Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[C:5]([O:31][CH3:32])[CH:4]=1.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[F:33][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([CH:25]5[CH2:26][CH2:27][N:28]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:29][CH2:30]5)=[CH:23][CH:24]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[C:5]([O:31][CH3:32])[CH:4]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cc(C(F)F)ccc1-c1cccn2nc(Nc3ccc(C4CCNCC4)cc3)nc12
Product: COc1cc(C(F)F)ccc1-c1cccn2nc(Nc3ccc(C4CCN(CC(=O)N(C)C)CC4)cc3)nc12

Procedure:
2-(4-{4-[8-(4-difluoromethyl-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(4-difluoromethyl-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.160 g, 0.356 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.055 mL, 0.534 mmol) in a manner analogous to Example 313 to give product (0.035 g, 18%). MP=199-202° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.79 (d, 1H), 7.70 (d, 1H), 7.55 (m, 3H), 7.32 (s, 1H), 7.25 (d, 1H), 7.15 (d, 2H), 7.10 (br m, 1H), 7.05 (m, 1H), 3.81 (s, 3H), 3.12 (s, 2H), 3.05 (s, 3H), 2.90 (m, 2H), 2.82 (s, 3H), 2.38 (m, 1H), 2.10 (m, 2H), 1.65 (br m, 4H): MS=535 (MH)+.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([F:47])[CH:37]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([F:47])[CH:37]=2)=[O:13])=[CH:7][C:6]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOc1cc(OCC(=O)O)ccc1C(C)(C)C
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOc1cc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a tetrahydrofuran (THF) (3 ml) solution of [4-tert-butyl-3-(2-methoxyethoxy)phenoxy]acetic acid (100 mg, 0.35 mmol) was added 1,1′-carbonyl-diimidazole (63 mg, 0.39 mmol) and the mixture was stirred for 1 hour at ambient temperature. To the mixture was added N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (99 mg, 0.39 mmol) and triethyl amine (150 ul, 1.1 mmol) and the mixture was stirred for 1 hour at ambient temperature. After filtration to separate solvent and the resulting percipitate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=1/1 to furnish 78 mg (46% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCOCC.C1CCCCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: CCOCC
Product: COc1ccc2c(c1)C(O)(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 20 g (0.123 mol) of 6-methoxy-1-indanone in 500 mL of ether cooled to -20° C. was added 72 mL (0.129 mol) of 1.8M phenyllithium in cyclohexane/ether and the mixture was stirred at room temperature for 1 h. An additional (10 mL) phenyllithium solution was added and stirred at room temperature for 1 h. To the reaction mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×250 mL), and the organic layer was dried over sodium sulfate and concentrated in vacuo to afford 32.3 g of crude (contains solvent) 6-methoxy-1-phenyl-indan-1-ol.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[CH:13]=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:22](NC1C=C(C(O)=O)C=C(C=1)C(O)=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C.C(NC1C=C(C(O)=O)C=C(C=1)C(O)=O)CCCCCCCCC.C(NC1C=C(C(O)=O)C=C(C=1)C(O)=O)CCCCCCCCCC.C(NC1C=C(C(O)=O)C=C(C=1)C(O)=O)CCCCCCCCCCC.CC(NC1C=C(C(O)=O)C=C(C=1)C(O)=O)CCCCCCCCCC.C(NC1C=C(C(O)=O)C=C(C=1)C(O)=O)CCCCCCCCCCCC.C(NC1C=C(C(O)=O)C=C(C=1)C(O)=O)CCCCCCCCCCCCC.C(NC1C=C(C(O)=O)C=C(C=1)C(O)=O)CCCCCCCCCCCCCC.CC(C)CCCCCCCCCCCCCNC1C=C(C(O)=O)C=C(C=1)C(O)=O.C(NC1C=C(C(O)=O)C=C(C=1)C(O)=O)CCCCCCCCCCCCCCCC.C(NC1C=C(C(O)=O)C=C(C=1)C(O)=O)CCCCCCCCCCCCCCCCC.C(NC1C=C(C(O)=O)C=C(C=1)C(O)=O)CCCCCCCCCCCCCCCCCC>>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]([C:19]([OH:21])=[O:20])[CH:13]=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCNc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: CCCCCCCCCNc1cc(C(=O)O)cc(C(=O)O)c1
Agent: CC(C)CCCCCCCCCCCCCNc1cc(C(=O)O)cc(C(=O)O)c1
Agent: CCCCCCCCCCC(C)Nc1cc(C(=O)O)cc(C(=O)O)c1
Agent: CCCCCCCCCCCCCCCCCCCNc1cc(C(=O)O)cc(C(=O)O)c1
Product: CCCCCCCCCCCCCCCCNc1cc(C(=O)O)cc(C(=O)O)c1

Procedure:
Similarly, the dimethyl alkylaminoisophthalates in Example 8 provide: 5-octylaminoisophthalic acid, 5-nonylaminoisophthalic acid, 5-decylaminoisophthalic acid, 5-undecylaminoisophthalic acid, 5-dodecylaminoisophthalic acid, 5-(1-methylundecyl)aminoisophthalic acid, 5-tridecylaminoisophthalic acid, 5-tetradecylaminoisophthalic acid, 5-pentadecylaminoisophthalic acid, 5-(14-methylpentadecyl)aminoisophthalic acid, 5-heptadecylaminoisophthalic acid, 5-octadecylaminoisophthalic acid, and 5-nonadecylaminoisophthalic acid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)=[O:10].O>CO>[CH3:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=1)[OH:10]
Reactant: Cn1ccnc1C(=O)c1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1ccnc1C(O)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
0.6 g of sodium borohydride is added to a solution of 3.6 g of 1-methyl-α-(3-trifluoromethylphenyl) -1H-imidazole-2-methanone in 25 ml of methanol. The mixture is stirred for 30 minutes and 150 ml of water are added. The precipitate obtained is filtered off and washed with water. It is recrystallized from an ethanol/water mixture.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cccc(Cn2ccnc2)c1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
To a solution of imidazole (1.00 g, 14.69 mmol, 1 equivalent) and Cs2CO3 (5.93 g, 1.2 equivalents) was added 3-methoxybenzyl bromide (3.24 g, 1.1 equiv.) dropwise at 5° C. The mixture was stirred for 1.5 h at 5° C., filtered and concentrated under reduced pressure to give 1-(3-methoxy-benzyl)-1H-imidazole (2.30 g) as a pale yellow oil was directly used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:4]1[C:24]([OH:25])=[C:23]([C:26](=[O:28])[CH3:27])[CH:22]=[CH:21][C:5]=1[O:6][CH:7]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[C:8]([O:10]CC)=[O:9])[CH2:2][CH3:3]>O1CCOCC1.Cl>[CH2:1]([C:4]1[C:24]([OH:25])=[C:23]([C:26](=[O:28])[CH3:27])[CH:22]=[CH:21][C:5]=1[O:6][CH:7]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[C:8]([OH:10])=[O:9])[CH2:2][CH3:3]
Reactant: CCCc1c(OC(C(=O)OCC)c2ccc(Cl)c(Cl)c2)ccc(C(C)=O)c1O
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1c(OC(C(=O)O)c2ccc(Cl)c(Cl)c2)ccc(C(C)=O)c1O
Yield: 40.1 %

Procedure:
A mixture of 4.8 g of Ethyl 2-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-2-(3,4-dichlorophenyl)acetate in 100 ml of dioxane and 15 ml of concentrated hydrochloric acid was refluxed for 70 hours. The reaction mixture was then cooled, concentrated in vacuum to give 2.9 g of the crude solid, which was crystallized from hexane to give 1.8 g of pure product, melting point 177°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C@H:51]1[C@@H:55]([OH:56])[CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]1>CC#N.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:50][C@H:51]3[C@@H:55]([OH:56])[CH2:54][N:53]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:52]3)=[O:16])=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](O)C1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](NC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Reaction time: 2 h
Yield: 140.5 %

Procedure:
To a solution of 2-(3-fluorophenyl)pyrimidine-5-carboxylic acid (900 mg, 4.12 mmol) in CH3CN/DMF (10 mL/3 mL) was added HATU (1.73 g, 4.54 mmol), DIPEA (1.44 mL, 0.83 mmol) and cis-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (918 mg, 4.54 mmol). After 2 hrs, the solvents were removed in vacuo and the residue purified by chromatography (silica, 100% DCM to 5% MeOH/DCM) to give the desired product, cis-tert-butyl 3-(2-(3-fluorophenyl)pyrimidine-5-carboxamido)-4-hydroxypyrrolidine-1-carboxylate (2.33 g, 80%).
Reaction SMILES: [C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Na+].[I-].O=C(C1C=CC=CC=1)C[O:14][C:15](=[O:43])[C@H:16]([OH:42])[CH2:17][N:18]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:31][CH:30]=1)[NH:19][C:20]([C:22]1[O:26][N:25]=[C:24]([OH:27])[CH:23]=1)=[O:21].CCN(CC)CC.CC(O)=O>CC(C)=O.[Zn]>[C:15]([C@H:16]([OH:42])[CH2:17][N:18]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:33][CH:34]=1)[NH:19][C:20]([C:22]1[O:26][N:25]=[C:24]([O:27][CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:23]=1)=[O:21])([OH:43])=[O:14]
Reactant: CCCC(=O)OCCl
Reactant: O=C(COC(=O)[C@H](O)CN(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(O)no1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Agent: [Zn]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCCC(=O)OCOc1cc(C(=O)NN(Cc2ccc(-c3cccc(Cl)c3)cc2)C[C@@H](O)C(=O)O)on1
Temperature: 60 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
A mixture of chloromethyl butyrate (20.5 μL, 164 μmol) and NaI (24.5 mg, 164 μmol) in acetone (2.0 mL, 27 mmol) was stirred at 60° C. for 1 hour, then cooled to room temperature and added to a mixture of (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid 2-oxo-2-phenylethyl ester (30.0 mg, 54.5 μmol) and Et3N (38.0 μL, 273 μmol) in acetone (1 mL). The resulting mixture was stirred at room temperature for 2 hours, concentrated, dissolved in AcOH (2 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and lyophilized. Zinc (178 mg, 2.7 mmol) and AcOH (1.0 mL, 18 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was filtered and purified by reverse phase preparative HPLC to yield the title compound (2.5 mg). MS m/z [M+H]+ calc'd for C25H26ClN3O8, 532.14. found 532.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>C(#N)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CBr)c1
Reactant: O=C(Nc1nc2cccc(-c3ccc(O)cc3)n2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)c1

Procedure:
To a solution of cyclopropanecarboxylic acid [5-(4-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (WW-022) (0.05 g, 0.17 mmol) in acetonitrile (3 mL), potassium carbonate (0.047 g, 0.34 mmol) was added and the mixture was refluxed for 30 min. 3-Methoxybenzylbromide (0.047 mL, 0.34 mmol) was then added and the solution was refluxed overnight. The mixture was filtered and purified by preparatory HPLC. LCMS method: 1, RT: 5.16 min; MI: 415 [M+1]. NMR 1H (DMSO): 0.79-0.83 (m, 4H), 2.06 (brs, 1H), 3.76 (s, 3H), 5.08 (s, 2H), 6.88 (dd, 1H), 77.03-7.08 (m, 2H), 7.16 (d, 2H), 7.24 (dd, 1H), 7.31 (t, 1H), 7.60-7.67 (m, 2H), 8.00 (dd, 2H).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: O=Cc1ccc(F)cc1
Product: Fc1ccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-fluorobenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-fluorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11](O)[C:12]1[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH2:21][N:22]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26]=1[Cl:35])=[O:24].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH2:21][N:22]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26]=1[Cl:35])=[O:24]
Reactant: COc1ccc(OC)c(C(O)c2c(CN(CCC(C)C)C(=O)c3ccc(OC)c(OC)c3Cl)nc3ccccn23)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC)c(Cc2c(CN(CCC(C)C)C(=O)c3ccc(OC)c(OC)c3Cl)nc3ccccn23)c1
Temperature: 60 °C
Yield: 58.3 %

Procedure:
A solution of 58 mg (0.1 mmol) of N-({3-[(2,5-dimethoxyphenyl) hydroxymethyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide in 5 mL dichloromethane is treated with 116 mg (1.0 mmol) triethylsilane and 114 mg (1.0 mmol) trifluoroacetic acid. The solution is heated in a sealed tube at 60° C. for 18 hr and diluted with 15 mL sat. NaHCO3 and extracted with 3×10 mL dichloromethane. The combined organics are washed with 10 mL water and 10 mL brine. The resulting organic layer is dried over anhydrous MgSO4 and the solvent removed in vacuo to give the crude material. The residue is prep-plate chromatographed (9% MeOH/CH2Cl2/0.5% NH4OH) to afford 33 mg (58%) N-({3-[(2,5-dimethoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 567.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[N:12]1([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.0 g (6.7 mmol) of 4-formylbenzoic acid was dissolved in 20 ml of dichloromethane. 0.67 ml (8.0 mmol) of pyrrolidine, 1.35 g (8.0 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 2.8 ml (20.5 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 5 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the crude product was obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)CCC.O>CN(C=O)C.[Pd].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.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>[F:19][C:10]1[C:9]([O:8][CH2:7][C:5]2[S:6][C:2]([C:33]3[N:34]=[CH:35][S:36][CH:37]=3)=[C:3]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:4]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2-c2cscn2)cc1
Temperature: 120 °C
Yield: 364.4 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.20 g, 0.043 mmol) in 5 ml of anhydrous DMF was added 4-tributylstannyl thiazole (0.16 g, 0.43 mmol) and degassed the reaction mixture for 10 minutes. Tetrakis(triphenylphosphine) palladium (0) (0.05 g, 0.043 mmol) was then added and the reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to room temperature added water (25 mL) and extracted the compound with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400 M) using ethyl acetate/Hexane (40:60) as the eluent to provide the title compound as white solid (0.072 g, 36%). 1H NMR (DMSO-d6, 400 MHz): δ 3.80 (s, 3H), 5.56 (s, 2H), 7.01 (d, J=8.80 Hz, 2H), 7.13 (m, 1H), 7.41-7.50 (m, 4H), 7.90 (br s, 1H), 8.18 (br s, 1H) and 9.18 (s, 1H). MS ES+ (460.32), HPLC (method II) Rt=16.37 min.
Reaction SMILES: [N:1](=[C:3]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1)[OH:2].Cl>C1COCC1.CCO>[NH:1]([CH:3]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1)[OH:2]
Reactant: ON=C1CCn2c1cc1ccccc12
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: ONC1CCn2c1cc1ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of the oxime from Step 1 (2.5 g, 13.4 mmol) in THF (30 mL) and EtOH (30 mL), at 0° C. there was added pyridine-borane complex (3.12 g, 33.6 mmol) and then, slowly, 12N aqueous HCl (3.9 mL, 47 mmol). The mixture was stirred at 0° C. for 15 minutes, then at r.t. for 20 hours. The solvents were evaporated and the residue dissolved in H2O (100 mL) and extracted with EtOAc (2×20 mL). The aqueous fraction was then brought to pH 8 with 2.5N aqueous NaOH and the precipitate filtered to afford the title compound as a white solid, m.p.: 159°-161° C.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-][CH2:10][CH3:11].[Na+]>C1COCC1>[C:2]1([CH:10]=[CH:11][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 50 mg (0.47 mmol) benzaldehyde and 100 mg (0.047 mmol) Rink amide resin bound compound 1 in 5 mL THF, 12 μL 2M sodium ethoxide was added. It was shaken at room temperature for 2 hours. The resulting Resin bound compound 2 was collected in a 3 mL filtering column and washed with water (3×2 mL), DMF (2×2 mL) and methylene chloride (3×2 mL). After drying under vacuum, 5 mg Resin bound compound 2 was treated with 1.5 mL 5% trifluoroacetic acid in methylene chloride for 20 minutes. The solid was filtered off and washed with 1 mL methylene chloride, combined methylene chloride solution was concentrated and dried under vacuum to give 0.5 mg product 3. MS m/z252 (M+ +1). ##STR55##
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7]/[C:8]/2=[CH:11]\[C:12](O)=[O:13])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>ClCCl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7]/[C:8]/2=[CH:11]\[C:12]([Cl:20])=[O:13])=[CH:4][CH:3]=1
Reactant: CC1(C)C/C(=C\C(=O)O)c2cc(F)ccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1(C)C/C(=C\C(=O)Cl)c2cc(F)ccc21
Temperature: 25 °C

Procedure:
To an ice cold, stirred suspension of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetic acid (9.0 g, 0.0409 mol) in dichloromethane (200 ml) was added oxalyl chloride (15.6 g, 0.123 mol, Aldrich). The stirring suspension was allowed to warm to 25° C. during 2 h. The resulting solution was concentrated by spin evaporation in vacuo with the addition of dichloromethane (4×75 ml) to give (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetyl chloride as an uncharacterized oil. Dichloromethane (approximately 70 g) was added to dissolve this residual oil and the resulting solution was divided equally and used without other purification in Examples 15i, 16 and 17.
Reaction SMILES: [CH2:1]([N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:10](=O)[C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:20]([NH:28][NH2:29])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)/[C:10](=[N:29]/[NH:28][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NNC(=O)c1ccccc1
Reactant: CCCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-hexyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3): δ 0.88 (t, 3H), 1.28 to 1.39 (m, 6H), 1.68-1.74 (m, 2H), 3.73 (t, 2H), 3.87 (s, 3H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.59 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 13.98 (br s, 1H).