Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH2:6][CH2:5]2.[CH:15]([C:17]1([C:20]2[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][CH:25]=2)[CH2:19][CH2:18]1)=[CH2:16].C(=O)([O-])[O-].[K+].[K+].C(O)(C)(C)C>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[CH:15]([C:17]1([C:20]2[CH:21]=[C:22]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[CH2:6][CH2:5]4)[CH:23]=[N:24][CH:25]=2)[CH2:19][CH2:18]1)=[CH2:16]
Reactant: Brc1ccc2c(c1)CCc1nncn1-2
Reactant: C=CC1(c2cncc(B(O)O)c2)CC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: C=CC1(c2cncc(-c3ccc4c(c3)CCc3nncn3-4)c2)CC1
Temperature: 80 °C

Procedure:
To a vial containing the title compound from Example 22 Step B (35 mg, 0.14 mmol), the title compound from Example 73 Step D (30 mg, 0.16 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.0 mg, 2.8 μmol), and potassium carbonate 285 mg, 0.42 mmol) was added tert-butanol (1.6 mL) and water (0.19 mL). The vial was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction solution was then cooled to room temperature and concentrated under reduced pressure to provide the title compound: LCMS m/z 315.05 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1ccccc1)C2=O
Temperature: 25 °C
Yield: 90 %

Procedure:
4-carboxyphthalic anhydride (benzene tricarboxylic acid anhydride) (1.0 g, 0.0052 mol), aniline (0.96 g, 0.0104 mol), and 70-80 mls of glacial acetic acid were added to a 100 ml round-bottom flask equipped with a reflux condenser, heating mantle and stir plate. The system was placed under a N2 atmosphere. A white solid precipitated out of the clear pale yellow solution within 1 minute. The mixture was heated to a gentle reflux. More precipitate formed during the course of the reaction. After 12 hours the mixture was cooled to room temperature and concentrated under vacuum with a rotary evaporator. The crude material was reprecipitated in 1,4-dioxane and IN HCl. The resultant white precipitate was filtered through a Buchner funnel and washed three times with 15 ml of water. The product was dried in air for 24 hours and then in vacuo for 48-72 hours to afford 1.25 g (90%) 109 as a white fluffy solid: mp=257-258° C.; Rf0.83 (A): Rf0.76 (B): Rf0.62 (D): IR (cm−1): 2800-3125 (OH), 3071 (C═CH), 2665 (C—H), 1788 (C═O), 1719 (bs, C═O), 1602 (C═C), 1596 (C═C), 1504 (C═C), 1487 (C═C), 1399 (C—O), 1124 (C—O), 724 (C═CH); MS m/z (rel intensity) 267 (16), 266 (100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: Cc1cnn(-c2ccc(C=O)cc2)c1
Product: Cc1cnn(-c2ccc(C=CC=O)cc2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-methyl-1H-pyrazol-1-yl)-benzaldehyde (prepared as described in Reference Example 4) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]=2[C:11]([OH:13])=O)[C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3]1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].Cl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl>CS(C)=O>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:11]([C:9]1[CH:8]=[C:7]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[C:4]2[CH:20]([CH3:21])[CH3:22])=[O:13]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)c1cn(C)c2c(C(=O)O)cc(N3CCOCC3)cc12
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCOCC3)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
1-Methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxylic acid (62.5 mg, 0.21 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone.HCl (58.5 mg, 0.31 mmol) and 1-hydroxy-7-azabenzotriazole (47.8 mg, 0.35 mmol) were stirred in 2 mL of DMSO for 10 min under nitrogen. N-methylmorpholine (0.095 mL, 0.87 mmol) was added along with EDC (67.4 mg, 0.35 mmol) and the mixture was stirred at rt overnight under nitrogen. Ice-water was added but no solid crashed out. The reaction mixture was concentrated until only DMSO was left and purified using a reversed-phase HPLC (30×100 Varian Polaris C18, 15-80% gradient of MeCN in water with 0.1% TFA over 12 minutes). Fractions containing the desired product were evaporated until a minimum of water remained and saturated solution of NaHCO3 was added. The light orange solids that crashed out were filtered off and dissolved in DMF. Water was added and the solids that crashed out were filtered, air-dried for 15 min and dried in vacuum-oven overnight to give N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxamide (24 mg, 26.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (s, 1H) 8.33 (t, J=4.93 Hz, 1H) 7.04 (d, J=2.27 Hz, 1H) 6.96 (s, 1H) 6.80 (d, J=2.27 Hz, 1H) 5.87 (s, 1H) 4.33 (s, 1H) 4.31 (s, 1H) 3.72-3.78 (m, 4H) 3.60 (s, 3H) 3.06-3.12 (m, 1H) 3.00-3.06 (m, 4H) 2.22 (s, 3H) 2.11 (s, 3H) 1.26 (d, J=6.8 Hz, 6H). MS (ES) [M+H]+ 437.0.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].O[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>>[C:6]1([NH:5][C:3]([CH2:2][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: O=C(CCl)Nc1ccccc1
Product: O=C(Cc1ccc2[nH]ccc2c1)Nc1ccccc1

Procedure:
The title compound was prepared by a method analogous to that described in Example 1 from chloroacetanilide and 5-hydroxyindole. MS CI (MH+)=267.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[C:8]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(N(CC)CC)C.O>C(OCC)C>[C:8]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]([S:14]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CO
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)COS(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A suspension of ethyl glycolate (374 μl, 3.957 mmol) and biphenyl-4-sulfonyl chloride (1 g, 3.957 mmol) in anhydrous diethyl ether (2 ml) at 0° C. was treated dropwise with triethylamine (1.1 ml, 7.914 mmol). The temperature was maintained at 0° C. with stirring for a further 2 h. After this time, water was added and the phases separated. The aqueous phase was extracted with fresh diethyl ether. The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by column chromatography over silica gel (Rf=0.26, 25% ethyl acetate in hexane) affording 16 as a colourless oil (1.055 g, 83%). δH (400 MHz, CDCl3) 1.25 (3H, t, J=6.8 Hz, CH3), 4.20 (2H, q, J=6.8 Hz, CH2), 4.65 (2H, s, CH2), 7.44-7.51 (3H, m, ArH), 7.61 (2H, d, J=7.6 Hz, ArH), 7.76 (2H, d, J=8 Hz, ArH), 8.01 (2H, d, J=8 Hz, ArH); δc (100.6 MHz, CDCl3) 14.2, 62.2, 65.0, 127.6, 128.1, 128.9, 129.0, 129.4, 134.4, 139.2, 147.4, 166.2; MS (ES+) 338.1 (100%, [M+H2O]+).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[N:32]2[N:36]=[C:37]([CH:39]=O)[N:38]=[C:31]2[N:30]=1>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:39][C:37]3[N:38]=[C:31]4[N:30]=[C:29]([CH3:28])[CH:34]=[C:33]([CH3:35])[N:32]4[N:36]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Solvent: CO
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C(C)(C)C#N)c(F)c4)(C4CCCC4)OC3=O)nc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile (0.40 g, 1.1 mmol) in MeOH (7 mL) was added 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.19 g, 1.08 mmol) and borane-dimethylamine complex (76 mg, 1.3 mmol) and stirred at room temperature for 3 hours. The reaction was quenched with 10 mL saturated NH4Cl and 5 mL water. To this was added 20 mL CH2Cl2 and the pH of the aqueous phase was adjusted to 3. The layers were separated, and the aqueous layer was extracted with 3×30 mL 10% MeOH in CH2Cl2. The organic layers were combined, and dried over Na2SO4. After filtering off the solids, the liquid was concentrated by rotary evaporation to an oil. The oil was flash chromatographed, and the resulting product was further purified by preparatory HPLC. Yield: 28 mg, 5%. MS (ESI): 530 (M−H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:22]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:21]=4[CH2:20][CH2:19][C:18]=3[C:17]([CH3:30])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:21]2[CH2:20][CH2:19][C:18]3[C:17]([CH3:30])=[N:16][N:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)[C:23]=3[C:22]=2[CH:24]=1
Reactant: COc1ccc2c(c1)-c1c(c(C)nn1-c1ccc(OCc3ccccc3)cc1)CC2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)-c1c(c(C)nn1-c1ccc(O)cc1)CC2
Reaction time: 2 h

Procedure:
1-(4-Benzyloxyphenyl)-8-methoxy-3-methyl-4,5-dihydro-1H-benzo[g]indazole (42 mg, 0.1 mmol) was dissolved in methanol/tetrahydrofuran (2/1, v/v, 1.5 mL) and a catalytic amount of 10% Pd/C (wet) was added. The flask was purged with nitrogen and hydrogen, then stirred under 1 atmosphere of hydrogen for 2 hours. The mixture was filtered through Celite and washed with methanol, and the filtrate was concentrated. The reaction was assumed to be quantitative. LC-MS (C19H18N2O2 calculated 306) m/z 307 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(NC(=O)CN2CCOCC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(NC(=O)CN2CCOCC2)nc1
Reaction time: 16 h
Yield: 86.9 %

Procedure:
A solution of 58c (550 mg, 1.58 mmol) in CH2Cl2(10 ml) was treated with trifluoro acetic acid (1.22 ml) at 20-35° C. for 2 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the clear solution was concentrated under vacuum and the resultant solid was washed with diethyl ether to get the desired compound as a creamy white solid (400 mg, 87%). MS (ES) m/e 290.1 (M−H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.Cl.[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:31]([NH:33][CH3:34])=[O:32].CCN(C(C)C)C(C)C>C(#N)CC.CS(C)=O>[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][C:37]=1[N:38]1[CH2:39][CH2:40][N:41]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][S:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:42][CH2:43]1)[C:31]([NH:33][CH3:34])=[O:32]
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CS(C)=O
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)c(Cl)c1
Temperature: 90 °C
Yield: 11.2 %

Procedure:
To a suspension of (R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (97 mg, 0.386 mmol) in propiononitrile (1.2 mL) was added (cyanomethyl)trimethylphosphonium iodide (113 mg, 0.463 mmol) and 3-chloro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (112 mg, 0.386 mmol) and DIEA (202 μl, 1.158 mmol). The vial was heated to 90° C. for 16 hours. The crude rxn was cooled to RT, DMSO (1 ml) was added, and purified via HPLC (55-90, basic). The fractions were collected, concentrated until a precipitate was visible and filtered. The solids were washed with water and collected to retrieve the product as a white solid (21 mg, 11% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1H), 8.41 (d, J=4.5 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.6, 2.0 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H), 4.88 (ddd, J=13.5, 2.7, 2.5 Hz, 1H), 4.27 (dd, J=10.6, 3.0 Hz, 1H), 3.40 (s, 2H), 2.92-3.14 (m, 5H), 2.64-2.85 (m, 6H), 2.51-2.64 (m, 3H), 2.45 (dd, J=13.4, 1.5 Hz, 2H). [M+H] calc'd for C23H27ClN6O2S, 487. found, 487.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:39])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[O:23][CH:22]3[CH:24]([N:31]4[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]4=[O:38])[O:25][CH:26]([CH2:27][N:28]=[N+:29]=[N-:30])[CH:21]3[O:20]2)=[CH:15][CH:14]=1)C.Cl>O.CCO>[N:28]([CH2:27][CH:26]1[CH:21]2[CH:22]([O:23][CH:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:39])=[O:5])=[CH:14][CH:15]=3)[O:20]2)[CH:24]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[O:25]1)=[N+:29]=[N-:30]
Reactant: CCOC(=O)CCCCCOc1ccc(C2OC3C(CN=[N+]=[N-])OC(n4ccc(=O)[nH]c4=O)C3O2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NCC1OC(n2ccc(=O)[nH]c2=O)C2OC(c3ccc(OCCCCCC(=O)O)cc3)OC12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sodium hydroxide (NaOH, 20.8 g, 522 mmol) in H2O (125 mL) was added to a suspension of 7 (89.8 g, 174 mmol) in EtOH (400 mL) and stirred for 4 h at room temperature. The solvent was removed and the resulting residue was diluted with H2O (300 mL). The suspension was then treated dropwise with 1M aqueous HCl (522 mmol, 522 mL) to afford a white precipitate, which was subsequently partitioned with EtOAc (1.5 L). The organic layer was then washed with H2O (2×1 L), dried (MgSO4), filtered and concentrated in vacuo to give a white foam (8, 80.2 g, 164 mmol, 95%) as a mixture of two diastereomers: 1H-NMR (400 MHz, (CD3)2SO3) δ=12.01 (s, 1H, 1H′), 11.49 (s, 1H, 1H′), 7.78 (d, J=8.0, 1H), 7.74 (d, J=8.0, 1H′), 7.43 (d, J=8.5, 2H), 7.37 (d, J 8.5, 2H′), 6.96 (d, J=8.5, 2H), 6.93 (d, J=8.5, 2H′), 6.07 (s, 1H′), 5.93 (s, 1H), 5.91 (s, 1H, 1H′), 5.67 (d, J=8.0, 1H), 5.66 (d, J=8.0, 1H′), 5.20-4.81 (m, 2H, 2H′), 4.31 (m, 1H, 1H′), 3.96 (m, 2H, 2H′), 3.62 (m, 2H, 2H′), 2.22 (m, 2H, 2H′), 1.70 (m, 2H, 2H′), 1.54 (m, 2H, 2H′), 1.41 (m, 2H, 2H′); 13C-NMR (400 MHz, (CD3)2SO3) δ=175.3, 175.3, 164.1, 164.0, 160.7, 160.6, 151.2, 151.2, 144.3, 143.7, 129.3 (2C), 129.3 (2C), 128.6, 128.6, 115.1 (2C), 115.0 (2C), 107.6, 103.5, 103.1, 102.8, 93.5, 92.5, 85.9, 85.1, 83.2, 82.8, 82.6, 81.5, 68.3, 68.3, 52.7, 52.5, 34.5, 34.5, 29.2, 29.1, 26.0, 25.9, 25.1, 25.1; IR (film) ν=3354, 3183, 2941, 2101, 1684, 1245, 1069, 1050, 1023, 995, 824; HRMS (MALDI-FTMS) mn/z 510.1600 (510.1595 calculated for C22H25N5O8Na (M+Na)+).
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]4[C:47]([F:48])=[CH:46][C:45]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:44][C:43]=4[F:53])[N:36]=3)=[O:34])[C:13]([N:14]3[CH2:19][C@H:18]([C:20]([F:23])([F:22])[F:21])[CH2:17][C@H:16]([NH:24]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].Cl.O1CCOCC1>CO.C1COCC1>[NH2:24][C@H:16]1[CH2:17][C@@H:18]([C:20]([F:21])([F:22])[F:23])[CH2:19][N:14]([C:13]2[C:12]([NH:32][C:33]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]4[C:43]([F:53])=[CH:44][C:45]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:46][C:47]=4[F:48])[N:36]=3)=[O:34])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(C(C)(C)O)cc3F)n1)c2N1C[C@@H](NC(=O)OC(C)(C)C)C[C@@H](C(F)(F)F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)c1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@@H](N)C[C@@H](C(F)(F)F)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]-3-[({6-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (0.015 g, 0.020 mmol) in MeOH (0.8 mL), THF (0.8 mL) and 1.0 M aq. NaOH (0.8 mL, 0.8 mmol) was stirred at room temperature for 0.5 h. The solution was then concentrated under reduced pressure and the remaining aqueous phase was extracted with EtOAc. The organic extract was concentrated to dryness under reduced pressure. The residue was treated with 4.0 M HCl in dioxane (0.20 mL, 0.80 mmol) for 20 min. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in 4.5 mL of MeOH, neutralized with NH4OH solution, and purified by preparative LCMS (Waters SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford two separated diastereoisomers of the title compound as white powders.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][OH:17])[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>C(OCC)(=O)C.O>[CH3:38][O:37][C:33]1[CH:32]=[C:28]([CH:27]=[C:26]([O:25][CH3:24])[C:34]=1[O:35][CH3:36])[C:29]([N:11]1[CH2:12][CH2:13][CH2:14][C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)([CH2:15][CH2:16][OH:17])[CH2:10]1)=[O:30]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C(=O)N2CCCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine (1.08 g, 3.94 mmol) and sodium carbonate (0.21 g, 2.00 mmol) in 1/1 ethyl acetate/water (50 mL). Cool the reaction mixture to 0° C. with an ice bath. Add 3,4,5-trimethoxybenzoyl chloride (0.83 g, 3.58 mmol). Warm to ambient temperature. After 18 hours, separate the layers and extract the aqueous layer three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel to give the title compound: Rf=0.5 (silica gel, 1/1 ethyl acetate/hexane). Elemental Analysis calculated for C23H27Cl2NO5: C 58.97; H 5.81; N 2.99; Found C 58.85; H 5.90; N 2.96.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(Cl)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(Cl)c1OCc1ccccc1
Reaction time: 12 h
Yield: 89.6 %

Procedure:
A solution of 50 g of 4-bromo-6-chloro-2-methylphenol and 42.5 g of benzyl bromide dissolved in 200 ml of N,N-dimethylformamide was stirred at room temperature, to which 37.4 g of potassium carbonate was added, and the mixture was stirred for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was added to 400 ml of diethyl ether, washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 63 g of 4-bromo-6-chloro-2-methyl-1-benzyloxybenzene (90% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:6]1.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CCCC(=O)C.O>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:17]2[CH2:18][CH2:19][CH:14]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:6]=3)[CH2:15][CH2:16]2)[CH:24]=1
Reactant: COCCn1cc(C2CCNCC2)c2cccnc21
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCCC(C)=O
Product: COCCn1cc(C2CCN(Cc3cccc(C(=O)OC)c3)CC2)c2cccnc21

Procedure:
0.42 g (1.62 mmol) of 1-(2-methoxyethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 0.45 g (1.94 mmol) of 3-bromomethylbenzoic acid methyl ester were solved in 9 ml of 4-methyl-2-butanone and 0.67 g (4.86 mmol) of potassium carbonate and 0.02 g (0.16 mmol) of sodium iodide were added. The mixture was refluxed for 18 hours and, after cooling, water was added, the organic layer separated and washed with water and brine. The solvent was distilled off. The crude material weighed 0.67 g and was used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]2)[C:5]([F:15])=[C:4](Cl)[N:3]=1.O.[NH2:18][NH2:19]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]2)[C:5]([F:15])=[C:4]([NH:18][NH2:19])[N:3]=1
Reactant: NN
Reactant: CC1(O)CCN(c2nc(Cl)nc(Cl)c2F)C1
Solvent: O
Solvent: CS(C)=O
Product: CC1(O)CCN(c2nc(Cl)nc(NN)c2F)C1
Yield: 21.7 %

Procedure:
1-(2,6-Dichloro-5-fluoro-4-pyrimidinyl)-3-methyl-3-pyrrolidinol (0.486 g, 1.83 mmol) and hydrazine monohydrate (0.53 mL, 10.96 mmol) in DMSO (5 mL) were heated at 50° C. until the reaction was deemed complete. Purification by RP-HPLC provided 1-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-3-methyl-3-pyrrolidinol as a brown solid (0.104 g, 21%). LCMS: (M+H)+=262.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[O:25]([CH2:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[O:25]([CH2:32][C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(Cl)COc1ccccc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C(COc1ccccc1)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 18.3 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.157 mmol) obtained in Example 1, (3), and 2-phenoxyacetyl chloride (27 mg, 0.315 mmol), the title compound (13 mg, yield 18%) was obtained as pale brown crystals in the same manner as that of Example 1, (4).