Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:29])([F:28])[F:27])[N:15]=3)=[CH:10][C:9]=2[N+:30]([O-])=O)[CH2:3]1>CCO.C([O-])(O)=O.[Na+]>[F:33][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:27])([F:28])[F:29])[N:15]=3)=[CH:10][C:9]=2[NH2:30])[CH2:3]1
Reactant: O=[N+]([O-])c1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCCC(F)(F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1N1CCCC(F)(F)C1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Stannous chloride dihydrate (478 mg; 2.13 mmol; 5 eq.) was added to a solution of Example 11 (200 mg; 0.43 mmol; 1 eq.) in EtOH (20 mL) and the resulting mixture was stirred at 70° C. for 3 hours, then at room temperature for 16 hours. The solution was diluted with sat. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (c-hexane/ethyl acetate, 70/30) followed by crystallization from n-pentane afforded the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=1)([O:7][CH3:8])[CH2:5][CH3:6].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>>[CH3:1][O:2][CH2:3][C:4]([O:7][CH3:8])([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH:14]=1)[CH2:5][CH3:6]
Reactant: CCC(COC)(OC)c1cncc(O)c1
Reactant: BrCc1ccc2ccccc2c1
Product: CCC(COC)(OC)c1cncc(OCc2ccc3ccccc3c2)c1
Yield: 37.2 %

Procedure:
Using the procedure described in Example 12, 2-(5-hydroxypyrid-3-yl)-2-methoxybut-1-yl methyl ether (0.21 g) was reacted with 2-bromomethylnaphthalene (0.25 g) to give 2-methoxy-2-[5-(naphth-2-ylmethoxy)pyrid-3-yl]but-1-yl methyl ether (0.13 g, 37%), as an oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][C:22]1[N:26]([CH2:27][C:28](O)=[O:29])[N:25]=[C:24]([C:31]([F:34])([F:33])[F:32])[CH:23]=1>>[Br:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:28](=[O:29])[CH2:27][N:26]3[C:22]([CH3:21])=[CH:23][C:24]([C:31]([F:34])([F:33])[F:32])=[N:25]3)[CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: Brc1sc(C2CCNCC2)nc1CCc1ccccc1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(CCc3ccccc3)c(Br)s2)CC1

Procedure:
4-[5-Bromo-4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine (II-3, 127 mg) is reacted analogously to Example I-81 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (118 mg). After chromatographic purification, this gives 1-{4-[5-bromo-4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (52 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([C:21](O)=[O:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[NH3:37].Cl>C1COCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@:9]([C:21](=[O:22])[NH2:37])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CCOC(=O)[C@](CC(=O)OCc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@](CC(=O)OCc1ccccc1)(NC(=O)OC(C)(C)C)C(N)=O
Yield: 55 %

Procedure:
A solution of (R)-1-benzyl hydrogen 3-t-butyloxycarbonylamino-3-ethoxycarbonylsuccinate (1.0 g) obtained in Example 19 in THF (20 mL) was added with triethylamine (0.62 mL) and isobutyl chloroformate (0.55 mL, 0.57 g) in this order at −15° C. with stirring, and the mixture was stirred for 30 minutes. A solution of 25% aqueous ammonia (0.30 mL) was dropped into the reaction mixture at the same temperature. The reaction mixture was stirred at the same temperature for 30 minutes, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and then the extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (1:1) for purification, and then crystallized from ethyl acetate/n-hexane to obtain the title compound (0.60 g, yield: 55%) as colorless crystals. Optical rotation [α]D25 was +1.28° (c 0.50, ethanol).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1.Cl.[CH3:23][NH:24][O:25][CH3:26]>ClCCl>[CH3:26][O:25][N:24]([CH3:23])[C:19]([CH:16]1[CH2:15][CH2:14][O:13][CH2:18][CH2:17]1)=[O:21]
Reactant: CNOC
Reactant: O=C(O)C1CCOCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCOCC1
Reaction time: 2 h
Yield: 114.5 %

Procedure:
Add 1,1′-carbonyldiimidazole (333.41 g, 1.2 eq) to a solution of tetrahydro-2H-pyran-4-carboxylic acid (223 g, 1.71 mol) in dichloromethane (2.23 L) portion wise over 15 minutes. Stir for two hours. Add N,O-dimethylhydroxylamine hydrochloride (183.86 g, 1.1 eq) portionwise and stir for three hours. Wash the organics with saturated aqueous ammonium chloride, then with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo to give N-methoxy-N-methyl-tetrahydropyran-4-carboxamide (339 g, 114%) as crude material and use as such in next reaction. 1H NMR (300 MHz, DMSO-d6) δ 4.02 (m, 2H), 3.71 (s, 3H), 3.46 (m, 2H), 3.19 (s, 3H), 2.91 (m, 1H), 1.86 (m, 2H), 1.65 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=3)[C:11]([CH:20](O)[C:21]([NH2:23])=[O:22])=[C:10]2[CH2:25][CH3:26])[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:20][C:21]([NH2:23])=[O:22])=[C:10]2[CH2:25][CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(C(O)C(N)=O)c2c(OC)cccc2n1Cc1cccc(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(CC(N)=O)c2c(OC)cccc2n1Cc1cccc(Cl)c1

Procedure:
By the method in Example 75, Part F, 280 mg (0.75 mmol) of 1-[(3-chlorophenyl)methyl]-2-ethyl-4-methoxy-alpha-hydroxy-1H-indole-3-acetamide was reduced with 0.12 mL (0.75 mmol) of triethylsilane in 2 mL of trifluoroacetic acid to give by chromatography on silica gel (eluted ethyl acetate) 125 mg (48% yield) of 1-[(3-chlorophenyl)methyl]-2-ethyl-4-methoxy-1H-indole-3-acetamide.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:26](OC)=[O:27])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[N:8]2[C:17]=1[CH2:16][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:9]2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C(OCC)C>[F:25][C:20]1[CH:19]=[C:18]([C:7]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C:17]3=[C:5]([CH2:3][OH:2])[C:6]=2[CH2:26][OH:27])[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(F)c(F)c2)n2c1Cc1ccccc1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Product: OCc1c(CO)c(-c2ccc(F)c(F)c2)n2c1Cc1ccccc1C2
Reaction time: 2 h

Procedure:
A solution of the 3-(3,4-difluorophenyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline-1,2-dicarboxylic acid dimethyl ester (7.94 g, 20 mmol) in anhydrous dichloromethane (180 mL) was added dropwise into a stirred suspension of LiAlH4 (1.75 g, 46 mmol) in anhydrous diethyl ether (50 mL) at 10-15° C. The reaction mixture was further stirred for 2 hours after the addition was completed. The mixture was cooled in an ice bath and the excess hydride was destroyed by the sequential addition of water (2.5 mL), 15% aqueous NaOH (2.5 mL), and water (9.0 mL) at 0° C. The reaction mixture was filtered and the solid residue was washed with hot THF (300 mL). The combined filtrate and washings was evaporated to dryness in vacuo to dryness and the solid residue was recrystallized from dichloromethane/ether to give [3-(3,4-difluorophenyl)-2-hydroxymethyl-5,10-dihydropyrrolo[1,2-b]isoquinolin-1-yl]methanol (DA-1112), 4.57 g (67%); mp 145-146° C.; 1H NMR (DMSO-d6) δ 4.06 (2H, s, CH2), 4.28 (2H, d, J=5.1 Hz, CH2), 4.50 (2H, d, J=5.1 Hz, CH2), 4.55 (1H, t, J=5.1 Hz, exchangeable, OH), 4.62 (1H, t, J=5.1 Hz, exchangeable, OH), 5.02 (2H, s, CH2), 7.17-7.22 (1H, m, ArH), 7.24-7.35 (3H, m, 3×ArH), 7.34-7.36 (1H, m, ArH), 7.50-7.58 (2H, m, ArH) m/z 341.00 (M+H)+ Anal. Calcld. for C20H17F2NO2: C, 70.37; H, 5.02; N, 4.10. Found: C, 70.31; H, 4.91; N, 4.19.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=3[N:14]=2)[C:6]=1[CH3:24].ClC1C=CC=C(C(OO)=[O:33])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CO.ClCCl>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:15]=3[N:14]=2)=[O:33])[C:6]=1[CH3:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2[nH]c(SCc3nccc(OCCO)c3C)nc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2[nH]c(S(=O)Cc3nccc(OCCO)c3C)nc2c1
Reaction time: 4.5 h
Yield: 61.6 %

Procedure:
0.9 g of 2-[4-(2-hydroxyethoxy)-3-methylpyridine-2-yl]methylthio-5-methoxy-1H-benzimidazole was dissolved in a mixture comprising 5 ml of methanol and 80 ml of dichloromethane to obtain a solution. 0.51 g of m-chloroperbenzoic acid was added to this solution at -60° C. The obtained mixture was stirred at -50° to -40° C. for 4.5 hours, followed by the addition of 0.38 g of triethylamine. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained mixture and the resulting mixture was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to obtain a crude product. This crude product was crystallized from dichloromethane/isopropyl ether to obtain 0.58 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:9])[CH2:4][CH2:3]1.[CH3:31][C:32](=[CH2:38])[CH2:33][O:34][C:35](Cl)=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:26][CH2:27][N:28]([C:35]([O:34][CH2:33][C:32]([CH3:38])=[CH2:31])=[O:36])[CH2:29][CH2:30]2)=[O:9])[CH2:6][CH2:7]1
Reactant: C=C(C)COC(=O)Cl
Reactant: CN1CCN(C(=O)c2c(N3CCNCC3)n(-c3ccccc3)c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C)COC(=O)N1CCN(c2c(C(=O)N3CCN(C)CC3)c3ccccc3n2-c2ccccc2)CC1
Yield: 94 %

Procedure:
Reaction in analogy to Example 60 from 1-phenyl-2-(1-piperazinyl)-indole-3-carboxylic acid-4-methyl-piperazide and chloroformic acid-2-methyl-2-propenyl ester. After working up with methylene chloride and heated sodium carbonate solution, the crystalline residue of the organic phase was triturated with ether, suction-filtered and washed with ether. Melting point: 141°-143° C., yield: 94% of the theory.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1>CN(C=O)C>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OC1CCC(NCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC2CCC(NCc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.3 %

Procedure:
Add dropwise a solution of 4-benzylamino-cyclohexanol (675 mg, 3.28 mmol) in DMF (2 mL) to a suspension of NaH (196 mg, 4.92 mmol) in DMF (3 mL). Stir at room temperature for 45 min then at 50° C. for additional 40 min. Add a solution of 6-chloro-nicotinonitrile (500 mg, 3.61 mmol) in DMF (1.8 mL) dropwise and stir overnight at 60° C. Cool down the reaction mixture and evaporate the solvent. Wash the residue with water (10) and extract with EtOAc/hex (2/1, 15 mL). Combine the organic layers and dry over sodium sulfate. Filter and concentrate. Purify the resulting residue through an SCX column. Further purified by chromatography [CH2Cl2/NH3 (2.0M in methanol) 20/1] to provide the title compound (890 mg, 88%).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[O:3].[Br:14][C:15]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:16]=1[NH2:17].CCN(C(C)C)C(C)C.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:14][C:15]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:16]=1[N:17]1[C:6](=[O:8])[C:5]2[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1][C:2]1=[O:3]
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2c(=O)n1-c1ccc([N+](=O)[O-])cc1Br
Yield: 44.2 %

Procedure:
To a solution of methyl 2-isocyanatobenzoate (0.266 g, 1.5 mmol) and 2-bromo-4-nitroaniline (0.325 g, 1.5 mmol) in DMF (2 mL) was added DIEA (0.79 mL). The reaction mixture was stirred at room temp for 24 hr, with addition of DBU (0.22 mL) at 17 hr. The reaction mixture was extracted with EtOAc, washed with 1 N HCl and brine, dried and concentrated to give crude product, which was chromatographed on silica gel with 10% EtOAc/CH2Cl2 to give 3-(2-bromo-4-nitrophenyl)-1,3-dihydroquinazoline-2,4-dione (0.24 g, 44%). ES-MS (M+H)+=362, 364 (Br).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([C:18]([OH:20])=O)[N:15]([CH3:17])[N:16]=2)=[C:8]([CH2:21][OH:22])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:27][C:18]([C:14]2[N:15]([CH3:17])[N:16]=[C:12]([O:11][CH2:10][C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH2:21][OH:22])[CH:13]=2)=[O:20])[CH2:26][CH2:25][CH2:24]1
Reactant: CCCCc1noc(CO)c1COc1cc(C(=O)O)n(C)n1
Reactant: NC1CCC1
Product: CCCCc1noc(CO)c1COc1cc(C(=O)NC2CCC2)n(C)n1
Yield: 78 %

Procedure:
As described for example 112h, 5-(3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 0.16 mmol) was converted, using cyclobutylamine instead of 2,2,2-trifluoroethylamine HCl, to the title compound (45 mg, 78%) which was obtained as a colorless oil. MS: m/e=363.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[CH:25]=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27](O)[CH2:28][CH2:29][OH:30].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:10]=[C:9]1[CH:25]1[O:30][CH2:29][CH2:28][CH2:27][O:26]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCO
Reactant: O=Cc1nc(-c2ccccc2)c(-c2ccccc2)n1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(Cn2c(C3OCCCO3)nc(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A mixture of 1-benzyl-2-formyl-4,5-diphenyl-imidazole (6.8 g), propane-1,3-diol (7.6 g) and polymer-bound pyridinium 4-toluenesulphonate (1.0 g) in toluene (250 ml) was stirred at reflux under a Dean & Stark water trap for 8 hours. TLC analysis (using a 1:1 v/v mixture of ethyl acetate and hexane) showed about 20% unreacted aldehyde. A further quantity of polymer-bound pyridinium 4-toluenesulphonate (250 mg) and propane-1,3-diol (3.5 g) were added, and the mixture was heated at reflux for a further period of 6 hours. After cooling to room temperature the mixture was decanted from the catalyst and washed with water (3×100 ml). The organic solution was dried over magnesium sulphate and evaporated, to give 1-benzyl-2-(1,3-dioxan-2-yl)-4,5-diphenylimidazole (7.2 g), in the form of a pale pink solid.
Reaction SMILES: O[NH:2][CH:3]=[N:4][C:5](=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C(O)(=O)C.O1CCOCC1>[C:8]1(/[CH:7]=[CH:6]/[C:5]2[O:14][N:2]=[CH:3][N:4]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(C=Cc1ccccc1)N=CNO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C(=C/c1ncno1)\c1ccccc1
Yield: 7.7 %

Procedure:
N-[(Hydroxyamino)methylene]-cinnamamide (850 mg, 4.5 mmol) was dissolved in acetic acid/dioxane (20 mL 1:1 v:v), and heated to reflux for 2 h. The cooled solution was made basic (pH 8) with K2CO3, and partitioned between ethyl acetate and water. The organics were dried over Na2SO4, and concentrated in vacuo. The resultant solids were triturated with hot ethyl acetate, and the soluble portion was purified by flash column chromatography on silica eluting with 2:1 hexane:ethyl acetate to afford 5-[(E)-2-phenylethenyl]-1,2,4-oxadiazole (60 mg, 8% yield) as a white powder. M.p. 53–55° C. 1H NMR (CDCl3, 300 MHz) δ8.43 (s, 1H), 7.85 (d, J=16 Hz, 1H), 7.60 (m, 2H), 7.45 (m, 3H), 7.05 (d, J=16 Hz, 1H). MS (EI ionization) 171 (M+−H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH:20]([CH2:25][OH:26])[CH2:19]2)([CH3:15])([CH3:14])[CH3:13]>ClCCl.CCOCC>[C:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH:20]([CH:25]=[O:26])[CH2:19]2)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc2c(c1)CC(CO)C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)CC(C=O)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
To a suspension of pyridinium chlorochromate (FCC, Fluka, 3.24 g, 15 mmole) in dichloromethane (20 ml), there was added at room temperature, a solution of 5-tert-butyl-2-indanmethanol (2.04 g, 10 mmole) in dichloromethane (10 ml). The mixture was stirred for 5 h at room temperature. It was diluted in ether (50 ml), filtered on CELITE®, then on a FLORISIL® column (Fluka), and concentrated. Bulb-to-bulb distillation provided 5-tert-butyl-2-indancarbaldehyde (1.47 g, purity>99%, yield 72%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:15]([O:12][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])[CH:14]=[CH2:13]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(Br)cc1C(=O)O

Procedure:
The reaction of methyl 5-bromo-2-hydroxyl-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-5-bromo-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.98 (s, —CO2H); 7.73 (m, larom. H); 7.62 (m, 1 arom. H); 7.07 (m, 1 arom. H); 5.99 (m, —CH═CH2); 5.47, 5.25 (2 d-like, CH═CH2); 4.62 (d-like, CH2—CH═CH2). 13C-NMR (100 MHz, d6-DMSO): 165.99 (C═O); 156.10; 135.10; 133.00; 132.65; 123.86; 117.15; 116.12; 111.34; 68.84.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][C:38]([C:44]#[N:45])=[CH:39][CH:40]=4)[CH:35]=3)[S:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][C:38]([C:44]#[N:45])=[CH:39][CH:40]=4)[CH:35]=3)[S:22]([N:25]([C:26]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:32])[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)S(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: t-butyl N-[N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]sulfamoyl]carbamate, ethyl bromoacetate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].[NH2:23][C:24]1[C:28]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:27][NH:26][N:25]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[N:25]3[N:26]=[CH:27][C:28]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[C:24]3[N:23]=2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2]
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: CCOc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Product: CCOc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1C(F)(F)F
Yield: 68.5 %

Procedure:
Reaction of 1-(4-ethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (164 mg, 0.5 mmol), prepared from 4-ethoxy-3-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl -pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (155 mg, 68%). MS (ISP) 453.5 [(M+H)+]; mp 178° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:23]([C:26]2[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:54]=[CH:55][CH:56]=1)[CH2:37][N:38]1[C:42]([CH3:43])=[C:41](B2OC(C)(C)C(C)(C)O2)[C:40]([CH3:53])=[N:39]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:33][C:34]1[CH:35]=[C:36]([CH:54]=[CH:55][CH:56]=1)[CH2:37][N:38]1[C:42]([CH3:43])=[C:41]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:3]=2)[C:40]([CH3:53])=[N:39]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCOCC5)cc4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCOCC5)cc4)cnc32)cc1
Yield: 58.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)morpholine (intermediate 43) (150 mg, 0.268 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (133 mg, 0.402 mmol) in sodium carbonate (86 mg, 0.805 mmol), Pd(PPh3)2Cl2 (10 mg, 0.0134 mmol), Toluene/ethanol/water (5/5/5 ml) to afford 100 mg (58.82% yield) of titled compound. MS: m/z=636.1 (M+1).