Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.C(OC([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH2:36])=[N:31]1)=O)(C)(C)C.CC(O)=O>CC(N(C)C)=O>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[N:3]=[C:2]2[NH:36][C:32]1[CH:33]=[C:34]([CH3:35])[NH:30][N:31]=1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(Br)c3n2)nc1
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(Br)cccc23)n[nH]1
Temperature: 100 °C
Yield: 21.8 %

Procedure:
To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-quinazoline (0.19 g, 0.49 mmol) in DMA (1.0 mL) were added 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.30 g, 1.53 mmol) and HOAc (0.065 mL, 1.1 mmol) and the mixture was heated to 100° C. for 5 h. The mixture was allowed to cool to rt and purified by reverse phase HPLC (ammonium acetate modifier). Fraction 1 containing pure product was treated with saturated aq NaHCO3 (2-4 mL) and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with sat aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to afford 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (48 mg, 20%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.22 (br s, 1H), 10.87 (br s, 1H), 8.57-8.81 (m, 2H), 8.24 (d, J=7.5 Hz, 1H), 8.02 (d, J=5.3 Hz, 2H), 7.54 (t, J=7.9 Hz, 1H), 5.95 (s, 1H), 2.17 (s, 3H); LC-MS (ESI) m/z 449/451 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=[O:22])[C:16]=2[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:19][C:18]([CH3:20])([CH3:21])[C:17](=[O:22])[C:16]=2[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccccc4)cc3)OC(C)(C)C2=O)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2=C(c3ccc(O)cc3)OC(C)(C)C2=O)cc1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a stirred solution of 5-(4-(benzyloxy)phenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (1.0 g, 3.0 mmol) in methanol (50 mL) was added Pd(OH)2 (150 mg, 1.07 mmol) at RT under an inert atmosphere. The reaction mixture was stirred under an atmosphere of hydrogen for 1 h. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo to afford 5-(4-hydroxyphenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (600 mg, 64%) as a pale yellow solid
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20]CC1(C)OC1.C1(C(N)C2C=CC=CC=2)C=CC=CC=1>CO>[ClH:20].[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1(CCl)CO1
Agent: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: NC(c1ccccc1)c1ccccc1
Solvent: CO
Product: Cl
Reaction time: 72 h

Procedure:
b,c) 1-Diphenylmethyl-3-hydroxy-3-methylazetidine. 12.5 g (117.3 mmol) of 1-chloro-2,3-epoxy-2-methylpropane are added to a solution of 21.5 g (117.3 mmol) of diphenylmethylamine dissolved in 50 ml of methanol, and the mixture is left for 3 days at room temperature and subsequently for 3 days under reflux. The methanol is evaporated off under reduced pressure, the resulting solid is washed with acetone and filtered off, and 28.8 g (85%) of 1-diphenylmethyl-3-hydroxy-3-methylazetidine hydrochloride, melting point 187°-197° C., are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]#[CH:18])=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[N:7][C:6]1=[O:28].[OH-].[Na+].Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][Cl:42]>ClCCl>[Cl:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][O:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]#[CH:18])=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:20]=[CH:21][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:23][CH:24]=2)=[N:7][C:6]1=[O:28]
Reactant: ClCCCCCCBr
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1OCCCCCCCl
Reaction time: 0.08 h

Procedure:
To a solution of 482 mg (1.13 mmol) 1-(2-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in 2 ml dichloromethane is added 1 ml 1M aqueous NaOH. After stirring for 5 minutes the solvents are evaporated. The residue is dissolved in 4.8 ml DMEU and 0.25 ml (1.70 mmol) 1-bromo-6-chlorohexane are added. After stirring for 3 days at rt additional 0.083 ml 1-bromo-6-chlorohexane are added and stirring at rt is continued for 1 day. The reaction mixture is poured onto water, extracted with ethyl acetate and purified by flash chromatography (hexanes/ethyl acetate 6:1).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH2:22]C(C)C)[N:5]([P@@:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:27][O:28][K].Cl>>[OH:28][NH:27][C:3](=[O:2])[C@H:4]([N:5]([P@@:13]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:22]
Reactant: NO[K]
Reactant: COC(=O)[C@@H](CC(C)C)N(Cc1ccccc1)[P@](C)(=O)c1ccccc1
Agent: Cl
Product: C[C@H](C(=O)NO)N(Cc1ccccc1)[P@](C)(=O)c1ccccc1
Reaction time: 16 h

Procedure:
N-((R)-Methylphenylphosphinyl)-N-benzyl-D-leucine methyl ester (181 mg, 0.55 mmol) is treated with a solution of NH2OK (2.2 mL, 1.76M in methanol) prepared as described in Fieser and Fieser, Vol. 1, p. 478). The reaction is stirred for 16 hours at which time TLC indicates completion. The reaction mixture is neutralized with 1M aqueous HCl and the volatiles are removed. The desired product is purified over flash silica eluting with THF. The resulting residue is crystallized by dissolving in ethyl acetate and adding hexane until the solution becomes cloudy. N-Hydroxy-2(R)-[[(R)-methylphenylphosphinyl]-benzylamino]-propionamide is obtained as hard, dense colorless crystals: MS-IS m/z 333 [M+H]+, 355 [M+Na]+. (R1 =benzyl, R2 =methyl, R3 =phenyl, R4 =phenyl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([Cl:27])=[N:21][C:22]([C:23]([O:25]C)=[O:24])=[C:11]2[CH2:10][N:9]=1.[OH-].[K+].CO>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([Cl:27])=[N:21][C:22]([C:23]([OH:25])=[O:24])=[C:11]2[CH2:10][N:9]=1
Reactant: COC(=O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A solution of 2 g (0.005 mole) of 6-(2-chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, methyl ester 0.7 g (0.012 mole) of potassium hydroxide, 60 ml of methanol and 2 ml of water was refluxed under argon for 2.5 hrs. The solution was evaporated in vacuo at 50°-60°. An aqueous solution of the residue was acidified with acetic acid to give a gelatinous, white precipitate. The precipitate was collected by filtration, washed with water and air dried on the funnel overnight to give off-white solid. Recrystallization from a solution of ethanol and methylene chloride gave white plates with mp 250°-253° (dec).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:25]=[CH:26][C:27]([Cl:32])=[C:28]([CH:31]=1)[CH:29]=O)(=[O:3])[CH3:2].[CH2:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][NH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:25]=[CH:26][C:27]([Cl:32])=[C:28]([CH2:29][N:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:33]2)[CH:31]=1)(=[O:3])[CH3:2]
Reactant: c1ccc2c(c1)CNC2
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(C=O)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(CN3Cc4ccccc4C3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.1 %

Procedure:
To a mixed solution of the above 5-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-2-chlorobenzaldehyde 83 (325 mg), 2,3-dihydro-1H-isoindole (98 mg), acetic acid (82 mg) in 1,2-dichloroethane (5 ml) was added sodium triacetoxyborohydride (219 mg). The mixture was stirred at room temperature for 3 hours, and cooled to 0° C. A saturated aqueous sodium hydrogen carbonate solution was added thereto to basify the reaction mixture. The mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0-1:1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(1,3-dihydro-isoindol-2-ylmethyl)benzene 84 (234 mg) as a colorless solid. APCI-Mass m/Z 574/576 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:22])=O>>[Cl:22][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Product: O=C(Cl)c1ccc(C=CC(=O)c2ccccc2)cc1
Yield: 100.4 %

Procedure:
A 1-L reaction vessel was charged with 80.0 g (0.32 mole) of 4-carboxychalcone and 377.7 g (3.17 mole) of thionyl chloride, and heated under reflux for 1 hour. Thereafter, thionyl chloride was removed by distilling, and thus 87.0 g of 4-(chlorocarbonyl)-chalcone was obtained (101% yield). This reaction is shown by the reaction formula in FIG. 1(b).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH:5]([C:15]1[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]=1[F:40])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[CH3:2].[CH3:42][CH2:43]O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:41])[CH:5]([C:15]1[CH:20]=[C:19]([O:21][CH2:42][CH3:43])[CH:18]=[C:17]([O:22][Si:23]([C:36]([CH3:37])([CH3:39])[CH3:38])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]=1[F:40])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(O)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 49 g (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-2-fluoro-5-hydroxy-phenyl]-(4-cyano-phenylamino)-acetic acid ethyl ester described in example 3.3 in 900 ml THF 24.86 g triphenylphosphine, 5.53 ml EtOH and 21.82 g di-tert-butyl azodicarboxylate were added sequentially. The solution was stirred for 4 hrs at room temperature and then evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/EtOAc) to yield 27.6 g (RS)-[3-(tert-butyl-diphenyl-silanyloxy)-5-ethoxy-2-fluoro-phenyl]-(4-cyano-phenylamino)-acetic acid ethyl ester as slightly yellow, amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6](=O)[CH:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])[CH3:8])=[O:4].C([O-])(=O)C.[NH4+:29]>C(O)C>[NH2:29][C:6](=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])[CH3:8]
Reactant: COC(=O)CC(=O)C(C)OC(=O)c1ccc(-c2ccccc2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: COC(=O)C=C(N)C(C)OC(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A mixture of biphenyl-4-carboxylic acid 3-methoxycarbonyl-1-methyl-2-oxo-propyl ester (1275 g, 3.9 mol, 1 eq) and ammonium acetate (640 g, 8.3 mol) in ethanol (10 L) was heated with stirring at 70-75° C. until the keto ester compound is completely consumed (1-2 h). The mixture was then kept at 0-5° C. for 1.5 h. The precipitated solid was collected by filtration and washed with hexanes (2.5 L). The product was dried overnight under vacuum at 50° C. to obtain 1244 g (90% yield, 98% HPLC purity) of the title compound.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH3:16])[CH:8]=[CH:7][C:6]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:5]=2[O:4]1.[Br:17]Br.O>C(Cl)(Cl)Cl>[Br:17][C:7]1[C:6]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]([CH2:2][F:1])([CH3:16])[CH:8]=1
Reactant: BrBr
Reactant: CC1(CF)C=Cc2cc([N+](=O)[O-])ccc2O1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(CF)C=C(Br)c2cc([N+](=O)[O-])ccc2O1

Procedure:
To 8.24 g of 2-fluoromethyl-2-methyl-6-nitro-2H-1-benzopyran dissolved in 100 ml of chloroform was added dropwise 2.7 ml of bromine with stirring under cooling with water, and the mixture was stirred for 20 hours at room temperature. After the solvent was removed, 100 ml of dioxane and 2N NaOH solution were added to the residue and stirred at room temperature for 16 hours. When ice-water was added to the reaction mixture, crystals were separated out. The crystals were collected by filtration, washed with water and dissolved in methylene chloride. It was washed with water and dried. The solvent was evaporated off to obtain 11.01 g of 4-bromo-2-fluoromethyl-2-methyl-6-nitro-2H-1-benzopyran with a melting point of 116°-117° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1Cl.[O:17]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[C:27]1[CH:28]=[CH:29][C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:25][CH:26]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1cccc(Oc2ncnc(N)c2Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.3 %

Procedure:
Into a 20-mL microwave vial was placed 6-(3-aminophenoxy)-5-chloropyrimidin-4-amine (400.00 mg; 1.69 mmol.), (4-phenoxyphenyl)boronic acid (542.62 mg; 2.54 mmol), palladium acetate (18.97 mg; 0.08 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (69.39 mg; 0.17 mmol), potassium carbonate (700.77 mg; 5.07 mmol) suspended in dioxane (8.00 ml) and water (0.80 ml). The reaction mixture was run in the microwave for 20 minutes at 140° C. The reaction mixture was allowed to cool to rt. Na2SO4 was added to the mixture which was subsequently filtered through a plug of silica gel and concentrated under reduced pressure. The crude mixture was purified using Biotage column chromatography eluting from 80-100% EtOAc/hexanes, then 0-100% MeOH/EtOAc. Fractions containing the desired product were combined and concentrated under reduced pressure. The residue was lyophilized overnight to afford 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine as a yellow solid (177.00 mg, 74% yield).
Reaction SMILES: C[NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[CH:50]=[N:49][C:48]([C:51]([O:53]C)=O)=[N:47]3)=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[N:37]=2)[CH:34]=1.N>>[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([C:35]([CH2:45][N:46]3[CH:50]=[N:49][C:48]([C:51]([NH2:2])=[O:53])=[N:47]3)=[C:36]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[N:37]=2)[CH:34]=1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: COC(=O)c1ncn(Cc2c(-c3ccc(F)cc3)nc3ccc(F)cn23)n1
Agent: N
Product: NC(=O)c1ncn(Cc2c(-c3ccc(F)cc3)nc3ccc(F)cn23)n1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate and ammonia. m/e+ 355 for C17H13F2N6O (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([C:15]4[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=O)[O:25]C(C)(C)C)[CH3:22])=[CH:17][C:16]=4[F:33])[CH:14]=3)[CH:11]=2)[CH2:3][CH2:2]1.Cl.[C:35](OCC)(=O)C>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([N:12]=[C:13]([C:15]4[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:25])[CH3:35])[CH3:22])=[CH:17][C:16]=4[F:33])[CH:14]=3)[CH:11]=2)[CH2:2][CH2:3]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1ccc(-c2cc3ccc(OCC4CC4)cn3n2)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc(-c2cc3ccc(OCC4CC4)cn3n2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)pyrazolo[1,5-a]pyridin-2-yl]-3-fluorophenoxy}-1-methylethyl]carbamate (200 mg), 4 M hydrogen chloride/ethyl acetate (2 mL), and ethyl acetate (2 mL) was stirred at room temperature for 2 hr. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (2 mL) and acetic anhydride (2 ml). The mixture was stirred at room temperature overnight. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and by preparative HPLC (C18, water/acetonitrile (containing 0.1% trifluoroacetic acid)). The desired fraction was neutralized with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (60.6 mg) as off-white crystals.
Reaction SMILES: C[O:2][C:3]1[CH:16]=[C:15]2[C:6]([CH:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:9]32[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[CH:5][CH:4]=1.Br>>[OH:2][C:3]1[CH:16]=[C:15]2[C:6]([CH:7]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:8][C:9]32[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C1(CCNCC1)OC2c1ccccc1
Agent: Br
Product: Oc1ccc2c(c1)C1(CCNCC1)OC2c1ccccc1

Procedure:
A suspension of 2.0 g. of 1,3-dihydro-6-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidine], (Example 73), and 32 ml. of a 48% hydrobromic acid solution is heated at reflux, effecting the separation of a hydrobromide salt as a crystalline precipitate. The mixture is poured into ice-water with stirring, the precipitate collected by filtration, the filter cake washed with water, and dried. Recrystallization from ethanol gives colorless crystals, m.p. 274°-276°, dec.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.Cl.[CH3:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OC(=O)C)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[CH:7]=[C:2]([NH:30][C:29]4[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:32][CH:31]=4)[C:3]4[CH:19]=[N:18][N:17]([CH3:20])[C:4]=4[N:5]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1ncc2c(Nc3ccc(S(C)(=O)=O)cc3)cc(-c3cccc4[nH]ncc34)nc21
Temperature: 100 °C
Yield: 17.1 %

Procedure:
A solution of 4-chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.04 g, 0.14 mmol) in dioxane was treated with 4-methylsulphonylaniline hydrochloride (0.058 g, 0.28 mmol) in the presence of (tris(dibenzylidene acetone)dipalladium(0), Pd2(dba)3 (0.13 g, 0.014 mmol), XANPHOS (0.016 g, 0.028 mmol) and cesium carbonate (0.18 g, 0.56 mmol) and the reaction mixture were heated overnight at 100° C. The reaction mixture was diluted with ethylacetate and water. The aqueous portions were extracted with ethyl acetate and the organic portions pooled and dried over anhydrous sodium sulfate. The solvent were removed and the crude material purified (Biotage) to obtain 10 mg of 104. 1H NMR (400 MHz, MeOD) δ 8.69 (s, 1H), 8.12 (s, 1H), 7.97 (d, J=8.7, 2H), 7.78-7.55 (m, 4H), 7.59-7.44 (m, 2H), 4.17 (s, 3H), 3.35 (s, 1H), 3.14 (s, 3H). MS (ESI) m/z 419.2 (M+1)+
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[N:11]=1.C1COCC1.[OH-].[Na+]>CCO>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:19])=[O:2])[O:8][CH:9]=1
Reactant: COC(=O)CCCc1nc(-c2ccccc2N)co1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccccc1-c1coc(CCCC(=O)O)n1

Procedure:
Combine 4-[4-(2-amino-phenyl)-oxazol-2-yl]-butyric acid methyl ester (2.36 g, 9.1 mmol) with THF (3 mL), EtOH (3 mL) and 2N NaOH (20 mL) and stir until hydrolysis is complete. Concentrate the mixture, dilute the residue with water and adjust the pH to 3.5-4.0 with aq HCl. Extract the mixture with EtOAc and dry the extracts over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for recovery of 4-[4-(2-amino-phenyl)-oxazol-2-yl]-butyric acid (1.63 g, 73%). MS (ES): (M+1)+ 247.1 m/z.
Reaction SMILES: Cl[C:2]1[CH:3]=C[C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:12]=2[NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[O:21])=[O:10])=[N:6][CH:7]=1.B(Br)(Br)Br.[CH2:34]([Cl:36])Cl>>[Cl:36][C:34]1[C:5]([NH:8][C:9]([C:11]2[C:12]([NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]#[N:29])=[CH:26][CH:27]=3)=[O:21])=[CH:13][CH:14]=[C:15]([OH:17])[CH:16]=2)=[O:10])=[N:6][CH:7]=[CH:2][CH:3]=1
Reactant: COc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: N#Cc1ccc(C(=O)Nc2ccc(O)cc2C(=O)Nc2ncccc2Cl)cc1
Reaction time: 72 h
Yield: 90 %

Procedure:
To a suspension of compound N-(5-chloro(2-pyridyl)){2-[(4-cyanophenyl)-carbonylamino]-5-methoxyphenyl}carboxamide (500 mg, 1.2 mmol) in DCM (100 mL) at −78° C. was added BBr3 (2 mL). The mixture was stirred at ambient temperatures for 72 hours. The solid was collected by filtration and was washed by DCM and water, dried under vacuum. The filtrate was concentrated and extracted with EtOAc. The organic extract was washed with brine, dried and evaporated. The resulting solid was combined with the solid obtained from filtration to give the title compound. Total yield is 90% (430 mg). MS found for C20H13ClN4O3 (M+H)+: 393.0.