Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.[Li+].CC([N-]C(C)C)C.C1CCCCC1.[CH2:31]=[C:32]1[O:36][C:34](=[O:35])[CH2:33]1>C1COCC1.CN(C=O)C>[C:32]([CH:33]1[CH:3]2[CH2:4][C:5](=[O:8])[CH:6]=[CH:7][C:2]2([C:9]#[C:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:1][C:34]1=[O:35])(=[O:36])[CH3:31]
Reactant: O=C1C=CC(O)(C#Cc2ccccc2)C=C1
Reactant: C=C1CC(=O)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: CC(=O)C1C(=O)OC2(C#Cc3ccccc3)C=CC(=O)CC12
Temperature: -30 °C
Reaction time: 0.67 h
Yield: 53 %

Procedure:
4-Hydroxy-4-(phenylethynyl)-2,5-cyclohexadien-1-one, the product of Example 2A, (10.5 g, 0.05 mole) was dissolved in dry THF (100 mL). The reaction was cooled to -30° C. and treated with 1.96M LDA in cyclohexane (25.5 mL, 0.05 mole). During the addition of the LDA solution, a beige-colored slurry formed. The reaction was cooled to -78° C. and stirred at that temperature for 40 min. Dry DMF (10 mL) was added. The reaction immediately became homogeneous. Diketene (6.3 mL, 0.08 mole) was added rapidly and the reaction was stirred for 20 min before an additional portion of diketene (4.0 mL 0.05 mole) was added. The stirred reaction was allowed to warm slowly to 0° C., then quenched into ice (300 g) and concentrated hydrochloric acid (45 mL). The resulting mixture was extracted with CH2Cl2. The combined extracts were washed with water, dried over anhydrous sodium sulfate overnight, filtered and concentrated. The resulting solution was concentrated in vacuo. The residue was treated with Et2O (300 mL) and cooled to 0° C. for 1 hr. The resulting solid was isolated by filtration and washed with Et2O to yield 7.8 g (53%) of the title compound as a light tan solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl.Cl.NC1C2C(=CC=CC=2O)C(S(O)(=O)=O)=CC=1N.S(=O)(O)[O-].[Na+]>CCO.O>[OH:1][C:2]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1ccccc1-c1cccc(C=O)c1O
Agent: Cl
Agent: Nc1cc(S(=O)(=O)O)c2cccc(O)c2c1N
Agent: O=S([O-])O
Solvent: CCO
Solvent: O
Product: O=Cc1cccc(-c2ccccc2)c1O
Temperature: 60 °C
Reaction time: 18 h
Yield: 155 %

Procedure:
To an agitated solution of 2-hydroxy-3-(2′-methylphenyl)benzaldehyde (0.030 g, 0.14 mmol) in EtOH (0.80 mL) was added 1,2-diamino-8-hydroxy-naphthalene-4-sulfonic acid dihydrochloride (0.033 g, 0.10 mmol) and sodium bisulfite (0.03 g) in water (0.20 mL). The solution was heated to 60° C. and agitated over 18 hours. The solution was cooled to room temperature, the tan precipitate was isolated by filtration and washed with water and ethyl acetate to provide the title compound (0.043 g, 89%) MS(ES) m/z 445 [M−H].
Reaction SMILES: N([O-])=O.[Na+].[C:5]([C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[O:11][C:12]1[C:17](N)=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:8])([CH3:7])[CH3:6].[I-:23].[K+].S(=O)(O)[O-].[Na+]>O.Cl>[C:5]([C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[O:11][C:12]1[C:17]([I:23])=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])O
Solvent: O
Product: CC(C)(C)c1ccccc1Oc1ncccc1I
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
A solution of sodium nitrite (157 mg, 2.28 mmol) in water (1 mL) was added to a mixture of 2-(2-tert-butylphenoxy)-3-aminopyridine (prepared above according to 1b) (500 mg, 2.07 mmol) in (1:1) conc. HCl:water (14 mL) at 0° C. The mixture was stirred at 0° C. for 15 min and a solution of potassium iodide (1.0 g, 6.22 mmol) in water (2 mL) was added. The mixture was stirred at 60° C. for 1.5 h and allowed to cool down to rt. A solution of sodium bisulfite was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (anhydrous sodium sulfate), filtered and evaporated. The residue was purified by flash-chromatography (dichloromethane:hexanes/20:100) to afford 394 mg (56%) of 2-(2-tert-butylphenoxy)-3-iodopyridine. (M+H)+=354.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](O)=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1.C1C=CC2N(O)N=[N:24]C=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH2:24])=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1
Reactant: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnccc1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.2 %

Procedure:
To a stirred solution of 4-(4-chloro-2-fluorophenyl)nicotinic acid (1.1 g, 4.37 mmol) (as prepared in Ex. 2, Part A) in anhydrous DMF (10 mL) cooled to 0° C. was added HOBT (1.339 g, 8.74 mmol), EDC (1.257 g, 6.56 mmol), DIEA (3.05 mL, 17.49 mmol) followed by ammonium chloride (1.169 g, 21.86 mmol). The reaction mixture was allowed to warm to RT and stirred for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)nicotinamide (0.900 g, 3.59 mmol, 82% yield) LC/MS (ESI) m/e 251 [(M+H)+, calcd for C12H9ClFN2O 251]; LC/MS retention time (method A): tR=1.34 min.
Reaction SMILES: S1C=CC(CC=O)=C1.[S:9]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][OH:22])[CH:17]=[CH:18][CH:19]=2)=[CH:10]1>C(Cl)Cl.CCOCC>[S:9]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([CH2:20][CH:21]=[O:22])[CH:17]=[CH:18][CH:19]=2)=[CH:10]1
Reactant: OCCc1cccc(-c2ccsc2)c1
Agent: O=CCc1ccsc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCc1cccc(-c2ccsc2)c1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 3-thiophenylacetaldehyde but using 2-(3-thiophen-3-yl-phenyl)-ethanol. The title compound: ES-MS: 200.9 [M−H]−; single peak at tR=4.53 min (System 2); Rf=0.63 (CH2Cl2/Et2O, 95/5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[OH:15][C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:18]3[CH2:19][CH2:20][C@@H:16]([OH:15])[CH2:17]3)=[O:13])[S:10][C:3]=12
Reactant: O[C@@H]1CCNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Yield: 36 %

Procedure:
This material was prepared by the coupling of lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate and (R)-3-hydroxypyrrolidine in a manner as previously described for example 2a to give 3.06 g (36%) of an off-white solid. 1H NMR (DMSO-d6): δ 8.73 (1H, d, J=5.1 Hz), 8.15, 8.09 (1H, s), 7.69 (1H, d, J=5.1 Hz), 5.10–5.06 (1H, m), 4.43–4.29 (1H, m), 4.05–3.89 (2H, m), 3.72–3.43 (2H, m), 2.08–1.79 (2H, m).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[CH2:3]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: C#CCN1CC[C@@H](O)C1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CC[C@@H](O)C3)c21

Procedure:
Using Method C above, (R)-3-Hydroxy-1-prop-2-ynyl-pyrrolidine (60 mg, 0.48 mmol) (Example 92A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P)4Pd (18 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-[3-(3-hydroxy-pyrrolidin-1-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 45 mg, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]S(=O)(=O)[CH:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:11]=2[CH:28]=1)=[O:5])[CH3:2]>C(Cl)(Cl)(Cl)Cl.C(O)(C)(C)C.O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:12]1[C:11]2[CH:28]=[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=[CH:9][C:10]=2[NH:17][C:16](=[O:18])[CH2:15][CH:14]=1
Reactant: CCOC(=O)Nc1ccc2c(c1)C(c1ccccc1Cl)S(=O)(=O)CCC(=O)N2
Solvent: O
Solvent: CC(C)(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Nc1ccc2c(c1)C(c1ccccc1Cl)=CCC(=O)N2
Reaction time: 0.5 h

Procedure:
93.1 g of 8-(ethoxycarbonylamino)-6-(2-chlorophenyl)-1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocine 5,5-dioxide are dissolved at 80° in a mixture of 1.3 l of carbon tetrachloride, 1.3 l of t-butanol and 33.5 ml of water. After cooling to 35°, the mixture is treated rapidly with 212 g of potassium t-butylate (in three portions) while cooling strongly. The temperature thereby rises to 45°-50°. After the reaction has faded away, the cooling bath is removed and the mixture is stirred for a further 30 minutes. The mixture is poured on to ice and extracted several times with chloroform. The organic solvents are evaporated and the residue is chromatographed on 310 g of silica gel. The desired product is eluted with toluene/chloroform (1:3). After recrystallization from ethyl acetate/petroleum ether, there is obtained ethyl 5-(2-chlorophenyl)-2,3-dihydro-2-oxo-1H-1-benzazepine-7-carbamate of melting point 241°.
Reaction SMILES: ClC1C=CC(C(C)(C)CC(O)(C(F)(F)F)C=O)=C(OC)C=1F.C(O[C:26](=O)[C:27]([C:43]([F:46])([F:45])[F:44])([OH:42])[CH2:28][C:29]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([F:39])[C:33]=1[O:40][CH3:41])([CH3:31])[CH3:30])C.[NH2:48][C:49]1[CH:58]=[CH:57][CH:56]=[C:55]2[C:50]=1[CH:51]=[CH:52][NH:53][C:54]2=[O:59]>CC1C=CC=CC=1C.C(OCC)(=O)C.[Cl-].[Na+].O.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]([CH3:31])([CH3:30])[CH2:28][C:27]([OH:42])([C:43]([F:46])([F:44])[F:45])[CH:26]=[N:48][C:49]2[CH:58]=[CH:57][CH:56]=[C:55]3[C:50]=2[CH:51]=[CH:52][NH:53][C:54]3=[O:59])=[C:33]([O:40][CH3:41])[C:34]=1[F:39]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(Cl)c(F)c1OC)C(F)(F)F
Reactant: Nc1cccc2c(=O)[nH]ccc12
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: COc1c(C(C)(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COc1c(C(C)(C)CC(O)(C=Nc2cccc3c(=O)[nH]ccc23)C(F)(F)F)ccc(Cl)c1F
Yield: 30.4 %

Procedure:
560 mg of the mixture that consists of (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl ester (since aldehyde constitutes two-thirds of the mixture, 560.2 mg of the mixture corresponds to 336.1 mg (0.981 mmol) of aldehyde) is heated for two hours to 120° C. with 157.1 mg (0.981 mmol) of 5-amino-isoquinolin-1(2H)-one and 0.557 mg (1.962 mmol) of titanium tetraisopropylate in 6 ml of o-xylene. After cooling, the batch is diluted with ethyl acetate and mixed with brine. The organic phase is separated and worked up as usual. After chromatography on a Flashmaster, 144.7 mg (30.4%) of the desired compound is obtained (relative to the proportion of aldehyde in the mixture).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)C1C=CC=CC=1)([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)[C:3](=[O:4])[CH2:2][Br:1])([CH3:8])[CH3:7]
Reactant: O=C(Br)CBr
Reactant: CC(C)N(c1ccccc1)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)CBr)c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
Bromoacetyl bromide (6.0 mL) in methylene chloride (100 mL) is added dropwise to a 0° C. solution of N-Isopropyl-N-(3,4-methylenedioxy-phenyl) aniline, prepared as in Part A, (12.0 g) in methylene chloride (100 mL) and triethylamine (9.41 mL) and the resultant mixture is allowed to attain RT overnight. The reaction mixture is washed with 1N hydrochloric acid (3×80 mL), water (2×80 mL), brine (80 mL), dried, (MgSO4) and concentrated in vacuo to afford crude N-Isopropyl-N-(3,4-methylenedioxy-phenyl) bromoacetamide (16.3 g) as a black mobile oil which is used without further purification: 1H NMR (300 MHz, CDCl3) δ6.82 (d, 1H, J=8.2), 6.61 (m, 2H), 4.90 (m, 1H, J=6.8), 3.58 (s, 2H), 1.07 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Cl:11])[N:7]([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[C:6]=2[C:5](=[O:17])[NH:4][C:3]1=[O:18].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])=[O:22].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O>[N+:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21](=[O:22])[CH2:20][N:4]1[C:5](=[O:17])[C:6]2[N:7]([CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])[C:8]([Cl:11])=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:18])([O-:31])=[O:30]
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(Cl)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Temperature: 60 °C
Reaction time: 26 h

Procedure:
A mixture of 6.02 g of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloroxanthine, 5.86 g of 2-bromo-1-(2-nitrophenyl)ethanone, and 5.00 g of potassium carbonate in 150 mL of NAN-dimethylformamide is stirred for approximately 26 hours at 60° C. For working up, the cooled reaction mixture is poured onto a mixture of 500 mL of 1 N sodium hydroxide solution and 200 g of ice. The precipitate formed is suction filtered and dried. Yield: 6.32 g (65% of theory); Rf value: 0.50 (silica gel, cyclohexane/ethyl acetate (4:6)); mass spectrum (ESI+): m/z=432, 434 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:63][CH2:64][C:65]1[CH:66]=[CH:67][C:68]2[C:72]([CH3:74])([CH3:73])[O:71][B:70]([OH:75])[C:69]=2[CH:76]=1>CN(C=O)C.CC(=O)OCC.O>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:25]([F:26])([F:27])[F:28])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:63][CH2:64][C:65]4[CH:66]=[CH:67][C:68]5[C:72]([CH3:74])([CH3:73])[O:71][B:70]([OH:75])[C:69]=5[CH:76]=4)=[O:21])=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
To a solution of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (3.6 g, 8.3 mmol) and HATU (5.24 g, 13.8 mmol) in DMF (25 mL) was added DIPEA (3.3 mL, 18.4 mmol). The reaction mixture was stirred at rt for 10 min and 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (2.1 g, 9.2 mmol) was added. The reaction mixture was stirred overnight. Water was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (3:1 to 1:1) to give the final title compound 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-2-methylbenzamide (3.1 g; yield 61%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.94 (t, J=6.0 Hz, 1H), 7.84 (d, J=6.5 Hz, 2H), 7.66-7.62 (m, 3H), 7.53-7.43 (m, 3H), 4.49 (d, J=6.0 Hz, 2H), 4.39 (d, J=18.5 Hz, 1H), 4.36 (d, J=18.5 Hz, 1 H), 2.42 (s, 3 H), 1.47 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 99.75% at 254 nm; MS: m/z=608.8 (M+1, ESI+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][C:16]=1[O:29][CH2:30][CH2:31][F:32].FC(F)(F)C(O)=O>COCCO>[F:32][CH2:31][CH2:30][O:29][C:16]1[CH:17]=[C:18]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])[CH:19]=[CH:20][C:15]=1[NH:14][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1OCCF
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COCCO
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OCCF)ncc1C(F)(F)F
Temperature: 95 °C
Reaction time: 6 h
Yield: 29.3 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol), (4-amino-3-(2-fluoroethoxy)phenyl)(morpholino)methanone (0.13 g, 0.47 mmol), trifluoroacetic acid (0.07 mL, 0.9 mmol) in 2-methoxyethanol (2.5 mL) was stirred at 95° C. for 6 hours. The reaction was the concentrated. The crude product was purified by reverse phase HPLC to give the title compound (61 mg, 29%). Additional compounds made using the above procedure are shown in Table 6 below.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.BrC1C([N+]([O-])=O)=CC=C[N:13]=1.N>[Cu]>[NH2:13][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12
Reactant: O=[N+]([O-])c1cccnc1Br
Reactant: Brc1nccc2cc[nH]c12
Agent: [Cu]
Agent: N
Product: Nc1nccc2cc[nH]c12

Procedure:
7-Bromo-1H-pyrrolo[2,3-c]pyridine(600 mg, 3.05 mmol)prepared from 2-bromo-3-nitropyridine in a similar manner to that of Preparative Example 1, powdery copper (194 mg) and cuprous chloride (603 mg) were added to 84 ml of a concentrated aqueous solution of ammonia. The obtained mixture was kept at 120° C. by heating in a sealed tube for 15 hours and treated to give 170 mg of 7-amino-1H-pyrrolo[2,3-c]pyridine. This product was reacted and treated in a similar manner to that of Examples 1 and 2 to give 57 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)[CH3:28].C(=O)(O)[O-].[Na+]>COCCOC.O>[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2)cc1

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester (3.0 g, 6.9 mmol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (2.2 g, 7.6 mmol), dichloro-bis(triphenylphosphine)palladium(II) (0.25 g, 0.35 mmol), and sodium bicarbonate (1.7 g, 20.7 mmol) were combined in DME (30 mL) and H2O (10 mL), and the reaction was stirred at 80° C. for 2 hours. After aqueous work-up, the crude material was purified by silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33](O)=[O:34])=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl.C(N(C(C)C)C(C)C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=2[NH:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(O)c1ccccc1Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccccc4Nc4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C

Procedure:
4-(6,7-Dimethoxyquinolin-4-yloxy)benzenamine (60 mg, 202 μmol), 2-(4-fluorophenylamino)benzoic acid (56 mg, 243 μmol), and HATU (108 mg, 283 μmol) were combined in a resealable tube. DCM (1012 μl, 202 μmol) and N-ethyl-N-isopropylpropan-2-amine (71 μl, 405 μmol) were added, and the reaction mixture in the tube was allowed to stir at RT. Upon completion (as judged by LCMS), the reaction mixture was concentrated in vacuo, dissolved in minimal DMSO and purified by preparative HPLC {15-85% (0.1% TFA in CH3CN) in H2O over 20 min}. Fractions containing pure product were combined and neutralized with saturated aqueous NaHCO3 then extracted with EtOAc, dried over MgSO4, filtered, and concentrated in vacuo to afford pure N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-2-(4-fluorophenylamino)benzamide as a off-white solid. MS Calcd for C30H24FN3O4: [M]+=509. Found: [M+H]+=510.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[OH:20].Cl[CH2:22][C:23](Cl)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CC#N>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:23](=[O:24])[CH2:22][O:20][C:13]=2[CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(N)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc2c(c1)OCC(=O)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.9 %

Procedure:
DIPEA (2.2 mL, 12.5 mmol) was added to 2-amino-5-methoxyphenol hydrochloride (1 g, 5.7 mmol) in THF (13 mL). The reaction mixture was cooled to 0° C., chloroacetyl chloride (0.5 mL, 6.3 mmol) was added portionwise and then stirred at 0° C. for 5 minutes. Further DIPEA (1.1 mL, 6.3 mmol) was added and the mixture was allowed to warm to r.t. and stirred for 3 days. The majority of the THF was removed in vacuo. EtOAc (50 mL) and water (50 mL) were added. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic fractions were washed with brine (20 mL), dried (MgSO4), filtered and the solvent was evaporated in vacuo. To a portion of the crude material (0.250 g, 1.159 mmol) in MeCN (6 mL) was added potassium carbonate (0.449 g, 3.246 mmol) followed by THF (2 mL). The reaction mixture was stirred at r.t. for 5 h and then concentrated in vacuo. Water (5 mL) was added and the solid collected by filtration, washed with water (3×5 mL) and dried in vacuo to give the title compound (0.173 g, 17%) as a red solid. δH (DMSO-d6) 10.53 (1H, br s), 6.80 (1H, d, J 8.5 Hz), 6.58-6.51 (2H, m), 4.52 (2H, s), 3.69 (3H, s). LCMS (ES+) 180.1 (M+H)+, RT 2.27 minutes (Method 1).