, 129.99, 129.85, 128.61, 127.95, 123.77, 123.08, 118.41, 111.33, 94.78, 62.82, 62.34, 42.68, 29.41, 25.67. Anal.: calc. for C29H23ClN2O3+0.2 H2O: C, 69.37; H, 5.16; N, 6.22. Found: C, 69.29; H, 5.20, N: 6.04.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:13][C:14](=[O:35])[CH:15]([CH2:19][C:20]([N:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:17][CH3:18])[C:9](=[O:12])[CH2:10][F:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:33]1[C:34]2[N:22]([C:20](=[O:21])[CH2:19][CH:15]([CH2:16][CH2:17][CH3:18])[C:14]([NH:13][CH:8]([C:9](=[O:12])[CH2:10][F:11])[CH2:7][C:6]([OH:36])=[O:5])=[O:35])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)O)C(=O)CF
Reaction time: 2 h
Yield: 5.6 %

Procedure:
A solution of [3S/R, (2R)]-3-[2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoylamino]-5-fluoro-4-oxo-pentanoic acid tert-butyl ester (1.43 g, 2.88 mmol) in anhydrous DCM(20 ml) was treated with a solution of TFA (10 ml) in anhydrous DCM (10 ml) with stirring. The mixture was stirred at 0° C. for 2 h then at room temperature for 2 h. The mixture was concentrated under reduced pressure and then the residue was dissolved in dry DCM. This process was repeated several times in order to remove excess trifluoroacetic acid. The off-white solid was recrystallized from Et2O/40/60 hexanes to give the title compound as a white powder (71 mg): IR (solid) 1746, 1689, 1641, 1541, 1436, 1374, 1284, 1207, 1160 cm-1; 1H NMR (400 MHz, d6-DMSO) δ 0.80-1.00 (3H, m), 1.20-1.76 (4H, m), 2.30-2.90 (2H, m), 2.95-3.24 (1H, m), 3.26-3.59 (2H, m), 4.25-4.79 (1.5H, m), 5.02-5.43 (1.5H, m), 7.36-7.58 (4H, m), 8.10-8.30 (4H, m), 8.54-8.91 (1H, m); 13C NMR (100 MHz, DMSO) δ 14.31, 20.03, 20.13, 21.92, 22.51, 34.36, 34.77, 41.20, 41.62, 44.06, 51.77, 52.84, 83.45, 85.22, 116.70, 120.54, 123.91, 124.01, 127.85, 126.01, 138.20, 172.15, 172.36, 172.96, 173.00, 175.32, 175.48, 202.60, 203.10; 19F (376 MHz, DMSO) δ −226.68, −226.73, −231.21, −232.95, −233.38, −233.52.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>C(Cl)Cl>[CH3:32][O:31][C:4]1[CH:3]=[C:2]([O:1][C:40]([O:41][CH3:42])=[O:43])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]2[CH3:20]
Reactant: COC(=O)Cl
Reactant: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(-c2ccc3c(c2CNc2ccccc2OC)C(C)=CC(C)(C)N3)c(OC)c1
Reaction time: 0.17 h
Yield: 57 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-1, 20.0 mg, 0.0465 mmol) was dissolved in anhydrous methylene dichloride (1.0 mL), triethylamine (13 μL, 0.093 mmol) and methyl chlorocarbonate (3.6 μL, 0.047 mmol) were added thereto under ice cooling, and then the mixture was stirred for 10 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (12.9 mg) as a colorless amorphous product. (Yield 57%)
Reaction SMILES: [NH2:1][C@H:2]([C:10]([N:12]1[CH2:23][CH2:22][CH2:21][C@@H:13]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:24]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:25]([C:28](O)=[O:29])([CH3:27])[CH3:26]>>[NH:24]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[C:25]([C:28]([NH:1][C@H:2]([C:10]([N:12]1[CH2:23][CH2:22][CH2:21][C@@H:13]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)C(C)(C)NC(=O)OCc1ccccc1
Yield: 85.4 %

Procedure:
H-L-Phe-D-Pro-OtBu (0.853 g, 2.68 mmol) and Z-Aib-OH (954 mg, 4.02 mmol) were condensed as described in Step 1 above. The oily product was purified by flash chromatography on silica gel (CHCl3/MeOH=99/1) to yield 1.23 g (85%) of the titled compound.
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([O:14][CH3:15])[C:10]([NH:12][CH3:13])=[O:11].[H-].[Na+].Cl[C:19]1[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][N:20]=1.O.CN(C)[CH:33]=[O:34]>>[Cl:25][C:24]1[C:19]([O:34][CH2:33][C:9]([C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=2)([O:14][CH3:15])[C:10]([NH:12][CH3:13])=[O:11])=[N:20][CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CNC(=O)C(OC)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CNC(=O)C(COc1ncc(C(F)(F)F)cc1Cl)(OC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-hydroxymethyl-α-methoxy-N-methyl-phenylacetamide (1.00 g, 4.8 mmol) in N,N-dimethylformamide (5 ml) was stirred at 0° C., and 60% oily sodium hydride (0.19 g, 4.8 mmol) was added thereto. The mixture was stirred at 0° C. for 30 minutes, and then 2,3-dichloro-5-trifluoromethyl-pyridine (1.24 g, 5.7 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then ice and water were added in this order. The mixture was extracted with ether, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1/1) to give the desired compound (3-chloro-5-trifluoro-methyl-2-pyridyloxymethyl)-α-methoxy-N-methyl-phenylacetamide (1.40 g, 75%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.[IH:21]>>[I:21][C:14]1[CH:19]=[C:18]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[N:17]=[CH:16][N:15]=1
Reactant: I
Reactant: COc1ccc(B(O)O)cc1F
Reactant: Clc1cc(Cl)ncn1
Product: COc1ccc(-c2cc(I)ncn2)cc1F

Procedure:
The compound was prepared according to Example 1 using 3-fluoro-4-methoxyphenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CCC)=[N+:2]=[N-:3].[CH2:22](C1C=CC(C(Cl)=O)=CC=1)[CH2:23]CCCC.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:23][CH:22]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 84 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 4-hexylbenzoyl chloride (0.293 g, 1.30 mmol) was reacted with 2-azidoethanamine (0.112 g, 1.30 mmol) and triethylamine (0.264 g, 2.61 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-hexylbenzamide (0.299 g, 84%). 1H NMR (300 MHz, CDCl3) δ 7.75 (d, 2H), δ 7.43 (t, 1H), δ 7.17 (d, 2H), δ 3.55 (q, 2H), δ 3.46 (t, 2H), δ 2.59 (t, 2H), δ 1.58 (m, 2H), δ 1.29 (m, 4H), δ 0.87 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.6, 147.3, 131.7, 130.3, 128.8, 127.5, 50.9, 39.7, 35.9, 31.6, 31.1, 22.7, 14.2 ppm; HRMS (ESI) calcd for C15H22N4O (M+) 274.1794. Found 274.1789.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH2:22]([N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Cl.O1CCOCC1.C(O)(C(F)(F)F)=O>COCCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]([CH3:20])[CH:17]=[CH:18][N:19]=2)=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][N:24]([CH2:22][CH3:23])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4-c4nccn4C)n3)cc2CC1
Temperature: 120 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine. A solution of crude 2-(1-Methyl-1H-imidazol-2-yl)-phenylamine (220 mg, 1.27 mmol) in DMF (8 mL) was treated with 2,4,5-trichloropyrimidine (233 mg, 1.27 mmol) and potassium carbonate (526 mg, 3.81 mmol). The mixture was then heated to 80° C. and was allowed to stir overnight. The reaction mixture was then cooled and DMF was removed en vacuo. The residue was taken up in ethyl acetate (20 mL) and was poured over saturated NH4Cl (20 mL). The organics were then extracted with ethyl acetate (3×20 mL). Combined extracts were dried over sodium sulfate, filtered and reduced. The product was then isolated and purified by flash column chromatography (0% ethyl acetate/hexane-75% ethyl acetate hexane) to afford 140 mg of (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine as an off white solid. 216d) A solution of (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine (47 mg, 0.15 mmol) in 2-methoxyethanol (3 mL) was treated with 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (28 mg, 0.15 mmol) and 4N HCl/Dioxane (0.074 mL, 0.29 mmol). The reaction mixture was heated to 120° C. and was allowed to stir for approximately 4 hours. The reaction mixture was then reduced en vacuo and the product was purified and isolated by prep HPLC to afford 44.5 mg of 5-Chloro-N*2*-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-N*4*-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-pyrimidine-2,4-diamine as the TFA salt. The product was isolated as a foam, LC/MS (ESI)=474.42 (M+H). 1H NMR (400 MHz, CDCl3) δ 7.89 (t, 1H, J=7.58 Hz), 7.74 (m, 2H), 7.66 (d, 1H), 7.45 (d, 1H, J=7.83 Hz), 7.39 (s, 1H), 7.08 (s, 1H), 6.97 (m, 2H), 6.81 (d, 1H, J=8.08 Hz), 3.72 (m, 2H), 3.49 (m, 2H), 3.33 (m, 2H), 3.21 (s, 3H), 2.87 (m, 2H), 2.67 (m, 2H), 1.40 (t, 3H, J=7.07 Hz).