Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:5]([CH3:16])[NH:4][C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.[OH-].[Na+].O>[CH3:16][CH:5]1[CH:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:7][CH:2]([CH3:1])[CH2:3][NH:4]1
Reactant: COc1ccc(C2CC(C)C(=O)NC2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2CC(C)CNC2C)cc1
Yield: 65.7 %

Procedure:
A solution of 5.8 g (25 mmol) of 3,6-dimethyl-5-(4-methoxyphenyl)-3,4,5,6-tetrahydro-2-pyridone in 60 ml of dry tetrahydrofuran was added dropwise under nitrogen to a suspension of 1.63 g of lithium aluminium hydride (63 mmol) in 25 ml of dry tetrahydrofuran. After the reaction mixture had been refluxed for 2 hours, it was cooled and, while cooling with ice, 1.6 ml of water in 10 ml of tetrahydrofuran, 3.2 ml of 2N sodium hydroxide and 3.2 ml of water were successively added dropwise. After refluxing for a short periode of time the resulting precipitate was filtered off and rinsed thoroughly with warm tetrahydrofuran; the filtrate was evaporated under reduced pressure. The resulting crude product was purified by means of flash chromatography over 100 g of silicagel (Merck, grain size 0.040-0.063 mm) using a mixture of ethyl acetate, methanol and concentrated ammonia (93:6.5:0.5) as an eluent. After combining and evaporating the desired fractions, totally 3.6 g (65%) of 2,5-dimethyl-3-(4-methoxyphenyl)piperidine were obtained.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccccc1Cl
Yield: 25 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-chlorophenylboronic acid (available from Combi-Blocks Inc.; 63 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (23 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ 13.04 (br s, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.33-7.56 (m, 5H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[C:2]1=[N:11][OH:12].C[O-].[Na+].Br[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.O>CO>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[O:19][CH2:18][CH2:17][O:12][N:11]=[C:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: O=C1C(=NO)Oc2ccccc21
Reactant: BrCCOC1CCCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C(=NOCCOC2CCCCO2)Oc2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
5 g (0.03 mol) of benzofuran-2,3-dione 2-oxime (XI-1) are dissolved in 30 ml of methanol, and at 20° C. 15 ml of a 2 molar solution of sodium methoxide in methanol are added dropwise. The solvent is distilled off under reduced pressure. The crystalline residue is dissolved in 30 ml of N-methyl-2-pyrrolidinone and treated with 6.27 g (0.03 mol) of 2-(2-bromoethoxy)-tetrahydropyran at 20° C. The reaction mixture is stirred for 16 hours at 20° C., poured into 100 ml of water and the resulting mixture is extracted twice with 100 ml of dichloromethane each time. The solvent is distilled off under reduced pressure and the residue is chromatographed over silica gel using a mixture of diethyl ether/dichloromethane/petroleum ether (1:1:2). 5.55 g (62.1% of theory) of benzofuran-2,3-dione 2-{O-[2-(tetrahydropyran-2-yloxy)-ethyl]-oxime} (XIV-2) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([C:11]#[C:12][CH2:13][CH3:14])[C:5]=1[NH2:15]>CC#N.[Pd](Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]2[C:5]=1[NH:15][C:12]([CH2:13][CH3:14])=[CH:11]2)=[O:16]
Reactant: CCC#Cc1cc(Cl)cc(C(=O)OC)c1N
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: CCc1cc2cc(Cl)cc(C(=O)OC)c2[nH]1
Yield: 93.8 %

Procedure:
To a solution of 2-amino-3-but-1-ynyl-5-chlorobenzoic acid methyl ester (82 mg, 0.35 mmol) in MeCN was added palladium(II)chloride (3 mg, 0.02 mmol) and the reaction mixture was immersed into a preheated oil bath and refluxed for 20 min. The solvent was removed in vacuo and the residue was dissolved in ether and filtered through a short pad of silica. The resulting residue was purified by flash column chromatography (1:9 EtOAc:cyclohexane) to give the desired product (78 mg, 95%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ 9.56 (br s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 6.22 (s, 1H), 3.97 (s, 3H), 2.82 (q, J=7.5 Hz, 2H), 1.38 (t, J=7.5 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[CH3:29])#[N:19].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.ClCCl>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[CH3:29])#[N:19].[C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:8]2[C:9]3[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:25])=[CH:22][C:21]=1[CH3:29])#[N:19]
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1cc(C(=O)O)ccc1C#N
Solvent: ClCCl
Product: Cc1cc(C(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)ccc1C#N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Cyano-3-methyl-benzoic acid is synthesized based on the method described in patent EP1512687A1. To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (20 mg, 0.09 mmol), 4-dimethylaminopyridine (22 mg, 0.01 mmol) and 4-cyano-3-methyl-benzoic acid (29 mg, 0.18 mmol) at 0° C. in dichloromethane (2 mL) is added DCC (38 mg, 0.18 mmol). After stirring for 10 min the reaction is warmed to room temperature. A precipitate forms and stirring is continued for 16 h. The mixture is filtered and the filtrate is diluted with dichloromethane (10 mL), washed with water and a saturated sodium chloride solution. The combined organic extracts are dried over sodium sulfate, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:1) to furnish 1-(4-cyano-3-methyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 2.47 (s, 3H), 6.91 (s, 1H), 7.14 (dd, J=8.0, 4.9 Hz, 1H), 7.43-7.48 (m, 2H), 7.49-7.54 (m, 2H), 7.61 (dd, J=8.7, 1.6 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H), 8.03 (d, J=1.0 Hz, 1H), 8.44 (dd, J=4.8, 1.5 Hz, 1H), 8.55 (d, J=1.8 Hz, 1H). HRMS (ESI) m/z 363.1245 [(M+H)+: Calcd for C23H15N4O: 363.1246].
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH:16]=2)[C:11](=[O:38])[C:10]([CH:39]=O)=[N:9]1)[CH3:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH2:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[C:15]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:16]=2)[C:11](=[O:38])[C:10]([CH2:39][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:9]1)[CH3:7]
Reactant: C1CCNC1
Reactant: CCn1nc(C=O)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCn1nc(CN2CCCC2)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reaction time: 1.5 h
Yield: 77.3 %

Procedure:
A solution of pyrrolidine (0.167 mL, 2.017 mmol) and 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carbaldehyde (0.87 g, 1.833 mmol) in 1,2-dichloroethane (DCE) (19 mL) and 2 drops of acetic acid was treated with sodium triacetoxyborohydride (0.583 g, 2.75 mmol). The reaction mixture was stirred for 1.5 h and then concentrated. The residue was purified by automatic silica gel column chromatography (Combiflash RF), eluting with [dichloromethane/methanol/ammonium hydroxide (80:20:2)]/dichloromethane (0-60%) to afford 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)cinnolin-4(1H)-one (750 mg, 1.416 mmol, 77% yield) as a light yellow gummy solid. LCMS: (M+H)+: 530.3
Reaction SMILES: [C:1]([O:4][C@@:5]1([CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C@@H:16]([OH:25])[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:29][O:30][CH2:31]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]([O:4][C@@:5]1([CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C@@H:16]([O:25][CH2:29][O:30][CH3:31])[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: COCOC
Reactant: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OCOC)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
400 mg of 17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3β-ol is combined in 2.8 ml of absolute dichloromethane and 1.8 ml of formaldehyde dimethylacetal with a mixture of 600 mg of kieselguhr W 20 and 300 mg of phosphorus pentoxide and stirred for 45 minutes at room temperature. The mixture is vacuum-filtered from the insoluble components and washed with dichloromethane containing 3-5% triethylamine. The crude product obtained after evaporation is chromatographed on silica gel, thus producing 280 mg of 17β-acetoxy-3β-methoxymethoxy-1α-methyl-17α-n-propyl-5α-androstane.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:5][N:6]=1.[NH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>CC(O)C>[OH:30][C:26]1[CH:25]=[C:24]([NH:23][C:2]2[O:3][C:4]([C:7]3[N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]4[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:5][N:6]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2ccccc21
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(O)c3)o2)cc2ccccc21
Temperature: 80 °C
Yield: 73.9 %

Procedure:
A mixture of tert-butyl 2-(2-chlorooxazol-5-yl)-1H-indole-1-carboxylate 21 (0.23 g, 0.723 mmol) and commercially available 3-aminophenol 8 (0.079 g, 0.724 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-((3-hydroxyphenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 22 (0.209 g, 74% yield) as solid. MS (ES) m/z 392 (M+H+).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9].C(N(CC)CC)C.II.Cl.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.O>[N:4]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:8]([OH:10])=[O:9])=[C:1]=[S:3]
Reactant: S=C=S
Reactant: Cc1ccc(C(=O)O)cc1N
Agent: Cl
Agent: II
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)O)cc1N=C=S
Temperature: 25 °C
Reaction time: 26 h
Yield: 91 %

Procedure:
Carbon disulfide (0.26 mL, 4.4 mmol) was added to a mixture comprising 3-amino-4-methylbenzoic acid (0.23 g, 1.5 mmol), tetrahydrofuran (1.0 mL), water (1.0mL) and triethylamine (0.51 mL, 3.6 mmol), followed by stirring at room temperature for 26 hours. The obtained reaction mixture was dropwise added to a tetrahydrofuran (1.0 mL) solution of iodine (0.41 g, 1.6 mmol) over a period of two minutes at 0° C., followed by stirring at 0° C. for further two hours. Thereafter, 1M hydrochloric acid (1.5 mL) and sodium sulfite (38 mg, 0.30 mmol) were added and mixed. Then, ethyl acetate (6 mL) was added, and the organic layer was separated and concentrated under reduced pressure to dryness. To the residue, ethyl acetate (6 mL) and water (1 mL) were added, and the organic layer was concentrated under reduced pressure to dryness to obtain 3-isothiocyanato-4-methylbenzoic acid as a ocher solid (0.26 g, yield: 91%, HPLC purity: 95%, HPLC retention time: 3.9 min). LC-MS ES-192 (retention time: 4.3 min, condition 1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:17][C:18]1[NH:19][C:20]([CH3:40])=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32](F)=[CH:31][CH:30]=2)[N:24]=1.O>CN(C)C=O>[CH3:17][C:18]1[NH:19][C:20]([CH3:40])=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([O:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:4][CH2:3]3)=[CH:31][CH:30]=2)[N:24]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1cc(-c2cccc(-c3ccc(F)c4ccccc34)n2)c(C)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2cccc(-c3ccc(OC4CCN(Cc5ccccc5)CC4)c4ccccc34)n2)c(C)[nH]1
Temperature: 70 °C
Yield: 317.3 %

Procedure:
To a 20 mL round-bottomed flask equipped with condenser and N2 inlet were added 121 mg (0.633 mml) 4-hydroxy-N-benzylpiperidine and 5 mL dry dimethylformamide, followed by 32 mg (0.791 mmol) sodium hydride (60% in oil). The reaction was heated to 70° C. to ensure complete formation of the alkoxide, and then 100 mg (0.316 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-fluoro-naphth-1-yl)pyridine in 2 mL dry dimethylformamide was added, and the reaction was heated at 80° C. for 10 min. The reaction was cooled, poured into water, and extracted into ethyl acetate. After combining with another run on a larger scale, the combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford 489 mg (54%) of an oil.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.S(Cl)([Cl:14])=O>ClC1C=CC=CC=1Cl.CN(C=O)C>[Cl:14][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ccnc(C(F)(F)F)c1
Solvent: Clc1ccccc1Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Cl)ccn1
Temperature: 75 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
4-Hydroxy-2-trifluoromethylpyridine (6.4 g, 39 mmol) was dissolved in 1,2-dichlorobenzene (64 g). Thionylchloride (23.2 g, 195 mmol) and DMF (10 drops) were added to the reaction mixture which was then heated to 70 to 80° C. After about 2 hours the reaction was completed and excess thionyl chloride was removed at an elevated temperature. The desired product was distilled under reduced pressure (50° C., 15 mbar) to yield 4-chloro-2-trifluoromethyl-pyridine (6.5 g, 36 mmol, yield: 92%). If required, remaining DMF was removed using an aqueous work-up.
Reaction SMILES: C([O:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[C:17]1[C:26]2[O:25][CH2:24][CH:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:22]3[C:33](=[O:35])[NH:34][C:20]([C:21]=23)=[CH:19][CH:18]=1)(=O)C1C=CC=CC=1.[OH-].[Li+].O>O1CCCC1.CO>[OH:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[C:17]1[C:26]2[O:25][CH2:24][CH:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:22]3[C:33](=[O:35])[NH:34][C:20]([C:21]=23)=[CH:19][CH:18]=1
Reactant: Cc1noc(COC(=O)c2ccccc2)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(CO)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.6 %

Procedure:
A solution of [3-methyl-4-(2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-7-yl)isoxazol-5-yl]methyl benzoate (15.0 mg, 0.0320 mmol) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL) was treated with 2.0 M lithium hydroxide in water (0.10 mL, 0.20 mmol) and stirred at room temperature for 20 min. The reaction mixture was quenched with 6 N hydrogen chloride in water (to pH ˜2) and then concentrated. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) gave the desired product (8 mg, 69%) as a racemic mixture. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J=4.8 Hz, 1H), 7.77 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.31 (dd, J=7.4, 4.9 Hz, 1H), 7.09 (d, J=7.9 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.51 (s, 1H), 4.77 (dd, J=11.4, 1.8 Hz, 1H), 4.42 (dd, J=11.4, 3.1 Hz, 1H), 4.36 (s, 2H), 3.15 (s, 1H), 2.06 (s, 3H); LCMS calculated for C19H17N4O4 (M+H)+: m/z=365.1. found: 365.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.B(O)(O)[C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=1>COCCOC.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>[C:18]([C:17]1[C:12]([NH:11][C:3]2[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:13]2[S:22][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:20][C:14]2=[N:15][CH:16]=1)#[N:19]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
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
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C(=O)O)cc4)sc23)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 4-carboxylphenylboronic acid (350 mg, 2.12 mmol) and 100 mg of tetrakis(triphenylphosphine)palladium(0) in 50 mL of ethylene glycol dimethyl ether and 35 mL of saturated aqueous sodium bicarbonate is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of chloroform to 10% methanol in chloroform to provide 4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl]benzoic acid as yellow crystals, mp>300° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.40 (s, 1H), 7.78 (s, 1H), 7.86 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 8.03 (s, 1H), 8.08 (s, 1H), 8.64 (s, 1H), 9.80 (s, 1H), 13.14 (s, 1H); MS 470.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: NC1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 40.7 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (39 mg, 41% over 2 steps) as a orange-red solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.22 (m, 2H), 8.09 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.71 (dd, J=9.2, 2.8 Hz, 1H), 7.15 (m, 3H), 4.51 (d, J=10.3 Hz, 1H), 4.02 (m, 1H), 3.37 (m, 1H), 2.85 (tt, J=7.7, 4.6 Hz, 1H), 2.20 (m, 1H), 1.97 (m, 1H), 1.75 (m, 2H), 1.22 (m, 4H); ESI MS m/z 532 [C29H27ClFN5O2+H]+; HPLC 99.0% (AUC), tR=10.81 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.Cl.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>ClCCl.CN(C)C1C=CN=CC=1>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH:29][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 2-bromoisonicotinic acid (1.4 g, 6.93 mmol, 1.20 equiv) in dichloromethane (50 mL), EDC.HCl (1.64 g, 8.56 mmol, 1.50 equiv), 4-dimethylaminopyridine (1.04 g, 8.51 mmol, 1.50 equiv), and 3-(trifluoromethyl)benzylamine (1.0 g, 5.71 mmol, 1.00 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The resulting solution was diluted with 100 mL of dichloromethane. The resulting mixture was washed with 2×50 mL of sat. NH4Cl, 2×50 mL of sat. Na2CO3, and 2×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10-1:5). The product was obtained as 1.2 g (59%) of a white solid.