Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:15]=2)[C:10]([CH:35]2[CH2:38][CH2:37][CH2:36]2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.O>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([CH:35]2[CH2:36][CH2:37][CH2:38]2)=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(C2CCC2)c2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(C2CCC2)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Tert-butyl6-(tert-butyldiphenylsilyloxy)-3-cyclobutylindazole-1-carboxylate (12.26 g) which can be prepared according to the method described in Reference example 13, etc. was dissolved in THF (83 mL; manufactured by Kanto Chemical Co., Inc.). Then, 1 mol/L-TBAF-THF solution (46 mL) was added and the mixture was stirred for 1 hour at room temperature. To the reaction solution, water and brine were added and extraction was carried out three times with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (6.4457 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]=[C:9]2[O:22][CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:10]=[C:9]2[O:22][CH2:23][C:24]([N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2nc(-c3ccccc3)cc(OCC(=O)N3CCOCC3)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2nc(-c3ccccc3)cc(OCC(=O)N3CCOCC3)c2c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of acetyl chloride (0.55 cc) in methylene chloride (5 cc) is added in the course of 10 minutes to a stirred solution of 4-[(6-amino-2-phenyl-4-quinolyl)oxyacetyl]morpholine (2.55 g), prepared according to Example 39, and triethylamine (1.2 cc) in methylene chloride (25 cc). The mixture is stirred for 1 hour at room temperature (approximately 20° C.) and the solvent evaporated off under reduced pressure. The residue is stirred for 10 minutes in an ethyl acetate/water (5:2 by volume) mixture, filtered off, dissolved in a toluene/acetic acid (50:50 by volume) mixture and precipitated with ethyl ether. After filtration and drying, 4-[(6-acetylamino-2-phenyl-4-quinolyl)oxyacetyl]morpholine (2 g), m.p. 261° C., is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9](=[O:12])(=[O:11])[NH2:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:13][CH2:14][C:15]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:2]=1[Cl:1])=[O:16]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(S(N)(=O)=O)cc1Cl
Product: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1

Procedure:
2-Chloro-4-sulphamoylaniline (50 g) and α-chloroacetyl chloride (24 ml) were refluxed together for 45 min. and the product worked up as in Example 2(a) to yield 59.5 g, m.p. 162°-164°
Reaction SMILES: [N+](C1C=CC(COC(C2N3[C@H](SC=2)C([CH:20]([O:34]C(=O)C)[C:21]2[N:22]=[C:23]4[CH:32]=[N:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]4[CH:33]=2)(Br)C3=O)=O)=CC=1)([O-])=O.P([O-])([O-])([O-])=O>[Pd].C1COCC1>[CH:33]1[N:24]2[C:25]3[C:30]([N:31]=[CH:32][C:23]2=[N:22][C:21]=1[CH:20]=[O:34])=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: CC(=O)OC(c1cn2c(cnc3ccccc32)n1)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=Cc1cn2c(cnc3ccccc32)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(5R,6RS)-6-((RS)-Acetoxy imidazo[1,2-a]quinoxalin-2-ylmethyl)-6-bromo-7-oxo-4-thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid p-nitrobenzyl ester (951 mg) and 10% Pd—C (50% wet, 477 mg) were added to a mixture of THF (48 mL) and 0.5 mol/L phosphate buffer (pH 6.5, 48 mL). The mixture was hydrogenated at 400 kPa at room temperature for 4 h. The reaction solution was filtered and Pd—C was washed with water and n-butanol. The reaction mixture was cooled to 0° C. and 1 N NaOH was added to adjust the ph to 8.5. The aqueous layer was separated and then the organic layer was extracted with water. The combined aqueous layer was concentrated to 57 g and applied to Diaion HP-21 resin (60 mL, Mitsubishi Kasei Co. Ltd.) column chromatography. After adsorbing, the column was eluted with water and then 5, 10, 15 and 20% acetonitrile:water solution (each 60 mL). The combined fractions were concentrated under high vacuum at 35° C. and lyophilized to give the title compound as a yellow amorphous solid, yield 148 mg (26.1%), mp 300° C. (dec). 1H NMR (D2O) δ 5.92 (s, 1H), 6.23 (s, 1H), 6.66 (s, 1H), 7.11-7.22 (m, 3H), 7.25 (d, 1H, J=7.9 Hz), 7.50 (s, 1H), 8.03 (s, 1H); IR (KBr) 3413, 1748, 1592, 1553 cm−1; Imax (H2O) 340, 293, 237, 218 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1
Reactant: COc1cccc(O)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1cccc(Oc2nc(Nc3cc(C)[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-methoxy-phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(3-Methoxy-phenoxy)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 377(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[F:52][C:53]1([F:58])[CH2:57][CH2:56][NH:55][CH2:54]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:52][C:53]1([F:58])[CH2:57][CH2:56][N:55]([C:25]([C:10]2[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[N:19][CH:18]=3)=[O:24])[CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:27])[CH2:54]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Reactant: FC1(F)CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CCC(F)(F)C3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (11 mg, 0.030 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol), 1-hydroxybenzotriazole hydrate (5 mg, 0.030 mmol), CH2Cl2 (2 mL) were added 3,3-difluoropyrrolidine hydrochloride (9 mg, 0.061 mmol) and N,N-diisopropylethylamine (21 μL, 0.12 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=3)([CH2:12][CH2:13]1)[CH2:10][O:9]2)(=O)=O.[C-:29]#[N:30].[Na+]>CS(C)=O.C(Cl)Cl>[O:22]([C:18]1[CH:17]=[C:16]([C:11]23[CH2:12][CH2:13][C:8]([CH2:7][CH2:6][C:29]#[N:30])([CH2:15][CH2:14]2)[O:9][CH2:10]3)[CH:21]=[CH:20][CH:19]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of 110A compound (100 mg, 0.25 mmol) and NaCN (61 mg, 1.2 mmol) in DMSO (3 mL) was stirred at 80° C. overnight. The mixture was cooled to rt, diluted with DCM, washed with 1N aq HCl, dried (MgSO4), and concentrated in vacuo. The crude was chromatographed (SiO2; continuous gradient of hexanes/EtOAc from 100:0 to 50:50) to afford the title compound (62 mg, 75% yield) as a colorless oil. LCMS [M+H]+=334.3. 1H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 2H), 7.31-7.25 (m, J=7.9, 7.9 Hz, 1H), 7.14-7.09 (m, 1H), 7.00 (dd, J=8.6, 1.1 Hz, 3H), 6.96 (t, J=2.0 Hz, 1H), 6.84 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 3.96 (s, 2H), 2.47-2.41 (m, 2H), 2.12-2.03 (m, 2H), 2.00-1.89 (m, 4H), 1.84-1.78 (m, 2H), 1.74-1.64 (m, 2H).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16])[CH3:13]>>[Cl:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:18][CH:19]=3)[C:6]=2[N:7]=1
Reactant: Clc1ncc2scc(Br)c2n1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2csc3cnc(Cl)nc23)cc1
Yield: 71.6 %

Procedure:
Ethyl 4-(2-chlorothieno[3,2-d]pyrimidin-7-yl)benzoate (185 mg, 72% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromo-2-chlorothieno[3,2-d]pyrimidine (200 mg, 0.81 mmol) and 4-(ethoxycarbonyl)phenylboronic acid (157 mg, 0.81 mmol).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 18.3 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (225 mg, 0.427 mmol) from Example 27B in DMF (3 mL) was added N-methyl piperazine (0.142 mL, 1.281 mmol) followed by diisopropyl ethylamine (0.223 mL, 1.281 mmol) and tetrabutyl ammonium iodide (157.72 mg, 0.427 mmol). The reaction mixture was heated at 60° C. for 15 h. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using a phenyl-hexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN). The appropriate fractions were concentrated followed by trituration with ether to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea (46 mg, 18%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.25 (s, 1H), 8.55 (s, 1H), 7.60 (d, 2H), 7.40 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.50 (s, 1H), 4.25 (m, 2H), 3.98 (s, 3H), 2.55-2.30 (m, 10H), 2.15 (s, 3H), 1.98 (m, 2H), 1.28 (s, 9H); LC-MS (ESI)m/z 590 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.[C:10]([O:14][C:15](=[O:21])[C@@H:16]([CH:18]([CH3:20])[CH3:19])[NH2:17])([CH3:13])([CH3:12])[CH3:11].CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:7]=[C:2]([NH:17][CH:16]([CH:18]([CH3:20])[CH3:19])[C:15]([O:14][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:21])[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)C(Nc1cncc(Br)c1)C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 69.1 %

Procedure:
To a nitrogen degassed mixture of 3,5-dibromopyridine (5.0 g, 21.11 mmol), D-Valine t-butylester HCl (Aldrich Chemical, 4.43 g, 21.11 mmol) and sodium tert-butoxide (6.09 g, 63.3 mmol), in Toluene (200 ml) was added BINAP (2.63 g, 4.22 mmol) followed by tris(dibenzylideneacetone)-dipalladium(0) (Strem Chemical, 1.933 g, 2.111 mmol). The reaction was sealed and heated at 90° C. for 1 hr. The reaction was cooled, quenched into brine (100 mL), aqueous KHSO4 (20 mL) and ethyl acetate (200 mL). Aqueous sodium bicarbonate was added to adjust the pH to 8.0 and the organic layer removed. The aqueous layer was washed with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered thru a pad of silica and the filtrate concentrated to oil. The oil was chromatographed on silica eluting with 5-30% ethyl acetate/hex to give 4.8 gm of compound I-2a, 69%.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=1>CC(=O)CC.O>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][O:46][C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)[CH:15]=2)[O:10][C:9]([C:22]2[N:27]=[CH:26][N:25]3[CH:28]=[CH:29][CH:30]=[C:24]3[CH:23]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCCl)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCOc3ccc(F)cc3)cc12
Yield: 68.8 %

Procedure:
A mixture of 6-(3-chloro-propoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 101A) (125 mg, 0.29 mmol), potassium carbonate (120 mg, 0.87 mmol), potassium iodide (48 mg, 0.29 mmol) and 4-fluorophenol (65 mg, 0.58 mmol), in butanone (3.5 ml) was heated in a sealed tube at 130° C. for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were washed with, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/dichloromethane: 0-100%) to yield the title compound (100 mg, 69%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH2:18][CH3:19])[C:15]([C:20](O)=[O:21])=[C:11]2[O:12][C:13]=1[CH3:14].[CH:23]1([CH2:26][NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:23]1([CH2:26][N:27]([CH2:28][CH2:29][CH3:30])[C:20]([C:15]2[C:16]([CH2:18][CH3:19])=[N:17][N:10]3[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[C:13]([CH3:14])[O:12][C:11]=23)=[O:21])[CH2:25][CH2:24]1
Reactant: CCCNCC1CC1
Reactant: CCc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C(=O)O
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)C(=O)c1c(CC)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Temperature: 50 °C

Procedure:
To a stirred solution of 3-(2,4-dichloro-phenyl)-6-ethyl-2methyl-pyrazolo[5,1-b]oxazole-7-carboxylic acid (Intermediate IA) (37 mg, 0.11 mmol, 1 eq.) in DMF (0.8 ml) is successively added cyclopropylmethyl-propylamine (0.017 ml, 0.12 mmol, 1.1 eq.), DIPEA (0.038 ml, 0.22 mmol, 2 eq.) and HATU (46 mg, 0.12 mmol, 1.1 eq.) at RT. The reaction mixture is heated at 50° C. for 2 h then poured into EtOAc and washed with K2CO3 2M in water (2×). The organic layer is dried over Na2SO4, filtered and concentrated to dryness and the resulting crude residue is purified by column chromatography (SiO2; gradient elution iso-hexane/EtOAc 6:1 to 1:1) to yield the title compound as a yellow oil. MS: m/z 434.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.90 (1H, d), 7.73 (1H, d), 7.65 (1H, dd), 3.46 (2H, t), 3.30 (2H, s), 2.70 (2H, q), 2.34 (3H, s), 1.60 (2H, m), 1.11 (3H, t), 1.02 (1H, m), 0.63 (3H, m), 0.48 (2H, m), 0.20 (2H, m).
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:8][CH:7]=1.[F:38][C:39](B(O)O)([F:41])[F:40]>>[Br:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[C:21]([CH:26]=1)[C:20]([NH:19][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:6]2[CH:11]=[CH:10][C:9]([C:39]([F:41])([F:40])[F:38])=[CH:8][CH:7]=2)=[CH:8][CH:7]=1)[C:3]([OH:2])=[O:37])=[O:36]
Reactant: OB(O)C(F)(F)F
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2O)cc1)C(=O)OC
Product: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Yield: 40.9 %

Procedure:
5-Bromo-2-heptyloxy-benzoic acid (0.231 g, 0.738 mmol) and the (2S)-Amino-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g, 0.738 mmol) were then combined as per general procedure A with HBTU (0.335 g, 0.885 mmol) and diisopropylethylamine (0.285 g, 2.21 mmol) to yield the (2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.200 g). The methyl ester of the title compound was the prepared from (2S)-(5-Bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.080 g, 0.140 mmol) and the trifluoromethylboronic acid (0.050 g, 0.281 mmol) as per general procedure F, which was further hydrolyzed as per general procedure C to give the title compound (0.020 g). 1H-NMR(400 MHz, CDCl3): 1.14(t, 3H), 1.53 (m, 8H), 1.92(m, 2H), 3.6(m, 2H), 4.21(m, 2H), 5.21(m, 1H), 7.12(d, 1H), 7.22(m, 2H), 7.36(d, 1H), 7.5(d, 2H), 7.58(m, 2H), 7.66(m, 1H), 7.78 (m, 6H), 8.62 (S, 1H), 8.9 (bs, 1H).
Reaction SMILES: N1(CC[CH2:8][NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:42]=[CH:41][C:32]5[O:33][C:34]([F:40])([F:39])[O:35][C:36]([F:38])([F:37])[C:31]=5[CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[O:11])C=CN=C1.NC[CH2:45][CH2:46][N:47]1[CH:51]=[CH:50]N=[CH:48]1>>[N:47]1([CH2:48][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:42]=[CH:41][C:32]5[O:33][C:34]([F:39])([F:40])[O:35][C:36]([F:37])([F:38])[C:31]=5[CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[CH:15]=[CH:14][N:13]=2)=[O:11])[CH2:46][CH2:45][CH2:50][CH2:51]1
Reactant: NCCCn1ccnc1
Reactant: O=C(Nc1ccc(Oc2ccnc(C(=O)NCCCn3ccnc3)c2)cc1)Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Product: O=C(Nc1ccc(Oc2ccnc(C(=O)NCCN3CCCC3)c2)cc1)Nc1ccc2c(c1)C(F)(F)OC(F)(F)O2

Procedure:
The title compound was prepared in the same manner described for N-[3-(1H-imidazol-1-yl)propyl]-4-[4-({[(2,2,4,4-tetrafluoro-4H-1,3-benzodioxin-6-yl)amino]carbonyl}-amino)phenoxy]pyridine-2-carboxamide, substituting 1-(2-aminoethyl)pyrrolidone for 1-(3-aminopropyl)imidazole. 1H-NMR (MeOH-d4) δ 8.45 (d, 1H), 8.00 (d, 1H), 7.65 (dd, 1H), 7.56 (m, 3H), 7.22 (d, 1H), 7.10 (m, 2H), 7.04 (dd, 1H), 3.57 (t, 2H), 2.77 (t, 2H), 2.67 (m, 4H), 1.83 (m, 4H); MS LC-MS [M+H]+=576.2, RT=3.16 min.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:23]=3[C:38]3[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:3])=[O:34]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1ccncc1
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-c2ccncc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 4-pyridyl boronic acid as in Example 38 to afford 0.011 g (9%). 1HNMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H24NO4F3 507, found 508 (M+1, 100%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:20][CH3:21])=[CH:6][C:7]([CH2:11][C:12]2[C:13]([NH2:19])=[N:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[OH-].[K+].[CH3:24]I>CO>[CH2:1]([C:4]1[C:9]([O:10][CH3:24])=[CH:8][C:7]([CH2:11][C:12]2[C:13]([NH2:19])=[N:14][C:15]([NH2:18])=[N:16][CH:17]=2)=[CH:6][C:5]=1[O:20][CH3:21])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCc1c(O)cc(Cc2cnc(N)nc2N)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Yield: 75 %

Procedure:
A mixture of 1.43 g. of 6-allyl-α-(2,4-diamino-5-pyrimidyl)-5-methoxy-m-cresol, 5 ml. of 1-N potassium hydroxide and 300 ml. of 40% aqueous methanol was treated with 0.32 ml. of methyl iodide and stirred at room temperature for 48 hours. The methanol was removed by distillation and the residue was extracted with ethyl acetate. Working-up of the ethyl acetate extract yielded 5-(4-allyl-3,5-dimethoxybenzyl)-2,4-diaminopyrimidine of melting point 185°-187° C. (from methanol) in a yield of 75%.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][C:11]([CH3:16])([N+:13]([O-:15])=[O:14])[CH3:12])(=O)=O.[Al].O>CC(C)=O>[CH3:12][C:11]([N+:13]([O-:15])=[O:14])([CH3:16])[CH2:10][CH2:9][CH2:8][I:1]
Reactant: CC(C)(CCCOS(C)(=O)=O)[N+](=O)[O-]
Reactant: [I-]
Agent: [Al]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(CCCI)[N+](=O)[O-]
Reaction time: 17 h
Yield: 97.1 %

Procedure:
A solution of sodium iodide (17.41 g, 3.9 equiv, 116.6 mmol) in acetone (100 mL, 0.3 M) was added a flask which contained 4-methyl-4-nitropentyl methanesulfonate (6.73 g, 29.9 mmol). The flask was sealed with a septum and covered with aluminum foil and allowed to stir for 17 h. Water (20 ml) was added to the suspension and the acetone was removed by rotovap at reduced pressure. The aqueous solution was extracted with ethyl acetate (150 mL) and washed with 5% aqueous sodium thiosulfate solution (40 ml) and brine (40 ml). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give a yellow oil (7.46 g, yield 92.0%). 1H NMR (CDCl3, 400 MHz): δ 1.60 (s, 6H), 1.78-1.82 (m, 2H), 2.01-2.04 (m, 2H), 3.14-3.18 (t, 2H). LRMS (ESI+) for C6H12INO2 (257.0); Found: 258 (MH+).