Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](B(O)O)=[CH:11][N:10]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[CH:38][C:39]2[N:40]([C:42]([C:45]3[S:46][C:47]([S:50][CH3:51])=[CH:48][CH:49]=3)=[CH:43][N:44]=2)[CH:41]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:36]3[CH:37]=[CH:38][C:39]4[N:40]([C:42]([C:45]5[S:46][C:47]([S:50][CH3:51])=[CH:48][CH:49]=5)=[CH:43][N:44]=4)[CH:41]=3)=[CH:11][N:10]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2cnc3ccc(Br)cn23)s1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)s1
Yield: 64.3 %

Procedure:
736 mg 3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 25), 550 mg 6-bromo-3-[5-(methylsulfanyl)-2-thienyl]imidazo[1,2-a]-pyridine (compound in Production Example 58) and 100 mg tetrakis (triphenylphosphine)palladium were stirred at 80° C. for 3 hours in a solution mixture of 5 mL toluene, 5 mL ethanol and 2.5 mL of 2 N aqueous sodium carbonate under nitrogen atmosphere. The reaction solution was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate, the solvent was removed, and the resulting residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 685 mg of the title compound (pale greenish yellow crystals; recrystallization solvent, ethyl acetate/methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:18]=1[C:29]([F:32])([F:31])[F:30].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:17]2[C:18]([C:29]([F:31])([F:32])[F:30])=[CH:19][C:20]([N+:26]([O-:28])=[O:27])=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])[C:9](=[O:13])[O:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)Nc1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(c1ccc(Cl)cc1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
Ethyl 4-chlorophenylcarbamate (1.2281 g) was dissolved in tetrahydrofuran (30 ml), and to the solution were added sodium hydride (246.1 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (1.3870 g). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (75 g, hexane:ethyl acetate=5:1) to give the title compound (1.7323 g, 78%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH:4]([OH:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[C:19]([N:23]=[C:24]=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][CH2:3][CH:4]([O:18][C:24](=[O:25])[NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)=[O:6]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)C(O)CCBr
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)OC(CCBr)C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
By a procedure similar to that described in Step 1a above, 4-bromo-2-hydroxy-N(3-trifluoromethylphenyl)butanamide (0.52 g, prepared as described in Example 10, Step 1b above) was treated with t-butylisocyanate and triethylamine in dichloromethane to give the title compound (0.03 g, m.p. 107°-109° C.). NMR (CDCl3): δ 1.4(9H,s); 2.4(2H,m); 3.6(2H,t); 5.1(1H,bs); 5.3(1H,t); 7.3(2H,m); 7.6(1H,d); 7.8(1H,bs); 8.8(1H,bs). MS: M+ 424, 426. Under the extended time of this reaction, the major product was that of base-catalysed cyclisation (0.16 g, m.p. 114°-116° C.), identical to material described in Example 10, Step 3 above and Example 11, Step 2 below.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[O:10])[CH:7]=1.[H-].[Na+].[C:33]([CH:37]1[CH2:39][O:38]1)([CH3:36])([CH3:35])[CH3:34].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH2:39][CH:37]([OH:38])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[O:16])=[O:10])[CH:7]=1
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)N4CCNC4=O)cc3Cl)ccn2)cn1
Reactant: CC(C)(C)C1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)N4CCN(CC(O)C(C)(C)C)C4=O)cc3Cl)ccn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
A 0° C. solution of Example C9 (0.30 g, 0.696 mmol) in DMF (3 mL) was treated with NaH (60% in mineral oil, 0.070 g, 1.741 mmol), stirred at RT for 0.5 h, treated drop-wise with 2-(tert-butyl)oxirane (0.139 g, 1.393 mmol), stirred at RT for 1 h, then heated at 60° C. overnight. Additional 2-(tert-butyl)oxirane (0.1 mL) was added, the mixture heated at 60° C. for 7 h, cooled to RT, treated with additional NaH (60% in mineral oil, 0.070 g, 1.741 mmol), stirred for 20 min, treated with -(tert-butyl)oxirane (0.139 g, 1.393 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM) to afford N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)-2-oxoimidazolidine-1-carboxamide (29 mg, 7.5%). 1H NMR (400 MHz, DMSO-d6): δ 10.95 (d, J=2.7 Hz, 1 H), 8.41 (d, J=8.1 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 7.97 (s, 1 H), 7.57 (d, J=11.3 Hz, 1 H), 7.20 (d, J=2.5 Hz, 1 H), 6.64 (dd, J=5.7, 2.5 Hz, 1 H), 4.84 (d, J=5.5 Hz, 1 H), 3.84 (s, 3 H), 3.80 (m, 2 H), 3.58 (m, 2 H), 3.31 (m, 2 H), 3.05 (m, 1 H), 0.87 (s, 9H); MS (ESI) m/z: (M+H+): 531.2.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:21][C:22]#[N:23]>CN(C)C=O>[S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:21][C:22]#[N:23])[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc2c1SCCC2
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1SCCC2
Temperature: 60 °C
Yield: 98.8 %

Procedure:
Under argon, 2 g (12.03 mmol) of 8-thiochromanol are dissolved in 15 cm3 of DMF. 5 g (36.09 mmol) of potassium carbonate and a catalytic amount of potassium iodide are added. Then 5.45 g (72.18 mmol) of chloroacetonitrile dissolved in 5 cm3 of dimethylformamide (DMF) are added dropwise. The mixture is heated at 60° C. for 4 hours, and then the solvent is evaporated off. The residue is taken up in H2O and extracted with methylene chloride and then dried over MgSO4. After evaporation, the product is purified over a silica column. Eluant: methanol/CH2Cl2 1:99. 2.44 g of 2-(thiochroman-8-yl-oxy)acetonitrile are obtained (melting point: 66° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](O)=[O:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[CH2:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](=[O:35])[NH:66][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NCc1ccccc1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)C(C)C)ccc1OC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)NCc2ccccc2)C(C)C)ccc1OC

Procedure:
To a stirring solution of (3S*,4R*)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (70 mg, 0.138 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (42 mg, 0.166 mmol) and triethylamine (77 μL, 0.552 mmol) in CH2Cl2 (3 mL), benzylamine (18 μL, 0.166 mmol) is added. The resulting solution is refluxed for 2 h and then quenched by the addition of aqueous NaHCO3 solution. The organic layer is separated, and the aqueous phase is extracted 3 times with CH2Cl2. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude material is purified by preparative HPLC (C18-ODB-AQ, 5 μm, 20×50 mm, YMC, eluent: CH3CNIH2O+0.1 % HCOOH flow: 20 mL/min). The HPLC fractions are collected and lyophilized to afford the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.2. MS (LC-MS): 598.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.60 min.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N(C)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.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Nc1nc2cccc(Br)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2cccc3nc(N)nn23)cc1
Temperature: 150 °C

Procedure:
5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (2 g, 9.4 mmol), 4-methoxybenzeneboronic acid (1.71 g, 11.26 mmol), potassium phosphate (3.98 g, 18.77 mmol) and tetrakis(triphenylphosphine)palladium (0.54 g, 0.47 mmol) were added to a microwave tube containing a stirrer bar. Dimethylacetamide (12 mL) and water (4 mL) were then added and the reaction was heated to 150° C. for 10 min. The reaction was filtered through silica and washed through with methanol and concentrated under reduced pressure. The crude was suspended in diethyl ether and the solid collected and was used without further purification. Yield: 1.70 g, 71%; LCMS method: 1, RT: 3.43 min, MI: 241 [M+1]. NMR 1H (DMSO): 3.82 (s, 3H), 6.16 (brs, 2H), 6.96 (d, 1H), 7.06 (d, 2H), 7.29 (d, 1H), 7.46 (t, 1H), 7.92 (d, 2H).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([S:12](=[O:39])(=[O:38])[NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]=[C:24]3[C:27]3([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:30][CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].O>C(O)C>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:27]2([C:24]3[C:25]4[C:20](=[CH:19][CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:13][S:12]([N:9]5[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]5)(=[O:38])=[O:39])[CH:26]=4)[CH2:21][CH2:22][N:23]=3)[CH2:30][CH2:29][CH2:28]2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)N1CCN(S(=O)(=O)NCCOc2ccc3c(c2)C(C2(c4ccc(Cl)cc4)CCC2)=NCC3)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)N1CCNCC1
Yield: 100 %

Procedure:
4-(2-{1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yloxy}-ethylsulfamoyl)-piperazine-1-carboxylic acid ethyl ester (450 mg, 0.782 mmol, example 54, procedure 1) and a 10% solution of potassium hydroxid in ethanol (20 ml) were heated under reflux for 15 h. The solvent was reduced and water was added to the residue. The mixture was extracted with dichloromethane. The combined organic layers were washed with sodium chloride, dried with potassium sulphate and evaporated. The residue was purified by column chromatography with silica gel using dichloromethane/methanol 3%->5% as the eluent to give the desired product as a yellow oil (394 mg, 0.782 mmol, 61%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.Br[C:26]1[S:27][C:28]([CH3:31])=[N:29][N:30]=1.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O.O>[CH3:31][C:28]1[S:27][C:26]([N:16]2[CH2:15][CH2:14][CH:13]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]4=[O:1])=[CH:8][C:9]=3[F:19])[CH2:18][CH2:17]2)=[N:30][N:29]=1
Reactant: Cc1nnc(Br)s1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(c4nnc(C)s4)CC3)c(F)c2)C(=O)O1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 550 mg), 2-bromo-5-methyl-1,3,4-thiadiazole (EXAMPLE 87, Step 1, 323 mg) and potassium hydrogenphosphate (571 mg) in dimethyl sulfoxide (16 mL) is stirred under N2 at 100° C. for 2 hrs, cooled to ambient temperature, diluted with water (20 mL) and extracted with methylene chloride (3×20 mL). The combined organic phase is washed with water (20 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which is then chromatographed on silica gel (230-400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (2/98-3/97). Pooling and concentration of those fractions with an Rf =0.44 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 193-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=3[O:20][CH2:21][C@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:29](O)(=[O:32])[CH2:30][OH:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[CH:17][C:18]=2[O:20][CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:30](=[O:31])[CH2:29][OH:32])[N:13]=[CH:12][N:11]=1
Reactant: COc1cc(OC[C@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: O=C(O)CO
Product: COc1cc(OC[C@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 47 %

Procedure:
The procedure described in Example 1 was repeated using N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (90 mg) and glycolic acid (19 mg) to give the title compound in 47% yield; NMR Spectrum (DMSO-d6) 9.90 (s, 1H), 8.42 (s, 1H), 8.15 (dd, 1H), 7.70-7.60 (m, 1H), 7.40 (t, 1H), 6.90 (d, 1H), 6.78 (d, 1H), 4.65-4.53 (m, 2H), 4.42-4.37 (m, 1M), 4.20-4.11 (m, 1H), 4.03 (d, 1H), 3.90 (s, 3H), 3.45-3.35 (m, 3H), 2.10-1.82 (m, 41); Mass spectrum MH+ 461.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:5]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C(=O)O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C(=O)OCc1ccc2ccccc2c1)C(F)(F)F
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (2.96 g, 19.0 mmol), 2-(bromomethyl)naphthalene (4.19 g, 19.0 mmol), and potassium carbonate (7.86 g, 56.9 mmol) in 50 ml of anhydrous DMF was stirred at 30° C. overnight. Diluted with 150 ml of EtOAc, washed with 150 ml of H2O, 2×100 ml of 1N NaOH, 2×100 ml of 1N HCl, diced (Na2SO4) and concentrated to give an oil that was purified by ISCO using EtOAc in hexanes (5%) as eluents to provide the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[N:3]=[C:4]([CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([NH:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[N:7]=1
Reactant: Cc1cccc(N)c1
Reactant: CCOC(=O)c1c(Cl)nc(Cl)nc1CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(Cl)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
To a solution of ethyl 2,4-dichloro-6-((1,3-dioxoisoindolin-2-yl)methyl)pyrimidine-5-carboxylate (45.3 mg, 0.119 mmol) in MeCN (1 mL) was added m-toluidine (0.020 mL, 0.187 mmol) and N,N-diisopropylethylamine (0.037 mL, 0.212 mmol). The mixture was stirred at RT for 12 h. Saturated aq NaHCO3 was added to the mixture, which was subsequently extracted with EtOAc. The organic layers were washed again with saturated aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure and the residue was washed with IPE to give the title compound as a pale brown solid (37.1 mg, 69%). 1H NMR (400 MHz, CDCl3) δ ppm 1.50 (t, J=7.2 Hz, 3H), 2.36 (s, 3H), 4.52 (q, J=7.2 Hz, 2H), 5.20 (s, 2H), 6.97-6.98 (m, 1H), 7.23-7.27 (m, 1H), 7.33 (br s, 1H), 7.45-7.47 (m, 1H), 7.73-7.78 (m, 2H), 7.89-7.94 (m, 2H), 10.67 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:26][N:25]=[C:24]1S(C)(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:22][N:23]1[C:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:26][N:25]=[C:24]1[NH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Reactant: Cn1c(-c2ccccc2)nnc1S(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(Oc3ncccc3-c3ccnc(N)n3)cc2)nnc1-c1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a slurry of 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine (0.150 g, 0.54 mmol) and 4-methyl-3-(methylsulfonyl)-5-phenyl-4H-1,2,4-triazole (0.14 g, 0.59 mmol) in 0.6 mL THF was added lithium bis(trimethylsilyl) amide, 1.0 m solution in tetrahydrofuran (1.1 ml, 1.1 mmol). The reaction became a solid, and was sealed and heated to 70° C., at which point it became a heterogeneous brown mixture that could be stirred. After 2 h, the reaction did not appear to make further progress. The reaction was quenched with sat'd aqueous NH4Cl and partitioned between DCM and water. The aqueous layer was extracted 1×DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was absorbed onto silica gel from MeOH/DCM and dried. The residue was purified by silica gel chromatography, 40 g (0-100% 90/10 DCM/MeOH in MC) to give 4-(2-(4-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a white solid. MS m/z=437 [M+H]+. Calc'd for C24H20N8O: 436.5.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([F:34])[C:32]=1[F:33])[NH2:29]>ClCCCl>[CH2:2]([CH:3]([NH:29][C:28]1[CH:27]=[C:26]([F:25])[C:32]([F:33])=[C:31]([F:34])[CH:30]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(=O)CC
Reactant: Nc1cc(F)c(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCC(CC)Nc1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-Pentanone, acetic acid and sodium triacetoxyborohydride were added to a 1,2-dichloroethane solution of 3,4,5-trifluoroaniline, for stirring at ambient temperature for 14 hours, to obtain N-(1-ethylpropyl)-3,4,5-trifluoroaniline.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>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.O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([C:35]2[CH:36]=[C:31]([NH2:30])[CH:32]=[CH:33][CH:34]=2)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
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: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc2nc(Cl)nc(-c3cccc(N)c3)c2cc1OC
Temperature: 60 °C
Yield: 92.6 %

Procedure:
Twenty-five grams of 2,4-dichloro-6,7-dimethoxyquinazoline was suspended in 2.25 L of a mixed solution consisting of toluene:tetrahydrofuran:a 2 N sodium carbonate solution=1:1:1. To the reaction mixture was added 21.5 g of 3-aminophenyl boronic acid ½ sulfate, and the mixture was degassed, the atmosphere in the reaction vessel was replaced with nitrogen. To the reaction mixture was added 2.23 g of tetrakis(triphenylphosphine)palladium(0), followed by stirring at 60° C. under a nitrogen atmosphere. Eighteen hours after initiation of the reaction, 1.2 g of tetrakis(triphenylphosphine)palladium(0) was added to the reaction mixture, and the stirring was continued. Thirty hours later, 1.2 g of tetrakis(triphenylphosphine)palladium(0) was further added to the reaction mixture, and stirring was further continued. Forty-eight hours after initiation of the reaction, the reaction mixture was cooled, and it was then transferred into a separatory funnel, so as to separate an organic layer. The obtained organic layer was washed with 300 mL of brine, and was then dried over anhydrous magnesium sulfate. The desiccant was removed by passing it through 250 g of silica gel. The silica gel was washed with 1.5 L of ethyl acetate, and the obtained organic layers were combined and concentrated to dryness. The residue was triturated with 200 mL of ethyl acetate, and the obtained solid was then filtrated. The solid was washed with 100 mL of diethyl ether and 200 mL of a mixed solution consisting of n-heptane:ethyl acetate=1:1, and dried under aeration to give 28.2 g of a target product. Yield: 92.5%