Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:44]=[CH:45][CH:46]=[C:47]([F:48])[C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3F)cc2)OC1(C)C
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 81.3 %

Procedure:
Into a 250 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,3-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum and the residue was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined, washed with brine and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and elution with dichloromethane/methanol (10/1) gave 480 mg (82%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]3[CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16](=O)[CH2:17][CH2:18][C:19](=O)[CH3:20].O.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[CH3:20][C:19]1[N:1]([C:2]2[C:10]3[O:9][C:8]4[CH2:11][CH2:12][CH2:13][CH2:14][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: Nc1cccc2c3c(oc12)CCCC3
Reactant: CC(=O)CCC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C)n1-c1cccc2c3c(oc12)CCCC3
Yield: 72.1 %

Procedure:
A mixture of 6-amino-1,2,3,4-tetrahydrodibenzofuran (230 mg), 2,5-hexanedione (145 mg) and conc. hydrochloric acid (1 drop) in ethanol (3 ml) was refluxed for 1 hour and poured into water. The mixture was neutralized with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from a mixture of ethanol and water to give 6-(2,5-dimethylpyrol-1-yl)-1,2,3,4-tetrahydrodibenzofuran (235 mg).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[O:16]=[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([NH:26][C:27](=[O:31])[C:28](O)=[O:29])=[CH:25][C:19]=2[O:18]1>>[F:1][C:2]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([C:28](=[O:29])[C:27]([NH:26][C:24]2[CH:23]=[CH:22][C:20]3[NH:21][C:17](=[O:16])[O:18][C:19]=3[CH:25]=2)=[O:31])[CH2:9][CH2:10]1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Reactant: Fc1ccc(CC2CCNCC2)c(F)c1
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccc(F)cc2F)CC1

Procedure:
The title compound is prepared from 4-(2,4-difluoro-benzyl)-piperidine and N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid (Example 43e) according to the method described in Example 43f. The residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 231° C. (isopropanol)
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH:4]=1.CN(C)C=O.P(Cl)(Cl)([Cl:25])=O>ClCCl>[Cl:25][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cnc(Nc2ncc(C#N)s2)cc1CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2ncc(C#N)s2)cc1CCl

Procedure:
2-(4-Hydroxymethyl-5-methyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (9-8, 0.400 g, 1.62 mmol) was stirred in 5 mL of anhydrous dichloromethane. N,N-Dimethylformamide (0.125 mL, 1.62 mmol) was added followed by the addition of phosphorous oxychloride (0.151 mL, 1.62 mmol). After 2 hours the reaction was concentrated in vacuo. Half-saturated NaHCO3 (aq) was added and the resulting precipitate was filtered and washed with water. Air drying provided the titled product, 9-9 contaminated with BINAP oxide. 1H NMR (DMSO-d6) δ 8.24 (s, 1H), 8.22 (s, 1H), 7.17 (s, 1H), 4.80 (s, 2H), 2.28 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27](Cl)=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O1CCCCC1[O:40][C@H:41]([CH3:44])[CH2:42][OH:43].[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27]([O:43][CH2:42][C@H:41]([OH:40])[CH3:44])=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: C[C@H](CO)OC1CCCCO1
Reactant: O=C(Nc1nc2cc(-c3ccc(C(F)(F)F)c(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](O)COc1ccc2nc(C(=O)Nc3nc4cc(-c5ccc(C(F)(F)F)c(Cl)c5)ccc4[nH]3)cn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (80 mg) and (R)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol (100 μL) in dry DMF (1 mL) was added NaH (40 mg, dispersion in mineral oil) and the mixture was stirred at room temperature for 1 h. Then, water (10 mL) was added and the reaction mixture stirred for 10 minutes. The precipitated solid was filtered and dissolved in 1:1 mixture of methanol and DCM (5 mL). To this was added 2 M solution of hydrochloric acid in methanol (1 mL) and stirred at room temperature for 2 h. After air drying, the product was purified by column chromatography (12 g pre-packed silica gel column cartridge) using DCM and 2N ammonia in methanol to afford 6-((R)-2-hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (37 mg). LCMS (m/z): 532. 1H NMR (400 MHz, DMSO-d6): δ 12.5 and 11.5 (1H, brs) 8.85 (1H, s) 8.15 (1H, d) 7.92 (1H, brs) 7.87-7.93 (3H, m) 7.55-7.63 (2H, m) 7.08 (1H, d) 5.01 (1H, d) 4.17 (2H, d) 4.03-4.07 (1H, m) 1.18 (3H, d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.C[O:13][C:14]([C:16]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]2[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=2[CH:17]=1)=O>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:14]([C:16]2[CH:26]=[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]3[CH2:20][C:21]([CH3:24])([CH3:23])[O:22][C:18]=3[CH:17]=2)=[O:13])=[N:6][CH:5]=1
Reactant: COC(=O)c1cc(OCC(C)C)c2c(c1)OC(C)(C)C2
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc(NC(=O)c2cc(OCC(C)C)c3c(c2)OC(C)(C)C3)nc1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 6-aminonicotinic acid methyl ester (1.0 g, 6.57 mmol) and 4-isobutoxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (14a) (185 mg, 0.66 mmol). Purification by column chromatography eluting with 15-25% EtOAc in hexane gave a pale yellow solid (127 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=1.52 Hz, 1 H) 8.69 (s, 1 H) 8.42-8.48 (m, 1 H) 8.35 (dd, J=8.72, 2.15 Hz, 1 H) 6.96 (s, 1 H) 6.87 (s, 1H) 3.95 (s, 3 H) 3.82 (d, J=6.32 Hz, 2 H) 3.01 (s, 2 H) 2.06-2.14 (m, J=13.33, 6.60, 6.60 Hz, 1 H) 1.51 (s, 6 H) 1.04 (d, J=6.82 Hz, 6 H); LCMS for C22H26N2O5 m/z 399.10 (M+H+).
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:11]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)[CH3:12]>C(O)C>[CH2:11]([N:13]1[CH2:18][CH2:17][C:16]2[NH:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:15]=2[CH2:14]1)[CH3:12]
Reactant: CCN1CCC(=O)CC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCN1CCc2[nH]c3ccccc3c2C1
Temperature: 80 °C

Procedure:
To a solution of phenylhydrazine hydrochloride (1 equiv) in ethanol was added 1-ethylpiperidin-4-one hydrochloride (1 equiv) and heated at 80° C. for 16 h. After completion of the reaction (monitored by LCMS). The reaction mixture was concentrated under vacuum and basified with aq. saturated NaHCO3, extracted with EtOAc, the organic layer was separated dried over sodium sulfate and concentrated under reduced pressure to obtain 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm) 7.8 (bs, 1H), 7.4 (d, 1H), 7.2-7.0 (m, 3H), 3.7 (s, 2H), 2.9 (s, 4H), 2.7-2.6 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33].O.[NH2:36][NH2:37].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:22])[F:21])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:37][N:36]=1
Reactant: NN
Reactant: COc1ccccc1CC(=O)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1cccc(OC(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-methoxyphenylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (840 mg, 1.8 mmol) produced in Synthesis Example 27 in DMF (7 mL) was added hydrazine monohydrate (purity of 80%, 285 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-methoxybenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (770 mg, yield 92%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[C:14](=[O:16])[NH:17][C:18]2[C:19]([C:25]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(O)Cc1nccn1Cc1ccccc1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1nccn1Cc1ccccc1
Yield: 43 %

Procedure:
Synthesized from (1-benzyl-1H-imidazol-2-yl)-acetic acid (Tetrahedron Letters, 37 (51), 9259, 1996) and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2. Yield 43%.
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16]>>[Cl:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Oc1nc2ccccc2s1
Reactant: ClCCCCBr
Product: ClCCCCOc1nc2ccccc2s1

Procedure:
2-hydroxybenzothiazole (0.2 g, 1.32 mmol) and 1-bromo-4-chlorobutane (0.227 g, 1.32 mmol) were reacted in the same manner as in Example 1 to afford the compound K24 (0.302 g, 94%).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].CCN(C(C)C)C(C)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[C:21](Cl)=[O:22]>O1CCOCC1>[OH:4][CH2:3][CH:2]([NH:1][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([N+:27]([O-:29])=[O:28])=[C:18]([O:17][CH3:16])[CH:19]=1)[CH2:5][OH:6]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: NC(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC(CO)CO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 2-amino-propane-1,3-diol (1 equiv) in 1,4-dioxane (0.062 M) was added DIEA (2 equiv) and a solution of 3-methoxy-4-nitrobenzoyl chloride (1 equiv) in 1,4-dioxane (1.86 M) dropwise at room temperature. The resulting mixture was stirred at room temperature for 15 min. The solution was concentrated and the crude material was triturated in a 5:1 mixture of water:DCM (0.5 M), filtered, and dried to afford the title compound the solid (85% yield) that was used in the next step without further purification. MS (ESI) m/z 271.1 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[F:7][C@:8]12[C@@H:27]([OH:28])[CH2:26][C@@:25]3([CH3:29])[C@@H:18]([CH2:19][CH:20]=[C:21]3[C:22](=[O:24])[CH3:23])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:31])[CH2:10][CH2:11][C:12](=[O:30])[CH:13]=1>ClCCl.[O-2].[O-2].[O-2].[Cr+6]>[F:7][C@:8]12[C:27](=[O:28])[CH2:26][C@@:25]3([CH3:29])[C@@H:18]([CH2:19][CH:20]=[C:21]3[C:22](=[O:24])[CH3:23])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:31])[CH2:10][CH2:11][C:12](=[O:30])[CH:13]=1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.5 ml of dry pyridine in 220 ml of dry dichloromethane is added 5.1 g of chromium trioxide in small portions. When all the solid has dissolved, 25 g of dry Celite is added followed (with stirring) by a solution of 3.0 g of 9-fluoro-11β-hydroxypregna-4,16-diene-3,20-dione. The mixture is then stirred at room temperature for 30 minutes, filtered and the solids are washed with a small amount of dichloromethane. The filtrate and the washings are combined, washed with 5% hydrochloric acid, a dilute sodium bicarbonate solution and water, dried and evaporated to afford the product as a solid. One crystallization from acetone-hexane gives 2.65 g of the title compound, melting point 208°-211°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:54])[C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41](B4OC(C)(C)C(C)(C)O4)[CH:40]=3)=[CH:35][NH:36]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:25]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:54])[C:34]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:2]4[CH:3]=[C:4]([NH:10][C:11]5[CH:16]=[CH:15][C:14]([C:17]([N:19]6[CH2:24][CH2:23][O:22][CH2:21][CH2:20]6)=[O:18])=[CH:13][N:12]=5)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=4)[CH:40]=3)=[CH:35][NH:36]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(C)(C)c1ccc2c(=O)c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)c[nH]c2c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cccc(-c3c[nH]c4cc(C(C)(C)C)ccc4c3=O)c2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Yield: 17 %

Procedure:
A solution of 5-Bromo-1-methyl-3-[5-(morpholine-4-carbonyl) -pyridin-2-ylamino]-1H-pyridin-2-one (19 mg, 0.050 mmol), 7-tert-Butyl-3-[3-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-quinolin-4-one (20 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0052 mmol), and sodium carbonate (16 mg, 0.15 mmol) in 2 mL 1,2-dimethoxyethane and 1 mL water was microwaved at 170° C. for 12.5 minutes. The resulting mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (5% methanol/dichloromethane) to yield 7-tert-Butyl-3-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-1H-quinolin-4-one (5.7 mg, 0.0085 mmol). MS (ESI) 590.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl:29][CH2:30]Cl>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:23]([CH3:25])[CH3:24])[C:20]([O:22][CH2:30][Cl:29])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)O)C(C)C
Reactant: ClCCl
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)OCCl)C(C)C

Procedure:
2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyric acid was esterified by the method described in Example A-I-1, step d. The title compound (2.96 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.85.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH3:14])=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH2:9][N:8]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:13][CH2:12][C:11]=2[CH3:14])=[CH:20][CH:19]=1)=[O:31]
Reactant: CCOC(=O)Cl
Reactant: CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(C)=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)C1
Temperature: 110 °C
Yield: 97 %

Procedure:
Compound 11 (31 mg, 0.074 mmol) was dissolved in methylene chloride (2 mL) at room temperature. Ethyl chloroformate (14 ul, 2 eq) was added to the solution and it was heated to 110° C. in the microwave for 1 hour. The solvent was removed and the crude mixture was flashed with ethyl acetate/hexane to produce 28.4 mg (97% yield) of Compound 12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:14])[CH:11]=NO.S(=O)(=O)(O)[OH:16]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[NH:9][C:10](=[O:14])[C:11]2=[O:16]
Reactant: O=C(C=NO)Nc1ccc(F)cc1Cl
Reactant: O=S(=O)(O)O
Product: O=C1Nc2c(Cl)cc(F)cc2C1=O
Reaction time: 1 h

Procedure:
N-(2-Chloro-4-fluorophenyl)-2-(hydroxyimino)-acetamide (5.4 g, 24.9 mmol) was added portionwise to conc. sulfuric acid (70 mL) at 70° C. The mixture was stirred for 1 h, poured onto ice-water (200 mL) and filtered. The filter-cake was dried in vacuo to give crude 7-chloro-5-fluoroindole-2,3-dione which was used immediately without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Br)cc1C(=O)O
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
Methyl 5-bromo-2-methylbenzoate (see Japanese Unexamined Patent Publication No. 9-263549) (16.12 g) was dissolved in methanol (100 ml), and thereto was added 10% aqueous sodium hydroxide solution (50 ml). The mixture was stirred at 50° C. for 40 minutes. Under ice-cooling, the mixture was adjusted to pH 1 by addition of 10% aqueous hydrochloric acid solution, and diluted with water. Precipitated powder was collected by filtration, and dried to give 5-bromo-2-methylbenzoic acid (14.1 g). ESI-Mass m/Z 213/215 (M−H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH2:19][C:20]([N:22]([CH2:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21])[C:5](=[O:18])[N:6]2[CH3:17].Cl.[CH3:32][NH:33][CH3:34].C(N(CC)CC)C>CN(C)C=O>[CH2:29]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](=[O:21])[CH2:19][N:4]1[C:3]2[C:7](=[N:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:2]=2[N:33]([CH3:34])[CH3:32])[N:6]([CH3:17])[C:5]1=[O:18])[CH3:30]
Reactant: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(Cl)c21)c1ccccc1
Reactant: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(C(=O)Cn1c(=O)n(C)c2nc(-c3ccccc3)nc(N(C)C)c21)c1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
A mixture of 6-chloro-N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide obtained in Example 45 (0.6 g), dimethylamine hydrochloride (0.2 g), triethylamine (0.4 g) and dimethylformamide (20 ml) is stirred at 100° C. for four hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added water and chloroform. The chloroform layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from diisopropyl ether to give the desired compound (0.34 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[N:41][CH:40]=[N:39]2)[CH2:32][CH2:31][CH2:30][CH2:29]1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:33]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[N:41][CH:40]=[N:39]2)[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ncn(CCCCNC2CCCC2)n1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCCn2cncn2)C2CCCC2)c1)c1ccncc1
Yield: 37.1 %

Procedure:
A solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.040 g), cyclopentyl-(4-[1,2,4]triazol-1-yl-butyl)-amine (0.055 g) and EEDQ (0.050 g) in acetonitrile (2 ml) was stirred at reflux, under nitrogen, for 4 h. The solvent was evaporated and the residue was purified by flash chromatography eluting with dichloromethane:methanol:ammonia (95:5:0.5 then 90:10:1 v/v/v) to give the title compound as an orange oil (0.022 g).