Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([C:20]([CH:22]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23]2)=O)[CH3:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([C:20]2([CH:22]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23]3)[CH2:2][CH2:1]2)[CH3:19])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC[Mg]Br
Reactant: CN(C(=O)C1CCN(Cc2ccccc2)C1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1(C2CCN(Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 37.7 %

Procedure:
A stirred solution of ethylmagnesium bromide (3.0 M in ethyl ether, 2.1 mL, 6.3 mmol) in THF (17.0 mL) was cooled to −78° C. To this solution was added a solution of titanium (IV) isopropoxide (0.76 mL, 2.6 mmol) in THF (1.7 mL) dropwise with the temperature below −70° C. After stiring for three minutes, the solution of 4-[(1-benzyl-pyrrolidine-3-carbonyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.5 mmol) in THF (1.7 mL) was added. The resulting solution was slowly warmed to room temperature, heated at reflux for one hour and then cooled to 8° C. Ethylmagnesium bromide (3.0 M in ethyl ether, 1.8 mL, 5.4 mmol) was added followed by a solution of titanium (IV) isopropoxide (0.66 mL, 2.2 mmol) in THF (1.0 mL) rapidly. The reaction mixture was stirred at room temperature for one hour and partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (60% ethyl acetate in hexane with 0.5% triethylamine) to give pale yellow oil (390 mg, 38%). ESI MS m/z 414.3 (M+H+).
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[CH:14]=[C:15]([OH:25])[N:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[N:17]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH2:28]([O:30][C:31]([C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1)=[O:32])[CH3:29]>C1COCC1>[CH2:28]([O:30][C:31](=[O:32])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40]([C:14]2[C:13]([CH2:12][O:11][C:1]34[CH2:8][CH:7]5[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]5)[CH2:2]3)[CH2:10]4)=[N:17][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[C:15]=2[OH:25])=[O:41])[CH:34]=1)[CH3:29]
Reactant: Cc1ccccc1-n1nc(COC23CC4CC(CC(C4)C2)C3)cc1O
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)c2c(COC34CC5CC(CC(C5)C3)C4)nn(-c3ccccc3C)c2O)c1
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A solution of 5-(adamantan-1-yloxymethyl)-2-o-tolyl-2H-pyrazol-3-ol (160 mg, 0.47 mmol) in anhydrous THF (4 mL) was added to a suspension of sodium hydride (26 mg of 60% dispersion in oil, 0.65 mmol) in THF (2 mL) under a dry argon atmosphere at room temperature. The mixture was stirred for 30 min. and a solution of 3-ethoxycarbonylphenyl isocyanate (99 mg, 0.5 mmol) in THF (1 mL) added. Stirring was continued for 1 h and the mixture partitioned between 5% KHSO4 (40 mL) and EtOAc (40 mL). The organic phase was washed with brine (30 mL), and dried (MgSO4). Filtration and evaporation of the solvent afforded the product as a red solid, (250 mg, 100%).
Reaction SMILES: [CH:1](=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2)[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:2][CH:1]=[C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: CC=C1c2ccccc2C=Cc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC=C1c2ccccc2C=Cc2ccccc21

Procedure:
A mixture of 5-ethylidene-5H-dibenzo[a,d]cycloheptene (10.9 g., 0.05 mole), N-bromosuccinimide (8.9 g., 0.05 mole), benzoyl peroxide (15 mg.) and 150 ml. of carbon tetrachloride is stirred and heated to refluxing on the steam-bath for 4 hours. After cooling, the succinimide is separated by filtration and washed with carbon tetrachloride. The combined filtrate and washings are evaporated to dryness under reduced pressure. Crystallization of the residual solid from petroleum ether gave 5-(2-bromoethylidene)-5H-dibenzo[a,d]cycloheptene in a yield of 10.65 g. (72%), m.p. 87.5°-89.5°C. An analytical sample, after recrystallization from petroleum ether, melted at 89°-90°C.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4]1.[OH:9][C:10]1[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[C:22]([CH3:25])([CH3:24])[CH3:23]>C(O)C>[OH:9][C:10]1[C:17]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:16][C:13]([CH:14]=[N:2][N:3]2[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4]2)=[CH:12][C:11]=1[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cn(N)cn1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCO
Product: Cc1cn(N=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.5 g of 1-amino-4-methylimidazole hydrochloride are dissolved in 200 ml of ethanol. 6.2 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde are added and the mixture is stirred at room temperature overnight. The solution obtained is then evaporated in a vacuum. The residue is treated with 150 ml of methylene chloride and 150 ml of water, stirred and saturated sodium bicarbonate solution is added up to a neutral reaction (pH=7). The methylene chloride phase is separated and the aqueous phase is extracted with 50 ml of methylene chloride. The methylene chloride phases are combined, washed once with 10% sodium chloride solution, dried and evaporated. The residue is triturated with cold ether. The solid is removed by filtration, washed with ether and n-hexane and dried at 70° in a vacuum. There is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-4-methylimidazole of m.p. 150°-151°.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:14][N:15]=[C:16]=[O:17].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:14][NH:15][C:16]([NH:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][Cl:2])[N:5]=1)=[O:17]
Reactant: Nc1nc(CCl)cs1
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a suspension of 4-(chloromethyl)thiazol-2-amine hydrochloride (7.55 g, 41 mmol) in DCM (150 mL) at 0° C. was added 3,4-dichlorobenzyl isocyanate (8.27 g, 41 mmol). A solution of DIPEA in DCM (30 mL) was added over a period of 30 minutes and the mixture was stirred overnight at room temperature. Evaporation of the volatiles followed by purification by column chromatography (EtOAc/heptanes 1/1) afforded 1-(3,4-dichlorobenzyl)-3-(4-(chloromethyl)thiazol-2-yl)urea as an off-white solid (10.5 g, 30 mmol) in 73% yield. 1H NMR (DMSO-d6): δ 10.80 (bs, 1H); 7.60 (d, 1H); 7.55 (s, 1H); 7.11 (t, 1H); 7.05 (s, 1H); 4.63 (s, 2H); 4.30 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=[O:15].[H-].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:15][C:14](=[O:16])[CH2:13][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:8]([CH2:26][C:23]3[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[C:7]=2[CH3:12])=[CH:22][CH:21]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)OCc1ccc(Cl)cc1)c(C)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-methoxy-2-methyl-3-indoleacetic acid (4 g, 18.3 mmol) in anhydrous DMF (20 mL) at 0°-5° C. was added NaH (1.6 g, 60% dispersion in oil, 40 mmol) and stirred at room temperature for 40 min., then cooled again to 0°-5° C., and treated with 4-chlorophenylmethyl chloride (5.9 g, 36.6 mmol) and let stand at room temperature overnight. Water (50 ml) was added and the mixture was extracted with ethylacetate (100 mL), washed with brine and dried (MgSO4), evaporated in vacuo, and purified by chromatography (silica gel, 10% ethylacetate in pentane) to yield 1-(4-chlorophenylmethyl)-5-methoxy-2-methyl-3-indoleacetic acid 4-chlorophenylmethyl ester.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C(=O)([O-])O.[Na+].O.[CH2:19]1[O:21][CH:20]1[CH2:22][OH:23]>CO>[CH2:19]([O:6][C:5]1[C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[O:8][C:2](=[O:1])[C:3]=1[OH:4])[CH:20]([CH2:22][OH:23])[OH:21]
Reactant: OCC1CO1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1O
Temperature: 50 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
Under an argon atmosphere, L-ascorbic acid (300 g) and sodium hydrogen carbonate (42.9 g) were added to water and the resultant mixture was stirred at room temperature for 30 minutes, then, glycidol (126 g) was added thereto. Thereafter, the mixture was heated up to 50° C. and stirred for 5 hours. Thereto, methanol was added and filtration was performed. The filtrate was concentrated under reduced pressure, and 457 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:65/35/5), and concentration was performed under reduced pressure to obtain 3-O-glyceryl ascorbic acid (296 g).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][CH2:14][CH3:15])[N:3]=1.C(O)(=[O:18])C>[OH-].[Na+]>[CH2:14]([O:13][CH2:12][C:4]1[NH:3][C:2](=[O:18])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1)[CH3:15]
Reactant: CCOCc1nc(N)c2nccnc2n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1nc2nccnc2c(=O)[nH]1

Procedure:
A solution of 30.0 g (0.146 mole) of 4-amino-2-(ethoxymethyl)pteridine in 800 ml of 5% aqueous sodium hydroxide is brought slowly to 75° C. and maintained at this temperature for 2 hours. After cooling, the solution obtained is acidified with acetic acid to pH 6 and is then extracted with chloroform. The organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The solid residue is recrystallized from ethanol in the presence of Norit. Yld: 19.5 g (65%), m.p.=168°-169° C. The product is identical to that obtained in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([NH2:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[CH3:20].[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([CH3:29])[C:27]=1[F:28].C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:28][C:27]1[C:26]([CH3:29])=[CH:25][C:24]([NH:17][C@H:12]([CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]2[CH:18]=[CH:19][C:2]([F:1])=[C:3]([CH3:20])[CH:4]=2)[C:13]([O:15][CH3:16])=[O:14])=[CH:23][C:22]=1[CH3:21]
Reactant: COC(=O)[C@H](N)CCCCOCc1ccc(F)c(C)c1
Reactant: Cc1cc(B(O)O)cc(C)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](CCCCOCc1ccc(F)c(C)c1)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 44 h
Yield: 68.6 %

Procedure:
To a suspension of crude (R)-methyl 6-(4-fluoro-3-methylbenzyloxy)-2-aminohexanoate (0.128 g, 0.453 mmol), 3,5-dimethyl-4-fluorophenylboronic acid (0.152 g, 0.906 mmol), Cu(OAc)2 (0.090 g, 0.498 mmol), and molecular sieves 4 Å (0.400 g) in 5 mL of dichloromethane, was added triethylamine (0.13 mL, 0.906 mmol). After stirring at room temperature under O2 (1 atm) for 44 h, the reaction mixture was filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as light yellow oil (0.126 g, 68% yield). GC-MS: tR=7.0 min; m/z 405 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH2:34][OH:35])(=[O:32])=[O:31])[CH:4]=1)#[N:2].C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([NH2:37])=[O:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH2:33][CH2:34][OH:35])(=[O:31])=[O:32])[CH:4]=1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)CCO)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=C(C(N)=O)C(c2ccc(C#N)cc2S(=O)(=O)CCO)NC(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h

Procedure:
The reaction was carried out under argon. (rac)-4-[4-Cyano-2-((2-hydroxyethyl)sulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (910 mg, 1.79 mmol) and HATU (5 eq., 3396 mg, 8.9 mmol) were initially charged in dry DMF (20 ml) at 0° C., and ammonium chloride (5 eq., 478 mg, 8.9 mmol) and DIEA (10 eq., 2309 mg, 17.9 mmol) were added after brief stirring (20 min). The mixture was stirred at RT for 16 h (HPLC control) and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). The title compound was obtained as a solid (740 mg, 81% of theory).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)=[O:4].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CCN(CC)CC>CC(C)=O>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]([C:17]1[CH:18]=[CH:19][C:20]([O:23][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[CH:21][CH:22]=1)[N:5]([C:3](=[O:4])[C:2]([F:1])([F:24])[F:25])[CH2:14][CH2:13]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 115.4 %

Procedure:
A solution of 2,2,2-trifluoro-1-[1-(4-hydroxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (3.387 g, 9.64 mmol), p-toluenesulfonyl chloride (2.206 g, 11.6 mmol) and Et3N (1.6 ml, 11.6 mmol) in acetone (50 ml) was refluxed under N2 for 5 hr, then concentrated in vacuo. The remaining residue was suspended in H2O (100 ml) and extracted with CHCl3 (4×75 ml). The combined extracts were dried over MgSO4 and concentrated in vacuo to give 5.622 g of orange oil. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 4.383 g (90% yield) of white solid.
Reaction SMILES: [CH2:1]([CH2:11]/[C:12](/[CH3:21])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18]Br)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH2:22]([NH2:32])[C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1.O>C1COCC1>[CH2:1]([CH2:11]/[C:12](/[CH3:21])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][NH:32][CH2:22][C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CBr
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CNCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 200 ml of THF was dissolved 20.5 g of geranylgeranyl bromide, 14.4 ml of piperonylamine was added and stirred at room temperature for one hour. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and then brine, dried over magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (using as a developing solvent hexane-ethyl acetate (4:1)→ethyl acetate) to give 17.6 g of N-geranylgeranylpiperonylamine as a yellow liquid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=1)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:18][CH2:17]1)=[O:11])=[O:6].[OH:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[OH:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=2)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)=[O:11])=[O:6])=[CH:44][CH:43]=1
Reactant: NCCNC(=O)c1cccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1
Reactant: O=Cc1ccc(O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCNCC(=O)c2cccc(C(=O)NCCNCc3ccc(O)cc3)c2)CC1

Procedure:
A solution of biphenyl-2-ylcarbamic acid 1-(2-{[3-(2-aminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (9.31 g, 17.1 mmol; prepared as described in Preparation 8) and 4-hydroxybenzaldehyde (2.30 g, 18.8 mmol, 1.1 eq) in 125 mL MeOH was stirred at room temperature for 2 hours. NaBH(OAc)3 (7.26 g, 34.2 mmol, 2.0 eq) was added to the reaction at room temperature in two portions separated in one hour interval. The reaction was stirred for an additional hour before being concentrated under vacuum. The residue was taken up in 100 mL DCM and stirred with 100 mL of 1.0 N HCl for 1 hour. The aqueous phase was adjusted to pH 9 using 10.0 N NaOH. The mixture was stirred for an additional 10 minutes. The organic phase was separated, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified using silica gel chromatography (7% MeOH in CH2Cl2 with 1% NH4OH as eluent). The title compound was obtained as an off-white solid (8.08 g, 73%). MS m/z: [M+H+] calcd for C38H43N5O5, 650.34; found, 650.2.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38](O)=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].[C:50]1([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[NH:56][C:57](=[O:89])[O:58][CH:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][N:67]([CH3:88])[C:68](=[O:87])[CH2:69][CH2:70][NH:71][C:72]2[CH:77]=[CH:76][C:75]([C:78](=[O:86])[N:79]([CH3:85])[CH2:80][CH2:81][CH2:82][NH:83][CH3:84])=[CH:74][CH:73]=2)[CH2:61][CH2:60]1>>[C:50]1([C:90]2[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=2)[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[NH:56][C:57](=[O:89])[O:58][CH:59]1[CH2:60][CH2:61][N:62]([CH2:65][CH2:66][N:67]([C:68](=[O:87])[CH2:69][CH2:70][NH:71][C:72]2[CH:73]=[CH:74][C:75]([C:78](=[O:86])[N:79]([CH2:80][CH2:81][CH2:82][N:83]([C:38](=[O:39])[CH2:37][O:36][C@@H:28]3[C:25]4([CH2:26][CH2:27][N:22]([CH2:21][CH2:20][C@:11]5([C:13]6[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=6)[O:10][CH2:9][N:8]([C:6](=[O:7])[C:5]6[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:3]([C:2]([F:49])([F:1])[F:48])[CH:4]=6)[CH2:12]5)[CH2:23][CH2:24]4)[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29]3)[CH3:84])[CH3:85])=[CH:76][CH:77]=2)[CH3:88])[CH2:63][CH2:64]1
Reactant: CNCCCN(C)C(=O)c1ccc(NCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Reactant: O=C(O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCNc1ccc(C(=O)N(C)CCCN(C)C(=O)CO[C@H]2Cc3ccccc3C23CCN(CC[C@@]2(c4ccc(F)cc4)CN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CO2)CC3)cc1
Yield: 62.2 %

Procedure:
The compound (119 mg, 0.17 mmol) obtained in Example 1j and the compound (98 mg, 0.16 mmol) obtained in Example 94c were used to give the title compound (130 mg; yield, 64%) as a white solid according to the method described in Example 11e.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:30][CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>CS(C)=O.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)c[nH]2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)cn2CCOC2CCCCO2)CC1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
Dissolve 4-[4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (5.29 g; 13.93 mmol); powdered KOH (111.46 mmol; 6.95 g) in DMSO (69 mL) and heat to 40° C. for 10 min. Add 2-(2-bromoethoxy)tetrahydro-2H-pyran (34.83 mmol; 5.48 mL) dropwise over 45 min, then stir for 30 min. Cool and dilute with EA and wash with 3×300 mL saturated sodium bicarbonate, brine, dry over MgSO4, filter and evaporate. Purify on 400 g silica gel with 0-10% EA/DCM to provide the title compound (6.848 g, 97%). MS (ES): m/z=508 (M+H).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.[CH2:19]([O:21][C:22]1[C:31]([O:32][CH2:33][CH3:34])=[C:30]([O:35][CH2:36][CH3:37])[C:29]([N+:38]([O-:40])=[O:39])=[C:28]2[C:23]=1[CH2:24][O:25][C:26]2=[O:27])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:17][CH3:18])[C:7]([O:15][CH3:16])=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]1[CH:24]1[C:23]2[C:28](=[C:29]([N+:38]([O-:40])=[O:39])[C:30]([O:35][CH2:36][CH3:37])=[C:31]([O:32][CH2:33][CH3:34])[C:22]=2[O:21][CH2:19][CH3:20])[C:26](=[O:27])[O:25]1
Reactant: COc1cc2c(c(OC)c1OC)C=[N+](C)CC2
Reactant: CCOc1c2c(c([N+](=O)[O-])c(OCC)c1OCC)C(=O)OC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOc1c(OCC)c2c(c([N+](=O)[O-])c1OCC)C(=O)OC2C1c2c(cc(OC)c(OC)c2OC)CCN1C

Procedure:
235 g (0.647 mole) of 2-methyl-6,7,8-trimethoxy-3,4-dihydro-isoquinolinium iodide (described in J. Chem. Soc. 1951, 1150), 201.4 g of 4,5,6-triethoxy-7-nitrophthalide and 107 g of potassium carbonate are added to 1.240 liters of methanol. After stirring for 24 hours at a temperature below the boiling point of the solvent, 730 ml of water is added and the reaction solution is allowed to crystallise. The crystals are collected by filtration, washed with water and dried, providing 270 g of C27H34O10N2.