Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][CH:6]=1)#[N:2].S(Cl)([Cl:15])=O>C(Cl)(Cl)Cl>[C:1]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Cl:15])=[CH:7][CH:6]=1)#[N:2]
Reactant: N#CCOc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#CCOc1ccc(CCl)cc1

Procedure:
Schema 5 illustrates yet another route for preparing the compounds of the present invention wherein R1 is a disubstituted amino. In schema 5, the appropriately substituted (4-hydroxyphenyl)methan-1-ol (SM4) was reacted with a bromomethylisocyanate and a reducing agent, for example potassium carbonate, in a solvent, for example, DMF, in the manner disclosed above to form the corresponding (4-(cyanomethoxy)phenyl)methan-1-ol (BBB). The methan-1-ol (BBB) was then reacted with sulfinyl chloride in a solvent, for example, chloroform, at 0° C. to form the corresponding 4-(cyanomethoxy)-1-(chloromethyl)benzene (CCC), which was in turn reacted with the appropriately substituted naphthol or phenol (SM14) and a reducing agent, for example, potassium carbonate, in a solvent, for example DMF, in the manner described above to yield the corresponding 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(cyanomethoxy)benzene (DDD). The 4-(cyanomethoxy)benzene (DDD) was reacted with borane in a solvent, for example, THF, at 0° C. to form the appropriately substituted 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(aminomethoxy)benzene (EEE). The 4-(aminomethoxy)benzene (EEE) was in turn reacted with the appropriate oxoalkyl chloride, for example, acetyl chloride, in a solvent, for example, pyridine or THF, at 0° C. to yield the corresponding 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(oxoalkylaminomethoxy)benzene (FFF). The 4-(oxoalkylaminomethoxy)benzene (FFF) was then reacted with borane in a solvent in the manner described above to yield the targeted 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(alkylaminomethoxy)benzene (VIII). At this point, additional moieties can be optionally added to the amino group by reacting the 4-(alkylaminomethoxy)benzene (VIII) with the appropriate substituted alkyl, alkoxy, or alkoxyalkyl halide and a base, for example, triethylamine, to yield the target 1-(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-((disubstituted amino)methoxy)benzene (IX).
Reaction SMILES: [NH:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[SH:4](=[O:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:3]1.C(N(CC)CC)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[C:25]1([CH2:31][C:32]([N:1]=[C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[SH:4](=[O:17])([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:3]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N=C1N[SH](=O)(c2ccccc2)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N=C1N[SH](=O)(c2ccccc2)c2ccccc21

Procedure:
2.4 g. 3-imino-1-phenyl-3H-1,2-benzisothiazole-1-oxide are boiled for 1 hour with 1.32 g. triethylamine and 1.6 g. phenylacetyl chloride in 50 cc. chloroform. After working up in the usual manner, there is obtained 3-(phenylacetylimino)-1-phenyl-3H-1,2-benzisothiazole-1-oxide in the form of yellow crystals which, after recrystallisation from ethyl acetate, melt at 120°C.
Reaction SMILES: [CH3:1]I.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH2:5][CH2:4]1>C(#N)C.CO>[CH3:1][N:3]1[CH2:4][CH2:5][CH:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH2:7][CH2:8]1
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: CI
Solvent: CO
Solvent: CC#N
Product: CN1CCC(c2cccc3c2CC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
Methyl iodide (130.6 mg, 0.92 mmol) was added to a solution of 4-piperidin-4-yl-1,3-dihydroindol-2-one (199 mg, 0.92 mmol) in acetonitrile (10 mL) and methanol (1 mL). The reaction was stirred at room temperature under nitrogen for 2 days. The solvents were removed and the residue was purified on a silica gel column to give 150 mg (70%) of 4-(1-methylpiperidin-4-yl)-1,3-dihydroindol-2-one as a tan solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1Br.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH:24]=[O:25]>>[CH3:1][O:2][CH:3]([O:17][CH3:18])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[C:5]=1[CH:24]([OH:25])[C:23]1[CH:26]=[CH:27][C:28]([O:29][CH2:30][CH3:31])=[C:21]([O:20][CH3:19])[CH:22]=1
Reactant: CCOc1ccc(C=O)cc1OC
Reactant: COc1cc(C(OC)OC)c(Br)c(OC)c1OC
Product: CCOc1ccc(C(O)c2c(C(OC)OC)cc(OC)c(OC)c2OC)cc1OC
Yield: 84 %

Procedure:
2-bromo-3,4,5-trimethoxybenzaldehyde dimethylacetal and 3-methoxy-4-ethoxybenzaldehyde are reacted in the same manner as described in Example 1-(1), whereby 2-(3-methoxy-4-ethoxy-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethylacetal is obtained as colorless syrup. Yield: 84%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1

Procedure:
The title compound, MS: m/e=324.8 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-methoxy-benzene boronic acid.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][NH:6][C:5](=[O:8])[C:4]1([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(Cl)([Cl:23])=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:23][CH2:2][CH:3]1[CH2:7][NH:6][C:5](=[O:8])[C:4]1([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1NCC(CO)C1(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C1NCC(CCl)C1(c1ccccc1)c1ccccc1

Procedure:
To 30.0 g. (0.11 mole) of 4-(hydroxymethyl)-3,3-diphenyl-2-pyrrolidinone in 200 ml. of chloroform was added 25.0 g. (0.20 mole) of thionyl chloride. To this stirring solution was added dropwise with ice bath cooling 20.0 g. (0.26 mole) of dry pyridine maintaining room temperature. The solution was refluxed for 2.5 hours. Upon cooling, the chloroform solution was washed successively with dilute hydrochloric acid solution and dilute sodium hydroxide solution. The chloroform was dried, filtered and concentrated in vacuo. The solid residue was recrystallized twice from ethyl acetate-isopropanol to give product melting at 218°-219° C.
Reaction SMILES: [NH2:1][C@H:2]([C:14]([NH:16][C:17]1[CH:18]=[N:19][N:20]([CH3:23])[C:21]=1[NH2:22])=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][C:41](ON1C(=O)CCC1=O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(Cl)(Cl)Cl>[NH2:22][C:21]1[N:20]([CH3:23])[N:19]=[CH:18][C:17]=1[NH:16][C:14](=[O:15])[C@@H:2]([NH:1][C:41](=[O:42])[CH2:40][CH2:39][NH:38][C:36]([O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:37])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10]
Reactant: Cn1ncc(NC(=O)[C@@H](N)CCCNC(=O)OC(C)(C)C)c1N
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl (4S)-4-amino-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-oxopentylcarbamate (4.90 g) and triethylamine (1.52 g) in chloroform (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (4.26 g). The mixture was stirred at room temperature for 17 hours. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-oxopentylcarbamate as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[NH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH:25]1[CH3:30]>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH2:28][CH2:29][CH:24]([NH2:23])[CH:25]([CH3:30])[CH2:26]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC1CNCCC1N
Product: COc1c(N2CCC(N)C(C)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 50 %

Procedure:
The condensation of 5-amino-1-cyclopropyl-6,7-difluoro-8-methoxy -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 4-amino-3-methylpiperidine was carried out in a similar manner as described in example 1, gave the titled product. Yield 50%, m.p 260–62° C., C20H25FN4O4, m/z 405 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:27])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1.[F:31][CH2:32][CH2:33]O>>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH2:33][CH2:32][F:31])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Reactant: OCCF
Product: CN1CCC(Oc2cc(OCCF)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1

Procedure:
Using an analogous procedure to that described in Example 51, 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline was reacted with 2-fluoroethanol to give the title compound; NMR Spectrum: (CDCl3) 2.0-2.1 (m, 2H), 2.15-2.3 (m, 2H), 2.35 (s, 3H), 2.3-2.4 (m, 2H), 2.8 (br s, 2H), 4.32 (m, 1H), 4.4 (m, 1H), 4.65 (m, 1H), 4.8 (m, 1H), 4.9 (m, 1H), 6.05 (s, 2H), 6.6 (s, 1H), 6.75 (d, 1H), 6.85 (s, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.3 (s, 1H); Mass Spectrum: M+H+ 475 and 477.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:26])=[C:12]([N:16]2[CH2:19][CH:18]([CH2:20]CS([O-])(=O)=O)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:26][C:11]1[C:12]([N:16]2[CH2:17][CH:18]([CH2:20][O:34][C:31]3[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=3)[CH2:19]2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC(CCS(=O)(=O)[O-])C2)c1F
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCC2CN(c3cccc(CO)c3F)C2)cn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 65.7 %

Procedure:
{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}methylmethanesulfonate (150 mg), 6-methylpyridin-3-ol (70 mg), and DMF (2 ml) were mixed, and potassium carbonate (120 mg) were added thereto, followed by stirring at 80° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. THF (2 ml) and a 1 M TBAF/THF solution (0.6 ml) were added to the obtained residue, followed by stirring at room temperature for 1 hour. CHCl3 and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-3-(3-{[(6-methylpyridin-3-yl)oxy]methyl}azetidin-1-yl)phenyl]methanol (74 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[C:6]([CH3:10])[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:15].C(N(CC)CC)C.[SH2:23]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH2:8][SH:23])=[C:6]([CH3:10])[CH:5]=[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:15]
Reactant: S
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CS

Procedure:
This material was synthesized according to the procedure of Song (Song, J. U.S. Pat. No. 3,810,929) using 2,4-dimethyl-3-chloromethyl-6-t-butylphenol (160.8 g, 0.71 m), triethylamine (80 g), tetrahydrofuran (200 ml) and excess hydrogen sulfide. This afforded upon work-up a slightly yellow odorous oil.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1COCC1.[CH3:26][NH2:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:27][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1cccc(OCCCCC=O)c1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOc1cccc(OCCCCCNC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.3 %

Procedure:
5-(3-(hexyloxy)phenoxy)pentanal (72 mg, 0.26 mmol) in 1,2-C12C2H4 (5 mL) was treated with a THF solution of MeNH2 (2.0 M, 0.4 mL, 0.8 mmol). The reaction was stirred in a sealed vial for several min at rt before NaBH(OAc)3 (76 mg, 0.36 mmol) was added in one portion. Again the vial was sealed and stirred at rt for 3 d. The reaction was diluted with H2O and extracted into DCM. The organic extracts were concentrated and the resulting material was purified by preparative TLC on silica gel (5% MeOH:DCM) to afford the title compound as clear oil (17 mg, 23%). 1H NMR (400 MHz, CDCl3) δ ppm 7.15 (t, J=8.21 Hz, 1 H), 6.44-6.51 (m, 3 H), 3.90-3.98 (m, 4 H), 2.64 (t, J=7.07 Hz, 2 H), 2.46 (s, 3 H), 2.28 (br. s, 1 H), 1.72-1.85 (m, 4 H), 1.40-1.67 (m, 6 H), 1.29-1.40 (m, 4 H), 0.91 (t, J=6.57 Hz, 3 H). MS ESI [M+H]+, calcd for [C18H31NO2+H]+: 294.45 found m/z 294.2 (100).
Reaction SMILES: BrCCBr.C[Si](C)(C)Cl.[C:10]([O:18][CH2:19]I)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1>C1COCC1.[Zn].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:10]([O:18][CH2:19][C:26]1[CH:27]=[C:22]([Cl:21])[N:23]=[CH:24][N:25]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=C(OCI)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=C(OCc1cc(Cl)ncn1)c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
Zinc (4.81 g, 73.6 mmol) was suspended in THF (6 mL), treated with 1,2-dibromoethane (0.313 mL, 3.63 mmol) and the resulting mixture was heated at 60° C. under argon for 30 minutes. The reaction mixture was allowed to cool to room temperature, treated with trimethylchlorosilane (0.120 mL, 0.938 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. A solution of iodomethyl benzoate (Intermediate 23, 3.15 g, 12.02 mmol) in THF (6 mL) was added and the resulting mixture was stirred at room temperature for 1 hour. This reaction mixture was added to a solution of 4,6-dichloropyrimidine (1.075 g, 7.21 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.695 g, 0.601 mmol) in THF (11 mL) and the resulting mixture was stirred at room temperature under argon for 18 hours. The reaction mixture was filtered through celite, diluted with saturated ammonium chloride solution and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and isohexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow solid (394 mg);
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][CH3:31])=[CH:22][CH:21]=1>>[CH3:31][O:30][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([C:19]2[NH:18][C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Reactant: COc1ccc(CN)c2ccccc12
Product: CCOC(=O)c1nc(-c2ccc(OC)c3ccccc23)[nH]c1-c1ccc(C)cc1
Yield: 84.5 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (16.0 g) and 1-(aminomethyl)-4-methoxynaphthalene (15.3 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(4-methoxy-1-naphthyl)-5-(4-methylphenyl)-imidazole-4-carboxylate (22.2 g), which was dissolved in ethyl alcohol (450 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(4-methoxy-1-naphthyl)-5-(4-methylphenyl)imidazole-4-carboxylic acid (12.1 g), melting point 226° C. (decomposition).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3([CH3:17])[O:16]CCO3)=[CH:9][CH:10]=2)[CH:5]([C:18]([O:20]CC)=O)[C:4]1=[O:23])[CH3:2].[NH2:24][C:25]1[S:26][C:27]([CH3:30])=[CH:28][N:29]=1>>[CH3:30][C:27]1[S:26][C:25]([NH:24][C:18]([CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12](=[O:16])[CH3:17])[CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]2=[O:23])=[O:20])=[N:29][CH:28]=1
Reactant: Cc1cnc(N)s1
Reactant: CCOC(=O)C1C(=O)N(CC)c2ccc(C3(C)OCCO3)cc21
Product: CCN1C(=O)C(C(=O)Nc2ncc(C)s2)c2cc(C(C)=O)ccc21
Yield: 63 %

Procedure:
Starting with 500 mg. (1.57 mmoles) of ethyl 1-ethyl-5-(2-methyl-4,5-dihydro-1,3-dioxol-2-yl)oxindole-3-carboxylate and 357 mg. (3.1 mmoles) of 2-amino-5-methylthiazole and employing the procedure of Example 17 gave 342 mg. (63% yield) of the desired product, m.p. 215° C. (dec.).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(Sc2cnc(NC(C)=O)s2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(Sc2cnc(N)s2)cc1
Yield: 86.5 %

Procedure:
A mixture of 2-acetylamino-5-(4-methoxylphenylthio)thiazole (1.7 g) in a mixture of ethanol (40 ml) and aqueous 6N hydrochloric acid (6 ml) was refluxed for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water The solution was adjusted to pH 10 using aqueous sodium hydroxide under cooling. The precipitates were collected by filtration, washed with water and recrystallized from ethanol to give 2-amino-5-(4-methoxyphenylthio)thiazole (1.25 g, yield: 86.8%).
Reaction SMILES: C([C:3]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7](O)=O)=O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:14][C:12]1[CH:13]=[CH:3][C:4]2[O:5][CH:6]=[CH:7][C:10]=2[CH:11]=1
Reactant: O=Cc1cc(Br)ccc1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Brc1ccc2occc2c1
Yield: 39.7 %

Procedure:
To a mixture of 2-formyl-4-bromophenoxy acetic acid (50 g, 0.192 mol), sodium acetate (100 g, 1.21 mol) in acetic acid (250 mL) at 100° C. was added acetic anhydride (100 mL) portions during a period of 3 h. The reaction mixture was then refluxed for 20 h. The solvent was removed by distillation and residue diluted with 3N HCl (500 mL) and refluxed for 2 h. The reaction mixture was then concentrated under vacuum and product extracted with pet. ether (3×200 mL). The organic layer was washed with 10% NaHCO3 solution and evaporated to give 5-bromo-1-benzofuran (15 g, 40%) as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[NH:5][N:4]=1.[I:14](O)(=O)=O.II>C(O)C>[I:14][C:7]1[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4][NH:5][C:6]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: [O-][I+2]([O-])O
Reactant: CC(=O)Nc1cc(C(F)(F)F)n[nH]1
Agent: II
Solvent: CCO
Product: CC(=O)Nc1[nH]nc(C(F)(F)F)c1I
Temperature: 65 °C
Reaction time: 3.25 h
Yield: 296.8 %

Procedure:
To a solution of N-[3-(trifluoromethyl)-1H-pyrazol-5-yl]acetamide (7.3 g, 38 mmol) in ethanol (120 mL) were added iodic acid (1.65 g, 9.4 mmol) and iodine (4.8 g, 18.9 mmol). The reaction was stirred for 3.25 h at 65° C. The reaction mixture was concentrated in vacuo and the residue was suspended in hot CH2Cl2 (150 ml) with stirring, the solid was filtered and resuspended in hot CH2Cl2 (100 ml) filtered and dried in vacuo to provide the title compound as a white solid (8.9 g) which was used in the subsequent step.
Reaction SMILES: Cl.N1C=CC=CC=1.[CH2:8]([N:11]([CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:31]C)[CH2:22]1)[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH3:10].[NH4+].[OH-]>O>[CH2:8]([N:11]([CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[OH:31])[CH2:22]1)[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH3:10]
Reactant: CCCN(CCOc1ccccc1)C1CCc2c(cccc2OC)C1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCN(CCOc1ccccc1)C1CCc2c(O)cccc2C1

Procedure:
A mixture of pyridine hydrochloride and the product of Example 1 was heated in an oil bath at 200° C. When the reaction was complete (TLC), it was cooled, diluted with H2O, made basic with NH4OH and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography (Silica: 8:2 pet ether/EtOAc). The product was dissolved in ether and converted to a hydrochloride salt by the addition of dry ether- HCl. Anal. Calcd. for C21H27NO2. HCl: C, 69.69; H, 7.80; N, 3.87. Found: C, 69.54; H, 7.90; N, 3.87. NMR of the free base (300 MHz, CDCl3): δ7.3-6.6(m, 8H), 4.0(t, 2H), 3.1-2.5(m, 9H), 2.1(m, 1H), 1.7-1.4(m, 3H), 0.9(t, 3H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:13][CH:14]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Nc1ccc(O)cc1)c1ccccc1

Procedure:
The preparation is carried out as in Example 1(a) from 353 g (2 mol) of benzenesulphonyl chloride and 229.2 g of 4-aminophenol (2.1 mol).