Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(CO)cc1
Reactant: Nc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCc1ccc(CNc2ccccn2)cc1
Yield: 73.6 %

Procedure:
Using general procedure B: Reaction of 4-hydroxymethyl-benzaldehyde (1.01 g, 7.42 mmol), 2-aminopyridine (697 mg, 7.42 mmol), acetic acid (0.5 mL) and sodium triacetoxyborohydride (3.2 g, 14.8 mmol) in THF (20 mL) at room temperature under N2 for 40 min., then one hour at 50° C., followed by purification of crude material using chromatography on silica gel (2:2:96 CH3OH—NH3 H2O—CH2Cl2), afforded the title compound (1.17 g, 74%) as white foam.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][C@@H:13]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=4[CH3:30])[CH2:19][CH2:18]3)=[O:16])[NH:12][C:11]2=[O:31])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.C(OCC)(=O)C>[C:1]1([S:7]([N:10]2[CH2:14][C@@H:13]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=4[CH3:30])[CH2:21][CH2:22]3)=[O:16])[N:12]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:11]2=[O:31])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1-benzenesulfonyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-imidazolidin-2-one (40 mg) in acetone (5 mL) was treated with benzyl bromide (0.02 mL) and potassium carbonate (25 mg). The reaction mixture was stirred at ambient temperature overnight, additional benzyl bromide (0.03 mL) and potassium carbonate (37 mg) were added, and the mixture was heated to 70° C. for 5 h. After cooling to room temperature, ethyl acetate and a diluted aqueous solution of Na2CO3 were added. The phases were separated and the inorganic one was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated. Purification by column chromatography (SiO2, n-heptane/ethyl acetate 3:1 to 1:1) yielded (S)-1-benzenesulfonyl-3-benzyl-4-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-imidazolidin-2-one (41 mg) as a white solid. MS: 533.3 ([M+H]+)
Reaction SMILES: COC(=O)[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:5](=[O:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[Cl-].[Na+].O>CS(C)=O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:4][C:5]([C:6]2[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=2)=[O:12])=[CH:18][CH:17]=1
Reactant: COC(=O)C(C(=O)c1ccncc1)c1ccc(OC)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC(=O)c2ccncc2)cc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-methoxyphenyl)-3-oxo-3-(pyridin-4-yl)propionic acid methyl ester (14.7 g), sodium chloride (6.0 g) and water (1.9 cm3) in dimethyl sulphoxide (200 cm3) was stirred at 150° C. for 2 hours. The solution was cooled to room temperature, poured into water (600 cm3) and extracted with ethyl acetate-diethyl ether (1:1; 2×400 cm3). The extracts were dried (magnesium sulphate), filtered and concentrated to give 2-(4-methoxyphenyl)-1-(pyridin-4-yl)ethanone as a brown solid (10.2 g; 87%). δH (250 MHz; CDCl3) 3.79 (3 H, s, OCH3), 4.44 [2 H, s, C(O)CH2Ar], 6.88 (2 H, d, J 9, methoxyphenyl H-2), 7.16 (2 H, d, J 9, methoxyphenyl H-3), 7.77 (2 H, d, J 6, pyridyl H-3) and 8.80 (2 H, d, J 6, pyridyl H-2).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(O)C>CN(C)C=O>[CH3:10][N:7]1[CH2:8][CH2:9][CH:4]([O:3][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:6]1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)COC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Sodium hydride (5.0 g of 50% dispersion in mineral oil) was added portionwise to a stirred solution of 4-hydroxy-1-methyl-piperidine (11.5 g) in dry dimethylformamide (80 ml). The mixture was stirred at room temperature for 1 hour and then cooled to 10° C. A solution of ethyl 4-chloroacetoacetate (8.2 g) in dry dimethylformamide (20 ml) was added dropwise with stirring and stirring was continued for a further 20 hours at room temperature. Ethanol (10 ml) was added and the solution was evaporated to dryness. The residue was partitioned between dichloromethane and dilute hydrochloric acid. The organic layer was separated, dried over sodium sulphate and evaporated to given an oil which was partitioned between acetonitrile and petrol to remove mineral oil. The acetonitrile extract was evaporated to give the title compound as an oil (10.3 g) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:4][CH:3]=1.[CH2:25]=[O:26].[OH-].[Na+]>C1COCC1>[OH:1][C:2]1[C:10]([CH2:25][OH:26])=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:13])=[CH:4][CH:3]=1
Reactant: C=O
Reactant: C[C@@H](Cn1ncc2ccc(O)cc21)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(O)c(CO)c21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of benzyl [(1S)-2-(6-hydroxy-1H-indazol-1-yl)-1-methylethyl]carbamate (30.83 g, 0.0949 mol) in THF (400 ml) was treated with aqueous concentrated formaldehyde (37%, 12 M. 0.285 mol, 24 mL) and cooled in an ice bath. To the mixture was slowly added aqueous 1 N sodium hydroxide (0.02 mol, 20 mL) and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was quenched with aqueous saturated sodium bicarbonate (250 mL) and then neutralized to pH 7 with aqueous 2 N hydrochloric acid. The mixture was extracted with ethyl acetate (200 mL×3), the combined organic layers were dried over magnesium sulfate and filtered and evaporated to give crude tan solid, 28.38 g, which was a mixture of desired product and dimerized byproduct by LC/MS 356 m/z and 663 m/z. This residue was purified by chromatography (silica gel, hexane/ethyl acetate 1:1) to give the title compound, (18.44 g, 56%) as a yellow foamy solid, which was not pure by LS/MS 354 m/z with minor 663 m/z.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[C@H:4]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:18][C:19]([F:40])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:40][C:19]([F:18])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:17])=[O:16])[CH2:12][CH:13]([CH3:14])[CH3:15])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:25][CH2:24]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC(C)C[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)C[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-leucinamide (772 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1221 mg) in 2-propanol (10 mL) was added piperidinium acetate (523 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight. After evaporation of the solvent, the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (888 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C:10](=[C:14]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[C:26]([Si:23]([CH3:25])([CH3:24])[O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH:14]([CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1CC(=C1CN(Cc2ccccc2)CCO1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CC(c1ccccc1)C1CNCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add Pd/C (10%) (470 mg) to a solution of 4-Benzyl-2-{2-[2-(tert-butyl-dimethyl-silanyloxy)-phenyl]-1-phenyl-ethylidene}-morpholine (470 mg, 0.97 mmol) in 10 ml of MeOH, bubble H2 and stir at room temperature for 4 h. Concentrate the solvent under reduced pressure to give a residue. Purify the residue by column chromatography eluting with CH2Cl2:MeOH 9:1 to afford pure the title compound as colourless oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:43])[C:35]5[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N+:36]=5[O-:42])=[C:30]([O:44][CH2:45][CH3:46])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:11][CH:12]([CH3:15])[CH3:13])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:43])[C:35]5[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N+:36]=5[O-:42])=[C:30]([O:44][CH2:45][CH3:46])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OCC)c2)CCN3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OCC)c2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 162.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.6 g) and isobutylaldehyde (0.27 ml) were dissolved in 1,2-dichloroethane (50 ml), and to the solution, triacetoxy sodium borohydride (1 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 12) (0.53 g) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4]1[N:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([O:12][CH3:13])[N:5]=1.[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]=[C:28]=[O:29])(=[O:26])=[O:25])(=[O:17])=[O:16]>C(Cl)Cl>[CH3:11][O:10][C:8]1[N:7]=[C:6]([O:12][CH3:13])[N:5]=[C:4]([N:3]([O:2][CH3:1])[C:28]([NH:27][S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:15]([CH3:14])(=[O:17])=[O:16])(=[O:26])=[O:25])=[O:29])[N:9]=1
Reactant: CONc1nc(OC)nc(OC)n1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COc1nc(OC)nc(N(OC)C(=O)NS(=O)(=O)c2ccccc2S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred suspension of N,4,6-trimethoxy-1,3,5-triazin-2-amine (0.01 mol) in dry methylene chloride (24 ml) is added 2-methylsulfonylbenzenesulfonyl isocyanate (0.014 mol). The mixture is stirred at ambient temperature for 24 hours. The solvent is then evaporated under reduced pressure. The residue is stirred in 1-chlorobutane (50 ml) for 5 hours. The solid is then filtered, washed with ether and dried to yield N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)(methoxy)aminocarbonyl]-2-(methylsulfonyl)benzenesulfonamide.
Reaction SMILES: [CH:1]1([CH:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][NH:5]2)[CH2:3][CH2:2]1.[C:18](Cl)(=O)[C:19]1C=CC=C[CH:20]=1.C1(C(Cl)=O)CC1.C([BH3-])#N.[Na+]>>[C:1]1([CH:4]2[C:13]3[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3)[CH2:7][CH2:6][NH:5]2)[CH:3]=[CH:2][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2c(cc1OC)C(C1CC1)NCC2
Agent: O=C(Cl)C1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1cc2c(cc1OC)C(c1ccccc1)NCC2

Procedure:
1,2,3,4-Tetrahydro-1-phenyl-6,7-dimethoxyisoquinoline was prepared by a procedure analogous to that described in example 4 for 1,2,3,4-tetrahydro-1-cyclopropyl-6,7-dimethoxy- isoquinoline but substituting in the first step benzoyl chloride for cyclopropylcarbonyl chloride. The 1,2,3,4-tetrahydro-1-phenyl-6,7-dimethoxyisoquinolinyl was reacted with 7-[N-3-(4-fluorophenyl)propionyl]amino-4,4-diphenylheptan-1-al in the presence of sodium cyanoborohydride as described in example 1 to give the desired product as glassy residue: MS showed (M+H)+ @ 685; 1H-NMR (CDCl3, δ): 1.0-1.2 (m, 4H), 1.65-1.75 (m, 1H), 1.95-2.05 (m, 2H), 2.06-2.15 ((m, 1H), 2.15-2.25 (m, 1H), 2.32-2.36 (t, 2H), 2.36-2.45 (m, 2H), 2.62-2.70 (m, 1H), 2.85-2.95 (m, 4H), 3.08-3.17 (q, 2H), 3.58 (s, 3H), 3.83 (s, 3H), 4.36 (s, 1H), 5.01 (broad t, 1H), 6.13 (s, 1H), 6.58 (s, 1H), 6.88-6.94 (m, 2H), 7.06-7.33 (m, 17H); IR (CHCl3) u 3300, 2950, 1645, 1505 cm-1. The hydrochloride salt was prepared as in example 1 to give 7-[N-3-(4-fluorophenylpropionyl]amino-1-[N-(1,2,3,4-tetrahydro-1-phenyl-6,7-dimethoxy- isoquinolinyl)]-4,4-diphenylheptane hydrochloride: mp 117-120° C.; Anal. Calcd for C45H49N2O3F-HCl 0.5H2O: C, 74.0; H. 7.30; N. 3.83; Found: C. 73.14; H, 6.74; N, 3.71.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=O)[CH2:14]2)[CH2:10][CH2:9]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Agent: CN(C)c1ccncc1
Agent: NC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2c(c1)CCC21CCNCC1
Reaction time: 3 h

Procedure:
To a solution of 1.0 g (3.21 mmol) of the intermediate obtained in Step B in 3.0 ml of dichloromethane was added 0.945 ml (6.74 mmol) of triethylamine and 50 mg of DMAP and finally 0.501 ml (3.53 mmol) of trifluroacetic acid anhydride. The reaction mixture was stirred for 3 hours and then diluted with 20 ml of dichloromethane. The solution was washed with water, dried over magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, hexane/ethyl acetate 2:1) gave 568 mg (1.91 mmol).
Reaction SMILES: CCC(OOC(OO)(CC)C)([O:5]O)C.[CH3:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:18]([OH:19])[C:17]=1O>>[CH3:15][C:16]1[CH:17]=[C:18]([OH:19])[CH:20]=[C:21]([CH3:23])[C:22]=1[OH:5]
Reactant: Cc1cc(C)c(O)c(O)c1
Reactant: CCC(C)(OO)OOC(C)(CC)OO
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following in the same manner as in Example 56 except that 11.2 g. (P=67.7) of methyl ethyl ketone peroxide was used instead of 4-methyl-2-pentanone peroxide, 4.68 g. (33.9 m.moles) of 3,5-dimethylcatechol and 2.17 g. (15.7 m.moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 73.3%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.CCCCCC.[CH3:20][C:21]1([CH3:28])[O:26][CH2:25][C:24](=[O:27])[CH2:23][O:22]1.[Cl-].[NH4+]>C1COCC1>[CH3:20][C:21]1([CH3:28])[O:26][CH2:25][C:24]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)([OH:27])[CH2:23][O:22]1
Reactant: CC1(C)OCC(=O)CO1
Reactant: Cc1ccnc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccnc(C2(O)COC(C)(C)OC2)c1
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 2.01 g of 2-bromo-4-methylpyridine in 10 ml of THF were added 4.3 ml of a 2.69 M n-butyllithium/hexane solution at −78° C., followed by stirring for 30 minutes. To the reaction mixture was added dropwise a solution of 1 g of 2,2-dimethyl-1,3-dioxan-5-one in 5 ml of THF, followed by stirring at −78° C. for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 700 mg of 2,2-dimethyl-5-(4-methylpyridin-2-yl)-1,3-dioxan-5-ol.
Reaction SMILES: C[Sn]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[C:27]([CH2:28][OH:29])=[C:26]([Cl:30])[N:25]=[C:24]3[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:17]=2)=[N:8][N:7]=[N:6]1)(C)C.C(Cl)Cl.[OH-].[Na+].[C:40]1([C:46](Cl)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O.O1CCCC1>[C:40]1([C:46]([N:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[C:27]([CH2:28][OH:29])=[C:26]([Cl:30])[N:25]=[C:24]4[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:17]=3)=[N:8][N:7]=[N:6]2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2[Sn](C)(C)C)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1-[(2'-(Trimethylstannyltetrazol-5-yl)-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole (1.046 Kg), methylene chloride (5.00 L), tetrahydrofuran (0.85 L) and 10N sodium hydroxide (192 ml) were charged to a 12 liter round-bottomed flask equipped with mechanical stirrer, condenser with N2 inlet, and thermometer. After stirring five minutes at room temperature, triphenylmethyl chloride (0.530 Kg) was added and the mixture stirred three hours. 10N Sodium hydroxide (20 ml) and additional triphenylmethyl chloride (50 g) were added and the mixture stirred overnight. Deionized (D.I.) water (3.70 L) and 10N sodium hydroxide (30 ml) were added and the phases allowed to separate. The organic phase was washed twice with 2.0 L portions of water, dried with sodium sulfate (100 g) and filtered into a 12 L round-bottomed flask equipped for distillation. Methylene chloride (~2.0 L) was distilled. Heating was discontinued and heptane (5.0 L) was added. The resulting slurry was stirred at ambient temperature over the weekend (~68 hours). The mixture was cooled to ~5° C. and the product isolated by vacuum filtration, washed with heptane (1.0 L) and dried 48 hours in in vacuo at 40°-50° C. Yield: 959.5 g, 80%. M.P.: 167°-169° C. Purity by HPLC: 99.8%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8]2)=[CH:2]1.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33]Cl>>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH2:32][CH2:33][N:19]1[CH2:18][CH2:17][CH:16]([C:9]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:8]=2)[CH2:21][CH2:20]1
Reactant: c1cnc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Reactant: COC(=O)c1ccccc1OCCCl
Product: COC(=O)c1ccccc1OCCN1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 1, part H, starting with 0.28 g (1 mmol) of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 0.26 g (1.2 mmol) of 2-(2-chloroethoxy)-benzoic acid methyl ester. After standard work-up and purification, 0.16 g (35% of yield) of the expected product were obtained.
Reaction SMILES: [Br:1][C:2]([Br:19])=[CH:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]COC)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.C(O)C>Cl.O1CCCC1.C(OCC)C>[Br:19][C:2]([Br:1])=[CH:3][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COCOc1ccc(-c2ccc(C=C(Br)Br)s2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc(C=C(Br)Br)s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 108.3 %

Procedure:
A mixture of 2-(2,2-dibromoethenyl)-5-(4-methoxymethoxyphenyl)thiophene (8.8 g, 0.02 mole), prepared by the method of Example 6, ethanol (10 mL), and two drops of concentrated hydrochloric acid in tetrahydrofuran (50 mL) was stirred at room temperature for approximately 18 hours. Gaseous hydrogen chloride was bubbled into the mixture for several seconds, after which 10 mL of methanol was added. The resultant mixture was stirred at room temperature for two hours. This mixture was poured into an aqueous saturated ammonium chloride solution and extracted with diethyl ether. The ether extract was washed with an aqueous saturated ammonium chloride solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, leaving a solid residue. This residue was dissolved in diethyl ether, and approximately 50 g of silica gel was added to the solution. The mixture was stirred briefly and filtered. The filtrate was evaporated under reduced pressure, yielding 7.8 g of 2-(2,2-dibromoethenyl)-5-(4-hydroxyphenyl)thiophene as a solid (mp 99°-101° C.).