Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)=[N:10][N:11]=2)[CH:8]=1)#[CH:2].C[Si]([CH2:30][N:31]=[N+:32]=[N-:33])(C)C.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[F-].[Cs+]>C1COCC1.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([O:13][CH2:12][C:9]3[N:7]4[CH:8]=[C:3]([C:1]5[N:33]=[N:32][N:31]([CH3:30])[CH:2]=5)[CH:4]=[CH:5][C:6]4=[N:11][N:10]=3)=[CH:15][CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#Cc1ccc2nnc(COc3ccnc4cc(OC)ccc34)n2c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(OCc3nnc4ccc(-c5cn(C)nn5)cn34)ccnc2c1
Reaction time: 1 h

Procedure:
To a mixture of 4-((6-ethynyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (0.200 g, 0.605 mmol), trimethylsilylmethyl azide (0.156 g, 1.21 mmol), sodium ascorbate (0.240 g, 1.21 mmol) in THF (4 mL) and water (1 mL) was added 1 drop of a copper sulfate (0.00966 g, 0.0605 mmol) solution. Stirred for 1 h. Concentrated. Suspended in water and extracted with CH2Cl2 (3×5 mL). Dried over sodium sulfate and concentrated. Took up crude mixture in DMF (4 mL). Added cesium fluoride (0.368 g, 2.42 mmol) and heated to 60° for 1 h. Concentrated. Purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate and volatiles were removed in vacuo. Product crashed out of solution and was isolated by filtration. MS m/z=388.1 [M+1]+. Calc'd for C20H17N7O2: 387.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=2)[O:10][CH:9]=1.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([C:16]2[CH:15]=[C:14]([Cl:19])[C:13]([OH:20])=[CH:12][C:11]=2[OH:10])=[N:22][NH:23][CH:9]=1
Reactant: O=c1c(-c2ccccc2Br)coc2cc(O)c(Cl)cc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccccc2Br)cc1Cl
Yield: 70 %

Procedure:
This compounds was synthesised in the same manner as described above. 3-(2-Bromo-phenyl)-6-chloro-7-hydroxychromen-4-one (0.4 g, 1.1 mmol), hydrazine hydrate (10 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-[4-(2-Bromo-phenyl)-1H-pyrazol-3-yl]-6-chloro-benzene-1,3-diol as a white solid (0.28 g, 70%); Rf 0.6 ethyl acetate/hexane (80/20).
Reaction SMILES: O1C(CCCCCCCC)C1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>O>[C:8]1([CH2:9][C:10]([OH:12])=[O:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCC1OC1CCCCCCCC(=O)O
Solvent: O
Product: O=C(O)Cc1ccccc1

Procedure:
adducts of 9,10-epoxystearic acid and water or C1-3 alcohols, such as for example 9,10-(hydroxy, methoxy)-octadecanoic acid and ether carboxylic acids corresponding to the following formula
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([CH3:13])[CH:7]=1>>[CH:1]1([C:6]2[CH:7]=[C:8]([CH3:13])[CH:9]=[C:10]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:11]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCC1
Reactant: Cc1ccc(O)cc1
Product: Cc1cc(C2CCCC2)c(O)c(C2CCCC2)c1
Temperature: 140 °C
Reaction time: 15 h
Yield: 36.9 %

Procedure:
840 g of cyclopentene are added dropwise to 648 g of p-cresol and 60 g of an acid-activated fuller's earth at 140° C. Next the mixture is stirred at 140° C for 15 h. After having removed the catalyst by filtration the mixture is fractionated. In the boiling range of 153°-156° C 540 g of 2,6-dicyclopentyl-4-methylphenol are obtained (0.8 mm Hg) and between 167°-170° C 422 g of a fraction (0.8 mm Hg) which is recrystallised from petroleum ether. Yield: 360 g of 2,5-dicyclopentyl-4-methylphenol. Melting point: 78° C.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:28])[CH:8]=3)[N:13]=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:11]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)nc(N3CCCC3)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI/CI): predicted mass C23H21N5O2, 399.2.
Reaction SMILES: [F:1][C:2]1[C:9]([CH2:10][O:11][CH2:12][CH2:13][OH:14])=[CH:8][C:7]([O:15][CH3:16])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.Cl[Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25].O>CN(C=O)C>[F:1][C:2]1[C:9]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])=[CH:8][C:7]([O:15][CH3:16])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(C=O)c(F)c(COCCO)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)c(F)c(COCCO[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
2-Fluoro-3-(2-hydroxyethoxymethyl)-5-methoxybenzaldehyde (305 mg) was dissolved in 3 ml of DMF, and 300 mg of imidazole and 283 mg of chlorotriisopropylsilane were added thereto. The resulting mixture was stirred at 50° C. for 2 hours, and then water was added thereto. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude product of the title compound (533 mg).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[C:57]([CH:60]([NH-:64])[C:61](=[O:63])[NH2:62])(=[O:59])[NH2:58].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:54]([OH:56])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:57]([CH:60]([NH-:64])[C:61](=[O:63])[NH2:62])(=[O:59])[NH2:58]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]C(C(N)=O)C(N)=O
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 82 mg of Z-Phe-His-OH, 64 mg of H-Leu-Val-Ile-dicarbamoylmethyl amide, 29 mg of HOBt and 45 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B9). Rf (B9)=0.37, Rf (B11)=0.46.
Reaction SMILES: NN=CC1C=CC(OCCCCCO[C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][C:16]=2[O:30][CH3:31])=CC=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(OCC1C=CC=CC=1C(O)=O)(=O)C1C=CC=CC=1>ClCCl>[CH3:31][O:30][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][CH:15]=1)[C:19]([N:21]([CH:25]([CH3:26])[CH3:27])[CH:22]([CH3:23])[CH3:24])=[O:20]
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C=NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(OCc1ccccc1C(=O)O)c1ccccc1
Solvent: ClCCl
Product: COc1cccc(C(=O)N(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide (3.0 g, 7.06 mmol) in 15 mL of dichloromethane is treated with 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (1.67 g, 8.47 mmol), hydroxybenzotriazole (1.14 g, 8.47 mmol), and 2-(benzoyloxymethyl)benzoic acid (1.81 g, 7.06 mmol) and stirred at room temperature over 2 hours. The reaction is concentrated in vacuo and purified by chromatography on silica gel (50 g) with 60% ethyl acetate/hexane as the eluent to afford 4-[5-[4-amino[2-(benzoyloxymethyl)benzoyl]iminomethyl]phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide as a colorless foam:
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CCCCCC.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>>[C:1]1([CH2:21][C:20]([O:23][CH2:24][CH3:25])=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: OB(O)c1cccc2ccccc12
Solvent: CCCCCC
Product: CCOC(=O)Cc1cccc2ccccc12

Procedure:
Ethyl 1-naphthaleneacetate was prepared by the general experimental method from 1-naphthaleneboronic acid (172 mg, 1.00 mmol). After workup by column chromatography (hexane/ethyl acetate, 5:1), ethyl 1-naphthaleneacetate is obtained as a colourless liquid in a yield of 77% of theory. 1H NMR (600 MHz, CDCl3): δ=8.04 (d, J=8.3 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.80-7.84 (m, 1H), 7.55-7.58 (m, 1H), 7.50-7.54 (m, 1H), 7.43-7.47 (m, 2H), 4.16-4.20 (m, 2H), 4.09 (s, 2H), 1.23-1.27 (m, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ=171.7, 133.9, 132.2, 130.8, 128.8, 128.1, 128.0, 126.4, 125.8, 125.6, 123.9, 61.0, 39.4, 14.3 ppm; MS (70 eV), m/z (%): 214 (100) [M+], 141 (34), 115 (45), 89 (9), 63 (6); IR (NaCl): ν=3047 (w), 2981 (m), 1733 (s), 1173 (m), 1029 (m) cm−1, elemental analysis: (theor): C=78.48, H=6.59, (exp): C=78.35, H=6.86.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]([C:16]3[N:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=3)=[CH:14][CH:15]=2)=[C:7]([CH3:32])[CH:6]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:17]1[CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[N:20]=[C:16]1[C:13]1[S:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:33])=[O:2])=[CH:6][C:7]=2[CH3:32])=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3-c3ccccc3Cl)s2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)O)ccc1-c1ccc(-c2nc(C(F)(F)F)cn2-c2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
(4-{5-[1-(2-Chloro-phenyl)-4-trifluoromethyl-1H-imidazol-2-yl]-thiophen-2-yl}-3-methyl-phenyl)-acetic acid methyl ester (123 mg, 0.25 mmol) was dissolved in 6 mL mixture of THF and water (3:1, V/V). Lithium hydroxide monohydrate (2.3 mg, 0.55 mmol) was added then. The mixture was stirred at room temperature for 3 hrs. The mixture was neutralized to pH 7 by 1N HCl, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0→5% MeOH/DCM) to give a white solid (47 mg, 39% yield). 1H-NMR. (400 MHz, CDCl3): δ 2.35 (s, 3H), 3.64 (s, 2H), 6.83 (s, 2H), 7.13-7.10 (m, 1H), 7.16 (m, 1H), 7.29-7.27 (m, 1H), 7.35 (m, 1H), 7.47-7.46 (m, 2H), 7.57-7.52 (m, 1H), 7.64-7.62 (m, 1H). MS (ES): 477.1, [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([CH:5](C)[CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[C:12]([NH:14][CH:15]([CH3:18])[CH2:16][OH:17])=[O:13])=[O:4]>[Ni]>[CH3:23][N:2]([CH3:1])[C:3]([CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[C:12]([NH:14][CH:15]([CH3:18])[CH2:16][OH:17])=[O:13])=[O:4]
Reactant: CC(CO)NC(=O)c1cccc(C#CCC(C)C(=O)N(C)C)c1
Agent: [Ni]
Product: CC(CO)NC(=O)c1cccc(C=CCCC(=O)N(C)C)c1
Yield: 40 %

Procedure:
Hydrogenation of the alkyne 9 (0.055 g, 0.18 mmol) using BER/Ni catalyst gave 40% 27, 5% of the saturated compound and 55% of starting material. The mixture was separated by reverse-phase HPLC chromatography (20% acetonitrile/80% water 20 min isocratic program) to give 27 (15 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:29]1[C:33]2C=CC=CC=2N=N1.Cl.CN.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:33][NH:29][C:25](=[O:27])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CNC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of N-tertiarybutoxycarbonyl-O-benzyl-L-tyrosine (7.4 g, 20 mM), 1-hydroxybenzotriazole (3 g, 20 mM), methylamine HCl (1.3 g, 20 mM) and N-methylmorpholine (2 g, 20 mM) in CH2Cl2 (20 ml) stired and cooled to 0° was added DCC (4.2 g, 20 mM). After being allowed to stir and warm to room temperature overnight the reaction mixture was filtered and washed with saturated aqueous sodium bicarbonate solution, 3N citric acid and brine. The dried organic extract was then concentrated in vacuo to give N-tertiarybutoxycarbonyl-O-benzyl-L-tyrosine N-methylamide as a solid. Recrystallisation from dichloromethane/hexane gave (4.5 g); m.p. 165°-172°; (Found: C, 68.85; H, 7.43; N, 7.39. C22H28N2O4 requires C, 68.73; H, 7.34; N, 7.29%); δ (CDCl3) 1.40 (9H, s, OC(CH3)3); 2.73 (3H, d, J=5 Hz, CONHCH3); 2.96 (2H, m, CH2Tyr); 4.25 (1H, m, α-CH); 5.03 (2H, s, CH2C6H5); 5.80 (1H, br, CONH); 6.86 (2H, d, J=8 Hz, Tyr); 7.12 (2H, d, J=8 Hz, Tyr); 7.3-7.5 (5H, m, C6H5).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccc2cc[nH]c2c1

Procedure:
Prepared by Procedure I and Scheme T using 6-bromo-1H-indole and 2-methylphenylboronic acid: ESMS m/e: 207.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]2O[CH:10]([CH:11]=1)[C:9]1[C:4]2=[CH:5][CH:6]=[C:7]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=1.[Na+].[I-].C[Si](Cl)(C)C>CC#N>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[CH:3]=1
Reactant: FC(F)(F)Oc1ccc2c(c1)C1C=C(Br)C2O1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)(F)Oc1ccc2cc(Br)ccc2c1
Reaction time: 2.5 h

Procedure:
2-Bromo-6-(trifluoromethoxy)-1,4-dihydro-1,4-epoxynaphthalene [ref: Schlosser, M., Castgnetti, E., Eur. J. Org. Chem. 2001, 3991-3997] (1.09 g, 3.55 mmol) and NaI (1.6 g, 10.7 mmol) were dissolved in dry CH3CN (40 ml), followed by addition of TMSCl (1.35 ml, 10.7 mmol). The reaction was stirred for 2.5 h, quenched with 5% Na2SO3, and extracted with ether. The ether solution was washed with 5% Na2SO3, brine, and dried over Na2SO4. The crude product was chromatographed (SiO2, hexanes) to give 2-bromo-6-(trifluoromethoxy)naphthalene as white crystals. NMR (500 MHz, CDCl3) δ: 7.36 (dd, J=2.6, 9.0 Hz, 1H); 7.60 (dd, J=2.0, 8.8 Hz, 1H); 7.63 (br s, 1H); 7.69 (d, J=8.8 Hz, 1H); 7.77 (d, J=9.0 Hz, 1H);8.01 (d, J=2.0 Hz, 1H).
Reaction SMILES: N[C:2]1[C:6]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[C:3]=1[C:25]#[N:26].C(O)(=O)C.[CH:31]([NH2:33])=[NH:32]>C(O)C>[CH:7]1([C:6]2[C:2]3[N:32]=[CH:31][N:33]=[C:25]([NH2:26])[C:3]=3[N:4]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[CH:5]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: N=CN
Reactant: N#Cc1c(N)c(C2CCCC2)cn1-c1ccc(Oc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ncnc2c(C3CCCC3)cn(-c3ccc(Oc4ccccc4)cc3)c12
Temperature: 85 °C
Yield: 72.6 %

Procedure:
A mixture of the 3-amino-4-cyclopentyl-1-(4-phenoxyphenyl)-1H-2-pyrrolecarbonitrile (185 mg, 0.539 mmol) in absolute ethanol (10 mL) was treated with formamidine acetate (450 mg, 4.33 mmol) then heated at 85° C. for 2 hours. The solvent was evaporated under reduced pressure then the residue was purified by preparative reverse phase HPLC to provide 145 mg (73%) of the title compound as a white solid after lyophilization: 1H NMR (DMSO-d6, 400 MHz) δ 8.19 (s, 1H), 7.44 (m, 5H), 7.19 (t, 1H), 7.13 (m, 4H), 5.79 (bs, 2H), 3.23 (m, 1H), 2.05 (m, 2H), 1.77 (m, 4H), 1.64 (m, 2H); RP-HPLC (Hypersil HS-C18, 5 μm, 100 A, 4.6×250 mm; 5%–100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 23.3 min.; MS: MH+ 371.5.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][O:14][CH:15]([O:21][CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[CH3:13][O:14][CH:15]([O:21][CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: COC(CCCCBr)OC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COC(CCCCN1C(=O)c2ccccc2C1=O)OC
Reaction time: 5 h

Procedure:
A mixture of potassium phthalimide (0.48 g) and 5-bromopentanal dimethyl acetal (0.50 g) in dry dimethylformamide (3 ml) was stirred at 90° for 5 h and then allowed to cool. The resultant yellow suspension was then partitioned between water (30 ml) and ethyl acetate (3×30 ml). The combined organic extracts were then dried (Na2SO4) and concentrated in vauco.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:4].[C:11]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](Cl)=[O:25])=[CH:16][CH:15]=1)(=[O:13])[CH3:12].C(N(CC)CC)C>ClCCCl>[C:11]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:25])=[CH:16][CH:15]=1)(=[O:13])[CH3:12]
Reactant: NCC(=O)NCC(F)(F)F
Reactant: CC(=O)c1ccc(C(=O)Cl)c2ccccc12
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C(=O)NCC(=O)NCC(F)(F)F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A solution of 2-amino-N-(2,2,2-trifluoroethyl)acetamide (21.90 g, 0.14 mol) in 1,2-dichloroethane (80 mL) was added dropwise over 15 min to a solution of the product of Example 7, Step A (32.50 g, 0.14 mol) in 1,2-dichloroethane (160 mL) at a temperature of 25 to 30° C. The resulting mixture was further stirred for 10 min at 25° C. A solution of triethylamine (14.20 g, 0.14 mol) in 1,2-dichloroethane (80 mL) was then added dropwise over 44 min at 25° C., and the mixture was stirred further for 20 min at 25° C. The solvent was removed under reduced pressure, and the residue was dissolved in hot acetonitrile (50 mL). The mixture was then cooled to 25° C., and water (40 mL) was added dropwise. The mixture was further cooled to 0° C. and filtered. The isolated solid was washed with water (100 mL) and dried overnight in a vacuum oven (approximately 16-33 kPa at 50° C.) to provide the title product as an off-white solid (37 g, 75% yield) melting at 169-169° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:53])[CH2:7][N:8]([CH2:47][C:48]([O:50]CC)=[O:49])[C:9](=[O:46])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:11]=1)C>>[C:48]([CH2:47][N:8]([C:9](=[O:46])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:11]=1)[CH2:7][C:6]([OH:53])=[O:5])([OH:50])=[O:49]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)N(CC(=O)O)CC(=O)O)c1

Procedure:
Sodium hydroxide hydrolysis of N-(2-ethoxy-2-oxoethyl)-N-[3-[3-(phenoxy)propoxy]-5-(octadecyloxy)benzoyl]glycine ethyl ester as in Example 11 gave N-(carboxymethyl)-N-[3-[3-(phenoxy)propoxy]-5-(octadecyloxy)benzoyl]glycine, mp 86°-90°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22][CH:23]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:22][CH:23]=2)[CH:7]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:22][CH:23]=2)[CH:9]=1
Reactant: BrCCCOc1cccc(-c2ccccc2)c1
Reactant: COC(=O)c1cc(O)cc(O)c1
Product: COC(=O)c1cc(OCCCOc2cccc(-c3ccccc3)c2)cc(OCCCOc2cccc(-c3ccccc3)c2)c1

Procedure:
Using this procedure, the reaction of 3,5-dihydroxybenzoic acid methyl ester with 3-(3-bromopropoxy)-1,1-biphenyl gave 3,5-bis[3-(1,1'-biphenyl-3-yloxy)propoxy]benzoic acid methyl ester as an oil. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 4-fluoro-2-methoxy-1-nitrobenzene (15 g, 87 mmol), tert-butyl piperazine-1-carboxylate (19.59 g, 105.2 mmol) and potassium carbonate (24 g, 174 mmol) in N,N-dimethylformamide (150 mL) was heated at 80′C for 8 hours. After cooling to ambient temperature, the mixture was poured in water (500 mL). The precipitate was filtered and washed with ethanol to give the title compound. MS: 338 (M+H+).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[OH:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C>[C:18]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[CH:27][CH:26]=1)(=[O:19])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccccc1)c1ccc(OCC(O)CCc2cccnc2)cc1
Yield: 21.4 %

Procedure:
Prepared according to the method described in Example 24b) from (±)-α-(chloromethyl)-3-pyridinepropanol (1.05 g), 4-hydroxybenzophenone (1.35 g), ethanol (30 ml) and aqueous sodium hydroxide (1.4 M, 5 ml). After work up the residue was purified by column chromatography over silica with ether then ethyl acetate to give the title compound as an oil (0.42 g).