Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([CH3:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30].CO[Na].CO>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:28][C@@H:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:7])[N:9]=[C:10]3[CH3:27])=[CH:15][CH:14]=2)=[CH:25][CH:24]=1
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1nc(C)c2cc(Oc3ccc(F)cc3)ccc2c1O
Agent: CO[Na]
Solvent: CO
Product: Cc1nc(C(=O)N[C@@H](C)C(=O)O)c(O)c2ccc(Oc3ccc(F)cc3)cc12
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 71.8 %

Procedure:
A mixture of 7-(4-Fluoro-phenoxy)-4-hydroxy-1-methyl-isoquinoline-3-carboxylic acid butyl ester (92 mg, 0.25 mmol), (S)-alanine (225 mg, 2.5 mmol) and a 0.5 N solution of MeONa in MeOH (5 ml, 2.5 mmol) was heated in a microwave oven with stirring for 20 min at 140° C. before the mixture was concentrated in vacuo. To the residue was added water (10 ml) and the mixture was washed with EtOAc (2×25 ml). The so purified aq. solution was acidified by the addition of 6 N HCl and extracted with EtOAc (1×25 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (69 mg); MS-(+)-ion M+1=385.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH:32][C:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=1)=[O:17])=[CH:27][CH:26]=2)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Product: CCOC(=O)c1cc2cc(NC(=O)c3cccc(-c4cc(Cl)cc(Cl)c4)n3)ccc2[nH]1

Procedure:
Carboxylic acid (131)(50 mg, 0.19 mmol) was coupled to aniline (58)(42 mg, 0.21 mmol) using Method D to give the crude product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:4][C:5]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1NCc1ccc(O)cc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncc(-c2cccs2)nc1NCc1ccc(O)cc1

Procedure:
A mixture of 4-[(3-amino-6-bromo-pyrazin-2-ylamino)-methyl]-phenol (25 mg, 0.085 mmol), 2-thiopheneboronic acid (13 mg, 0.10 mmol), Pd(PPh3)2Cl2 (2 mg, 0.0028 mmol), and NaHCO3 (21 mg, 0.25 mmol) in DME (0.5 mL) and water (0.15 mL) was put in a microwave reaction tube and reacted in a microwave reactor at 110° C. for 7 minutes. The reaction mixture was partitioned in ethyl acetate and water, and the organic layer was evaporated. The residue was purified on a C-18 reversed phase preparative HPLC eluting with Methanol/Acetonitrile containing 0.1% trifluoroacetic acid to 4-[(3-amino-6-thiophen-2-yl-pyrazin-2-ylamino)-methyl]-phenol trifluoroacetic add salt as a white solid (12 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=3)(=[O:34])=[O:33])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (65 mg, 0.189 mmol) and 3-fluorobenzenesulfonyl chloride (0.030 mL, 0.227 mmol), the title compound was obtained as an off white solid (64 mg, 67% yield). MS (ESI): 502.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:3]=1[CH:21]=[CH2:22].[H][H]>CO.[Pd]>[CH2:21]([C:3]1[CH:4]=[C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH:6]=[N:7][C:2]=1[CH3:1])[CH3:22]
Reactant: [H][H]
Reactant: C=Cc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1C
Agent: [Pd]
Solvent: CO
Product: CCc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1C
Reaction time: 24 h
Yield: 45.5 %

Procedure:
6-Methyl-5-vinyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (0.26 g, 0.86 mmol, from Example 35 above) was dissolved in MeOH (15 mL) and treated with 10% Pd/C (50 mg) and 1 atm hydrogen gas. After 1 day, the catalyst was removed, the solvent evaporated, and the residue was chromatographed (silica gel; hexanes-EtOAc, 1:1) to provide 5-ethyl-6-methyl-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine (0.12 g, 45%): MS (CI/NH3) m/z: 307 (M+H)+ ; 1H NMR (300 MHz, CDCl3) δ 1.23 (t, J=7 Hz, 3H), 1.42 (s, 9H), 2.23-2.38 (m, 2H), 2.47 (s, 3H), 2.60 (q, J=7 Hz, 2H), 3.86-3.93 (m, 2H), 4.12 (dd, J=3, 9 Hz, 1H), 4.29 (dd, J=5,10 Hz, 1H), 4.43-4.53 (m, 1H), 7.04 (d, J=3 Hz, 1H), 8.05 (d, J=3 Hz, 1H). The product from above (0.26 g, 0.85 mmol) was treated with 10 mL of 1:1 TFA-methylene chloride at 0° C. for 1 hour. The residue was diluted with saturated sodium bicarbonate and extracted into CHCl3. The organic layer was washed with water, dried over MgSO4, and evaporated to provide of the free base of the title compound (132 mg, 75%). This was dissolved in ether and treated with 1 M HCl in ether and the resulting salt collected by filtration to provide the title compound (52 mg, 25%). The mother liquor was evaporated to further provide 73 mg of the title compound: mp 150-153° C.; [α]D -7.6 (c 0.62, MeOH); 1H NMR (300 MHz, CD3OD) δ 1.34 (t, J=7 Hz, 3H), 2.63-2.76 (m, 2H), 2.72 (s, 3H), 4.04-4.19 (m, 2H), 4.49-4.63 (m, 2H), 4.88-4.97 (m, 1H), 8.14 (d, J=2 Hz, 1H), 8.40 (d, J=2 Hz); MS (CI/NH3): m/z 207 (M+H+). Anal. Calcd for C12H18N2O.2HCl.0.1 H2O: C, 51.29; H, 7.25; N, 9.97. Found: C, 51.21; H, 7.14; N, 9.77.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.Cl.[C:8](=[O:11])(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O1CCCC1>[CH:8]([C:3]1[S:4][C:5]([C:3]2[S:4][C:5]([C:2]3[CH:6]=[CH:5][S:4][CH:3]=3)=[CH:6][CH:2]=2)=[CH:6][CH:2]=1)=[O:11]
Reactant: O=C([O-])O
Reactant: Brc1ccsc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(-c3ccsc3)s2)s1
Yield: 40 %

Procedure:
In a two-necked round bottomed flask was added 5-dimethoxymethyl-5'-tributyl-stannyl-2,2'-bithiophene (5.6 g), bis(triphenylphosphine)palladium (II) chloride (0.32 g), 3-bromo-thiophene (1.5 g) (Aldrich Chem. Co., Milwaukee, Wis.) and tetrahydrofuran (20 ml). The reaction mixture was refluxed for 16 hours. To the reaction mixture was then added hydrochloric acid (1N, 3 ml) and was further refluxed for 3 hours. Saturated sodium bicarbonate aqueous solution was added to neutrality and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was separated by silica gel chromatography, eluted with n-hexane/ethyl acetate (9:1 →1:1 gradient) to give brownish solid product (0.7 g, 40%), melting point 155°-157° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1/[CH:18]=[CH:19]/[C:20]([Cl:22])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:22].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1/[CH:18]=[CH:19]/[C:20]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1c(F)cccc1F
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Fc1cccc(F)c1/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
To a solution of (E)-2,6-difluorocinnamic acid (331 mg, 1.8 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-2,6-difluorocinnamoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (250 mg, 1.4 mmol) and (E)-2,6-difluorocinnamoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20]O>>[CH3:20][O:18][C:17](=[O:19])[C@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Product: COC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 40 °C

Procedure:
After 25.0 ml (19.8 wt %) of methanol was added to 100 g of oily N-t-butyloxycarbonyl-3-cyclohexyl-L-alanine at room temperature (about 25° C.), the mixture was heated to 40° C. while stirring. When the temperature of liquid reached 40° C., methanol was evaporated under reduced pressure. Oily N-t-butyloxycarbonyl-3-cyclohexyl-L-alanine methyl ester was again obtained. Crystals of N-tbutyloxycarbonyl-3-cyclohexyl-L-alanine methyl ester prepared in Example 1 (1.0 g) were added to the oil as seed crystals. Cooling was gradually continued to 15° C. while stirring. The precipitated crystals were immediately separated by centrifuging, and were then washed with 5 ml of previously cooled methanol. After the obtained crystals were air-dried, the crystals were further dried at 30° C. overnight under reduced pressure to give 84.3 g of N-t-butyloxycarbonyl-3-cyclohexyl-L-alanine methyl ester as crystals. The powder X-ray chart for the crystals formed in this way resembled that shown in FIG. 1 for the crystals of Example 1.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CC(O)C>[CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][N:10]2[C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2c(c1)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(C(C)C)cc43)c2cc1OC
Yield: 43 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 43% yield from 6-isopropyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 128°-129° C.; LC-MS: 350 (MH+); anal. RP18-HPLC RT: 5.51 min.).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:19]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[N:22][N:21]4[CH2:30][CH2:31][CH2:32][C:20]=34)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:33][CH3:34])C1C=CC=CC=1.C1CC=CCC=1.CO>[Pd].C(O)C>[CH3:34][O:33][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:22][N:21]2[CH2:30][CH2:31][CH2:32][C:20]=12
Reactant: COc1cc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: C1=CCC=CC1
Product: COc1cc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 7-benzyloxy-6-methoxy-4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline (17 mg, 0.04 mmol) and 10% palladium on activated carbon (3 mg) in absolute ethanol (2 mL) is added 1,4-cyclohexadiene (100 mg, 1.2 mmol). The mixture is stirred at room temperature for 3 h, treated with methanol (500 μL), and heated at 60° C. for 3 h. The mixture is cooled, filtered, and loaded onto an SCX column. The column is washed with water, methanol, and 7 N ammonia in methanol. The appropriate fraction is concentrated in vacuo to yield the title compound, 10 mg (77%), as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([CH3:23])[CH2:14][CH2:15][NH:16][CH2:17][N:18]=[N:19][N+:20]([O-:22])=[O:21])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1.[Cl-].[Na+]>CN(C=O)C>[S:34]1[CH:35]=[CH:36][N:37]=[C:33]1[NH:32][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@H:13]([CH3:23])[CH2:14][CH2:15][NH:16][CH2:17][N:18]=[N:19][N+:20]([O-:22])=[O:21]
Reactant: C[C@H](CCNCN=N[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1nccs1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](CCNCN=N[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1nccs1
Temperature: -23 °C
Reaction time: 0.67 h
Yield: 66 %

Procedure:
(2S,3R)-2-tert-Butoxycarbonylamino-3-methyl-5-(nitroimino-amino)methylaminopentanoic acid (123 mg, 0.396 mmol) is dissolved in 1 mL of DMF and cooled to −23° C. TEA (51 μL, 0.37 mmol) is added followed by isobutyl chloroformate (48 μL, 0.37 mmol). After 40 min, 2-aminothiazole is added and the reaction mixture is allowed to come to 25° C. over 18 h. The reaction mixture is added to half-saturated aqueous sodium chloride and extracted with EtOAc. The combined organic layers are washed with 1N HCl, 5% sodium bicarbonate, saturated aqueous sodium chloride, and dried over magnesium sulfate. Concentration in vacuo and purification by chromatography on silica gel (elution with hexanes-EtOAc 1:5 then EtOAc) provides (2S,3R)-2-tert-butoxycarbonylamino-3-methyl-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide as a foam (101 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:27])([F:26])[F:28])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([CH2:18][OH:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of methyl 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-methylbenzoate (1.0 g) in tetrahydrofuran (30 mL) was added dropwise to a solution of lithium aluminum hydride (0.1 g) in tetrahydrofuran (50 mL) under ice cooling, and, after finishing the addition, the mixture was stirred for one hour at room temperature. The reaction solution was poured onto ice, and then 2N hydrochloric acid (30 mL) was added by portions. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of {4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-methylphenyl}methanol (0.9 g).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:15]([Cl:18])([Cl:17])[Cl:16])[NH:3]1.S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:24][CH3:25])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:15]([Cl:18])([Cl:16])[Cl:17])[NH:3]1
Reactant: CCO
Reactant: O=C(O)c1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)N2
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)N2

Procedure:
1,2-dihydro-4-oxo-2-trichloromethylquinazoline-6-carboxylic acid (0.5 g.), ethanol (6 ml.) and concentrated sulphuric acid (3 ml.) were heated together under reflux on a steam bath for 1.5 hours. The reaction mixture was filtered, and the filtrate was poured onto a minimum quantity of ice. The precipitate thus produced was filtered off, washed with water and dried, to give ethyl 1,2-dihydro-4-oxo-2-trichloromethylquinazoline-6-carboxylate, m.p. 243°-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:24]=1[C:25]#[N:26].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39]OS(C)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([CH3:9])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:39][CH2:38][O:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:24]=1[C:25]#[N:26]
Reactant: CS(=O)(=O)OCCOc1ccccn1
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCOc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide (50 mg, 0.12 mmol) dissolved in DMF (500 μL), methanesulfonic acid 2-(pyridin-2-yloxy)-ethyl ester (30 mg, 0.14 mmol) and K2CO3 (50 mg, 0.36 mmol) were added. The mixture was stirred at rt overnight then heated at 40° C. for 1 h. After filtration and dilution with MeOH the mixture was purified by prep HPLC yielding 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-methyl-N-{2-[2-(pyridin-2-yloxy)-ethoxy]-phenyl}-benzamide 51-1. MS: 553.2 (M+H)+, tR=5.2 min (method 3).
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH:7]([O:10][CH3:11])[O:8][CH3:9])[S:4][C:3]=1[S:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.C([Li])CCC.CCCCCC.[Cl:31][C:32]1[CH:43]=[CH:42][C:35]([C:36](N(OC)C)=[O:37])=[CH:34][CH:33]=1>O1CCCC1.O>[Cl:31][C:32]1[CH:43]=[CH:42][C:35]([C:36]([C:2]2[CH:6]=[C:5]([CH:7]([O:10][CH3:11])[O:8][CH3:9])[S:4][C:3]=2[S:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Reactant: COC(OC)c1cc(Br)c(Sc2ccc(Cl)cc2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COC(OC)c1cc(C(=O)c2ccc(Cl)cc2)c(Sc2ccc(Cl)cc2)s1
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
In an argon atmosphere, 3-bromo-2-(4-chlorophenylthio)-5-dimethoxymethylthiophene (500 mg, 1.32 mmol) obtained in Example 90 was dissolved in tetrahydrofuran (6 mL) and cooled to −78° C. n-Butyl lithium (a 1.6 mol/L hexane solution, 0.81 mL, 1.3 mmol) and tetrahydrofuran (1 mL) solution of 4-chloro-N-methoxy-N-methylbenzamide (528 mg, 2.64 mmol) were added thereto, followed by stirring for 10 minutes. Water was added to the reaction liquid and the product was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (15:1 hexane/ethyl acetate) to give 3-(4-chlorobenzoyl)-2-(4-chlorophenylthio)-5-dimethoxymethylthiophene (345 mg, 60%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.CN(C=O)C.S(Cl)([Cl:20])=O>>[Cl:20][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ncnc2ccc(I)cc12
Solvent: CN(C)C=O
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99 %

Procedure:
To a solution of 6-Iodo-quinazolin-4-ol (5.0 g, 18 mmol) in thionyl chloride (10 mL) was added slowly DMF (0.5 mL) and the mixture is heated immediately to reflux. Heating is continued for 4.5 hours, followed by cooling to room temperature. The reaction mixture was then evaporated under reduced pressure to dryness. The residue was then redesolved in DCM (20 mL), and to it was added toluene (50 mL), and the mixture was then evaporated under reduced pressure to dryness. The procedure was repeated one more time to rid the product of thionyl chloride to yield 5.2 g (99%) of desired product as a tan solid.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]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].COCCOC>[C:14]([C:13]1[CH:18]=[CH:19][C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:11][CH:12]=1)([O:16][CH3:17])=[O:15]
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: COC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
An oven-dried resealable Schlenk tube was purged with argon and charged with Pd2(dba)3 (2.3 mg, 0.0025 mmol, 1.0 mol % Pd), 2 [Example 1] (3.0 mg, 0.0076 mmol, 1.5 mol %), K3PO4 (150 mg, 0.71 mmol), and methyl 4-bromobenzoate (108 mg, 0.50 mmol). The tube was purged with argon, fitted with a rubber septum and then DME (1.0 mL) and morpholine (55 μL, 0.63 mmol) were added. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at 80° C. for 24 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc (20 mL), filtered through celite and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 89 mg (80%) of a colorless solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[O:8][CH:9]=2)=[N:22][CH:23]=1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ncnc3ccccc23)co1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=c1cc(CN2CCOCC2)occ1OCCCCCOc1ncnc2ccccc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(quinazolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 20 (100 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL). Morpholine (51 μL, 0.575 mmol) was added via syringe. The mixture was stirred at 45° C. for 1 h. CH2Cl2 (50 ml) was added and the solution washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The product was extracted with CH2Cl2 (5×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=99:01. 5-(5-(Quinazolin-4-yloxy)pentyloxy)-2-(morpholinomethyl)-4H-pyran-4-one EHT 3726 was obtained (8.2 mg, 8.5%) as a white solid.