Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.CC1(C)C(C)(C)OB([C:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C([O-])(O)=O.[Na+].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>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]=3)[CH:3]=2)[NH:7]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=C1Cc2cc(Br)ccc2N1
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: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)CC(=O)N3)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
To a suspension of 5-bromoindolin-2-one (600 mg, 2.83 mmol) in 1,4-Dioxane (9 ml) and H2O (3 ml) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.05 g, 3.40 mmol), Pd(PPh3)4 (164 mg, 0.142 mmol) and K2CO3 (1.17 g, 8.50 mmol). After stirring at 120° C. in microwave reactor for 1 h, the reaction mixture was diluted with sat. NaHCO3 aq. and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (CHCl3/MeOH) to give tert-butyl 4-(2-oxoindolin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (912 mg) as mixture with triphenylphosphin oxide.
Reaction SMILES: [CH3:1][C:2]1[CH:46]=[CH:45][CH:44]=[CH:43][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:42])[CH:8]([NH:21][C:22](=[O:41])[C@@H:23]([S:31]CC1C=CC(OC)=CC=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])=[O:10].C1(OC)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:46]=[CH:45][CH:44]=[CH:43][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:42])[CH:8]([NH:21][C:22](=[O:41])[C@@H:23]([SH:31])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])=[O:10]
Reactant: COc1ccc(CS[C@@H](Cc2ccccc2)C(=O)NC(C(=O)NCCc2ccccc2C)C(=O)NCCc2ccccc2C)cc1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: COc1ccccc1
Product: Cc1ccccc1CCNC(=O)C(NC(=O)[C@@H](S)Cc1ccccc1)C(=O)NCCc1ccccc1C
Reaction time: 3 h

Procedure:
Combine of N,N′-di-(2-methylphenethyl)-2-((S)-2-(p-methoxybenzylmercapto)-3-phenylpropionylamino)malonamide (0.175 g, 0.274 mmol), mercury (II) acetate (0.108 g, 0.34 mmol), and anisole (0.3 mL) in dichloromethane (10 mL). Cool in an ice bath and degas by repeatedly applying vacuum and filling the vessel with nitrogen. Add trifluoroacetic acid (4 mL). After 3 hours, purge with hydrogen sulfide (gas) for about 10 minutes. Filter and evaporate in vacuo to give a residue. Combine the residue with carbon tetrachloride and evaporate in vacuo to remove most of the trifluoroacetic acid. Chromatograph the residue on silica gel eluting with 1/2 ethyl acetate/hexane and then 1/1 ethyl acetate/hexane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(N)ccc1OCCCN1CCOCC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(OCCCN3CCOCC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 25.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.74 g) and 5-amino-2-(3-morpholinopropoxy) benzonitrile (0.76 g), the title compound (0.35 g) was obtained, melting point: 155–157° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:20])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=2)[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][C@@H:9]1[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccc(Cl)cc1
Reactant: C[C@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1Oc2ccccc2N(Cc2ccc(Cl)cc2)C(=O)[C@H]1NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
A solution of 0.10 g (342 mmol) ((6R,7S)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 1 ml dimethylformamide was added at 0° C. over a period of 20 minutes to a suspension of 0.015 g (342 mmol) sodiumhydride (55%) in 2 ml dimethylformamide. After 30 minutes 0.056 g (342 mmol) 4-chlorobenzylchloride was added and stirring was continued for 3 hours at 0° C. Extraction with water/ethylacetate and chromatography on silicagel with ethylacetate/heptane yielded 0.12 g (84%) [(6R,7S)-9-(4-chloro-benzyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester as white solid, MS m/e (%): 417.2 (M+H+, 69), 361.2 (100), 317.1 (91).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:12]2=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[C:29]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:22]([C:10]2[N:11]=[C:12]3[N:18]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:24])=[C:29]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH:28]=1
Reactant: CC(C)N1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1-n1cncn1
Agent: Cl
Product: CC(C)N1CCn2c1nc(C(=O)NCc1ccc(F)cc1-n1cncn1)c(OCc1ccccc1)c2=O
Yield: 76.2 %

Procedure:
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and (4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride (0.210 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.349 g (76% yield) of the title amide as white crystals; mp 171-172° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.24 (6H, d, J=6.8 Hz, 2×CH3), 3.66 (2H, t, J=9 Hz, CH2), 4.13 (2H, t, J=9 Hz, CH2), 4.41 (2H, d, J=6.3 Hz, NCH2), 4.43 (1H, m, CH), 5.10 (2H, s, OCH2), 7.06 (1H, dd, J=2.6 Hz and J=8.6 Hz, aromatic), 7.17 (1H, m, aromatic), 7.29-7.31 (3H, m, aromatics), 7.45-7.48 (2H, m, aromatics), 7.71 (1H, dd, J=5.9 Hz and J=8.6 Hz, aromatic), 8.0 (1H, s, CH), 8.36 (1H, broad t, NH), 8.39 (1H, s, CH). Anal. Calcd for C26H26FN7O3: C, 62.01; H, 5.20; N, 19.47. Found: C, 62.00; H, 5.20; N, 19.50.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:11])[C:3]=1[O:12][CH3:13].OS(O)(=O)=O.[CH3:19][CH2:20]O>>[CH2:19]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([O:12][CH3:13])[C:4]=1[I:11])[CH3:20]
Reactant: CCO
Reactant: COc1c(Br)ccc(C(=O)O)c1I
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)c(OC)c1I

Procedure:
A mixture of 4-Bromo-2-iodo-3-methoxy-benzoic acid (12.0 g, 0.0336 mol) and conc.H2SO4 (20 mL) in EtOH (200 mL) is refluxed overnight. After reaction, evaporated out EtOH and the mixture is extracted with ethyl acetate (3×1000 mL). The combined organic phase is washed with water and brine, dried over Na2SO4, concentrated in vacuo, purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate=20:1 to afford the desired product as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29]C(=O)OCC6C=CC=CC=6)[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][N:13](C4CCCCO4)[C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1.B(Br)(Br)Br.C(OCC)(=O)C.O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:28][CH2:27][CH2:26][C@H:25]([NH2:29])[CH2:24][CH2:23]5)[CH:19]=[CH:18][CH:17]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@H](NC(=O)OCc6ccccc6)CC5)n4)nn(C4CCCCO4)c3cn2)cn1
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@H](N)CC5)n4)n[nH]c3cn2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.5 %

Procedure:
To a solution of benzyl (4S)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate (70.0 mg, 0.13 mmol) in DCM (5.0 mL) at −10° C. was added dropwise 1 M of boron tribromide in DCM (0.33 mL, 0.33 mmol), and the reaction mixture was slowly warmed to room temperature (RT) and stirred at RT under N2 for 16 h. The reaction mixture was diluted into ethyl acetate and water. The organic layer was washed with aqueous saturated sodium bicarbonate solution, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was redissolved in DMSO (1 mL) and was purified by reverse phase HPLC to give 227 as a white solid (4.3 mg, 8.3%). 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.55 (s, 1H), 8.11 (s, 1H), 7.83 (s, 1H), 7.60 (t. J=7.8 Hz, 1H), 7.37 (d, J=7.1 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 3.85-3.75 (m, 1H), 3.74-3.58 (m, 2H), 3.33-3.40 (m, 1H), 2.95-2.85 (m, 1H), 2.12-1.93 (m, 2H), 1.86-1.58 (m, 3H), 1.56-1.33 (m, 2H); 2 protons not seen. LC/MS: m/z 389.4 [M+1]
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:14])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H][H]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][C:3](=[O:2])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:14][C:11](=[O:13])[CH3:10]
Reactant: [H][H]
Reactant: COC1=CC(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(OC(C)=O)c2ccccc2c1OC(C)=O
Reaction time: 1 h

Procedure:
A solution of 2-methoxy-1,4-naphthoquinone (20.0 g) in tetrahydrofuran (150 mL) was hydrogenated at atmospheric pressure over Pd-C (10%, 0.5 g) until the calculated amount of hydrogen was absorbed, approximately 4 hours. While still under a blanket of hydrogen, a solution of acetic anhydride (20 mL) and pyridine (18 mL) in tetrahydrofuran (50 mL) was added to the mixture. After stirring for 1 hour, the catalyst was filtered off and solvent evaporated from the filtrate. The residue was dissolved in ether (100 mL), washed with 1M hydrochloric acid (3×50 mL) and then with brine (2×50 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated. Recrystallization from ether afforded 2-methoxy-1,4-diacetyloxynaphthalene, m.p. 135°-136° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]4C(C#N)=CSC=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[N:55]1[CH:60]=[CH:59][CH:58]=[N:57]C=1C1C=CC(O)=CC=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:43]=[CH:44][C:45]([C:48]4[N:57]=[CH:58][CH:59]=[CH:60][N:55]=4)=[CH:46][CH:47]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: Oc1ccc(-c2ncccn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(-c4ncccn4)cc3)s1)CC2

Procedure:
The title compound 81 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 81A: 1H NMR (DMSO-d6): δ 8.83 (d, J=4.88 Hz, 2H), 8.32 (d, J=8.85 Hz, 2H), 8.03 (d, J=4.88 Hz, 1H), 7.79 (d, J=8.85 Hz, 1H), 7.67 (d, J=7.63 Hz, 1H), 7.34-7.49 (m, 5H), 7.04 (d, J=8.85 Hz, 2H), 4.84 (s, 2H), 4.07 (t, J=6.26 Hz, 2H), 3.72 (t, J=5.95 Hz, 2H), 3.18-3.12 (m, 2H), 3.03 (t, J=5.64 Hz, 2H), 2.01-2.07 (m, 2H). ESI (+)/MS: 649 (M+H)+.
Reaction SMILES: [Cl-].[Li+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([OH:24])=O)=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1.O=P(Cl)(Cl)Cl.[F:30][C:31]([F:50])([F:49])[C:32]1[CH:33]=[CH:34][C:35]([CH2:38][N:39]2[C:47]3[CH:46]=[CH:45][CH:44]=[C:43]([NH2:48])[C:42]=3[CH:41]=[N:40]2)=[N:36][CH:37]=1>CC(N(C)C)=O>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([NH:48][C:43]4[CH:44]=[CH:45][CH:46]=[C:47]5[C:42]=4[CH:41]=[N:40][N:39]5[CH2:38][C:35]4[CH:34]=[CH:33][C:32]([C:31]([F:50])([F:49])[F:30])=[CH:37][N:36]=4)=[O:24])=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1
Reactant: Nc1cccc2c1cnn2Cc1ccc(C(F)(F)F)cn1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)O)cnc3c2)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4cnn5Cc4ccc(C(F)(F)F)cn4)cnc3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
To a solution of 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid lithium chloride (0.0653 g, 0.188 mmol) in dry DMA (2.0 mL) at 0° C. was added POCl3 (0.0345 mL, 0.376 mmol) and the mixture was stirred at 0° C. for 30 minutes. 1-((5-(Trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-amine (0.055 g, 0.188 mmol) was added as a DMA solution (1.0 mL) and the mixture was gradually warmed to ambient temperature and stirred overnight. The mixture was concentrated under vacuum and 2M LiOH (2.5 mL) was added. The mixture was stirred for 10 minutes. The mixture was diluted with CHCl3 (20 mL) and with saturated aqueous NaHCO3 and the layers were mixed and separated. The aqueous phase was further extracted with CHCl3 and the combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The product was purified by preparative TLC (15% MeOH/CH2C12 adding 1% 7N NH3/MeOH) to provide 7-(2-(4-methylpiperazin-1-yl)ethoxy)-N-(1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a tan solid (0.028 g). The solid was dissolved in MeOH (2.0 mL) and HCl (1.88 mL, 3.76 mmol, 2.0M in Et2O) was added. The mixture was stirred for 2 hours and then concentrated. The resulting solid was washed with Et2O and finally with hexanes and dried under vacuum to provide the title compound (0.032 g, 24%). MS (ES+APCI) m/z=579 (M+H-3HCl).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH2:17])=[S:16])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:19][C:20](=O)[CH2:21][O:22][C:23](=[O:25])[CH3:24]>CN(C=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[S:16][CH:19]=[C:20]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[N:17]=2)=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCC(=O)CCl
Reactant: NC(=S)Nc1ccc(Oc2ccccc2)cn1
Solvent: CN(C)C=O
Product: CC(=O)OCc1csc(Nc2ccc(Oc3ccccc3)cn2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
(5-Phenoxy-pyridine-2-yl)-thiourea (0.86 mmol) is dissolved in DMF (1 ml) and acetic acid 3-chloro-2-oxo-propyl ester (1.1 eq.) in 1 ml DMF is added and stirred 2 h at 70° C. After cooling to RT the precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. “A9” is obtained after column chromatography (heptan/ethyl acetate) as colourless powder in a yield of 69%; mp. 158.5-160.5° C.; HPLC (method C): 1.89 min; LC-MS (method A): 1.938 min, 342.15 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 11.375 (s, 1H), 8.105 (d, 1H, J=2.8 Hz), 7.519 (dd, 1H, J=8.9 Hz, J=2.8 Hz), 7.389-7.347 (m, 2H), 7.120-7.088 (m, 2H), 6.995-6.978 (m, 2H), 6.918 (s, 1H), 5.007 (s, 2H), 2.064 (s, 3H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([NH:16][C:17]1[CH:26]=[C:25]([C:27]#[CH:28])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:8]([NH:16][C:17]1[CH:26]=[C:25]([C:27]#[C:28][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccccc1
Reactant: C#Cc1ccc(C(=O)OC)c(NC(=O)c2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#Cc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 mL of toluene suspension containing 0.15 g of methyl 2-(benzamido)-4-ethynylbenzoate, 0.090 mL of iodinated benzene, 5 mg of copper(I) iodide, 20 mg of bis(triphenylphosphine)palladium(II) chloride and 0.15 mL of triethylamine was stirred under nitrogen atmosphere at room temperature for 2 hours. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=8:1] to obtain 0.13 g of methyl 2-(benzamido)-4-(phenylethynyl)benzoate as white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:21][C:16]2[C:15]([NH:14][CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccccc1NCC1CCN(c2ccncc2)CC1
Product: O=C(Nc1ccccc1NCC1CCN(c2ccncc2)CC1)c1ccc(Cl)cc1
Yield: 55.2 %

Procedure:
Using a similar procedure to that described in Example 2, Part D, N1-[1-(4-pyridyl)piperidin-4-ylmethyl)-1,2-benzenediamine (167 mg, 0.59 mmol) and 4-chlorobenzoyl chloride (0.075 mL, 0.59 mmol) yielded 137 mg (55%) of the title compound.
Reaction SMILES: Cl.[C:2]1([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH:19]4[CH2:28][CH2:27][C:26]5[C:21](=[CH:22][C:23]([CH3:30])=[C:24]([CH3:29])[CH:25]=5)[C:20]4=[O:31])[CH2:14][CH2:13]3)[C:11](=[O:32])[NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)C>CO.O>[C:2]1([N:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:18][C@@H:19]4[CH2:28][CH2:27][C:26]5[C:21](=[CH:22][C:23]([CH3:30])=[C:24]([CH3:29])[CH:25]=5)[C@H:20]4[OH:31])[CH2:16][CH2:17]3)[C:11](=[O:32])[NH:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(cc1C)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: Cc1cc2c(cc1C)[C@@H](O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A slurry of 9.0 of 1-phenyl-8-[(1,2,3,4-tetrahydro-6,7-dimethyl-1-oxo-2-naphthalenyl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one, hydrochloride (1:1) (see example 192) in 200 ml of methanol is treated with 3.8 g of sodium borohydride in 40 ml of water. The sodium borohydride is added dropwise with ice cooling. The resulting mixture is stirred for 16 hours under nitrogen at room temperature. The mixture is diluted with water and extracted with methylene chloride. Concentration of the dried methylene chloride solution yields a crude solid. Trituration with absolute ethanol gives 6.6 g of the title compound, melting point 232°-233° C.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19]>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: O=Cc1cccc(B(O)O)c1
Product: Nc1ncc(-c2cccc(C=O)c2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-formylbenzene-boronic acid gives “A75”; method 1: HPLC/MS: 1.29 min, [M+H]=319;
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH3:45])[CH2:31][CH2:32][N:33]([S:41]([CH3:44])(=[O:43])=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1>>[CH3:29][N:30]([CH3:45])[CH2:31][CH2:32][N:33]([C:34]1[CH:35]=[CH:36][C:37]([NH:40]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:38][CH:39]=1)[S:41]([CH3:44])(=[O:43])=[O:42]
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)S(C)(=O)=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine Rf value: 0.3 (aluminium oxide, methylene chloride/ethanol=40:1) C29H32N4O5S
Reaction SMILES: C([O:3][C:4](=[O:43])[C@@H:5]([NH:13][C:14](=[O:42])[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]3[N:29]([C:33]4[C:38]([CH3:39])=[CH:37][C:36]([Br:40])=[CH:35][C:34]=4[CH3:41])[CH:30]=[C:31]([CH3:32])[C:23]=23)[CH2:18][CH2:17]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+].OS([O-])(=O)=O.[K+]>CCO>[Br:40][C:36]1[CH:37]=[C:38]([CH3:39])[C:33]([N:29]2[C:24]3=[N:25][C:26]([CH3:28])=[CH:27][C:22]([N:19]4[CH2:20][CH2:21][CH:16]([CH2:15][C:14]([NH:13][C@@H:5]([CH2:6][C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)[C:4]([OH:43])=[O:3])=[O:42])[CH2:17][CH2:18]4)=[C:23]3[C:31]([CH3:32])=[CH:30]2)=[C:34]([CH3:41])[CH:35]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CC1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Br)cc2C)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(N2CCC(CC(=O)N[C@@H](Cc3ccccc3)C(=O)O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.1 %

Procedure:
A mixture of (S)-2-(2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-acetylamino)-3-phenyl-propionic acid ethyl ester (140 mg), 4 M NaOH (1 mL) and EtOH (2 mL) was stirred at room temperature for 24 hours. 1 M KHSO4 (10 mL) was added into the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: CHCl3:MeOH=9/1) to obtain the title compound (35 mg) as an amorphous.