Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:29][CH3:30])[C:27]=1[CH3:28])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[N+:22]([O-])=O)=[O:7].C(O)(=O)C.O>C(O)C.C(OCC)(=O)C.[Fe]>[NH2:22][C:11]1[CH:12]=[C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:25]=[C:26]([O:29][CH3:30])[C:27]([CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2[N+](=O)[O-])cc(OC)c1C
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A suspension of compound 1f (2.80 g, 6.81 mmol) in a mixture of ethanol (120 mL), acetic acid (6 mL) and water (24 mL) was heated to reflux. Iron powder (1.90 g, 34 mmol) was added portionwise over 45 min. The reaction mixture was cooled to rt and diluted with ethyl acetate. The ethyl acetate solution was washed with saturated NaHCO3 solution, dried Na2SO4, and concentrated on a rotary evaporator to a volume of ˜30 mL. The solid precipitate was recovered by filtration and washed with ethyl acetate (2×). The filtrate was passed through a short silica gel column in ethyl acetate, and concentrated on a rotary evaporator. The residue was triturated with ethyl acetate and combined with the previously filtered solid to afford compound 1g (1.83 g, 70%) as a tan solid. ESI-MS m/e 383.3 (M+1).
Reaction SMILES: Cl.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]([C:14]1[N:15]=[CH:16][NH:17][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][C:23]=1[Cl:35])=[O:20])=[O:13].C=O.[CH3:38]CN(C(C)C)C(C)C.ClCCl>C1COCC1>[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]([C:14]1[N:15]=[CH:16][NH:17][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:38])[CH2:31][CH2:30]2)=[CH:24][C:23]=1[Cl:35])=[O:20])=[O:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Nc1nc2ccccc2[nH]1)c1nc[nH]c1C(=O)Nc1ccc(OC2CCNCC2)cc1Cl
Agent: C=O
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc(NC(=O)c3[nH]cnc3C(=O)Nc3nc4ccccc4[nH]3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.2 %

Procedure:
A flask was charged with N4-(1H-benzo[d]imidazol-2-yl)-N5-(2-chloro-4-(piperidin-4-yloxy)phenyl)-1H-imidazole-4,5-dicarboxamide hydrochloride (115 mg, 0.22 mmol), formaldehyde, 30% wt (0.030 mL, 4 mmol), DIEA (0.080 mL, 0.5 mmol), dichloromethane (20 mL) and THF (20 mL), and the reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was filtered, and the precipitate was discarded. The product was purified by reverse phase HPLC using ammonium acetate and acetonitrile as eluent to afford 60 mg (55% yield) of N4-1H-benzimidazol-2-yl-N5-(2-chloro-4-{[1-(methyl)piperidin-4-yl]oxy}phenyl)-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, DMSO-d6): δ 8.06 (s, 1H), 7.91 (d, 9 Hz, 1H), 7.46 (s, br, 2H), 7.21 (d, 3 Hz, 1H), 7.12-7.03 (m, 3H), 4.44-4.42 (m, 1H), 2.61-2.50 (m, 2H), 2.20-2.17 (m, 5H), 1.96-1.89 (m, 2H), 1.67-1.61 (m, 2H). MS (EI): 494 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 0.002 mol, Aldrich, Cat. No. 525057) in acetonitrile (10 mL) was added tert-butyl 2-bromoacetate (0.36 mL, 0.0025 mol, Aldrich, Cat. No. 124230) and cesium carbonate (1.0 g, 0.0031 mol). The suspension was stirred at r.t. overnight. The reaction mixture was partitioned with AcOEt and water. The organic layer was separated, washed with water and brine, dried over MgSO4. After filtration, the filtrate was concentrated to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=309.1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=O.CN(C)C.C(OP(Cl)(OCC)=O)C.[CH2:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH2:27]([N:34]1[CH2:39][CH2:38][N:37]([C:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7]3)=[O:3])[CH2:36][CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)C
Solvent: C1CCOC1
Product: O=C1Cc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
5-Carboxyoxindol (0.93 g) and 0.8 ml of trimethylamine were suspended in 10 ml of tetrahydrofuran (THF), and a solution of 1.0 g of diethylchlorophosphate in 10 ml of THF was added dropwise thereto at room temperature with stirring. The mixture was stirred for 3 hours at room temperature. To the mixture was added dropwise a solution of 1.1 g of benzylpiperazine in 10 ml of THF and was further stirred for 10 hours at room temperature. After completion of reaction, crystals which precipitated were filtered off and the filtrate was concentrated. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate and the mixture was extracted with chloroform. Organic layer was washed with water and a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off. Recrystallization of the residue from isopropyl alcohol gave 1.01 g of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH3:9][O:10][CH2:11]OC.COCC(=O)C>COCOC1C=C([Mg]Br)C=CC=1>[CH3:9][O:10][CH2:11][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: COCOC
Reactant: Oc1cccc(Br)c1
Agent: COCC(C)=O
Agent: COCOc1cccc([Mg]Br)c1
Product: COCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Methoxymethoxyphenyl bromide was prepared by the reaction of 3-bromophenol and dimethoxymethane using the general procedure described in Synthesis, 1976, 244. Methoxyacetone (4.41 g) was added to a solution of 3-methoxymethoxyphenylmagnesium bromide [prepared from 3-methoxymethoxyphenyl bromide (10.85 g) and magnesium (1.2 g) in tetrahydrofuran (100 ml)]. The mixture was stirred at ambient temperature for 15 hours and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 20:3 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained 2-hydroxy-2-(3-methoxymethoxyphenyl)-prop-1-yl methyl ether (7.87 g, 69%), as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1.[CH3:27][NH:28][CH3:29].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:28]([CH3:29])[CH3:27])[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1
Reactant: O=C1CCN(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CNC
Agent: Cl
Product: CN(C)C1CCN(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Yield: 170.2 %

Procedure:
Using a similar procedure to that described in Example 27, N-(5-chloropyridin-2-yl)-2-(4-oxopiperidin-1-ylcarbonyl)aminobenzamide (100 mg, 0.268 mmol) and dimethylamine (2.0 M solution, 2.7 mL, 5.4 mmol) yielded, after treatment with HCl, 100 mg of the title compound as a hydrochloride salt.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[C:26]#[CH:27]>CC(C)=O>[C:25]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1)#[C:26][CH3:27]
Reactant: C#CCBr
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2c(=O)cc(-c3ccccc3)oc2c1

Procedure:
A mixture of 7-hydroxyflavone (2.38 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.58 g of a product with the following characteristics: m.p. 199-200° C.; 1H NMR (CDC13) δ: 2.6 (m, 1H), 4.8 (s, 2H), 6.75-8.18 (m, 9H).
Reaction SMILES: [OH:1][CH:2]([C:31]([OH:34])([CH3:33])[CH3:32])[CH:3]([NH:12][C:13]([CH:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.I([O-])(=O)(=O)=O>C(Cl)Cl>[OH:34][C:31]([CH3:33])([CH3:32])[C:2](=[O:1])[CH:3]([NH:12][C:13]([CH:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)NC(CCc1ccccc1)C(O)C(C)(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)NC(CCc1ccccc1)C(=O)C(C)(C)O
Yield: 20.7 %

Procedure:
A solution comprised of benzyl 1-(2,3-dihydroxy-3-methyl-1-phenethylbutylcarbamoyl)-3-methylbutylcarbamate (0.250 g, 0.532 mmol) and Dess-Martin Periodate (0.451 g, 1.06 mmol) in dry methylene chloride (27 mL) was stirred vigorously and then a mixture of wet methylene chloride (20 mL, 95 mL of dry methylene chloride and 95 μL of water) was added by a separatory funnel. The mixture was stirred 18 hours at room temperature and concentrated to dryness in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4) and concentrated to dryness in vacuo. Product was purified from the residue by prep HPLC using 100% water to 20% water/acetonitrile over a 60 minute period. The desired fractions were collected and lyophilized to dryness to provide benzyl 1-(3-hydroxy-3-methyl-2-oxo-1-phenethylbutylcarbamoyl)-3-methylbutylcarbamate (0.05 g, 0.11 mmol) as a white solid. 1H NMR (CDCl3): 0.89-0.91 (m, 6H), δ 1.23-1.32 (2×s, 6H), δ 1.42-4.65 (m, 2H), δ 1.86-1.89 (m, 1H), δ 2.05-2.15 (m, 1H), δ 2.58-2.63 (m, 2H), δ 4.12 (m, 1H), δ 5.09-5.21 (m, 4H), δ 6.52 (d, 1H), δ 7.12-7.31 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2F)CC1

Procedure:
379 mg of the target compound (1.01 mmol, 32.5%) was obtained using 1-(2-methoxyphenyl)piperazine (1.2 g, 6.20 mmol), 2′-fluorobiphenyl-2-carbaldehyde (620 mg, 3.10 mmol) and NaBH(OAc)3 (2.0 g, 9.30 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH:14]=[O:15])[C:12]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[I-].[K+]>[CH2:1]([O:19][C:12]1[C:11]([O:10][CH3:9])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(C=O)c1OCc1ccccc1
Temperature: 70 °C
Yield: 81 %

Procedure:
Benzyl bromide (8.6 ml) was added to a stirred solution of 3-methoxysalicylaldehyde (10 g), potassium carbonate (14.76 g) and potassium iodide (0.12 g) in DMF (120 ml) under an atmosphere of argon. The reaction was heated at 70° C. for 16 hours. Water (200 ml) was added causing the precipitation of a brown oil which crystallised on cooling. The solid was filtered, washed with water, dissolved in dichloromethane and dried (MgSO4). The solvent was removed in vacuo to give an oil which crystallised on trituration with iso-hexane to give the product as an off white solid (12.85 g, 81%); NMR d (CD3SOCD3) 3.91 (s, 3H), 5.15 (s, 2H), 7.14-7.22 (m, 2H), 7.29-7.42 (m, 6H), 10.10 (t, 1H); M/z (+) 243 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:20][CH3:21])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C)c(C(F)(F)F)c1

Procedure:
A solution of commercially available 4-methyl-3-trifluoromethylbenzoic acid (24.5 g, 120 mmol) and conc. sulfuric acid (6.5 ml) in dry ethanol (245 ml) is refluxed for 23 h. After reaching room temperature the solvent is evaporated and the residue is neutralized by addition of saturated aqueous NaHCO3 solution. The mixture is extracted with ethyl acetate (3×40 ml). The organic extracts are combined, dried over Na2SO4 and evaporated to dryness to afford a pale yellow oil: HPLC: tR=7.15 min (purity: >96%, gradient A), ESI-MS: 233.3 [MH]+.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7]CC)=O)#[N:3].[O:10]=[C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:12]>C(O)C>[C:2]([CH:4]1[C:14]([CH3:16])([CH3:15])[CH2:13][C:11](=[O:10])[CH2:12][C:5]1=[O:7])#[N:3]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)C=C(C)C
Agent: [Na]
Solvent: CCO
Product: CC1(C)CC(=O)CC(=O)C1C#N
Temperature: 25 °C
Yield: 58.9 %

Procedure:
Sodium metal (11.5 g, 0.5 mol) was dissolved in dry ethanol (225 ml) at ambient temperature (20° C.). Ethyl cyanoacetate (60 g, 0.53 mol) was added dropwise with stirring at ambient temperature. To the resulting solution was added dropwise, with stirring, mesityl oxide, and the mixture was heated under reflux for 4 hours. After cooling, the mixture was extracted with diethyl ether to remove any unreacted starting material and acidified with 2M aqueous hydrochloric acid. The brown oil which separated out was extracted into diethyl ether, dried (Na2SO4) evaporated and triturated with 40°-60° C. petroleum ether to give a pale yellow solid, which on recrystallisation from diethyl ether gave 4-cyano-5,5-dimethyl-1,3-cyclohexanedione as a white crystalline solid (48.6 g, 58.9%) m.p. 130°-132° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13](/[CH:16]=[C:17]2\[CH2:18][N:19]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21][CH:22]\2O)=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43]([OH:46])(=[S:45])[CH3:44].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:43]([S:45][CH:22]1[CH2:21][CH2:20][N:19]([C:24]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:18]/[C:17]/1=[CH:16]\[C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[N:12]=1)(=[O:46])[CH3:44]
Reactant: CC(C)(C)OC(=O)NCCn1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccn(CCNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-3-({1-[2-(t-butoxycarbonylamino)ethyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol (3.67 g) in N,N-dimethylformamide (50 ml) were added thioacetic acid (4.6 ml) and N,N-dimethylformamide dineopentylacetal (18 ml). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride successively, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate and hexane (1:9 to 1:1) as the eluent to afford crude (E)-4-(acetylsulfanyl)-3-({1-[2-(t-butoxycarbonylamino)ethyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidine (4.29 g) as a brown oil. To a solution of the above oil in dichloromethane (50 ml) was added trifluoroacetic acid (1.5 ml) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes, and the solvent was removed in vacuo. The residue was purified twice by chromatography on silica gel using a mixture of methanol and dichloromethane (1:99 to 7:93) as the eluent to afford the title compound as a brown oil (1.46 g, overall yield: 37%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OO)(=[O:21])C>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([OH:21])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OO
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Solvent: CC(=O)O
Product: COc1cc(O)ccc1OCc1ccccc1
Reaction time: 18 h

Procedure:
24.2 g of 4-benzyloxy-3-methoxy benzaldehyde (Beilst. Vol. 8, II p 283) were dissolved in 100 ml of acetic acid and a mixture of 25 ml of peracetic acid and 50 ml of acetic acid was added without exceeding 45° C. The mixture was stirred for 18 hours at +40° C. and after concentration to dryness, the residue was chromatographed on silica (eluant: hexane-ethyl acetate 8-2) to obtain 9.1 g of the expected product melting at 84° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH:20][CH3:21])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[C:6]([O:22][CH3:23])[CH:5]=1)([CH3:3])[CH3:2].C(C1C=CC(C(=C)C(C)C(O)(C(F)(F)F)CO)=C(OC)C=1)(C)C>C(O)C.[Pd].[C]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:20][CH3:21])[CH2:11][C:12]([OH:19])([C:15]([F:17])([F:16])[F:18])[CH2:13][OH:14])=[C:6]([O:22][CH3:23])[CH:5]=1)([CH3:2])[CH3:3]
Reactant: CC=C(CC(O)(CO)C(F)(F)F)c1ccc(C(C)C)cc1OC
Agent: [Pd]
Agent: C=C(c1ccc(C(C)C)cc1OC)C(C)C(O)(CO)C(F)(F)F
Solvent: CCO
Product: CCC(CC(O)(CO)C(F)(F)F)c1ccc(C(C)C)cc1OC

Procedure:
The mixture of 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-hex-4-en-1-ol and 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-3-methyl-2-(trifluoromethyl)pent-4-en-1-ol (4.6 g, 13.84 mmol) is dissolved in ethanol (100 ml). Following addition of 10% Pd/carbon (0.7 g) hydrogen is introduced into the reaction mixture for four hours via a balloon. The catalyst is filtered off with suction (glass fibre filter) and the precipitate is washed with ethanol. Following removal of the solvent on a rotary evaporator, the residue (4.59 g, 99.2%) is used in crude form in the next step. It consists of a mixture of 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexan-1-ol and 4-(4-isopropyl-2-methoxyphenyl)-2-hydroxy-3-methyl-2-(trifluoromethyl)pentan-1-ol (ratio 30:70).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:16])([C:13]([NH2:15])=[O:14])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>C(Cl)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:16][C:9](=[O:16])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)([C:10]([NH2:12])=[O:11])[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C(O)(C(N)=O)c1ccc(Cl)c(Cl)c1
Solvent: O=C(Cl)c1ccccc1
Product: NC(=O)C(OC(=O)c1ccccc1)(C(N)=O)c1ccc(Cl)c(Cl)c1
Temperature: 5 °C
Yield: 109.4 %

Procedure:
13.1 g of 3,4-dichlorophenylhydroxymalonic acid diamide in 200 ml of benzoyl chloride were heated to 110° C. for 9 hours. The mixture was then cooled to 5° C. and the precipitate was filtered off with suction, washed with toluene and then recrystallised from 550 ml of i-propanol. 10 g of 3,4-dichlorophenylbenzoyloxymalonic acid diamide were isolated: melting point 225° C., with decomposition.
Reaction SMILES: [CH2:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:22]O>C(O)CC.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH2:12]([N+:11]([O-:22])=[CH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OO
Reactant: CCCCCCCCCCNCCCCCCCCCC
Agent: O=[W](=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: CCCCCCCCCC=[N+]([O-])CCCCCCCCCC
Temperature: 40 °C

Procedure:
To a solution of 29.8 grams of didecylamine in 120 ml of n-propanol is added sequentially 1.6 grams of sodium tungstate dihydrate and 14.3 grams of a 50% aqueous hydrogen peroxide solution at 5°-10° C. The reaction mixture is allowed to warm up to 40° C. and is maintained at that temperature for 20 hours. An additional 7.2 grams of 50% aqueous hydrogen peroxide solution is added to the solution at 40° C. After further stirring for another day, the reaction mixture is concentrated under reduced pressure. The residue is partitioned between chloroform and water. The combined organic extracts are washed with water and then dried over anhydrous sodium sulfate. Removal of the chloroform solvent leaves a crude product which is purified by recrystallization from heptane to afford the above-named compound as a white solid melting at 63°-65° C. in a yield of 9.8 grams.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1([C:48]2[CH:57]=[CH:56][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:50][CH:49]=2)[CH2:47][CH2:46]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(#N)C>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]([NH:44][C:45]2([C:48]3[CH:57]=[CH:56][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:50][CH:49]=3)[CH2:47][CH2:46]2)=[O:19])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c21
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(C2(NC(=O)c3cccc4c3NCC4)CC2)cc1
Reaction time: 2 h

Procedure:
1-(tert-butoxycarbonyl)indoline-7-carboxylic acid (300 mg, 1.14 mmol), HATU (475 mg, 21.2 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (262 mg, 1.37 mmol) were added to acetonitrile (7.6 ml). The solution was cooled in an ice bath and DIPEA (695 ul, 3.99 mmol) was added. After 2 hr at RT, the mixture was poured into a solution of NaHCO3 (½ sat.) and washed 3 times with EtOAc. The combined organic layers were washed with brine and dried with Na2SO4. The solvent was removed and the crude mixture purified by flash chromatography on silica gel. The Boc group was removed with 1:1 TFA/DCM using the standard procedure.