Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:4][C:5]([NH2:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([F:38])[C:24]=1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([F:38])[C:24]=1[C:2]1[C:3]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:4][C:5]([NH2:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1nc(-c2cccnc2)c(Br)cc1[N+](=O)[O-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Product: Nc1nc(-c2cccnc2)c(-c2c(F)cncc2F)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
A mixture of 3-bromo-5-nitro-2,3′-bipyridin-6-amine (Intermediate 1, step b, 1 g, 3.39 mmol), 3,5-difluoro-4-tributylstannanylpyridine (1.5 g, 3.71 mmol), bis(triphenylphosphino) palladium (II) chloride (0.24 g, 0.34 mmol) and copper (I) iodide (0.13 g, 0.68 mmol) in dioxane (15 mL) was heated at 150° C. for 6 hours in Biotage Initiator Microwave Synthesizer.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C@@H:20]3[C@@H:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][N:22]([C@H:31]([CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)[C:32]([O:34]CC4C=CC(OC)=CC=4)=[O:33])[CH2:21]3)[CH2:15][CH2:14]2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:1]([C:8]1[S:12][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C@@H:20]3[C@@H:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][N:22]([C@H:31]([CH:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)[C:32]([OH:34])=[O:33])[CH2:21]3)[CH2:15][CH2:14]2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(c4ncc(Cc5ccccc5)s4)CC3)[C@@H](c3ccccc3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(c3ncc(Cc4ccccc4)s3)CC2)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
To 44 mg of α-(R)-(3-(S)-((4-(5-benzyl-thiazol-2-yl) -piperidine-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxybenzyl ester (from Step D) were added 125 mg of anisole and 3 ml of triflouroacetic acid. The reaction was stirred at room temperature for 1 hour. The trifluoroacetic acid was evaporated under reduced pressure. The residue was purified by flash chromatography with 20% MeOH in EtOAc followed by 20% MeOH+2% NH4OH in EtOAc to give 36.7 mg of the title compound. ESI-MS 558 (M+H); HPLC A: 2.59 min.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:27])[CH:9]=[C:10]([N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[CH3:28][N:29](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:27][C:8]1[CH:9]=[C:10]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([C:2]([C:28]#[N:29])=[CH:3][N:4]=2)[N:7]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(Br)cnc23)cc1
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Temperature: 150 °C

Procedure:
A microwave vial was charged with 3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (220 mg, 0.49 mmol) from step 1a, zinc cyanide (34.8 mg, 0.3 mmol), Tris(dibenzylidenaceton)dipalladium(0) (22.7 mg, 0.025 mmol), 1,1′-Bis(diphenylphosphino)ferrocene (19.8 mg, 0.036 mmol) and DMF (2 mL). The resulting mixture was heated in a microwave for 15 min at 150° C. The solution was cooled, diluted with ethyl acetate, washed with saturated LiCl solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified silica gel chromatography (5% ethyl acetate/heptane) to provide 91 mg of 6-chloro-3-cyano-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:39])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])=[CH:8]2)=[O:4].[NH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:39])[C:5]([C:3]([NH:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:37])([F:38])[F:36])[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 69.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-8-pyridin-3-yl-3-(2-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.056 mmol), β-alanine (503 mg, 5.6 mmol) and NaOMe solution (9 mL, 4.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (15-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 23 mg of the title compound as a light tan solid. MS: (+) m/z 589.30 (M+1).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:14][C:13]2=[O:25])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=1)=[O:37]>C(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([C:36]([O:38][C:39]4[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=4)=[O:37])[CH2:21][CH2:20]3)=[CH:14][C:13]2=[O:25])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCNCC3)cc2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(C(=O)Oc4ccc(Br)cc4)CC3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a mixture of 1-(4-(methylsulfonyl)phenyl)-4-(piperidin-4-yloxy)pyridin-2(1H)-one hydrochloric acid (154 mg, 0.40 mmol) and diisopropylethylamine (0.35 mL, 0.20 mmol) in CH2Cl2 (1.5 mL) at room temperature was added 4-bromophenyl chloroformate (prepared according to procedures described at Step B of Example 2 substituting 4-bromophenol for 1,1,1-trifluoro-2-propanol) in CH2Cl2 (1.0 mL). The resulting mixture was stirred at room temperature for 3 hrs, diluted with CH2Cl2 and washed with water and brine. The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/Hexanes) to give the title compound (159 mg, 73%) as a light yellow solid. MS (ESI) 547, 549 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)=[CH:6][C:5]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-])=O.CO>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)=[CH:6][C:5]=1[NH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1cccc(-c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)c1
Solvent: CO
Product: Nc1ccc(-c2cccc(C(=O)O)c2)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To stirred solution 4′-nitro-3′-(phenylamino) biphenyl-3-carboxylic acid (0.5 g, 1.5 mmol) in methanol (5 mL) PtO2.H2O (30 mg, 0.0149 mmol) was added. The resulting mixture was stirred under H2 atmosphere at room temperature for 10 h. After completion of reaction (by TLC) it was filtered through celite, evaporated under vacuum to get the crude product. Flash chromatography gave 4′-amino-3′-(phenylamino) biphenyl-3-carboxylic acid which was isolated finally as dihydrochloride salt (0.4 g) 88% yield. 1H NMR (500 MHz, DMSO): δ 6.87 (t, J=7 Hz, 1H), 7.02 (d, J=6.5 Hz, 2H), 7.32 (m, 4H), 7.59 (m, 2H), 7.84 (d, J=7.8 Hz 1H), 7.91 (d, J=7.5 Hz, 1H), 8.09 (s, 1H). HRMS (ESI) calculated for C19H17N2O2: 305.1285, Found: 305.1279.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:43])[C:22]2[CH:27]=[N:26][C:25](S(C)(=O)=O)=[N:24][C:23]=2[N:32]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[CH2:39][CH2:38][CH2:37]3)[CH:33]=1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:43])[C:22]2[CH:27]=[N:26][C:25]([NH:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH:9]=3)=[N:24][C:23]=2[N:32]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[CH2:39][CH2:38][CH2:37]3)[CH:33]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(N4CCN(C)CC4)c3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 3-(4-methyl-piperazin-1-yl)-phenylamine (50 mg, 0.27 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (60 mg, 46%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 8.44 (s, 1H), 7.49 (br, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.20 (m, 2H), 7.09 (d, J=7.8 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 6.87 (br, 1H), 6.52 (d, J=7.9 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 3.02-2.90 (m, 8H), 2.45 (m, 4H), 2.26 (s, 3H), 2.14 (m, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]2=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[O:23]=[C:8]1[C:9]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1N1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC1(Cc2ccncc2)C(=O)N(N2CCCCC2)c2ccccc21

Procedure:
The product obtained from Example 23 could be reacted with sodium hydride and ethyl bromoacetate in a manner similar to Example 8 to render the product as an oil. Mass Spec. Calcd. for C22H25N3O4 :394 (M+H). Found: 394.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[CH:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:37]1([CH:43]([O:50][C:51]([C:53]2[N:58]3[C:59](=[O:62])[C@@H:60]([NH2:61])[C@H:57]3[S:56][CH2:55][C:54]=2[CH2:63][O:64][C:65](=[O:67])[NH2:66])=[O:52])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN1CCOCC1>ClCCl.C(N(CC)CC)C>[C:37]1([CH:43]([O:50][C:51]([C:53]2[N:58]3[C:59](=[O:62])[C@@H:60]([NH:61][C:15](=[O:17])/[C:14](/[C:12]4[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[S:10][CH:11]=4)=[CH:18]\[CH2:19][CH3:20])[C@H:57]3[S:56][CH2:55][C:54]=2[CH2:63][O:64][C:65](=[O:67])[NH2:66])=[O:52])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCC=C(C(=O)O)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: NC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CS(=O)(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(N)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Yield: 86.1 %

Procedure:
To a mixture of 2-(2-t-butoxycarbonylaminothiazol-4-yl)-pentenoic acid (75 mg), triethylamine (0.041 ml), and dichloromethane (3 ml) is added dropwise methanesulfonyl chloride (0.02 ml) at -60° C. with stirring. After stirring at the same temperature for 5 hours, a solution of 7beta-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate salt (153 mg) and N-methylmorpholine (0.05 ml) in dichloromethane (3 ml) is added dropwise to the mixture. After stirring for 3.5 hours, the mixture is quenched with diluted hydrochloric acid. The organic layer is separated, washed with water, dried, and concentrated. The residue is purified by silica gel column chromatography to give 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester (155 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:10]=[N:11][N:12]([CH2:14][O:15][CH3:16])[CH:13]=2)=[N:6][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]([N:33]2[CH2:37][CH:36]([CH2:38][OH:39])[O:35][C:34]2=[O:40])[CH:21]=[CH:22][C:23]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[F:17][C:18]1[CH:19]=[C:20]([N:33]2[CH2:37][CH:36]([CH2:38][OH:39])[O:35][C:34]2=[O:40])[CH:21]=[CH:22][C:23]=1[C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9]2[N:10]=[N:11][N:12]([CH2:14][O:15][CH3:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: COCn1cc(Nc2ccc(Br)cn2)nn1
Reactant: CC1(C)OB(c2ccc(N3CC(CO)OC3=O)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COCn1cc(Nc2ccc(-c3ccc(N4CC(CO)OC4=O)cc3F)cn2)nn1
Temperature: 25 °C
Yield: 152.9 %

Procedure:
5-bromo-N-(1-(methoxymethyl)-1H-1,2,3-triazol-4-yl)pyridine-2-amine (0.318 g, 1.119 mmol), 3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(hydroxylmethyl)oxazolidin-2-one (0.852 g, 2.527 mmol), sodium carbonate (0.357 g, 3.368 mmol), PdCl2(dppf)2 (0.064 g) were added into 20 mL dioxane and 2 drops of water, refluxed and reacted for 18 h under protection of nitrogen, cooled to room temperature, filtered, concentrated, chromatographed on a silica gel column (CH3OH:CH2Cl2=1:25), to obtain 0.709 g of crude 3-(3-fluoro-4-(6-((1-(methoxymethyl)-1H-1,2,3-triazol-4-yl)amino)pyridin-3-yl)phenyl)-5-(hydroxylmethyl)oxazolidin-2-one.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[C:10]2[CH:18]([C:23]([NH2:25])=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].O>CN(C=O)C.CCOC(C)=O>[CH3:37][O:36][C:34](=[O:35])[CH2:33][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]1[CH:18]([C:23](=[O:24])[NH2:25])[CH2:19][CH2:20][CH2:21][CH2:22][C:9]=1[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1CCCCc2c1c1c(O)cccc1n2Cc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(n2Cc2ccccc2)CCCCC1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
A slurry of 5-benzyl-1-hydroxy-5,6,7,8,9,10-hexahydro-cyclohepta[b]indole-10-carboxylic acid amide (Part F; 275 mg; 0.822 mmol) and Cs2CO3 (670 mg; 2.06 mmol) in 8 mL of DMF was treated with methyl bromoacetate (0.100 mL; 1.07 mmol). After stirring overnight at ambient temperature, the reaction mixture was poured into water and EtOAc (20 mL each). The layers were separated, and the organic phase was washed with water (3×20 mL), dried over Na2SO4 and concentrated in vacuo. Purification by radial chromatography (CHCl3) afforded 205 mg (0.504 mmol; 61%) of the title ester as a white foam. ES-MS: 407 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NCc1ccncc1
Product: O=C(NCc1ccncc1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(aminomethyl)pyridine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.40 (1H, br), 11.31 (1H, br), 10.15 (1H, br), 8.48 (2H, br m), 8.20 (1H, br s), 7.29 (5H, m), 7.14 (2H, t, J=8.7 Hz), 4.52 (2H, br m), 4.01 (2H, s); ES+ MS: 405 (M+H+, 100).
Reaction SMILES: C(OC([N:11]([C:23]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29])NC(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pt]=O>[NH2:11][C:23]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29]
Reactant: CCOC(=O)C1(N(NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)CC(=O)NC1=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)C1(N)CC(=O)NC1=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 64.1 %

Procedure:
To a solution of the compound of Example 1 (496 mg) in acetic acid (15 ml) was added platinum oxide (102 mg). This mixture was stirred vigorously at 50° C. under hydrogen (atmospheric pressure) for 6 hours. During this reaction, to remove carbon dioxide generated with the progress of the reaction, the gas in the reactor was replaced with hydrogen gas several times. The reaction mixture was filtered through a Celite pad and then the Celite was washed with a small amount of acetic acid. The filtrate combined with the washers was concentrated and to the resulting residue was added toluene to remove azeotropically the residual acetic acid and then the mixture was concentrated again. To the residue was added ethyl acetate and the insoluble material was filtered off, and then the ethyl acetate solution was concentrated to give a crude product which was then purified by a flash column chromatography (chloroform:methanol=30:1) to give the desired product (126 mg, 64%) as crystal. 1H NMR (CDCl3) data of this product were consistent with those of an optical active substance described in J. Med. Chem., 1998, 41, p. 4118 to 4129.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:15]=[C:14]([C:23]([F:26])([F:25])[F:24])[CH:13]=2)=[O:10])=[CH:4][C:3]=1[O:27]C.B(Br)(Br)Br>C(Cl)Cl>[C:2]1([N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([OH:27])[CH:4]=2)[C:9]([NH:11][C:12]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:15]=[C:14]([C:23]([F:25])([F:24])[F:26])[CH:13]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(NC(=O)Nc2cc(C(F)(F)F)nn2-c2ccccc2)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)nn1-c1ccccc1)N(c1ccccc1)c1ccc(F)c(O)c1
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of 1-(4-fluoro-3-methoxyphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea (0.985 g, 2.5 mmol) in DCM (30 mL) at ice-water bath was dropped a 1.0 M solution of BBr3 in DCM (25 mL) and it was stirred for 2 hours. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM. Extracts were dried over MgSO4 and concentrated. The crude product was purified on a silica gel column using a mixture of EtOAc-hexane as eluent to give phenyl 1-(4-fluoro-3-hydroxyphenyl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea as solid (0.327 g, 34%). 1H NMR (300 MHz, DMSO-d6) 6.59 (s, 1H), 6.65 (d, 1H), 6.78 (dd, 1H), 7.34 (m, 2H), 7.49 (m, 2H), 7.57 (d, 1H), 7.65 (d, 1H), 8.54 (s, 1H), 8.94 (s, 1H), 10.00 (s, 1H); LC-MS (ESI) m/z 381 (M+H)+.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3Br)[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1.[CH3:35][C:36]1(C)C(C)(C)OB(C=C)O1>O>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:21]2[CH2:26][CH2:25][N:24]([C:27]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=3[CH:35]=[CH2:36])[CH2:23][CH2:22]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccn1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Solvent: O
Product: C=Cc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(C)C)c3)cn2CCN2CCC2)CC1

Procedure:
a mixture of 6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine (70.00 mg; 0.13 mmol; 1.00 eq.), 4,4,5,5-Tetramethyl-2-vinyl-[1,3,2]dioxaborolane (0.03 ml; 0.16 mmol; 1.20 eq.), (4.77 mg; 0.01 mmol; 0.07 eq.) and in doxane 15 ml and water 1.5 ml, stirred at 50 C for overnight.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1[N:9]([CH3:31])[C:10]([CH2:29][CH3:30])=[C:11]([C:27]#[N:28])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)=O)C.O.[NH2:33]N>C(O)(=O)C>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:11]([C:27]#[N:28])=[C:10]([CH2:29][CH3:30])[N:9]([CH3:31])[C:8]=2[C:6]2[NH:5][CH:4]=[N:2][N:33]=2)=[CH:14][CH:15]=1)#[N:26]
Reactant: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(C(=O)N=CN(C)C)n1C
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCc1c(C#N)c(-c2ccc(-c3ccccc3C#N)cc2)c(-c2nnc[nH]2)n1C
Temperature: 90 °C
Yield: 38.8 %

Procedure:
Dissolve 4-cyano-3-(2′-cyano-biphenyl-4-yl)-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid dimethylaminomethyleneamide (183 mg, 0.45 mmol, prepared in preparation 47) in 2 mL of glacial acetic acid, add hydrazine monohydrate (0.70 mmol) and heat to 90° C. under nitrogen. After 90 minutes cool the reaction slightly, pour into 50 mL of ice-water and stir for twenty minutes. Filter off the resulting solid and rinse with 10 mL of water. Vacuum-dry overnight to give the title compound (66 mg, 39%). MS(ES+, m/e)=379 (M++1).