Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:36][C:37]1[C:45](/[C:46](/[NH:49]O)=[N:47]/[H])=[C:44]2[C:40]([C:41]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:42][NH:43]2)=[CH:39][CH:38]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:47]=[C:46]([C:45]3[C:37]([F:36])=[CH:38][CH:39]=[C:40]4[C:44]=3[NH:43][CH:42]=[C:41]4[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:49]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1c(F)ccc2c(CCC(=O)OCC)c[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(F)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To the solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D32) (676 mg) in tetrahydrofuran (50 mL) were added EDCI (824 mg) and HOBT (658 mg). The resulting solution was stirred at room temperature for 1 hour. Then ethyl 3-{6-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D145) (840 mg) was added and the solution was stirred at room temperature for another 2 hours. THF was removed in vacuo and the residue was dissolved in ethyl acetate (50 mL), washed with water (2×10 mL) and dried over sodium sulphate. The organic phase was concentrated. The residue was dissolved in THF (3 mL), TBAF (3 g) was added and the reaction solution was stirred under microwave (120° C., 2.5 hours). The reaction solution was poured into ethyl acetate (100 mL), washed with water (3×20 mL), dried over sodium sulphate. The organic phase was concentrate and the residue was purified by column chromatography to afford ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D146) (640 mg) as an off white solid. MS (ES): C24H23ClFN3O4 requires 471; found 472.2 (M+H+).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1>C(OCC)C>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:17])[C:14]([N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:32][CH:31]=3)[CH2:26][CH2:27]2)=[O:16])=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: COc1ccc(CC2CCNCC2)cc1
Reactant: CS(=O)(=O)Nc1ccc(NC(=O)C(=O)O)cc1
Solvent: CCOCC
Product: COc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc(NS(C)(=O)=O)cc3)CC2)cc1

Procedure:
The title compound is prepared from N-(4-methanesulfonylamino-phenyl)-oxalamic acid and 4-(4-methoxy-benzyl)-piperidine according to the method described in Example 1c. Melting Point: 206-208° C. (diethylether)
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[CH2:36][C:37]#N)([OH:3])=[O:2].[OH-:39].[Na+].[OH2:41].COC1C=C(C2(C3C=CC4OCOC=4C=3)C3C(=CC(OCCC)=CC=3)C(C3C=CC(OC)=CC=3OCC(O)=O)C2C([O-])=O)C=C(OC)C=1>CO>[C:1]([CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH3:26])[CH:21]=2)[CH:16]([C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH:15]1[CH2:36][C:37]([OH:41])=[O:39])([OH:3])=[O:2]
Reactant: [OH-]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(CC#N)C2c1ccc2c(c1)OCO2
Reactant: O
Agent: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(C(=O)[O-])C2(c1cc(OC)cc(OC)c1)c1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: CO
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(CC(=O)O)C2c1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
To a solution of 1RS,2RS,3RS)-3-(2-carboxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (290 mg, 0.56 mmol) in methanol (ca. 1 ml) was added aqueous 2N NaOH solution (0.3 ml) followed by H2O (8 ml) then (with caution) Na2O2 (120 mg). The mixture was heated to 70° C. and stirred for 20 h at which time HPLC showed only 15% hydrolysis. The mixture was stirred at 85° C. for 3 days with 3 (100 mg) portions of Na2O2 added each day. The reaction mixture was partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O then brine, dried (Na2SO4) and solvent removed in vacuo to afford the product as an oil (228 mg, 90% pure by HPLC) Final purification was obtained by crystallization as the bis cyclohexylamine salt. mp 210°-212° C.
Reaction SMILES: O.[Cl:2][C:3]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].B.O1CCCC1>C1COCC1>[Cl:2][C:3]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:4]=1[CH2:5][OH:6]
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 110.2 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzoic acid hydrate (5.0 g, 26.2 mmol, Acros) in THF (80 ml) was added dropwise 1 M borane-tetrahydrofuran complex (50 ml, 50 mmol, Aldrich) at ambient temperature under nitrogen. The resulting suspension was stirred at ambient temperature for 20 min and then heated to 80° C. for 1.5 h. To the reaction at ambient temperature was added a further amount of 1 M borane-tetrahydrofuran (20 ml, 20 mmol) and the suspension heated to 80° C. for 1 h. The solution was allowed to cool to ambient temperature and then carefully quenched by dropwise addition of methanol (40 ml). The solution was heated to 80° C. for 40 min. The solvent was removed in vacuo and the residue applied to a 50 g aminopropyl cartridge (pre-washed with methanol). The cartridge was eluted with methanol and the combined methanol fractions concentrated in vacuo to leave a white solid (4.58 g). A portion of the semi-crude material (1.5 g) was pre-absorbed on florosil and purified on silica (100 g) using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (0.92 g); LCMS: (System 4) (M-H)−=157, tRET=1.29 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[N:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2cc(Oc3ccc([N+](=O)[O-])nc3)ccn2)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
A solution of 2-(4-methyl-1H-imidazol-1-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.3 g, 4.37 mmol) in MeOH (20 mL)/THF (20 mL) was treated sequentially with NH4Cl (7.02 g, 131 mmol) and zinc dust (2.86 g, 43.7 mmol) and stirred at RT for 2 h. The mixture was diluted with THF, the solids removed via filtration through diatomaceous earth, washed with THF and the filtrate concentrated to dryness. The material was treated with THF, the solids removed via filtration and the filtrate concentrated to dryness, treated with DCM and sonicated. The resulting solid was collected via filtration and dried to afford 5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine (800 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, J=1.4 Hz, 1H), 8.28 (d, J=5.8 Hz, 1H), 7.83 (d, J=2.9 Hz, 1H), 7.63 (s, 1H), 7.31-7.30 (m, 2H), 6.70 (dd, J=5.8, 2.2 Hz, 1H), 6.51 (d, J=8.9 Hz, 1H), 6.05 (s, 2H), 2.14 (d, J=1.0 Hz, 3H); MS (ESI) m/z: 268.2 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]([OH:20])=O)=[N:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:38][CH2:39][C:40]1[C:41]([OH:48])=[N:42][C:43]([CH3:47])=[CH:44][C:45]=1[CH3:46]>ClCCl.O>[OH:48][C:41]1[C:40]([CH2:39][NH:38][C:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[N:10]=2)=[O:20])=[C:45]([CH3:46])[CH:44]=[C:43]([CH3:47])[N:42]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(c1ccccc1)n1nc(C(=O)O)c2ccccc21
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2nn(C(C)c3ccccc3)c3ccccc23)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
To a solution of 1-(1-phenylethyl)-1H-indazole-3-carboxylic acid (0.3 g, 1.12 mmol) in anhydrous dichloromethane (20 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (0.14 g, 1.0 mmol), 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.26 g, 1.37 mmol) and triethylamine (0.184 g, 1.83 mmol). The mixture was stirred at room temperature for 0.5 hours, and 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.15 g, 1.0 mmol) was added. The mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water (50 mL), and the mixture was extracted with dichloromethane (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol-50:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-1-(1-phenylethyl)-1H-indazole-3-carboxamide (70 mg, 18%). LRMS (M+H+) m/z: calcd. 400.47. found 400. 1H NMR (300 MHz, d6-DMSO): δ 11.59 (s, 1H), 8.24 (s, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.52-7.33 (m, 1H), 7.30-7.06 (m, 6H), 6.13 (d, J=7.0 Hz, 1H), 5.89 (s, 1H), 4.41-4.37 (m, 2H), 2.26 (s, 3H), 2.12 (s, 3H), 1.94 (d, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16].[C:19]([C:23]#[CH:24])([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C.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.[Cu]I>[CH3:20][C:19]([CH3:22])([CH3:21])[C:23]#[C:24][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16]
Reactant: C#CC(C)(C)C
Reactant: COc1nn(C)c(=O)n1Cc1cc(Br)ccc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1nn(C)c(=O)n1Cc1cc(C#CC(C)(C)C)ccc1C
Temperature: 25 °C
Reaction time: 31 h
Yield: 33 %

Procedure:
A mixture of 624 mg (2.0 mmol) of 4-(5-bromo-2-methylbenzyl)-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 299 of the present invention), 1.50 g (18.3 mmol) of tert-butyl acetylene, 67 mg (0.095 irmmol) of PdCl2(PPh3)2, 33 mg (0.17 mmol) of copper (I) iodide, 106 mg (0.40 mmol) of triphenylphosphine and 1.5 g of triethylamine in 8 ml of acetonitrile was stirred at room temperature under an atmosphere of nitrogen for 31 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated. The residue was subjected to silica gel column chromatography (eluted with hexane:ethyl acetate=6:1) to obtain 0.21 g (0.66 mmol) of 4-{5-(3,3-dimethyl-1-butynyl)-2-methylbenzyl}-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 526 of the present invention).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[CH3:30][C:31]1[C:35]([CH2:36][C:37](Cl)=[O:38])=[C:34]([CH3:40])[O:33][N:32]=1>>[CH3:30][C:31]1[C:35]([CH2:36][C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=[C:11]3[CH3:28])=[CH:6][CH:7]=2)=[O:38])=[C:34]([CH3:40])[O:33][N:32]=1
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Reactant: Cc1noc(C)c1CC(=O)Cl
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)Cc2c(C)noc2C)cc1

Procedure:
Synthesis in analogy to Example 17 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and (3,5-dimethyl-isoxazol-4-yl)-acetyl chloride to yield 2-(3,5-dimethyl-isoxazol-4-yl)-N-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-acetamide. LC/MS at 254 nm; [M+H] 521; Rt 3,083 min.
Reaction SMILES: [N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([O:10]C)=[O:9])[CH2:5]1)=[N+:2]=[N-:3].O.[OH-].[Na+]>CO>[N:1]([C@H:4]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@H]1C[C@H](N=[N+]=[N-])C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@H]1C[C@H](C(=O)O)C1

Procedure:
To a solution of trans methyl 3-azidocyclobutane carboxylate (2.38 g, 15.3 mmol) in methanol (5 ml) was added water (5 ml). The resulting cloudy mixture was stirred vigorously and treated dropwise (0.5 h) with an aqueous solution of sodium hydroxide (1 N, 15.3 ml) at such a rate that the temperature was kept under 25° C. The reaction mixture was stirred at 23° C. for 2 h and the methanol was evaporated in vacuo to a slightly yellow residue which was diluted with water (10 ml). The aqueous solution was washed with ether (2×10 ml), acidified with 1 N hydrochloric acid and extracted with dichloromethane (4×25 ml). The organic extracts were combined, washed with water, dried over anhydrous sodium sulfate and concentrated to a colorless oil which solidified on standing; 2.02 g, 93%; mp 39°-41° C. Anal. calcd for C5H7N3O2 : C 42.55, H 5.00, N 29.78; found: C 42.41; H 5.02, N 29.59; ir (KBr) νmax : 2100 (N3) and 1705 cm-1 with shoulder at 1735 (C=O of carboxylic acid); 1Hmr (CDCl3) δ: 4.19 (1H, m, H-1) and 3.5-2.0 ppm (5H, H-2, H-3, H-4).
Reaction SMILES: [CH:1]1(C(O)(CC2OC(C)(C)OC(=O)C=2)CCC2C=CC(C(CC)(CC)C#N)=C(F)C=2)CCC[CH2:2]1.[CH:34]1([C:39]([OH:64])([CH2:54][C:55]2[O:56]C(C)(C)O[C:59](=[O:61])[CH:60]=2)[CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3([C:51]#[N:52])[CH2:50][CH2:49]3)=[C:44]([F:53])[CH:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([C:39]2([CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]([CH2:1][CH3:2])([CH2:50][CH3:49])[C:51]#[N:52])=[C:44]([F:53])[CH:43]=3)[CH2:54][C:55](=[O:56])[CH2:60][C:59](=[O:61])[O:64]2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Reactant: CCC(C#N)(CC)c1ccc(CCC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F
Product: CCC(C#N)(CC)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F

Procedure:
The desired product was prepared analogously to step 4 of Example A(97), substituting 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-2-ethyl-butyronitrile from step 1 below in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-butyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. 1H NMR (CDCl3) δ: 1.01 (t, J=7.45 Hz, 6H), 1.62–1.90 (br, 8H), 2.03–2.17 (br, 4H), 2.20–2.29 (br, 2H), 2.37 (p, J=9.35 Hz, 1H), 2.75–2.82 (m, 2H), 2.86 (d, J=7.58 Hz, 2H), 3.53 (d, J=2.02 Hz, 2H), 6.94 (dd, J=13.01, 1.64 Hz, 1H), 7.04 (dd, J=7.83, 1.77 Hz, 1H), 7.57 (t, J=8.21 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:22])=O>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:10]=1)[C:5]([Cl:22])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Cl)c1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (700 mg, 2.67 mmol) was placed into 100 ml round bottom flask equipped with a stir bar. 3.0 ml of anhydrous chloroform was added to the flask followed by 2.0 ml of thionyl chloride and 1 drop of anhydrous DMF. The reaction mixture was stirred at 35° C. for 3 hours and then at room temperature overnight. LCMS of the sample after quenching a small amount with MeOH showed that no acid left. The solvent and excess thionyl chloride was removed under vacuum to give SKC-03-071. SKC-03-071 was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=O)=[CH:4][CH:3]=1.[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[CH:22][C:21]=1[C:31]#[N:32].CCOC(C)=O>ClC(Cl)C.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:31]([NH2:32])=[C:21]3[CH:22]=[N:23][N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:20]3=[N:19][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: N#Cc1cnn(-c2ccccc2)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc2c1cnn2-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 2-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-ethanone (300 mg, 0.99 mmol) in dichloroethane (3 mL) is stirred at room temperature while TiCl4 (311 mg, 1.64 mmol) is added dropwise. After the addition, the mixture is stirred at room temperature for 5 minutes and a solution of 5-amino-1-phenyl-1H-pyrazole-4-carbonitrile (150 mg, 0.815 mmol) in dichloroethane (3 mL) is added dropwise. After the addition, the mixture is heated to 125° C. for 5 hours. After cooling, the mixture is poured into a mixture of ice cold saturated aqueous NaHCOs solution (30 mL) and EtOAc (30 mL). The resultant precipitate is filtered through celite and washed with EtOAc (2×10 mL). The filtrate is extracted by EtOAc (3×15 mL). The organic layers are combined and washed with brine and dried (MgSO4). After filtering off the drying agent, the filtrate is concentrated and purified by column chromatography (silica gel, 0%˜40% EtOAc/hexane) to provide the titled compound 5-(4-chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-ylamine as light yellow solid:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C@H:24]1[N:29]([CH3:30])[CH2:28][CH2:27][N:26]([C:31]2[C:36]([F:37])=[C:35]([NH:38][NH2:39])[N:34]=[C:33]([CH3:40])[N:32]=2)[CH2:25]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([NH:39][NH:38][C:35]2[C:36]([F:37])=[C:31]([N:26]3[CH2:27][CH2:28][N:29]([CH3:30])[C@H:24]([CH3:23])[CH2:25]3)[N:32]=[C:33]([CH3:40])[N:34]=2)=[O:10])[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: Cc1nc(NN)c(F)c(N2CCN(C)[C@H](C)C2)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)[C@H](C)C2)n1
Yield: 50.5 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.079 g, 0.30 mmol), 4-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine (0.079 g, 0.31 mmol), NMM (0.10 mL, 0.90 mmol), HOAt (0.042 g, 0.31 mmol), and EDC (0.059 g, 0.31 mmol) were dissolved in DMF (4 mL) and treated in a manner similar to General Procedure A, Part B, to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.082 g, 49%). LCMS: (M+H)+=542.7.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](OCC)=[O:15])[CH3:2].O>C(O)C>[C:4]([C:5]1[O:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[C:14]=1[OH:15])([O:3][CH2:1][CH3:2])=[O:19]
Reactant: CCOC(=O)COc1ccc(Cl)cc1C(=O)OCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1oc2ccc(Cl)cc2c1O
Temperature: 80 °C
Yield: 87.3 %

Procedure:
12.3 g (0.11 mol) of potassium tert.-butylate were added in portions to a solution of 28.6 g (0.1 mol) of (2-carbethoxy-4-chlorophenoxy)-acetic acid ethyl ester in 50 ml of ethanol. The batch was warmed to 80° C. for 2 hours and was then cooled, and the reaction mixture was poured into 200 ml of water. The aqueous solution was first extracted with methylene chloride (to remove neutral impurities) and was then acidified with hydrochloric acid while cooling with ice. The acid solution was repeatedly extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate and then concentrated. 21 g (87.5% of theory) of 2-carbethoxy-5-chloro-3-hydroxy-benzofuran were obtained in the form of colorless crystals of melting point 100°-102° C.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[C:6]([Cl:9])=[N:5][S:4][N:3]=1.[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[Cl:9][C:6]1[C:7](=[O:8])[C:2]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:3][S:4][N:5]=1
Reactant: Oc1cccnc1
Reactant: O=c1c(Cl)nsnc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1c(Cl)nsnc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
To a stirred solution of 12.8 grams (0.07 mole) of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one and 6.7 grams (0.07 mole) of 3-hydroxypyridine in 300 ml of tetrahydrofuran was added dropwise 7.1 grams (0.07 mole) of triethylamine. During the addition the exothermic reaction caused the reaction mixture temperature to rise to 34° C. Upon complete addition, the reaction mixture was stirred for 16 hours during which time it cooled to ambient temperature. The reaction mixture was filtered to remove triethylamine hydrochloride. The filter cake was washed with tetrahydrofuran. The filtrate and wash were combined and evaporated under reduced pressure to a residual solid. The residue was triturated with 300 ml of distilled water and the insolubles collected by filtration. The filter cake was washed with water and recrystallized twice from ethanol. A sample of the recrystallized solid was dissolved in chloroform and subjected to analysis by thin layer chromatography. This analysis indicated that the solid contained impurities. The filtrates from the recrystallizations were combined and evaporated under reduced pressure to a residue. The residue was combined with the twice-recrystallized solid and dissolved in chloroform. The solution was slurried with silica gel in an effort to remove the impurities. The mixture was filtered and the filtrate was evaporated under reduced pressure to a residual solid. The solid was recrystallized from ethanol to give 7.0 grams (42%) of 3-chloro-5-(3-pyridyloxy)-4H-1,2,6-thiadiazin-4-one; m.p. 134.5°-135.5° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(-c2cccc3c2oc2ccccc23)cc1
Yield: 78.2 %

Procedure:
To a mixture of dibenzofuran-4-boronic acid (40 g, 0.19 mol), 4-bromobenzonitrile (34 g, 0.19 mol), sodium carbonate (120 g) in toluene (500 mL) and water (500 mL) was added tetrakis (triphenylphosphine)palladium (0) (11 g, 0.0095 mol) with stirring under N2 atmosphere. The reaction mixture was refluxed for 20 h. Toluene layer was separated, washed with water, dried and concentrated. The crude product was purified by column chromatography over silica gel (chloroform) to give the title compound (40 g, 79%).