Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[C:10]([Cl:17])[C:9]=2[Cl:18])=[C:4]([F:19])[C:3]=1[O:20][CH3:21].S(Cl)([Cl:24])=O.C1(C)C=CC=CC=1>CN(C)C1C=CN=CC=1.CN(C)C=O.C(#N)C.CO>[Cl:17][C:10]1[C:9]([Cl:18])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:20][CH3:21])[C:4]=2[F:19])[N:13]=[C:12]([C:14]([Cl:24])=[O:15])[CH:11]=1
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)O)cc(Cl)c2Cl)c1F
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1c(Cl)ccc(-c2nc(C(=O)Cl)cc(Cl)c2Cl)c1F
Temperature: 75 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of 33.5 g (95 mmol) of 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-dichloro-2-pyridinecarboxylic acid, 10.2 mL (140 mmol) of thionyl chloride, 0.1 mL of N,N-dimethylforamide (DMF) and 200 mL of toluene was heated at 75° C. for 5 h. The reaction progress was monitored by conversion of the acid chloride to its methyl ester (one drop of reaction mixture added to 5 drops of a 10% wt methanol solution containing 4-(dimethylamino)pyridine, briefly heating to reflux, dilution with acetonitrile and injection). LC analysis indicated 8 area % remaining carboxylic acid and 3 area % of an unidentified closely following product. Another 5 mL of thionyl chloride and 0.1 mL of DMF was added, and heating was continued for an additional 2 h. After stirring at room temperature overnight, the reaction mixture was filtered to remove a small amount of an insoluble material. The filtrate was concentrated in vacuo, and toluene added twice and re-concentrated in vacuo to remove residual thionyl chloride. The white solid obtained (38.6 g) was dried in a vacuum oven at 40° C. to give 33.3 g of a white solid, mp 134-136° C. LC internal standard analysis (conversion to its methyl ester as described above) indicated 98.1 wt %. EIMS m/e (relative intensity) 369 (4Cl, 80), 332 (3Cl, 38), 304 (3Cl, 82), 269 (2Cl, 100), 254 (2Cl, 30), 226 (2Cl, 73), 191 (30), 156 (46); 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.32 (dd, J=8, 2 Hz, 1H), 7.15 (dd, J=8, 7 Hz, 1H), 4.02 (dd, J=1 Hz, 3H); 19F NMR (376 MHz, 1H decoupled, CDCl3) δ 126.83.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:35])[CH2:15][NH:16][C:17](=[O:34])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:7]1.C1CCNCC1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>ClCCl>[C:46]([NH:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:35])[CH2:15][NH:16][C:17](=[O:34])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:7]1)(=[O:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c(N)c2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(=O)Nc1cc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3NC(=O)OC(C)(C)C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.8 %

Procedure:
To a mixture of 1-(3-amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (27 mg, 0.049 mmol), (piperidinomethyl)polystyrene (2.7 mmol/g, 60 mg, 0.15 mmol) and dichloromethane (2 mL) was added acetic anhydride (0.12 mmol) in dichloromethane (0.12 mL). The reaction mixture was stirred at room temperature for 3 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated to give 1-(3-acetylamino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (30 mg, quant.): ESI/MS m/e 590.4 (M++H, C29H37F2N5O6).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:15]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:15])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-methoxy-2-nitrobenzoic acid (25.0 g, 126 mmol) and K2CO3 (35.0 g, 253 mmol) in DMF (126 mL) was added MeI (15.8 mL, 253 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. To the mixture was poured the water (200 mL) and then stirred at 5° C. for 30 min. The precipitated solid was collected by filtration, washed with water and hexane. The solid was dried under reduced pressure to afford the compound 52 in a crude form (26.2 g, 98%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]([CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C1(C2COC(=O)C2)CCCC1.O[Li].O>C(O)(C)C.O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)[C:3]([OH:18])=[O:2])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)C1CCCC1
Agent: O=C1CC(C2CCCC2)CO1
Agent: [Li]O
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)CC(C(=O)O)C1CCCC1
Yield: 67.9 %

Procedure:
Preparation of 4-Cyclopentyl-dihydro-furan-2-one 2-Cyclopentyl-succinic acid 4-tert-butyl ester 1-methyl ester (13.4 g, 52.3 mmol) and LiOH.H2O (2.8 g, 66.7 mmol) are stirred in 200 mL of 3:1 isopropanol/H2O at room temperature overnight. The isopropanol is evaporated, and the aqueous solution is extracted with Et2O (3×100 mL). The aqueous phase is acidified to pH=4 with saturated KH2PO4 and extracted with Et2O (3×100 mL). The Et2O is dried over MgSO4 and evaporated to give 8.6 g (68% yield) of 2-cyclopentyl-succinic acid 4-tert-butyl ester. NMR (1H, 400 MHz, CDCl3) δ1.1-1.3 (2H, m); 1.4 (9H, s); 1.5 (4H, m); 1.7 (2H, m); 1.9 (1H, m); 2.4 (1H, dt); 2.6 (2H, m). The product is carried on.
Reaction SMILES: Cl.C(O[C:5]([CH:7]1[C:12](=O)[CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][N:9]([CH3:20])[CH2:8]1)=[O:6])C.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]2[N:46]=[C:5]([OH:6])[C:7]3[CH2:8][N:9]([CH3:20])[CH2:10][CH:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]=3[N:45]=2)[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C1CN(C)CC(c2ccccc2)C1=O
Agent: Cl
Solvent: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(O)c3c(n2)C(c2ccccc2)CN(C)C3)ccc1-n1cnc(C)c1
Temperature: 78 °C
Yield: 32.4 %

Procedure:
A mixture of 1-methyl-4-oxo-5-phenyl-piperidine-3-carboxylic acid ethyl ester hydrochloride (89 mg, 0.3 mmol), N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (111 mg, 0.33 mmol), and triethylamine (0.21 mL, 1.5 mmol) in ethanol (2 mL) was heated at 78° C. for 18 h. The mixture was cooled, diluted with ethyl acetate (40 mL), and then washed with saturated aqueous sodium carbonate solution (10 mL) and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by column chromatography on silica gel using ethyl acetate/0-30% ethanol as eluent to give the title compound (43 mg, 32%) as a brown solid (from ethyl acetate/cyclohexane). MS ISP (m/e): 443.5 [(M+H)+]. mp 152-155° C.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][OH:13])=[C:8]([Cl:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[C:8]([Cl:14])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)n1ncc(Cl)c(CO)c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(Cl)c(CO[Si](C)(C)C(C)(C)C)c1=O
Reaction time: 10 h

Procedure:
2-tert-butyl-4-hydroxymethyl-5-chloro 3(2H)-pyridazinone (1 g, 4.62 mmol) is dissolved in DMF in a 25 ml round bottom flask and to this were added imidazole (0.377 g, 5.0 mmol) and tert-butyldimethylsilyl chloride (0.762 g, 3.09 mmol). The mixture is stirred for 10 hours after which it is extracted in dichloromethane and the organic layer washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate/hexanes) affords the above mentioned product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([OH:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:19][CH:30]2[CH2:31][CH2:32][NH:27][CH2:28][CH2:29]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(OCc2ccccc2)cc1OC1CCNCC1

Procedure:
Using methods substantially equivalent to those described in Example 1-C, methyl 4-benzyloxy-2-hydroxybenzoate (2.0 g, 8.1 mmol), N-tert-butoxycarbonyl-4-hydroxy-piperidine (1.6 g, 8.1 mmol), triphenylphosphine (2.1 g, 8.1 mmol), and diethyl azodicarboxyalte (1.3 mL, 8.1 mmol) afforded, after purification by chromatography (SiO2: 5 to 15% EtOAc in hexanes), 2.57 g (74%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[NH:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[C:18]1[CH:26]=O>>[NH:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[C:9](=[CH:26][C:18]2[NH:17][C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=2)[C:10](=[O:16])[NH:11]3)[CH2:5][CH2:6]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: O=Cc1cc2c([nH]1)CCCC2
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1cc2c([nH]1)CCCC2

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (33 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[ClH:12].Cl.[CH2:14]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:12].[ClH:12].[C:4]([CH:3]([N:26]1[CH2:27][CH2:28][N:23]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH2:24][CH2:25]1)[CH3:2])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: O=C(CCBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)c1ccccc1)N1CCN(CC(=O)c2ccccc2)CC1

Procedure:
A mixture of 3-bromo-1-phenylpropan-1-one (1.5 g, 8.9 mmol), N-phenacyl piperazine dihydrochloride (2.05 g, 7.4 mmol) and K2CO3 (21.75 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-13), 0.64 g (76%), mp 204-205° C., M+ 336.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]([NH2:12])=O)[N:9]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(OCC)(=O)C.O>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]#[N:12])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C(N)=O)cs1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(C#N)cs1
Yield: 75 %

Procedure:
5.1 g (27.5 mmol) 2-Acetylaminothiazol-4-carboxamide was dispersed in 27 ml pyridine, and 10.5 g (55 mmol) p-tolylsulfonyl chloride was added, to carry out reaction at room temperature for 10 hr, and then 150 ml ethyl acetate and 100 ml water were added to separate the layers. The resultant organic phase was washed with diluted HCl till aqueous phase being acidic, and then washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.45 g 2-acetylamino-4-cyanothiazole (yield 75%) with mp 185-188° C. (ethyl acetate). 1H NMR (DMSO-d6) 2.18 (3H, s); 8.33 (1H, s); 12.55 (1H, s).
Reaction SMILES: CCOCC.[C:6]([C:9]1[C:10]([O:29]C)=[CH:11][C:12]([O:27]C)=[C:13]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[N:18]=[CH:17][CH:16]=2)[CH:14]=1)([OH:8])=[O:7].B(Br)(Br)Br>ClCCl>[C:6]([C:9]1[C:10]([OH:29])=[CH:11][C:12]([OH:27])=[C:13]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[N:18]=[CH:17][CH:16]=2)[CH:14]=1)([OH:8])=[O:7]
Reactant: COc1cc(OC)c(-c2ccnn2-c2ccccc2C)cc1C(=O)O
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccccc1-n1nccc1-c1cc(C(=O)O)c(O)cc1O

Procedure:
1.6 Ether hydrolysis of “1d” using boron tribromide in dichloromethane under standard conditions gives the compound 5-(5-carboxy-2,4-dihydroxyphenyl)-1-(2-methylphenyl)-1H-pyrazole (“1e”).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:18])=[CH:4][C:5]([Cl:17])=[C:6]([N:8]([S:12]([CH2:15][Cl:16])(=[O:14])=[O:13])C(=O)C)[CH:7]=1.Cl>C(O)C.[OH-].[Na+]>[NH2:1][C:2]1[C:3]([F:18])=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][S:12]([CH2:15][Cl:16])(=[O:14])=[O:13])[CH:7]=1
Reactant: CC(=O)N(c1cc(N)c(F)cc1Cl)S(=O)(=O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
3 g (0.0095 mol) of N-(5-amino-2-chloro-4-fluorophenyl)-N[(chloromethyl)sulfonyl]acetamide were dissolved in 30 mL of ethanol and 30 mL of 25% sodium hydroxide solution. The mixture was stirred for 3 hours at 50° C. and then cooled to room temperature. 6 N hydrochloric acid was added with stirring and cooling until the solution had a pH of 5-6. The suspension was further cooled to 0-5° C., filtered, washed with water and dried to yield 2.4 g (92%) of the title compound as a solid melting at 103.5-105.5° C. Recrystallization from toluene raised the melting point to 105-106° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([CH3:24])([CH3:23])[CH:20]([OH:22])[CH3:21])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl.O>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([CH3:24])([CH3:23])[C:20](=[O:22])[CH3:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CC(O)C(C)(C)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)C(C)(C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
DMSO (14.7 mL, 205 mmol) was added dropwise to a solution of oxalyl chloride (9.0 mL, 103 mmol) in CH2Cl2 (200 mL) at −78° C. The reaction mixture was stirred for 30 min and a solution of 3-(3,4-dichlorophenyl)-3-methylbutan-2-ol (12 g, 51.4 mmol) in CH2Cl2 (50 mL) was added by cannula over 15 min. After stirring 30 min, Et3N (43 mL, 308 mmol) was added, and the reaction mixture was allowed to warm to room temperature over 1 h. Water (200 mL) was added, and the organic layer was separated. The aqueous layer was further extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to give 3-(3,4-dichlorophenyl)-3-methylbutan-2-one (10.7 g, 89%). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, 1H), 7.37 (m, 1H), 7.08 (d, 1H), 1.95 (s, 3H), 1.59 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[OH:23][C:24]1([C:31]2[S:35][CH:34]=[N:33][CH:32]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[OH:23][C:24]1([C:31]2[S:35][CH:34]=[N:33][CH:32]=2)[CH2:25][CH2:26][CH:27]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:29]1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Product: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(O)(c3cncs3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[F:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][C:44]=1[OH:52].C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[CH:48][C:43]([F:42])=[C:44]([OH:52])[CH:45]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: OB(O)c1ccc(F)c(O)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(F)c(O)c3)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Yield: 99.2 %

Procedure:
A similar procedure as described in Example 41, step 1 was used, starting from 4-[3-[6-(3-bromo-5-ethanesulfonyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (213 mg, 0.32 mmol), 4-fluoro-3-hydroxy-phenylboronic acid (101 mg, 0.64 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol), and cesium carbonate (317 mg, 0.97 mmol) to afford 4-[3-[6-(5-ethanesulfonyl-4′-fluoro-3′-hydroxy-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (218 mg, 99%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C37H47FO9S (M+Na)+ 709.2817, found 709.2817.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1)[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 100.1 %

Procedure:
A mixture of 3-(5-nitro-pyrid-2-yl)propenoic acid ethyl ester [0.8 g Reference Example 5(a)], ethanol (30 ml) and 5% palladium on charcoal (0.13 g) was stirred at ambient temperature under an atmosphere of hydrogen for 7 hours, left to stand over night and then stirred for a further 24 hours. The reaction mixture was filtered through a short pad of diatomaceous earth. The filtrate was evaporated to give the title compound (0.7 g) as a green oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH:6]=[CH:5][N:4]=1>Cl>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=2)=[N:10][CH:11]=1
Reactant: COc1cc(-c2ccc(C(F)(F)F)cn2)ccn1
Agent: Cl
Product: O=c1cc(-c2ccc(C(F)(F)F)cn2)cc[nH]1
Yield: 91.2 %

Procedure:
2′-Methoxy-5-(trifluoromethyl)-2,4′-bipyridine (337 mg, 1.32 mmol) was stirred in concentrated hydrochloric acid (200 mL) at 120° C. for 18 h and then concentrated. The residue was dissolved in MeOH (100 mL) and made basic with 6 N NaOH and re-concentrated until most of the solvent had been removed. The solids were filtered off, washed with water and dried under vacuum to provide the title compound (289 mg, 89%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.08 (s, 1H) 9.10 (s, 1H), 8.36-8.33 (dd, J=8.4, 2.1 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.53 (d, J=6.8, 1H), 7.09 (d, J=1.3 Hz, 1H), 6.90 (dd, J=6.8, 1.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:34]([NH:41]O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.NO>CN(C)C=O.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:41][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: ONCc1ccccc1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: Cl
Agent: NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(ONCc1ccccc1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (100 mg, 0.344 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (83.5 mg, 0.515 mmol) in N,N-dimethylformamide (1.4 mL) was stirred for 1 hour. In a separate flask was placed N-benzylhydroxylamine hydrochloride (82.2 mg, 0.515 mmol), triethylamine (71.7 μL, 0.515 mmol), and N,N-dimethylformamide (2 mL). This solution was stirred for 20 minutes. The hydroxylamine solution was added to the acylimidazole solution and the resulting solution was stirred for 1 hour at 70° C. The solution was cooled to room temperature and water (10 mL) was added. The insoluble material was filtered and dried to give the title compound (110 mg, 81% yield, m.p. 169-179° C. dec.).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:28]=[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20]N5C=CC=CC5=O)[N:14]4[N:13]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.O.NN.[OH-].[K+].[CH2:34]([OH:37])[CH2:35]O>O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:28]=[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][C:9]5[CH:10]=[CH:2][N:3]=[C:34]([OH:37])[CH:35]=5)[N:14]4[N:13]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2cc(Nc3nc4cccc(Cn5ccccc5=O)n4n3)ccc12
Reactant: OCCO
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1n[nH]c2cc(Nc3nc4cccc(Cc5ccnc(O)c5)n4n3)ccc12
Temperature: 190 °C
Reaction time: 8 h
Yield: 4.77 %

Procedure:
4-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylmethyl)pyridin-2(1H)-one. To a solution/suspension of (2-methoxypyridin-4-yl)(2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)methanone (400 mg, 0.847 mmol), in a 50 mL pressure vial, hydrazine hydrate (1.232 mL, 25.4 mmol), and potassium hydroxide (1188 mg, 21.17 mmol) were added followed by ethylene glycol (10 mL). The reaction mixture was heated to 190° C., and was left to stir overnight, then checked by LCMS. Once the reaction was complete, water was added to the crude mixture and the product was extracted with ethyl acetate three times. The organics were washed with brine and dried over sodium sulfate. The crude was purified on semi-preparative HPLC (20-100% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, 20 min). The fractions containing the product were loaded on a strata-X column to remove trifluoroacetic acid, then methanol was evaporated in vacuo. 4-((2-(3-methyl-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)pyridin-2-ol (15 mg, 0.040 mmol, 4.77% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.38 (s, 1H), 11.70 (br s, 1H), 9.76 (s, 1H), 8.07 (d, J=1.17 Hz, 1H), 7.56-7.65 (m, 1H), 7.49-7.55 (m, 2H), 7.34 (d, J=6.64 Hz, 1H), 7.08 (td, J=1.56, 7.81 Hz, 2H), 6.53 (d, J=0.78 Hz, 1H), 6.19 (dd, J=1.56, 6.64 Hz, 1H), 4.31 (s, 2H), 2.43 (s, 3H); MS (ESI): m/z 371.7 [M+1]+.