Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([CH3:18])[C:16](I)=[C:12]3[N:11]=[C:10]([N:19]3[CH2:23][CH2:22][CH2:21][C@H:20]3[CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>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.C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:16]2[C:15]([CH3:18])=[N:14][N:13]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[CH:9][C:10]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[CH2:24][OH:25])=[N:11][C:12]=23)=[CH:30][CH:29]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cccc(-c2cc(N3CCC[C@H]3CO)nc3c(I)c(C)nn23)c1
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: CCO
Product: COc1ccc(-c2c(C)nn3c(-c4cccc(C)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
(S)-(1-(7-(3-Methylphenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (22 mg), 4-methoxyphenylboronic acid (17 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (10 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight at 90° C. under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (12 mg).
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[CH3:30])[O:20][C:19]=2[CH3:31])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[CH3:30])[O:20][C:19]=2[CH3:31])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1cc(F)ccc1-c1cc(C(Oc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)o1
Product: Cc1cc(F)ccc1-c1cc(C(Oc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(C)o1
Yield: 76 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{cyclohexyl[5-(4-fluoro-2-methylphenyl)-2-methyl-3-furyl]methoxy}benzoic acid (139 mg) as well as ethyl 3-(methylamino)propanoate (52 mg) to give the title compound (127 mg, 76%) as an amorphous compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]#[N:31])=[CH:19][CH:20]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To admixture of [4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]phenyl]methanol (4.50 g), 2-chloro-3-cyanopyridine (1.91 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60%, oil, 0.66 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.38 g, 77%) of 2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([CH2:13][OH:14])=[CH:8][C:7]=1[F:15].[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:7]([F:15])=[CH:8][C:9]([CH2:13][O:14][C:23]2[CH:24]=[C:25]3[N:32]([CH3:33])[CH2:31][CH2:30][N:26]3[C:27](=[O:29])[N:28]=2)=[CH:10][C:11]=1[F:12]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(F)c(F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3ccc(F)c(F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (4-(3,4-difluorophenoxy)-3,5-difluorophenyl)methanol (0.073 g, 0.269 mmol) in THF)(4 mL), sodium hydride (0.016 g, 0.404 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (0.050 g, 0.269 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[N:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]#[N:20]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:17]1[C:18]([C:19]#[N:20])=[CH:21][CH:22]=[CH:23][N:24]=1
Reactant: COc1cccc(O)c1
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ncccc2C#N)c1
Reaction time: 0.75 h
Yield: 90.1 %

Procedure:
3-Methoxyphenol (124 g) and anhydrous potassium carbonate (69 g) were heated together with stirring in dry DMF (500 ml) at 80° C. under an atmosphere of nitrogen. After 45 minutes, the greyish solution was cooled and 2-chloronicotinonitrile (138.5 g) and cooper bronze (10 g) were added (washed in with 100 ml DMF). The resulting brown reaction mixture was heated to 125°-130° C. After 21/2 hours, the reaction mixture was cooled and filtered to remove excess copper bronze and undissolved solid material. The resulting solution was added to water (3 liters) and left to stand overnight. The resulting precipitate was filtered, washed with water then dissolved in ether. The ether solution was dried, filtered and evaporated to afford 2-(3-methoxyphenoxy)-3-cyanopyridine as an off-white solid (203.5 g, 90%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[CH2:28]([N:31]=[C:32]=[O:33])[CH2:29][CH3:30]>C1COCC1>[CH2:28]([NH:31][C:32](=[O:33])[O:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27])[CH2:29][CH3:30]
Reactant: CCCN=C=O
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Solvent: C1CCOC1
Product: CCCNC(=O)OCCOc1c(C)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
A mixture of the compound of Example 20 (0.070 g, 0.19 mmol), propyl isocyanate (0.088 mL, 0.94 mmol), and TEA (0.14 g, 1.1 mmol) in THF (4.0 mL) was stirred at 70° C. for 16 h. The mixture was filtered, washed with THF, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), dried and the solvent was removed under reduced pressure. The resulting solid was chromatographed on silica gel to yield 2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate (0.035 g, 41%) as an off-white solid: Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.90 (s, 2H), 7.23 (t, J=5.27 Hz, 1H), 6.74 (d, J=2.32 Hz, 1H), 6.52 (d, J=2.31 Hz, 1H), 4.27 (t, J=4.29 Hz, 2H), 3.99 (t, J=4.29 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.02-2.86 (m, 2H), 2.29 (s, 6H), 1.50-1.30 (m, 2H), 0.84 (t, J=7.33 Hz, 3H); MS (APCI) m/z 456 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1COCC1>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=3)[N:3]=2)[CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)cnc2c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2nc(N3CCOCC3)cnc2c1

Procedure:
Into 10 ml of THF was dissolved 1.16 g of 2-chloro-6-nitroquinoxaline, and then 20 ml of morpholine was added thereto, followed by heating under refluxing for 30 minutes. Then, the solvent was removed by evaporation. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and saturated saline. After the solvent was removed by evaporation, the residue was crystallized from diethyl ether to obtain 1.5 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[N:9]([CH3:12])=[C:10]=[S:11].O1CCCC1>C(#N)C>[NH2:8][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[NH:7][C:10]([NH:9][CH3:12])=[S:11]
Reactant: CN=C=S
Reactant: Nc1ccncc1N
Solvent: CC#N
Solvent: C1CCOC1
Product: CNC(=S)Nc1ccncc1N

Procedure:
A mixture of 4.4 parts of 3,4-pyridinediamine, 4.0 parts of isothiocyanatomethane, 90 parts of tetrahydrofuran and 40 parts of acetonitrile was stirred and refluxed overnight. The reaction mixture was evaporated, yielding 7.3 parts of N-(3-amino-4-pyridinyl)-N'-methylthiourea as a residue (intermediate 95).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:21][CH2:20][CH2:19][CH2:18][C:16]=2[N:17]=1>CN(C)C=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH2:21][CH2:20][CH2:19][CH2:18][C:16]=3[N:17]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: S=C=NCCC1=CCCCC1
Reactant: Nc1nc2c(s1)CCCC2
Solvent: CN(C)C=O
Product: S=C(NCCC1=CCCCC1)Nc1nc2c(s1)CCCC2
Temperature: 25 °C
Yield: 13.3 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-amino-4,5,6,7-tetrahydrobenzothiazole (1.54 g, 10 mmol) in N,N-dimethylformamide (100 mL) was heated at 100° C. for 120 h. The reaction was cooled to room temperature, the solvent removed under reduced pressure, the residue taken up in ethyl acetate and washed with 1N HCl. The organic layer was concentrated and the residue recrystallized from ethyl acetate-hexanes to provide 426 mg (13%) of the titled product:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.O[Li].O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Cc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(Cc2ccc(CC(=O)O)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 64.1 %

Procedure:
A 25-mL flask, with stirrer bar, was charged with methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate (64 mg, 0.17 mmol, 1.0 eq.) and THF (3 mL). Water (3 mL) and LiOH.H2O (21 mg, 0.50 mmol, 3.0 eq.) were added. The resulting mixture was stirred at room temperature for 17 hrs until the starting ester was consumed. The reaction mixture was diluted with water (10 mL) and acidified with 2N HCl. The mixture was extracted with ethyl acetate. The organic extract was washed with sat. sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (88 mg) was purified by chromatography on silica gel using dichloromethane/methanol (10:0 to 9:1) as eluent to afford 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetic acid (40 mg, 66% yield) as a white solid. MW=366.84. 1H NMR (DMSO-d6, 500 MHz) δ 12.31 (br s, 1H), 8.40-8.33 (m, 2H), 7.62-7.53 (m, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.26 (s, 1H), 7.21 (d, J=8.0 Hz, 2H), 4.10 (s, 2H), 3.51 (s, 2H), 2.78 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:51][CH2:52][N:53]2[CH:57]=[CH:56][N:55]=[N:54]2)(=O)=O)=CC=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:51][CH2:52][N:53]4[CH:57]=[CH:56][N:55]=[N:54]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCCn1ccnn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2,4-difluorophenyl)urea (55 mg), potassium carbonate (31 mg), and 2-(1H-1,2,3-triazol-1-yl)ethyl 4-methyl-1-benzenesulfonate (36 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for one hr. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 46 mg (yield 72%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1O
Reactant: ClCCCCBr
Product: COc1ccccc1OCCCCCl

Procedure:
Prepared by Procedure U and Scheme AK using 2-methoxyphenol and 1-bromo-4-chlorobutane.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1)([CH3:14])[CH3:13].[C:21](Cl)(=[O:24])[CH:22]=[CH2:23].[NH4+].[Cl-]>C1COCC1>[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21](=[O:24])[CH:22]=[CH2:23])([CH3:14])[CH3:13]
Reactant: C=CC(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Production in a way similar to: D. A. Evans, K. T. Chapman, J. Bisha J. Am. Chem. Soc. 1988, 110, 1238; A Studer, T. Hintermann, D. Seebach Helv. Chim. Acta 1995, 78, 1185. 6.88 ml of a 1.6M solution of n-BuLi in hexane (11.0 mmol) is slowly added to a solution of 1.299 g (10.0 mmol) of (S)-4-isopropyl-oxazolidin-2-one in 15 ml of absolute THF at -78° C. The solution is stirred for 30 minutes at -78° C.; 1.22 ml (15.0 mmol) of acrylic acid chloride is added drop by drop; it is allowed to reach room temperature and hydrolyzed with 50 ml of saturated NH4Cl solution. It is extracted three times with 50 ml of Et2O each. After drying on MgSO4, the solvent is removed. By flash-chromatographic purification with pentane/Et2O (10:1), 1.63 g (8.9 mmol, 89%) of 20 is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:7]2.O1CCC[CH2:23]1.[H-].[Na+].IC>C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:23])=[N:7]2
Reactant: C1CCOC1
Reactant: COc1ccc(Br)c2ccc(NC(=O)OC(C)(C)C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c2ccc(N(C)C(=O)OC(C)(C)C)nc12
Reaction time: 2 h

Procedure:
5-Bromo-2-t-butyloxycarbonylamino-8-Methoxyquinoline (1.21 g) and tetrahydrofuran (20 ml) were combined at room temperature under a nitrogen atmosphere. Sodium hydride (60% dispersion in oil) (164 mg) was added and the reaction mixture stirred for 2 h whilst effervescence occurred and a yellow colour appeared. Iodomethane (0.43 ml) was then added and stirring was continued for 2 h after which time the reaction was diluted with ethyl acetate (100 ml), washed successively with water, saturated aqueous sodium bicarbonate and brine, then dried (magnesium sulphate) and evaporated in vacuo to give the title compound (1.1 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=1)[OH:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C(Cl)Cl>[F:1][C:2]([F:19])([F:20])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: OC(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc(OCCCC(F)(F)F)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of Intermediate 2B (115 mmol) in anhydrous CH2Cl2 (320 mL) was added Dess-Martin periodinane (50.2 g, 118 mmol) portionwise at 0° C. The reaction was stirred at 0° C. for 0.5 h then at rt for 3 h. To the reaction was added 100 mL of sat'd aq Na2CO3 and 250 mL of EtOAc. The reaction was stirred for another 2 h. The insoluble material was removed by filtration. The layers were separated. The organic layer was washed with sat'd aq Na2CO3. Additional solids that formed upon standing overnight were removed. The organic solution was washed with sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated to provide a dark brown liquid, which was purified by silica gel chromatography (220 g silica gel, elute with EtOAc in hexanes to provide Intermediate 2C (26 g, 76%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[C:17][Si](C)(C)C)=[CH:14][C:13]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][C:31]([CH3:39])([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]4)=[N:26][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[OH-].[K+]>CCO>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[CH:17])=[CH:14][C:13]([C:22]3[CH:27]=[N:26][C:25]([N:28]4[CH2:29][CH2:30][C:31]([CH3:39])([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:32][CH2:33]4)=[N:24][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C#C[Si](C)(C)C)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C#Cc1cc(-c2cnc(N3CCC(C)(C(=O)OCC)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
To an ice-cold solution of ethyl 1-[5-[2-(ethylcarbamoylamino)-7-(2-trimethylsilylethynyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (1.1 g, 1.94 mmol) in EtOH (40 mL) was added powdered KOH (0.24 g, 4.21 mmol) and the mixture stirred at rt for 4 h. After completion of reaction (by TLC), the solvent was evaporated under reduced pressure, water added and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine and water then dried over anhydrous Na2SO4. Solvent was evaporated under reduced pressure to obtain the product as a pale yellow solid (0.8 g, 83% yield). 1H NMR (DMSO-d6): δ 1.11 (t, J=7.20 Hz, 3H), 1.21 (m, 6H), 1.42 (m, 2H), 2.04 (m, 2H), 3.20 (m, 2H), 3.33 (q, J=7.20, 2H), 4.13 (q, J=6.80 Hz, 2H), 4.25 (m, 2H), 4.67 (s, 1H), 6.80 (br s, 1H), 7.61 (s, 1H), 7.94 (s, 1H); 8.78 (s, 2H) and 10.86 (br s, 1H). MS: 493.12 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]=[O:15].[CH3:16][Mg]Br.CCOCC>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([OH:15])[CH3:16]
Reactant: C[Mg]Br
Reactant: Cc1cccc2nc(C=O)c(Br)c(=O)n12
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc2nc(C(C)O)c(Br)c(=O)n12
Temperature: 9 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde (1.4162 g, 5.30 mmol) in THF (53.0 mL) was added methyl-magnesium bromide 3 M in Et2O (2.65 mL, 7.95 mmol) dropwise at 0° C. and the mixture was allowed to warm to 9° C. over 2 h. After 2 h, the reaction was quenched with satd aq NH4Cl (50 mL) and water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concd under reduced pressure to give an orange solid. The orange solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 25 min and 100% isocratic of EtOAc in hexane for 4 min as eluent to give 3-bromo-2-(1-hydroxyethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (1 H, dd, J=8.6, 7.0 Hz), 7.48 (1 H, d, J=9.4 Hz), 7.01 (1 H, d, J=7.0 Hz), 5.15 (1 H, d, J=6.7 Hz), 4.99 (1 H, qd, J=6.5, 6.3 Hz), 2.94 (3 H, s), 1.35 (3 H, d, J=6.7 Hz); Mass Spectrum (ESI) m/e=283.0 [M+1 (79Br)] and 285.0 [M+1 (81Br)].
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[C:16]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(C(C)(C)C)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-tert-butyl-benzaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 2H), 7.25 (m, 2H), 7.18 (m, 2H), 7.08 (d, 1H), 3.79 (s, 2H), 3.77 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H), 1.31 (s, 9H); MS 340 (M+1).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH:32]1([NH:35][C:3](=[O:31])[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[N:17][O:18][C:19]=4[C:20]([F:21])([F:23])[F:22])[N:12]=[CH:11]3)=[N:6][CH:5]=2)[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Product: O=C(NC1CC1)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 38 %

Procedure:
As described for Example 38b, 6-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using cyclopropylamine (66.14 μL, 0.9 mmol) instead of cyclopropanemethylamine, to the title compound (40 mg, 38%) which was obtained as a white solid. MS: m/e=458.2 [M+H]+.