Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C(OCC)(=O)C.C1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 4 g (10.75 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate, obtained in step 3.3. of Example 3, 5.50 g (28.96 mmol) of 4-(trifluoromethyl)-phenylboronic acid, 9.12 g (42.99 mmol) of hydrated potassium phosphate and 1.24 g (1.07 mmol) of tetrakis(triphenylphosphine)palladium, and after chromatography on silica gel, eluting with a 30/70 mixture of ethyl acetate and cyclohexane, 2.78 g of product are obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([OH:12])=[O:11]>>[CH3:9][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=2)[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)c(C)cn1
Product: Cc1cc(-c2ccc(C(=O)O)cc2)c(C)cn1

Procedure:
The title compound was prepared from 4-bromo-2,5-dimethylpyridine (WO 93/15062) and 4-carboxyphenylboronic acid using a similar procedure to Description 18 as a white solid (67%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:12]4[C:23]([N:25]5[CH2:30][CH2:29][N:28](C([O-])=O)[CH2:27][CH2:26]5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:34])[O:4][N:3]=1>Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:23]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:34])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(N3CCN(C(=O)[O-])CC3)n3c2c1OCC3c1ccccc1
Agent: Cl
Product: Cc1noc(C)c1-c1ccc2nc(N3CCNCC3)n3c2c1OCC3c1ccccc1

Procedure:
4-[7-(3,5-Dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]piperazine-1-carboxylate (Example 60) was stirred in 4 N HCl for 15 min. at room temperature and evaporated. Purification by preparative LCMS at pH 10 gave the desired compound which was isolated as the dihydrochloride salt. LCMS calc. for C24H26N5O2 (M+H)+: m/z=416.2. found: 416.2.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].BrCCCCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.O=[CH:61][CH2:62][CH2:63][CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66]>CCOCC.CCCCCC>[C:65]([O:67][CH2:68][CH3:69])(=[O:66])[CH2:64][CH2:63][CH2:62]/[CH:61]=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCC=O
Agent: [Br-]
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCCBr
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCC/C=C\CCCC(=O)OCC
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
Heptyltriphenylphosphonium bromide (16.8g), prepared from 1-bromoheptane and triphenylphosphine analogously to undecyltriphenylphosphonium bromide as described in Example 2(2), is suspended in dry ether (300 ml) and the mixture is treated whilst stirring under nitrogen with 1.7 M butyllithium in hexane (36 ml) from a syringe. The resulting bright red solution is cooled to 10° C. and treated dropwise with ethyl 5-oxopentanoate [5.5 g, prepared as described in Example 2 (1B)] in dry ether (37.5 ml). After 10 minutes, the reaction mixture is worked up by the procedure described in Example 2(2) to give ethyl (Z)-dodec-5-enoate as a yellow oil (8.6g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:16])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1.[I-].[CH3:18][S+](C)(C)=O.[OH-].[K+].[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH2:18][N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[OH:16])=[CH:4][CH:3]=1
Reactant: c1nc[nH]n1
Reactant: C[S+](C)(C)=O
Reactant: O=C(Cc1ccc(Cl)cc1)Cn1cncn1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: OC(Cc1ccc(Cl)cc1)(Cn1cncn1)Cn1cncn1

Procedure:
A mixture of 1-(4-chlorophenyl)-3-(1,2,4-triazol-1-yl)propan-2-one (15 g), trimethylsulphoxonium iodide (17.5 g), potassium hydroxide (8.57 g), 1,2,4-triazole (5.48 g) and tert-butanol (150 ml) was heated under reflux for 5 h, then cooled overnight. The excess tert butanol was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried, and evaporated to dryness to give a brown gum, which was purified by column chromatography on silica eluting with chloroform/methanol, 97:3 by volume, to give a high melting polymorph of 2-(4-chlorophenyl)-1,1-di(1,2,4-triazol-1-ylmethyl)ethanol, mp 170°.
Reaction SMILES: [CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[OH:27])[CH:2]=[CH2:3].[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>N1C=CC=CC=1>[CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[O:27][S:37]([CH3:36])(=[O:39])=[O:38])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Solvent: c1ccncc1
Solvent: O
Product: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of nucleoside 2 (3.50 g, 7.31 mmol) in anhydrous pyridine (23 cm3) at 0° C. was added methanesulphonyl chloride (1.69 cm3, 21.89 mmol). The reaction mixture was stirred for 1 h at room temperature, water (100 cm3) was added and extraction was performed using dichloromethane (3×150 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×200 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography using dichloromethane/methanol (99:1) as eluent to give 3 as a white solid material (3.64 g, 89%). δH (CDCl3) 8.95 (1H, br s, NH), 7.71 (1H, d, J 1.1, 6-H), 7.39-7.25 (10H, m, Bn), 6.52 (1H, d, J 8.0, 1′-H), 5.90 (1H, m, 2″-H), 5.34 (1H, d, J 7.9, 2′-H), 5.20-5.09 (2H, m, 3″-Ha, 3″-Hb), 4.91 (1H, d, J 11.2, Bn), 4.68 (1H, d, J 11.3, Bn), 4.64 (2H, s, Bn), 4.33 (1H, br s, 4′-H), 3.81 (1H, dd, J 2.5, 11.1, 5′-Ha), 3.73 (1H, dd, J 1.1, 11.1, 5′-Hb), 3.08 (1H, dd, J 5.5, 5.7, 1″-Ha), 2.99 (3H, s, CH3), 2.68 (1H, m, 1″-Hb), 1.51 (3H, d, J 0.8, CH3). δC (CDCl3) 163.4 (C-4), 150.8 (C-2), 137.9, 136.3 (Bn), 135.5 (C-6), 131.0 (C-2″), 128.8, 128.3, 127.5, 127.2 (Bn), 119.3 (C-3″), 111.6 (C-5), 84.1, 83.6, 82.4, 82.2 (C-1′, C-2′, C-3′, C-4′), 73.7, 68.9 (Bn), 66.2 (C-5′), 38.7 (CH3), 33.0 (C-1″), 11.9 (CH3) (Found: C, 60.5; H, 5.8; N, 4.9. C28H32N2O8S requires C, 60.4; H, 5.8; N, 5.0%).
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[C:11](O)=O.[N:14]([O-])=O.[Na+]>OS(O)(=O)=O>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:11]1[NH2:14]
Reactant: O=N[O-]
Reactant: O=C(O)[C@@H]1Cc2ccccc2[C@H]1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@@H]1CCc2ccccc2[C@@H]1O
Temperature: 2.5 °C

Procedure:
The hydrazide of (1S,2R)-1-hydroxy-2-carboxyindane (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2R)-1-hydroxy-2-aminotetralin is isolated as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH2:13](OC(OCC)(OCC)C)[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:13]([CH3:14])=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(-c2ccc(O)c(Cl)c2)o1

Procedure:
A mixture of 3-chloro-4-hydroxybenzoic acid hydrazide (6 g) and 1,1,1-triethoxyethane (90 ml) was refluxed under nitrogen for 19.5 h. On cooling and stirring, the solid which crystallised out of the reaction mixture was filtered off, washed well with ethyl acetate and dried to give the title compound (1.8 g) T.l.c. ethanol Rf 0.65.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:32]1[CH:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[N:11]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(=O)C.[K+]>[Pd].C(O)C>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C@@H:12]2[CH2:13][CH2:14][C@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[N:11]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc([N+](=O)[O-])cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Reaction time: 8 h

Procedure:
To 0.70 g (0.66 mmol) of 10% palladium on carbon was added a solution of 6.4 g (11 mmol) of tert-butyl(2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(6-chloropyridin-3-yl)methyl]-5-(4-nitrobenzyl)pyrrolidine-1-carboxylate from Step A above in 75 mL of anhydrous ethanol followed by 1.2 g (12 mmol) of potassium acetate. The resulting suspension was agitated under an atmosphere of hydrogen at 50 psi for 8 h. then filtered through a plug of Celite®. The plug was washed with ethanol (100 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 40% ethyl acetate in hexanes to afford the title compound (i-8) as a colorless solid (0.31 g, 76%). LC-MS: m/z (ES) 498.4 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=1.[Br-].[K+]>CC(C)=O>[CH2:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[CH:16][CH:17]=1)[CH:8]=[CH2:9]
Reactant: OCCCc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(CCCO)cc1
Yield: 79.9 %

Procedure:
Powdered potassium carbonate (4.14 g) and allyl bromide (3.99 g) were added to a stirred solution of 3-(4-hydroxyphenyl)propanol (4.56 g) in acetone (15 ml) under an atmosphere of argon. The mixture heated at reflux for 20 hours. After cooling to ambient temperature the solid potassium bromide was removed by filtration and washed with ether. The filtrate and washings were combined, washed with 2M aqueous sodium hydroxide (2×20 ml), water (1×20 ml), brine (20 ml), dried (MgSO4) and evaporated. The residue was purified by vacuum flash chromatography on silica gel (Merck 7736) using toluene as eluent to give 3-(4-allyloxyphenyl) propanol as a colourless oil (4.6 g). NMR(CDCl3): 1.3(1H,s), 1.8-2.0(2H,m), 2.6-2.7(2H,t), 3.6-3.7(2H,t), 4.45-4.55(2H,m), 5.2-5.5(2H,m), 5.95-6.15(1H,m), 6.8-6.9(2H,d) and 7.05-7.15(2H,d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([C:26]([NH2:28])=[O:27])[OH:25])[CH:17]=3)[C:12]2=[O:29])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([C:26]([NH2:28])=[O:27])[O:25][C:37](=[O:39])[CH3:38])[CH:17]=3)[C:12]2=[O:29])=[CH:4][CH:3]=1
Reactant: NC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)ON(CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O)C(N)=O
Reaction time: 2 h

Procedure:
A solution of 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-aminocarbonyl-N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.2 mmol) and triethylamine (0.2 mL, 1.4 mmol) are dissolved in THF (25 mL) and acetyl chloride (0.1 mL, 1.4 mmol) is added. The reaction mixture is stirred for 2 hours and subsequently poured into 2N HCl. The aqueous phase is extracted with EtOAc (3×100 mL) and the combined organics washed with 2N HCl (2×100 mL) H2O (2×100 mL), saturated NaHCO3 solution (2×100 mL), saturated NaCl solution (2×100 mL), dried over MgSO4 and concentrated in vacuo. The residue is triturated with hexanes and chromatographed (silica gel, 1:1 EtOAc/hexane). The resulting material is crystallized from cold CH2Cl2 /Et2O and dried in vacuo to give 2-[3-(4-fluorophenyl)-propyl]-6-{2-[N-(aminocarbonyl)-N-(acetyloxy)amino]-ethoxy}-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 113°-114°.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[CH:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][C:48]=1[S:57](Cl)(=[O:59])=[O:58].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][S:57]([C:48]1[CH:49]=[CH:50][C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]=1)(=[O:59])=[O:58])=[O:43]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNS(=O)(=O)c2ccc3ccccc3c2)s1
Reaction time: 8 h
Yield: 22.1 %

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (1.85 g) was dissolved in dimethylformamide (20 ml). 2-Naphthalenesulfonyl chloride (0.62 g) and triethylamine (1.75 ml) were added under ice-cooling, and the mixture was allowed to stand overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 0.32 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)naphthalene-2-sulfonamide.
Reaction SMILES: C(=O)([O-])O.[Na+].[I:6][C:7]1[N:8]=[C:9]([CH3:12])[NH:10][CH:11]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(#N)C>[I:6][C:7]1[N:8]=[C:9]([CH3:12])[N:10]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc(I)c[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(I)nc2C)cc1
Yield: 38.9 %

Procedure:
Sodium hydrogen carbonate (9 g) was added to a stirred solution of 4-iodo-2-methyl-1H-imidazole (9.0 g) in acetonitrile (125 ml) followed by a solution of p-toluenesulphonyl chloride (8.3 g) in acetonitrile (50 ml). The resulting mixture was maintained at ca. 40° for 5 h. The reaction mixture was filtered, concentrated in vacuo to ca. 30 ml and n-hexane (ca. 350 ml) was added, precipitating the title compound (7.8 g) as crystals, m.p. 113°-114°. Concentration of the mother liquors (to ca. 50 ml) afforded further title compound (6.1 g), m.p. 112°-114°.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]#N)[CH:8]=2)[N:3]=1.[C:27]1([Mg]Cl)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C[O:38]CC1.Cl>>[NH2:1][C:2]1[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:38])[CH:8]=2)[N:3]=1
Reactant: Cc1cccc(C#N)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: Cl[Mg]c1ccccc1
Reactant: C1CCOC1
Agent: Cl
Product: Cc1cccc(C(=O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 60 °C

Procedure:
To a sealed tube containing 2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylbenzonitrile (0.20 g, 0.581 mmol, prepared as in Example 14, Step 1) was added phenylmagnesium chloride, 2.0M solution in THF (1.16 mL, 2.323 mmol) under N2 atmosphere. The mixture was heated at 60° C. overnight and the conversion was completed, determined by LCMS. The mixture was allowed to cool to RT and treated with aqueous 2N HCl (1 ml) carefully. The resulted mixture was heated at 60° C. for 7 h until the imine was consumed. The product mixture was concentrated and then diluted with MeOH and purified on HPLC (10-100% MeCN/H2O with 0.1% TFA modifier) to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanone (TFA salt).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CO)cccc1OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: Cc1c(C=O)cccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 88.4 %

Procedure:
To a solution of (3-benzyloxy-2-methyl-phenyl)-methanol (622, 627 mg, 2.75 mmol) in tetrahydrofuran (60 mL) was added Dess-Martin periodinane (2.9 g, 6.87 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 50 minutes. The reaction mixture was quenched with a solution of saturated sodium thiosulfate, extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (623, 0.55 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[C:20]([CH:21]2OCC[O:22]2)=[CH:19][CH:18]=[C:17]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2>C(O)(=O)C>[Cl:1][C:2]1[C:20]([CH:21]=[O:22])=[CH:19][CH:18]=[C:17]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C4OCCO4)c3Cl)c2n1
Solvent: CC(=O)O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(C=O)c3Cl)c2n1

Procedure:
A solution of 8-[2,6-dichloro-3-(1,3-dioxolan-2-yl)benzyloxy]-2-methylquinoline (3.0, g) in 80% acetic acid (30 ml) was heated at 60° C. for 2 hours. The cooled reaction mixture was concentrated in vacuo, and aqueous sodium bicarbonate solution was added thereto. The mixture was extracted with chloroform, and the organic, layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate to give 8-(2,6-dichloro-3-formylbenzyloxy)-2-methylquinoline (2.28 g) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:46][CH2:47][N:42]([CH2:41][CH2:40][O:39][CH3:38])[CH2:43][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCOC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(2-methoxy-ethyl)-piperazine (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O3 [(M+H)+] 666.2972, observed 666.2971.
Reaction SMILES: C([N:3]([C:15]1[C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][C:22]2[C:21]([CH3:33])([CH3:32])[CH2:20][CH:19]=[C:18]([CH3:34])[C:17]=2[CH:16]=1)[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)C.[OH-].[K+]>>[CH2:26]([O:25][C:24]1[C:15]([NH:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)=[CH:16][C:17]2[C:18]([CH3:34])=[CH:19][CH2:20][C:21]([CH3:33])([CH3:32])[C:22]=2[CH:23]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCOc1cc2c(cc1N(CC)c1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Agent: [K+]
Agent: [OH-]
Product: CCCCCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Yield: 26.5 %

Procedure:
Following General Procedure E ethyl 4-[ethyl-(3-n-hexyloxy-5,5,8-trimethyl-5,6-dihydronaphthalen-2-yl)amino]benzoate (Compound 125, 0.036 g, 0.078 mmol) was saponified with KOH to give 0.0090 g (27%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O.[Cl-].[Ca+2].[Cl-]>>[C:1]1([CH2:7][CH2:8][C:9]([Cl:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Product: O=C(Cl)CCc1ccccc1

Procedure:
To a 100 ml eggplant-shaped flask were added 20.0 g (133.2 mmol) 3-phenylpropionic acid and 24.5 g (205.9 mmol) thionyl chloride, a reflux condenser pipe carrying a calcium chloride drying pipe and a sodium hydroxide acidic gas absorption device was mounted, the mixture was refluxed for 1 hour under magnetic agitation, distilled under reduced pressure to remove excessive thionyl chloride to give crude 3-phenylpropionyl chloride as a pale yellow oil, which was directly used in the reaction of following step without purification.