Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:44][C@H:45]1[CH2:53][O:52][CH2:51][C@H:50]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=2)[C@@H:49]([O:62][CH2:63][CH:64]([CH3:66])[CH3:65])[C@H:48]([CH3:67])[O:47][C:46]1=[O:68]>C(Cl)Cl>[OH:1][C:2]1[C:3]([C:10]([NH:44][C@H:45]2[CH2:53][O:52][CH2:51][C@H:50]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([CH3:61])=[CH:57][CH:56]=3)[C@@H:49]([O:62][CH2:63][CH:64]([CH3:65])[CH3:66])[C@H:48]([CH3:67])[O:47][C:46]2=[O:68])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: Cc1ccc(C[C@H]2COC[C@H](N)C(=O)O[C@@H](C)[C@@H]2OCC(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Cc3ccc(C)cc3)[C@@H](OCC(C)C)[C@H](C)OC2=O)c1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 76.8 %

Procedure:
To a mixture of 3-hydroxy-4-methoxypicolinic acid (0.198 g, 1.17 mmol), HATU (0.47 g, 1.25 mmol), and N-methylmorpholine (0.47 g, 4.7 mmol) in CH2Cl2 (9 mL) was added (3S,7S,8R,9S)-3-amino-8-isobutoxy-9-methyl-7-(4-methylbenzyl)-1,5-dioxonan-2-one (272 mg, 0.78 mmol), and the tan mixture was stirred at room temperature for 7 h. The resulting homogeneous solution was adsorbed to Celite® and purified by flash chromatography (SiO2, 0→30% acetone/hexanes) to give 3-hydroxy-N-((3S,7S,8R,9S)-8-isobutoxy-9-methyl-7-(4-methylbenzyl)-2-oxo-1,5-dioxonan-3-yl)-4-methoxypicolinamide (0.30 g, 77%) as a white foam: 1H NMR (400 MHz, CDCl3) δ 11.95 (s, 1H), 8.54 (d, J=8.3 Hz, 1H), 7.97 (d, J=5.2 Hz, 1H), 7.09 (d, J=2.1 Hz, 4H), 6.85 (d, J=5.2 Hz, 1H), 5.01 (m, 2H), 4.02 (dd, J=11.7, 7.3 Hz, 1H), 3.92 (s, 3H), 3.46 (m, 4H), 3.34 (dd, J=8.3, 6.5 Hz, 1H), 3.13 (m, 2H), 2.31 (s, 4H), 1.93 (m, 2H), 1.50 (d, J=6.4 Hz, 3H), 0.96 (d, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.15, 168.90, 155.31, 148.71, 140.62, 136.76, 135.58, 130.20, 129.15, 129.05, 109.56, 84.61, 79.28, 75.92, 72.53, 72.16, 56.08, 51.53, 47.47, 34.60, 29.20, 21.03, 19.50, 18.83; HRMS-ESI (m/z) [M+H]+ calcd for C27H36N2O7, 500.2523. found, 500.2529.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([C:16]([O:18]CC)=[O:17])=[CH:4]1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([N:3]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)c2ccccc2)n(CC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1cc(C(=O)O)cc1C(=O)c1ccccc1

Procedure:
The entire batch of ethyl 1-ethyl-5-benzoylpyrrole-3-carboxylate from the preceding Example was taken up in 40 ml. of methanol and 20 ml. of 1 N sodium hydroxide, and heated in an open flask on a steam bath for 1 hour. The aqueous residue was cooled, extracted with 20 ml. of ether, and made acidic with conc. hydrochloric acid. 1-Ethyl-5-benzoylpyrrole-3-carboxylic acid (585 mg., m.p. 157°-158° C., m/e 243) was recovered by filtration. For analysis, the product was recrystallized from acetone/hexane (380 mg., m.p. 158°-160° C.).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:18])[CH2:12][NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.O>C1COCC1.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([CH2:12][N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)CNCC(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)N(CC(=O)Nc2ccc(Cl)c(Cl)c2)CC(C)C)cc1
Yield: 75.4 %

Procedure:
To a solution of N-(3,4-dichloro-phenyl)-2-isobutylamino-acetamide hydrobromide (0.090 g) in THF were slowly added a solution of triethylamine (0.064 mg) in THF (5 mL) and a solution of 4-methoxybenzoyl chloride (47 mg) in THF (5 mL) and the reaction mixture was stirred at room temperature for 24 hours. Then water was added to the reaction mixture and the precipitate was isolated by filtration and then purified by column chromatography to yield the title compound (78 mg). MS (m/e): 409.2 (M−H, 100%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[N:6][C:7]([CH2:11][CH2:12][CH3:13])=[CH:8][C:9]=1[NH2:10])[CH3:2].C[Al](C)C.CO[C:20](=O)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[N:28]=1>ClCCCl>[CH2:1]([N:3]1[C:4]2[CH:5]=[N:6][C:7]([CH2:11][CH2:12][CH3:13])=[CH:8][C:9]=2[N:10]=[C:20]1[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[N:28]=1)[CH3:2]
Reactant: COC(=O)Cn1ccnc1-c1cccc(F)n1
Reactant: CCCc1cc(N)c(NCC)cn1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: CCCc1cc2nc(Cn3ccnc3-c3cccc(F)n3)n(CC)c2cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N3-ethyl-6-propyl-pyridine-3,4-diamine (82 mg, ˜0.45 mmol, contaminated with ˜10% of N-(4-amino-6-propyl-pyridin-3-yl)-acetamide) in 1,2-dichloroethane (4 mL) at room temperature under N2 is treated with 2.0 M AlMe3 (0.69 mL, 1.37 mmol). The resulting solution is stirred at room temperature for 30 min and then treated with a solution of [2-(6-fluoro-pyridin-2-yl)-imidazol-1-yl]-acetic acid methyl ester (97 mg, 0.41 mmol) in 1,2-dichloroethane via cannula, followed by a 1 mL rinse. The reaction mixture is then stirred at reflux overnight. After cooling, it is treated with MeOH (˜2 mL) and then further diluted with saturated aq NaHCO3 (˜10 mL) and some H2O. The mixture is stirred vigorously for 15 min and then extracted thrice with CHCl3 containing some (˜5%) MeOH. The combined extracts are dried over K2CO3 and concentrated. The crude material is purified by preparative thin layer chromatography. Developing with 15:1 CHCl3-MeOH yields 3-ethyl-2-{[2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-6-propyl-3H-imidazo[4,5-c]pyridine as an off-white solid. 1H NMR (CDCl3, 300 MHz) δ 8.70 (d, J=0.9 Hz, 1H), 8.17 (dd, J=8.0, 2.6 Hz, 1H), 7.89 (q, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.22 (d, J=0.9 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H), 6.88 (dd, J=8.6, 2.9 Hz, 1H), 6.27 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 2.86 (m, 2H), 1.78 (sextet, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H) ppm. Electrospray MS: m/z 365 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (291 mg, 1.13 mmol) [prepared according to the procedure of Example 176], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (409 mg, 1.22 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (654 mg, 1.39 mmol) in chloroform (10 mL). DIEA (1 mL, 5.73 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (427 mg, 0.76 mmol, 67%): LC-MS (ES) m/z=537 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.NC1C=[C:25]2[C:21]([C:22]([CH3:30])(C)[C:23](=[O:28])[N:24]2[CH3:27])=CC=1.[N+](C1C=C2C(C3(CCCC3)C(=O)N2)=CC=1)([O-])=O>>[CH3:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:23](=[O:28])[C:22]3[CH:21]=[CH:25][N:24]=[CH:27][CH:30]=3)[CH:10]=2)[C:6]2([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:7]1=[O:12]
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Reactant: CN1C(=O)C2(CCCC2)c2ccc(N)cc21
Agent: O=C1Nc2cc([N+](=O)[O-])ccc2C12CCCC2
Product: CN1C(=O)C2(CCCC2)c2ccc(NC(=O)c3ccncc3)cc21

Procedure:
Prepared in analogy to example 2 using 6′-amino-1′-methyl-spiro[cyclopentane-1,3′-indoline]-2′-one (prepared in analogy to procedures described in W. von der Saal et al., J. Med. Chem. 1989, 32(7), 1481-1491 for the preparation of 6-amino-1,3,3-trimethylindolin-2-one by methylation and nitro reduction of 6′-nitro-spiro[cyclopentane-1,3′-indolin]-2′-one (A. Mertens et al. J. Med. Chem. 1987, 30 (8), 1279-1287)). The title compound was obtained as light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][C:15](Br)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[S:30][CH:31]=2)O1>>[NH2:1][C:2]1[N:17]=[CH:16][C:15]([C:27]2[CH:28]=[C:29]([CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[S:30][CH:31]=2)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)=[O:5]
Reactant: Cc1cc(NC(=O)c2cc(Br)cnc2N)ccn1
Reactant: CC1(C)OB(c2csc(CN3CCOCC3)c2)OC1(C)C
Product: Cc1cc(NC(=O)c2cc(-c3csc(CN4CCOCC4)c3)cnc2N)ccn1

Procedure:
Reaction of 2-amino-5-bromo-N-(2-methyl-pyridin-4-yl)-nicotinamide with 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-ylmethyl]-morpholine gives the compound “A15”;
Reaction SMILES: [OH:1]N1[C:6](=O)[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[O-]O.[C:15]1([CH:21](C)[CH3:22])C=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:24]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:3]1([OH:12])[CH2:4][CH2:11][CH2:10][CH2:9][CH2:8][CH2:5][CH2:6][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:21][CH2:22]1.[C:24]1(=[O:1])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[CH2:24]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C1CCCCCCCCCCCCCC1
Agent: [O-]O
Product: O=C1CCCCCCCCCCCCCC1
Product: OC1CCCCCCCCCCCCCC1
Reaction time: 8 h

Procedure:
2 mmol of N-hydroxyphthalimide and 4 mmol of cumene hydroperoxide are added at a temperature of 130° C. to 200 mmol of cyclopentadecane in a round-bottomed flask having an attached reflux condenser. Air is passed at approximately 15 l/h through the reaction mixture for 8 hours at said temperature. Cyclopentadecanol is obtained at a selectivity of 19% and cyclopentadecanone at a selectivity of 48%, at a cyclopentadecane conversion rate of 46%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13](O)=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8](O)=[O:9])([O-:3])=[O:2].CO>C1COCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[C:6]([CH2:13][OH:14])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc(CO)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-nitrophthalic acid (40 g, 189.5 mmol) in THF (500 mL) was added dropwise over 1.5 h to a solution of borane-THF complex (1 M, 490 mL, 490 mmol), keeping the reaction temperature between 0° C. and 5° C. After the addition, the reaction mixture was allowed to warm slowly to ambient temperature and stirred for 18 h. MeOH (100 mL) was added carefully and the precipitated solid dissolved. The mixture was concentrated in vacuo to about 500 mL, cooled to 0° C., and 10 N NaOH was added to adjust the pH to 10-11. This mixture was extracted with EtOAc (3×600 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=207 (M−OH+CH3CN).
Reaction SMILES: [C:1](=O)([O:43]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32]([O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)=[O:33])[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][CH:4]=1.[OH-].[NH4+:55]>>[NH2:55][C:1]([O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32](=[O:33])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:19])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:5][CH:4]=1)=[O:43]
Reactant: [NH4+]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: [OH-]
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenyl 4-nitrophenyl carbonate was treated with concentrated ammonium hydroxide as described in Example 311 to afford the title compound as a white solid. 1H NMR (DMSO-d6): 0.78 (3H, d), 0.86 (3H, d), 1.2 (1H, dd), 1.4 (1H, br quintuplet), 1.85-1.95 (1H, m), 2.2 (1H, t), 2.65-2.80 (3H, m), 2.9-3.0 (2H, m), 3.25-3.30 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.0 (1H, d), 5.4 (1H, d), 6.18 (2H, d), 6.8 (2H, br d), 6.9 (2H, d), 7.0 (1H, d), 7.15 (2H, d), 7.2 (1H, s), 7.25-7.30 (2H, m); MS: 636 (MH+).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=1[F:46]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:43]2[CH:42]=[CH:41][C:40]([F:39])=[C:45]([F:46])[CH:44]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(F)c(F)c2)c1

Procedure:
5-(tert-Butyl)-3′,4′-difluoro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 3,4-difluorophenylboronic acid.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)(=[O:6])=[O:5].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(N(CC)CC)C.O>[N+:13]([C:9]1[CH:8]=[C:7]([S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
1-(β-chloroethylsulfonyl)-3-nitrobenzene (2.50 g, 10 mmol) was added to 20 g of toluene, to this solution were added 1.50 g of 49% aqueous potassium carbonate solution (potassium carbonate 5.3 mmol) and 50 mg (0.5 mmol) of triethylamine, and the mixture was stirred for 2 hours at 40° C. Then, 10 g of water was added and the mixture was separated to an organic phase and aqueous phase. This aqueous phase was extracted by chloroform, and the resulted organic phase was combined with the previous organic phase, dried over magnesium sulfate, the solvents were distilled off, to obtain 2.00 g (yield 94.3%) of (3-nitrophenyl)vinylsulfone.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(O)(=O)CCC(O)=O.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][O:25][C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>ClCCl.O>[CH3:8][C:5]1[N:4]=[N:3][C:2]([N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=3)[CH2:21][CH2:22]2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Agent: O=C(O)CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCC2CCN(c3ccc(C)nn3)CC2)cc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
A mixture of 10.4 parts of 3-chloro-6-methylpyridazine, 22.4 parts of ethyl 4-[2-(4-piperidinyl)ethoxy]benzoate butanedioate (1:1), 8.6 parts of sodium carbonate and 0.9 parts of N,N-dimethylformamide was stirred for 3 hours in an oil bath at ±150° C. After cooling, water and dichloromethane were added and the layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and ethanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and 2-propanone (75:25 by volume). The precipitated product was filtered off and dried, yielding 17 parts (56.8%) of ethyl 4-[2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]-ethoxy]benzoate; mp. 130.1° C. (comp. 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([NH2:16])[C:4]=1[C:5]([O:7]CC)=O.[CH3:17][N:18]=[C:19]=[O:20].CC(O)=O>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:4]=1[C:5](=[O:7])[N:18]([CH3:17])[C:19](=[O:20])[NH:16]2
Reactant: CCOC(=O)c1c(N)ccc(OC)c1OC
Reactant: CN=C=O
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(=O)n(C)c(=O)c2c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A cold solution of ethyl 2,3-dimethoxy-6-aminobenzoate (8.0 g, 35.5 mM) in pyridine (15.4 ml) was added to CH3NCO (3.2 g, 55.9 mM) in pyridine (11.5 ml) at 0° C. The solution was stirred at 0° C. for 30 minutes then at room temperature for 1 hour. The reaction mixture was concentrated to dryness. The resulting brown gummy residue was dissolved in 73 ml of 1N NaOH (4:1, MeOH: H2O, 2.9 g of NaOH pellets in 14.7 ml H2O and 58.3 ml MeOH) and refluxed for 2 hours. The solvent was removed in vacuo to give a light brown solid. This was dissolved in H2O (180 ml) and the pH adjusted to 5 with AcOH. The resulting solid was filtered and dried to afford 6.2 g (73%) of the desired product, mp 247°-250° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>C(OCC)C.O1CCCC1>[F:31][C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Brc1cccc2cc3ccccc3cc12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1cccc2cc3ccccc3cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
1.2 millimoles n-butyl lithium were dropped into a solution of 1 millimole bromoanthracene in 5 milliliters diethyl ether at 5° C. The solution was cooled to 0° C., was stirred for 1 hour, and then was cooled further to -78° C.; 1.2 millimoles N-fluorobenzenesulfonimide prepared according to Example 1 above in 5 milliliters tetrahydrofuran were dropped into the mixture which was stirred for 1 hour. The temperature was allowed to rise to 20° C. while stirring was continued. The reaction mixture was quenched by pouring into saturated ammonium chloride solution and extracted with diethyl ether. Fluoroanthracene was obtained in 76% yield.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[C:31]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:13]1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: NCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
680 mg of triethylamine was added to a solution of 1.0 g of 1-(3-aminopropyl)-4-(diphenylmethylene)-piperidine (prepared as described in Preparation 15') in 10 ml of methylene chloride at room temperature; a solution of 680 mg of acetyl chloride in 2 ml of methylene chloride was then added dropwise to it at -10° C., after which the mixture was stirred at the same temperature for 5 minutes. Methylene chloride was then added to the mixturem, which was then washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 1.14 g (a quantitative yield) of the title compound as an oil.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([Cl:18])[CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>C(Cl)CCl>[ClH:18].[Cl:18][C:13]1[CH:12]=[CH:11][C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[N:14]=1
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: Clc1ccc2c(n1)CCNC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-benzyl-2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine (98 mg, 0.38 mmol) and 1-chloroethyl chloroformate (0.05 mL, 0.46 mmol) in ClCH2CH2Cl (10 mL) is refluxed for 3 hr. The solvent is removed and the residue is dissolved in MeOH (10 mL) and the mixture is reflux for 30 min. Solvent is removed in vacuo and the residue is stirred with ether (10 mL) for 30 min at rt and filtered. The resulting light brown solid is used in the next step without further purification. MS (M+1): 169.1.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(OCC)(=O)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[C:27]([Cl:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[ClH:35].[C:27]([O:5][CH2:4][CH2:3][NH:2][CH3:1])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CNCCO
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CNCCOC(=O)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a mixture of 2-(methylamino)ethanol (30.04 g) and ethyl acetate (90 mL) was dropwise added a mixture of di-tert-butyl dicarbonate (87.30 g) and ethyl acetate (10 mL) under ice-cooling. After stirring at room temperature for 1 hr., benzoyl chloride (61.8 g) and pyridine (38.8 mL) were added under ice-cooling. After stirring at room temperature for 1 hr., a solid was filtered off. The solid was washed with ethyl acetate (100 mL) and the filtrate and the washing were combined, which was washed with water (100 mL) and saturated brine (100 mL). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), a 4N hydrogen chloride-ethyl acetate solution (200 mL) was added, and the mixture was stirred at room temperature for 30 min. Diethyl ether (100 mL) was added and a solid was collected by filtration. The solid was washed twice with ethyl acetate (100 mL) and dried under reduced pressure at 60° C. to give the title compound (57.4 g) as a white solid.