Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[CH3:26][N:27](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:2]1[N:3]=[C:4]([O:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2)#[N:27]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(Cl)cc3ccc(F)cc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3ccc(F)cc23)C1
Temperature: 160 °C
Yield: 65 %

Procedure:
To a solution of (S)-tert-butyl 3-((3-chloro-7-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (1 g, 2.73 mmol) in DMF (10 mL) was added Zn(CN)2 (0.64 g, 5.46 mmol) and Pd(PPh3)4 (0.316 g, 0.273 mmol) under N2. The mixture was heated at 160° C. for 30 minutes in a microwave reactor and was subsequently partition between EtOAc (50 mL) and water (50 mL). The aqueous phase was back-extracted with EtOAc (3×50 mL) and the organic layers were combined and washed with saturated aqueous NaCl (3×50 mL) and concentrated in vacuo. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=20:1-5:1 gradient) to give the title compound (0.65 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (s, 1H), 8.19-8.16 (dd, J1=5.2 Hz, J2=3.6 Hz, 1H), 7.97-7.95 (m, 2H), 5.73-5.69 (d, J=16 Hz, 1H), 3.71-3.67 (m, 1H), 3.58-3.50 (m, 3H), 2.25-2.24 (d, J=4 Hz, 2H), 1.42-1.39 (d, J=12 Hz, 9H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Na+].Cl>C1COCC1>[C:14]([O:13][C:11]([N:9]1[CH:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1CCC(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1CCC(C(=O)O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
Piperidine-1,2,5-tricarboxylic acid 1,2-di-tert-butyl ester 5-methyl ester (36.7 mmol, 12.6 g) was dissolved in 180 mL of 2:1 THF:H2O. To this solution was added 2N sodium hydroxide solution (52 mL) and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture is acidified to pH=3 with 1N HCl(aq) and extracted with dichloromethane (3×100 mL). The combined organics are then dried over Na2SO4 and the solvent removed in vacuo to yield the title compound (12.0 g, 100% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:16][CH:15]=1.I[CH3:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]([CH3:35])[CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: CI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc5ccccc45)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4cccc5ccccc45)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(naphth-1-ylmethyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(naphth-1-ylmethyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 8.17,(1H, d), 7.99-7.40,(13H, m), 5.19-5.05,(2H, m), 3.03,(1H, s), 2.85,(2H, s), 2.55,(3H, s), 2.32-2.23,(3H, m). LCMS; retention time 3.66 min, MH+ 448.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:26]([Mg]Br)[CH3:27]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
To a solution of 9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (673.0 mg, 1.886 mmol) in tetrahydrofuran (10.0 mL) was added ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.94 mL, 2.829 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a colorless solid (702.4 mg, 1.816 mmol, 97%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:26][CH2:27][C:28]#[N:29].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:38][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:12]2[C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([Br:1])=[C:3]([O:26][CH2:27][C:28]#[N:29])[CH:4]=[CH:5]3)=[CH:40][CH:41]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)[nH]c2ccccc12
Reactant: CC(C)(C)c1ccc(CBr)cc1
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)n(Cc2ccc(C(C)(C)C)cc2)c2ccccc12

Procedure:
The title compound was prepared as a solid (0.070 g, 19%) from {[1-bromo-6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile using 4-tert-butylbenzyl bromide and the procedure from step 4 of Example 2; 1H NMR (DMSO-d6) δ 0.73 (t, J=7.3 Hz, 3H), 1.06-1.30 (m, 4H), 1.15 (s, 9H), 1.48-1.63 (m, 2H), 2.69 (t, J=8.4 Hz, 1H), 5.31 (s, 2H), 5.47 (s, 2H), 6.74 (d, J=8.4 Hz, 2H), 7.05-7.17 (m, 3H), 7.17 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.7 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.70 (d, J=9.1 Hz, 2H), 8.05 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H); mass spectrum [(+) ESI], m/z 593/595 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH3:12][O:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][O:13][CH3:12])=[CH:17][CH:18]=1)[C:6]([CH3:11])=[CH:5]2
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Reactant: COCOc1ccc(I)cc1
Product: COCOc1ccc(-n2c(C)cc3cc(Br)ccc32)cc1
Yield: 8.4 %

Procedure:
5-Bromo-2-methylindole (5.59 g, 23.8 mmol) and 4-methoxymethyloxy iodobenzene (7.47 g, 23.8 mmol), were reacted according to the procedure used in Example 1a above to afford a colorless liquid (8.4%): 1H NMR (DMSO-d6): δ 2.23 (3H, s), 3.43 (2H, s), 5.26 (2H, s), 6.39 (1H, s), 6.94 (1H, d, J=8.7 Hz), 7.01 (1H, dd, J=2.2 Hz, J=8.6 Hz), 7.20 (2H, d, J=8.6 Hz), 7.34 (2H, d, J=8.6 Hz), 7.53 (1H, d, J=2.2 Hz); MS m/z (M+H)+ 346/348 (1 Br). Anal. for C17H16BrN02: Calc'd: C, 58.98; H, 4.66; N, 4.05. Found: C, 58.72; H, 4.53; N, 4.17.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C(C)(C)C)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2,2-dimethyl-propionamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and pivaloyl chloride (109 μl, 0.89 mmol). The title compound was obtained as brown powder (171 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[CH:64]=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[C:62](Br)=[CH:61][C:60]=3[Cl:71])=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[C:60]([Cl:71])=[CH:61][C:62]([C:25]4[CH:26]=[CH:27][C:22]([C:20]5[N:21]=[C:17]([C@@H:12]6[CH2:13][C@H:14]([CH3:16])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:37])[CH:6]([CH3:8])[CH3:7])[NH:18][CH:19]=5)=[CH:23][CH:24]=4)=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[CH:64]=3)=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
To a solution of [(S)-2-methyl-1-((2S,4S)-4-methyl-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (155 mg, 0.30 mmol) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (180 mg, 0.30 mmol, Preparation 1) dissolved in toluene (1.9 mL) and water (0.33 mL) was added potassium carbonate (210 mg, 1.52 mmol). The reaction mixture was sparged under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.036 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce the title intermediate as a brownish solid. (m/z): [M+H]+ calcd for C44H52ClF3N8O, 897.36. found 897.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[S:8][CH2:7]1)[CH3:2].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:20][C:19]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=3[Cl:17])=[CH:14][C:9]=2[S:8][CH2:7]1)[CH3:2]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC1CSc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CSc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 20 °C
Reaction time: 72 h
Yield: 68.3 %

Procedure:
To a solution of ethyl(6-hydroxy-2,3-dihydro-1-benzothiophen-3-yl)acetate (17.2 g) in DMF (300 mL) were added 2,4-dichlorobenzyl chloride (17.0 g) and K2CO3 (15.0 g) and the resulting solution was stirred at 20° C. for 72 h. The mixture was diluted with EtOAc, washed successively with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc) to give the title compound (19.6 g).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)[C:6]2=[O:15].[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:33][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([CH2:16][N:5]2[CH2:4][C:3]3[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:2]=3[Br:1])[C:6]2=[O:15])=[CH:18][CH:19]=1
Reactant: Nc1ccccc1N
Reactant: COc1cc2c(c(Br)c1OC)CN(Cc1ccc(C(=O)O)cc1)C2=O
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: COc1cc2c(c(Br)c1OC)CN(Cc1ccc(C(=O)Nc3ccccc3N)cc1)C2=O
Temperature: 25 °C
Yield: 29.6 %

Procedure:
4-((4-Bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzoic acid (380 mg, 0.92 mmol) in the step 3, 1,2-phenylene diamine (199 mg, 1.84 mmol, 2 equiv.), and BOP (610 mg, 1.38 mmol, 1.5 equiv.) were dissolved in DMF (4 mL). Triethylamine (0.25 mL, 1.8 mmol, 2 equiv.) was added thereto, and stirred at room temperature for 1 night. The reaction proceeded until no starting material is detectable by TLC. The resulting mixture thus obtained was distilled under a reduced pressure to remove DMF. The resulting material was dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The isolated organic layer was collected, dried over anhydrous MgSO4, and distilled under a reduced pressure to remove solvent. The resulting residue was subjected to a silica gel column chromatography (EtOAc/hexane=9:1) to obtain the title compound (135 mg, 29%).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28](Cl)[N:27]=[C:26]([Cl:32])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:33]1[CH2:37][CH2:36][CH2:35][C@H:34]1[CH2:38][N:39]1[C:43]2[N:44]=[CH:45][N:46]=[CH:47][C:42]=2[N:41]=[N:40]1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:32][C:26]1[N:25]=[C:24]([NH:23][NH:22][C:20](=[O:21])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:8][N:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[O:11])[C:29]([F:30])=[C:28]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[CH2:38][N:39]2[C:43]3[N:44]=[CH:45][N:46]=[CH:47][C:42]=3[N:41]=[N:40]2)[N:27]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(Cl)c1F)OCc1ccccc1
Reactant: c1ncc2nnn(C[C@@H]3CCCN3)c2n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(N2CCC[C@H]2Cn2nnc3cncnc32)c1F)OCc1ccccc1
Temperature: 65 °C
Yield: 23.7 %

Procedure:
{(2R)-2-(Cyclopentylmethyl)-3-[2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl}[(phenylmethyl)oxy]formamide (136 mg, 0.278 mmol) and 3-[(2S)-2-pyrrolidinylmethyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidine (63 mg, 0.308 mmol) were dissolved in DMSO (5 mL), then DIEA (59 μL, 0.308 mmol) was added, and the solution was heated at 65° C. overnight. When the reaction was complete as determined by LCMS, the solution was concentrated in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(2S)-2-(3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)-1-pyrrolidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (43 mg, 21%). LCMS: (M+H)+: 651.6.
Reaction SMILES: [NH2:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:41])[CH:3]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]2[C:54](=[O:55])[C:53]([C:56]([OH:58])=O)=[CH:52][CH:51]=[N:50]2)=[CH:45][CH:44]=1>>[F:41][C:4]1[CH:3]=[C:2]([NH:1][C:56]([C:53]2[C:54](=[O:55])[N:49]([C:46]3[CH:45]=[CH:44][C:43]([F:42])=[CH:48][CH:47]=3)[N:50]=[CH:51][CH:52]=2)=[O:58])[CH:40]=[CH:39][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[C:8]=12
Reactant: COc1ccc(Cn2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Product: O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CCNCC4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Yield: 34 %

Procedure:
Prepared by a 2-step process from tert-butyl 4-(4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-ylamino)piperidine-1-carboxylate (prepared as described in Example 101, Step A, using tert-butyl 4-aminopiperidine-1-carboxylate) and 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid according to the procedure of Example 101, Step B. The crude material was purified by silica gel flash column chromatography (60% MeOH in CH2Cl2) to afford 19 mg (34%) of the desired product. LRMS (ESI pos) m/e 559.1 (M+1). 1H-NMR (400 MHz, CD3OD/CDCl3) δ 8.41 (d, 1H), 8.33 (d, 1H), 8.14 (d, 1H), 8.02 (dd, 1H), 7.65 (m, 2H), 7.47 (d, 1H), 7.37 (t, 1H), 7.28 (t, 2H), 6.12 (d, 1H), 3.80 (m, 1H), 3.16 (d, 2H), 2.79 (t, 2H), 2.24 (d, 2H), 1.53 (m, 2H); 19F NMR (376 MHz, CD3OD/CDCl3) δ −113.1, −127.7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9](O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([O:23][C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1)[C:10]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: OC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Oc1ccc(F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(On2c3c(c4cc(Br)ccc42)CCCC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.7 %

Procedure:
To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ol (50 mg, 0.19 mmol) in THF (5 mL) was added p-fluorophenol (43 mg, 0.38 mmol), polymer supported triphenylphosphine (1.67 mmol/g, 228 mg, 0.38 mmol) and diisopropyl azodicarboxylate (77 mg, 0.38 mmol). The reaction was stirred at room temperature for 16 h, and additional diisopropyl azodicarboxylate (77 mg, 0.38 mmol) was added. The reaction was stirred for 16 h, filtered and concentrated. The crude product was purified by flash chromatography on silica (2% to 20% ethyl acetate/hexanes gradient) to provide 6-bromo-N-(4-fluorophenoxy)-2,3,4,9-tetrahydro-1H-carbazole (8 mg, 12%) as a white solid: 1H-NMR (DMSO-d6): δ 11.20 (s, 1H), 7.61 (d, 1H), 7.26 (d, 1H), 7.16-7.06 (m, 5H), 5.53 (t, 1H), 2.75-2.69 (m, 1H), 2.57-2.50 (m, 1H), 2.02-1.76 (m, 4H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.F[C:14]1[CH:43]=[CH:42][C:17]([C:18](/[N:20]=[C:21]2\[NH:22][C:23]3[CH:39]=[CH:38][C:37]([CH2:40][OH:41])=[CH:36][C:24]=3N\2[C@@H]2CC[C@H](C(OC)=O)CC2)=[O:19])=[CH:16][CH:15]=1>>[C:18](/[N:20]=[C:21]1\[NH:22][C:23]2[CH:24]=[CH:36][C:37]([CH2:40][OH:41])=[CH:38][C:39]=2[N:1]\1[C@@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:19])[C:17]1[CH:42]=[CH:43][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: CCOC(=O)[C@H]1CC[C@@H](N)CC1
Product: CCOC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccccc3)[nH]c3ccc(CO)cc32)CC1

Procedure:
The title compound was prepared in 6 steps from cis-ethyl 4-aminocyclohexanecarboxylate using a method analogous to the preparation of cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate. MS m/z=422.2 [M+H]. Calc'd for C24H27N3O4: 421.2.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]([C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:13](Cl)=[O:14])([CH3:9])([CH3:8])[CH3:7]>>[CH2:1]([NH:5][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:18]([OH:19])=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Product: CCCCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In the manner of Example 1, n-butylamine was reacted with 3,5-di-t-butyl-4-hydroxybenzoyl chloride to produce N-n-butyl-3,5-di-t-butyl-4-hydroxybenzamide; melting point 181°-183°C. When tested by the procedure in Example 2, the sample containing this compound lasted 950 hours, about 3.2 times as long as the control.
Reaction SMILES: C(O[C:4]([C:6]1[CH2:7][N:8]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:9][CH2:10][C:11]=1[NH:12][C:13]([O:15]C1C=CC=CC=1)=O)=[O:5])C.[CH3:31][N:32]([CH3:34])[NH2:33].C1CCN2C(=NCCC2)CC1.[OH-].[Na+]>C1COCC1.C(O)(=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:8]2[CH2:9][CH2:10][C:11]3[NH:12][C:13](=[O:15])[N:33]([N:32]([CH3:34])[CH3:31])[C:4](=[O:5])[C:6]=3[CH2:7]2)=[O:30])=[CH:28][CH:27]=1
Reactant: CN(C)N
Reactant: CCOC(=O)C1=C(NC(=O)Oc2ccccc2)CCN(C(=O)c2ccc(Cl)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)n1c(=O)[nH]c2c(c1=O)CN(C(=O)c1ccc(Cl)cc1)CC2

Procedure:
Ethyl-4-phenoxycarbonylamino-1-(4-chlorobenzoyl)-1,2,5,6-tetrahydropyridine-3-carboxylate (200 mg) was dissolved in THF (2 ml), N,N-dimethylhydrazine (142 μl) and DBU (10 μl) were added and the resultant mixture was shaken at 50° C. for 3 hours. 5 N sodium hydroxide solution (200 μl) was added and the resultant mixture was further shaken at 50° C. overnight. To the reaction solution, acetic acid (300 μl) was added to neutralize, and the reaction solution was then concentrated. The resultant residue was subjected to medium-pressure column fractionation (solvent; methanol:methylene chloride=0:100 to 7:93). The titled compound (105 mg) was obtained as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[N:4]=1)#[N:2].[Cl-].[N+:15]([C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][CH:19]=1)([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(Cl)Cl>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][C:19]3[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:25])[F:26])=[CH:23][C:18]=3[N+:15]([O-:17])=[O:16])[CH:9]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1ccc2cc(O)ccc2n1
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc2cc(Oc3ccc(C(F)(F)F)cc3[N+](=O)[O-])ccc2n1
Temperature: 100 °C
Yield: 35 %

Procedure:
The mixture of 2-cyano-6-hydroxyquinoline (0.50 g, 2.94 mmol), 2-nitro-4-trifluoromethylbenzene chloride (0.67 g, 2.94 mmol) and potassium carbonate (0.41 g, 2.97 mmol) in 30 ml of DMSO was heated to 100° C. for 30 min. Upon cooling to room temperature, the mixture was poured into 30 ml of cold water and exacted three times with methylene chloride. The combined organic layer was washed with water and dried over magnesium sulfate. The product was purified by flash chromatography using heptane/methylene chloride (1:2) as eluent in a yield of 35%.