Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][N:11]([C@@H:14]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([N:28]3[CH2:32][CH2:31][S:30][CH2:29]3)=[O:27])[CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.Cl.N(C1CCN([C@@H]2CN[C@H](C(N3CCSC3)=O)C2)CC1)[C:37]1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>ClCCCl.O.C(O)(=O)C>[C:22]([O:21][C:19]([N:17]1[CH2:18][C@@H:14]([N:11]2[CH2:10][CH2:9][CH:8]([N:1]([CH3:37])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)[CH2:15][C@H:16]1[C:26]([N:28]1[CH2:32][CH2:31][S:30][CH2:29]1)=[O:27])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N2CCC(Nc3ccccc3)CC2)C[C@H]1C(=O)N1CCSC1
Reactant: O=C([C@@H]1C[C@H](N2CCC(Nc3ccccc3)CC2)CN1)N1CCSC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CN(c1ccccc1)C1CCN([C@H]2C[C@@H](C(=O)N3CCSC3)N(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-[(2S,4S)-4-(4-Anilinopiperidino)-1-tert-butoxycarbonyl-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [product of Example 148 (3), 1.18 g] was dissolved in 1,2-dichloroethane (75 mL), and sodium triacetoxyborohydride (5.32 g), acetic acid (0.73 mL) and 37% formaldehyde solution (5.0 mL) were added thereto. The mixture was stirred at room temperature for 12 hr. The reaction mixture was added to water, and the mixture was extracted with chloroform. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(N-methylanilino)piperidino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (967 mg).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1.[N:26]1[N:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]2=[C:28]([C:35]([OH:37])=O)[CH:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:12]([O:13][CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)=[C:11]([NH:10][C:35]([C:28]2[CH:27]=[N:26][N:30]3[CH:29]=[CH:34][CH:33]=[N:32][C:31]=23)=[O:37])[CH:24]=1
Reactant: O=C(O)c1cnn2cnccc12
Reactant: Nc1cc(Cl)ccc1OC1CCC(O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1cc(Cl)ccc1OC1CCC(O)CC1)c1cnn2cccnc12
Temperature: 80 °C
Yield: 37.2 %

Procedure:
Diisopropylethylamine (0.35 mL, 2.01 mmol) was added at room temperature to a suspension of 4-(2-amino-4-chloro-phenoxy)-cyclohexanol (127 mg, 0.525 mmol), pyrazolo[1,5-c]pyrimidine-3-carboxylic acid (85 mg, 0.521 mmol) and HBTU (0.21 g, 0.55 mmol) in anhydrous acetonitrile (15 mL) and the resulting solution was heated at 80° C. overnight. The resulting mixture was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate (5%). The aqueous layer was extracted 3 times with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The brown oily residue was purified on a silica gel plug and by flash chromatography (DCM/MeOH/NH4OH) to give a pale yellow solid which was washed with dichloromethane and methanol to give 75 mg (38% yield) of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide as a white powder. MS=387 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:26][C:27]1[S:31][CH:30]=[N:29][CH:28]=1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:30]3[S:31][C:27]([CH3:26])=[CH:28][N:29]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Cc1cncs1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3ncc(C)s3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 5-methylthiazole
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CO.CN(C=O)C>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(C)cn1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(N(CCCCCCC(=O)NO)c2ccccn2)nc1
Reaction time: 72 h
Yield: 75 %

Procedure:
HONH2 (50% aqueous, 1 mL) was added to II (50 mg, 0.15 mmol) in MeOH (1 mL) and DMF (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (3×5 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:2 to 100:8) to furnish III as a pale brown oil (37 mg, 75%).
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1.[CH3:17][NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[CH:23][CH:22]=1>C(O)C>[CH3:17][N:18]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=2)=[CH:25][CH:26]=1)[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1
Reactant: CNCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Solvent: CCO
Product: CN(CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cncnc2)c[nH]1
Temperature: 125 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
2-Methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (30 mg, 0.128 mmol, 1 eq) and methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]ethyl}-amine (56.7 mg, 0.192 mmol, 1.5 eq) were dissolved in dry ethanol (300 μl) and stirred at 125° C. for overnight. Reaction mixture was evaporated and crude residue was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 2-(methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-amino)-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.069 mmol; yield: 54%, HPLC-MS/UV: [M+H]+=482.48; rt: 11.27 min; purity: 96%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.80 (t, J=6.68 Hz, 2H), 2.94 (s, 3H), 3.52 (s, 2H), 3.69 (t, J=7.09 Hz, 2H), 7.00 (d, J=8.76 Hz, 2H), 7.19 (d, J=8.10 Hz, 1H), 7.24 (s, 1H), 7.30 (d, J=8.45 Hz, 2H), 7.44 (d, J=7.75 Hz, 1H), 7.58 (t, J=8.10 Hz, 1H), 7.66 (s, 1H), 8.66 (s, 2H), 8.95 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>CC(C)=O.ClCCl.C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccnc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: Nc1nccc(CO)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
2-Amino-4-methoxycarbonylpyrimidine (3.0 g, 20 mmol, Reference Compound No. 3-1) was suspended in a mixture solvent of ethanol (150 mL) and dichloromethane (20 mL), then sodium borohydride (2.2 g, 59 mmol) was added thereto at room temperature, and the whole was stirred for 24 hours. Acetone (20 mL) was added gradually under ice-cooling, and then 2M hydrochloric acid was added until the bubbles were no longer formed. Saturated aqueous sodium hydrogencarbonate solution was added to adjust the pH of the reaction mixture to 8, and the precipitated solid was filtered out. The filtrate was concentrated under reduced pressure, then suspended in a 10% methanol-chloroform solution, and the mixture was filtered again with silica gel (5.0 g). The filtrate was evaporated under reduced pressure, the precipitated solid was filtered off with ethyl acetate, and dried under reduced pressure to give 1.8 g of the title Reference Compound as a pale yellow solid (Yield: 73%)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:15]([CH2:30][CH2:31][CH2:32][OH:33])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:32]([CH2:31][CH2:30][C:15]1[CH:14]=[C:13]([O:12][CH3:11])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)=[O:33]
Reactant: COc1cc(CCCO)c(OC2CCCCO2)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cc(CCC=O)c(OC2CCCCO2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
An oven-dried 25 ml 2-necked (14/20) round bottom flask, equipped with magnetic stirring bar nitrogen inlet and serum cap, is charged with a solution of oxalyl chloride (61 μl) in 2 ml methylene chloride. This solution is placed under a nitrogen atmosphere and cooled to -60° C. to -50° C. Dimethylsulfoxide (99 μl) is added (neat) dropwise to give a colorless solution. After 2.3 min a solution of 3-[4-methoxy-1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-naphthalenyl]-1-propanol (0.19 g) in 1 ml methylene chloride is added dropwise. The resulting mixture is stirred at -60° C. to -50° C. for 15 min and then treated with triethylamine (0.44 ml). This gives rise to a yellow colored milky suspension. The cooling bath is removed and the stirred mixture is allowed to warm to room temperature at which time the mixture is diluted with water and extracted with ether. The organic phase is washed three times with water (after adjusting the pH to 7 with 10% aqueous sodium bisulfate), dried with magnesium sulfate, filtered and concentrated to give 0.18 g of the crude title compound as an orange colored oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.S(O)(O)(=O)=[O:16].NO.[OH-].[Na+].Cl>[O-]S(S([O-])=O)=O.[Na+].[Na+].O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:11]([NH2:10])=[O:13])[C:9]([OH:14])=[O:16])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: O=C1NC(=O)C(c2ccc(O)cc2)N1
Agent: Cl
Agent: NO
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Product: NC(=O)NC(C(=O)O)c1ccc(O)cc1
Yield: 89.5 %

Procedure:
Crude 5-(p-hydroxyphenyl)hydantoin (85.6 g) is placed in a 1-liter round bottom flask with 41 g hydroxylamine sulfate, 1 g Na2S2O4, 60 g NaOH, and 300 ml H2O. The contents are refluxed for 1 hour and then cooled in an ice bath. Then 125 ml cold concentrated HCl are added. The solids are filtered and washed with 200 ml H2O. The solids are dried in a vacuum oven at 60° C. over the weekend yielding 58.8 g of ca. 95% pure p-hydroxyphenylhydantoic acid (by HPLC analysis).
Reaction SMILES: C[O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=2)[N:11]([CH3:20])[C:10]=1[CH3:21])=[O:8].B(Br)(Br)Br>>[OH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH3:20])[C:10]=1[CH3:21])=[O:8]
Reactant: COCCCNC(=O)c1c(C)n(C)c2cc(OC)ccc12
Agent: BrB(Br)Br
Product: Cc1c(C(=O)NCCCO)c2ccc(O)cc2n1C

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid (3-methoxy-propyl)-amide 63a by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (300 MHz, CD3OD) δ 7.52 (1H, d, J=8.6 Hz), 6.73 (1H, d, J=2.1 Hz), 6.68 (1H, dd, J=2.1, 8.6 Hz), 3.69 (2H, t, J=6.1 Hz), 3.57 (3H, s), 3.51 (2H, m), 2.57 (3H, s), 1.85 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 263. found 263.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1)=[O:4].Br[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:21][C:2]([F:1])([F:20])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: Fc1ccc(Br)nc1
Reactant: CC1(C)OB(c2ccc(C(=O)C(F)(F)F)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccc(F)cn2)cc1)C(F)(F)F
Temperature: 90 °C

Procedure:
Pd(dppf)Cl2 (2.5 g, 3.3 mmol) was added to a degassed, ambient temperature solution of 2,2,2-trifluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (20 g, 67 mmol), 2-bromo-5-fluoropyridine (11.6 g, 67 mmol) and sodium carbonate (12.7 g, 134 mmol) in N,N-dimethylformamide (4400 mL) and water (90 mL). After heating at 90° C. overnight, the reaction mixture was poured into ice (400 g) and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with petroleum ether/ethyl acetate (20:1) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][S:4](=[O:16])(=[O:15])[N:3]=1.[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:17]1([NH:23][C:24]([NH:1][C:2]2[C:7]3[C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][S:4](=[O:16])(=[O:15])[N:3]=2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOc1cccc2c1C(N)=NS(=O)(=O)O2
Reactant: O=C=NC1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOc1cccc2c1C(NC(=O)NC1CCCCC1)=NS(=O)(=O)O2
Reaction time: 18 h

Procedure:
0.15 g (0.61 mmol) of 4-amino-5-ethoxy-1,2,3-benzoxathiazine 2,2-dioxide is stirred with 0.1 g (0.79 mmol) of cyclohexyl isocyanate in 30 ml of dry tetrahydrofuran in the presence of 10 mg of DBU, first at room temperature for 1 hour and then at 40° C. for 18 hours. The mixture is concentrated under reduced pressure, and the residue is dissolved in dichloromethane and washed with water. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. This gives 0.15 g of crude product which, after dissolution in 14 ml of acetonitrile and 6 ml of water, is purified by means of reversed phase HPLC (Kromasil 100 C18, 250×40 mm, 5 μm, 0.01% HCOOH/H2O acetonitrile gradient 34/66, isocratic). This gives 55 mg (24.2% of theory) of compound I-24 as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:27])([CH3:26])[CH2:18][NH:19][S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[CH:13][CH:12]=1.C(N(CC)CC)C.O>C1COCC1>[OH:27][C:17]([C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)([CH3:26])[CH2:18][NH:19][S:20]([CH:23]([CH3:24])[CH3:25])(=[O:22])=[O:21]
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
Into a 100 mL single-neck flask, 77 mg of benzoyl chloride was added dropwise to 135 mg of [2-(4-aminophenyl)-2-hydroxypropyl][(methylethyl)sulfonyl]amine and 56 mg of triethylamine in THF (20 mL) while stirring under a nitrogen atmosphere at room temperature. The reaction was allowed to stir at this temperature for 2 h. The mixture was then poured into H2O and the desired product was extracted into ethyl acetate. The organic layer was backwashed once with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 233 mg as a solid. This material was purified via silica gel chromatography employing the Chromatotron, using a 2000 micron rotor and eluting with a solvent of ethyl acetate to yield the intermediate title compound (151 mg, 80%) as a white solid. Ion spray M.S. 375.2 (M*−1).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH:1]=[N:14][OH:15])=[CH:4][CH:5]=1)=[O:8]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(C=NO)cc1
Yield: 98.3 %

Procedure:
A suspension of methyl 4-formylbenzoate (4.92 g), hydroxylamine hydrochloride (5.21 g) and sodium acetate (6.15 g) in ethanol (50 ml) was refluxed for 2 hours. The mixture was poured into water and extracted with ethyl acetate and the separated organic layer was washed with brine and dried over magnesium sulfate. The solvents were removed under reduced pressure to give 4-methoxycarbonyl-benzaldehyde oxime (5.28 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][N:35]=[C:34]([C:37](OCC)=[O:38])[CH:33]=2)=[CH:28][CH:27]=1)([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:14][N:13]=1)[CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C1COCC1.C(OCC)C>[CH3:7][C:8]([C:26]1[CH:27]=[CH:28][C:29]([C:32]2[O:36][N:35]=[C:34]([CH2:37][OH:38])[CH:33]=2)=[CH:30][CH:31]=1)([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:14][N:13]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)c1cc(-c2ccc(C(C)(c3ccc(OCc4ccccn4)cn3)C(C)C)cc2)on1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(C)(c1ccc(-c2cc(CO)no2)cc1)c1ccc(OCc2ccccn2)cn1
Reaction time: 0.17 h

Procedure:
Lithium aluminum hydride (7.80 mL of a 1.0 M solution in THF, 7.80 mmol) was added to a stirred solution of 1c (2.46 g, 5.22 mmol) in diethyl ether (10.0 mL) at 0° C. After approximately 10 min, 1N NaOH was added to quench the reaction followed by dilution with EtOAc. The resulting mixture was dried (magnesium sulfate), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-100% EtOAc/hexanes as eluent) to afford the title compound 1d. m/z (ES) 430 (MH)+. 1HNMR (500 MHz, CDCl3): δ 8.61 (d, 1H, J=4.5 Hz), 8.40 (d, 1H, J=2.5 Hz), 7.75 (m, 1H), 7.67 (d, 2H, J=8.5 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.47 (d, 2H, J=8.5 Hz), 7.29 (m, 1H), 7.19 (m, 2H), 6.53 (s, 1H), 5.23 (s, 2H), 4.81 (s, 2H), 3.08 (m, 1H), 1.68 (s, 3H), 0.87 (d, 3H, J=6.6 Hz), 0.80 (d, 3H, J=6.9 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C([O-])=O.[Na+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCc1ccc(OC(F)(F)F)cc1
Temperature: 110 °C

Procedure:
8.55 g of 4-trifluoromethoxybenzaldehyde, 0.63 g of bis(triphenylphosphine) palladium dichloride and 6.12 g of sodium formate were placed in a flask fitted with a reflux condenser, 45 ml of DMF were added and the mixture was stirred and heated at 110° C. The course of the reaction was monitored by means of GC. After conversion was complete (GC monitoring), the reaction mixture was allowed to cool to 21° C. and the catalyst was separated off by filtration through silica gel. The filter was rinsed with methyl tert-butyl ether and the filtrate washed with 3×100 ml of water in order to remove the DMF. This gave 6.0 g (69% of theory) of 4-trifluoromethoxybenzyl alcohol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[Cl-].[NH4+]>CN(C)C=O>[F:18][C:19]([F:27])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: C#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2ccc(C(F)(F)F)cc2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 60.9 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.19 g of 4-trifluoromethylphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of 4-(4-trifluoromethylphenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (20)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:11][N:10]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:50]=[CH:51][CH:52]=1)[O:34][CH2:35][CH2:36][C:37]1[CH:49]=[CH:48][C:40]([CH2:41][N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:39][CH:38]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:24]=[CH:25]/[C:26]([N:45]2[CH2:44][CH2:43][N:42]([CH2:41][C:40]3[CH:48]=[CH:49][C:37]([CH2:36][CH2:35][O:34][C:33]4[CH:50]=[CH:51][CH:52]=[C:31]([O:30][CH3:29])[CH:32]=4)=[CH:38][CH:39]=3)[CH2:47][CH2:46]2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[CH:11][N:10]=1
Reactant: COc1cccc(OCCc2ccc(CN3CCNCC3)cc2)c1
Reactant: O=C(O)/C=C/c1ccc(Oc2ccc(OCc3ccc(F)cc3)cn2)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cccc(OCCc2ccc(CN3CCN(C(=O)/C=C/c4ccc(Oc5ccc(OCc6ccc(F)cc6)cn5)c(Cl)c4)CC3)cc2)c1
Yield: 103.1 %

Procedure:
To a solution of (E)-3-[3-chloro-4-({5-[(4-fluorobenzyl)oxy]pyridin-2-yl}oxy)phenyl]prop-2-enoic acid (212 mg) in DMF (7.0 mL) were added 1-{4-[2-(3-methoxyphenoxy)ethyl]benzyl}piperazine (190 mg), HOBT (89 mg) and WSC (112 mg) at room temperature, then the reaction mixture was stirred over night. The reaction mixture was basified with saturated aqueous NaHCO3, extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/4 to 0/1 and then MeOH/AcOEt=1/9) to afford (E)-3-[3-chloro-4-({5-[(4-fluorobenzyl)oxy]pyridin-2-yl}oxy)phenyl]-1-(4-{4-[2-(3-methoxyphenoxy)ethyl]benzyl}-piperazin-1-yl)prop-2-en-1-one (387 mg) as a colorless amorphous. To a solution of that amorphous (387 mg) in AcOEt (7.0 mL) was added 6 M aqueous HCl (0.088 mL) at room temperature, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered off, and the crude crystal was recrystallized from EtOH—H2O to afford (E)-3-[3-chloro-4-({5-[(4-fluorobenzyl)oxy]pyridin-2-yl}oxy)phenyl]-1-(4-{4-[2-(3-methoxyphenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one hydrochloride as a colorless powder (333 mg).