Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[NH:10][N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:20]1[N:27]=[CH:26][CH:25]=[C:24]([I:28])[C:21]=1[CH:22]=[O:23]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:20]1[C:21]([CH:22]=[O:23])=[C:24]([I:28])[CH:25]=[CH:26][N:27]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Reactant: O=Cc1c(I)ccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(I)c3C=O)ncc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
In a 1 L round-bottomed flask, 6-tert-butyl-8-fluorophthalazin-1(2H)-one (5.6 g, 25.4 mmol, Eq: 1.00) was combined with THF (300 ml) to give a colorless solution. Sodium hydride (1.12 g, 28.0 mmol, Eq: 1.1) was added. The reaction mixture was stirred at ambient temperature for 10 min. 2-Fluoro-4-iodonicotinaldehyde (7.02 g, 28.0 mmol, Eq: 1.1) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction was complete as determined by LCMS analysis. The reaction mixture was quenched with saturated NH4Cl. The reaction mixture was poured into 200 mL H2O and extracted 3× with CH2Cl2. The organic layers were washed with brine, then dried over Na2SO4 and concentrated in vacuo. The resultant bright yellow solid was transferred into a filter funnel and the flask washed twice with a small volume of EtOAc to ensure complete transfer of the solid into the funnel. The liquid was filtered through. The solid was triturated twice with Et2O and dried under vacuum to afford the desired product as a cream-colored solid (8.09 g, 17.9 mmol, 70.5% yield). (M+H)+=452 m/e. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H) 7.49-7.54 (m, 1 H) 7.54 (d, J=1.77 Hz, 1 H) 8.03 (d, J=5.31 Hz, 1 H) 8.30 (d, J=2.53 Hz, 1 H) 8.37 (d, J=5.31 Hz, 1 H) 9.98 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+].O>C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Oc1ccc(Cl)c(Cl)c1
Yield: 63.6 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(3,4-dichlorphenoxy)phenyl]acetate (7.2 g.), sodium hydroxide (1.7 g.) and water (50 ml.) was treated in a similar manner to that of Example 5-(2). The resultant residue was pulverized with benzene, and the precipitates were collected by filtration and dried to give 2-[2-amino-3-(3,4-dichlorophenoxy)phenyl]acetic acid (4.2 g.). mp 125° to 127° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:15].[O:16]([NH2:18])[CH3:17].C(=O)(O)[O-].[Na+]>C1COCC1.O>[ClH:15].[CH3:17][O:16][N:18]=[C:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C1CCNCC1
Reaction time: 0.17 h
Yield: 128.3 %

Procedure:
A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.0 g) and methoxylamine hydrochloride (2.93 g) in THF (66 mL) was treated with sodium bicarbonate (2.95 g) dissolved in water (20 mL). The biphasic mixture was stirred vigorously for 10 minutes, diluted with water, and extracted with ethyl acetate (×3). The combined extracts were dried over magnesium sulfate, filtered and concentrated to afford 2.12 g of the title compound, which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ ppm 1.49 (s, 9H), 2.34 (t, 2H, J=6.07 Hz), 2.57 (t, 2H, J=6.07 Hz), 3.51 (t, 2H, J=6.07 Hz), 3.56 (t, 2H, J=6.07 Hz), 3.85 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][CH:14]=[C:13]([C:16](=[N:18][NH:19][C:20]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=3)=[S:21])[CH3:17])[C:12]=2[OH:36])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.O>C(O)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][CH:14]=[C:13]([C:16](=[N:18][NH:19][C:20]([NH:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([N+:33]([O-:35])=[O:34])[CH:24]=3)=[S:21])[CH3:17])[C:12]=2[OH:36])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=S)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
Methyl 4-{[(2-{1-[5-(4-t-butylphenyl)-4-hydroxy-3-thienyl]ethylidene}hydrazino)carbonothioyl]amino}-2-nitrobenzoate (95 mg, 0.18 mmol) synthesized in Synthetic Example 92 was dissolved in isopropyl alcohol (1.8 mL), and 0.2 M sodium hydroxide aqueous solution (2.0 mL, 0.40 mmol) was added thereto, followed by stirring overnight at room temperature. After completion of the stirring, 1 M hydrochloric acid (0.40 mL, 0.40 mmol) and water were added thereto, and the precipitated solid was filtered to obtain 57 mg of the desired product as a pale yellow solid (yield 61%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([N:17]=[C:18]=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Si]([O:27][C:28]1[CH:33]=[C:32]([O:34][Si](C(C)(C)C)(C)C)[CH:31]=[CH:30][C:29]=1[C@H:42]1[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44][CH2:43]1)(C(C)(C)C)(C)C>CN(C)C=O>[CH2:10]([NH:17][C:18](=[O:19])[O:48][C@H:45]1[CH2:44][CH2:43][C@H:42]([C:29]2[CH:30]=[CH:31][C:32]([OH:34])=[CH:33][C:28]=2[OH:27])[CH2:47][CH2:46]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C=NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N-Diisopropylethylamine (398 μl) and benzylisocyanate (154 μl) was added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (200 mg) in anhydrous dimethylformamide (1 ml). After 16 hr at 50° C., the reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml) and stirred for 16 hr at room temperature. The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to give the title compound (20 mg, 13%) as a pale yellow gum. δH (CD3OD) 1.40-1.60 (4H, m), 1.80-1.90 (2H, m), 1.00-1.20 (2H, m), 2.70-2.82 (1H, m), 4.20-4.30 (2H, s), 4.55-4.65 (1H, m), 6.20-6.30 (2H, m), 6.86 (1H, d), 7.15-7.40 (5H, m); m/z (ES+) 342 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]([CH3:10])[S:5][CH:6]([CH3:9])[CH2:7][CH:8]=1)=[O:2]>[Ni].C(OCC)(=O)C>[CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH3:9])[S:5][CH:4]1[CH3:10])=[O:2]
Reactant: CC1CC=C(C=O)C(C)S1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC1CCC(C=O)C(C)S1
Temperature: 90 °C
Yield: 87.9 %

Procedure:
100 g of 3-formyl-5,6-dihydro-2,6-dimethyl-2H-thiopyran prepared as described in Example 11(a), 60 ml of ethyl acetate and 30 g of Raney nickel were introduced into a stirred autoclave having a capacity of 300 ml. The autoclave was closed, and flushed with nitrogen. Hydrogen was forced in until the total pressure reached 30 bar, after which the mixture was heated to 90° C. and hydrogenated under these conditions until the pressure remained constant. It was then cooled, the catalyst was filtered off and the filtrate was purified by distillation under reduced pressure. 89 g (88% of theory) of 3-formyl-2,6-dimethyltetrahydrothiopyran of boiling point 127°-129° C./10 mbar were obtained.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:35](O)[CH2:36][OH:37]>C1C=CC=CC=1>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6]2([O:37][CH2:36][CH2:35][O:9]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: OCCO
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc(C2(C#N)CCC3(CC2)OCCO3)cc1OC1CCCC1
Reaction time: 1.5 h

Procedure:
A solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (1.0 g, 3.19 mmol, prepared by the procedures described in PCT applications PCT/US3/01990 (WIPO publication No. WO 93/19748) and PCT application PCT/US93/02325 published as WIPO number WO 93/19750) in benzene (25 mL) was treated with p-toluenesulfonic acid (5 mg) and ethylene glycol (0.18 mL, 3.19 mmol) and was heated to reflux under an argon atmosphere; water was removed from the mixture via a Dean-Stark trap. After 1.5 h, ether (200 mL) was added, the solution was washed with aqueous 5% sodium bicarbonate and brine, was dried (potassium carbonate) and was evaporated to provide a clear colorless oil. 1H NMR(250 MHz, CDCl3) δ 7.0 (m, 2H), 6.85 (d, J=7 Hz, 1H), 4.8 (m, 1H), 4.0 (m, 4H), 3.85 (s, 3H), 1.58-2.20 (m, 16H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: C1CCNC1
Reactant: COc1cc(C(=O)O)ccc1Br
Product: COc1cc(C(=O)N2CCCC2)ccc1Br

Procedure:
Starting with 4-bromo-3-methoxybenzoic acid and pyrrolidine, Int02.07 was prepared analogously to the procedure for the preparation of Int02.04.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH:6]1([CH2:12][N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:22][CH3:23])[C:15]([C:24]3[N:25]=[C:26]([CH2:29]O)[S:27][CH:28]=3)=[CH:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.N1C=CC=CC=1>ClCCl>[Cl:5][CH2:29][C:26]1[S:27][CH:28]=[C:24]([C:15]2[C:16]3[C:21](=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][CH:17]=3)[N:13]([CH2:12][CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH:14]=2)[N:25]=1
Reactant: COc1cccc2c(-c3csc(CO)n3)cn(CC3CCCCC3)c12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2c(-c3csc(CCl)n3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Methanesulfonyl chloride (174 μl, 2.25 mmol) was added to a solution of 1-(cyclohexyl)methyl-3-[2-(hydroxymethyl)thiazol-4-yl]7-methoxy-1H-indole (0.40 g, 1.12 mmol) and pyridine (182 μl, 2.25 mmol) in dichloromethane (8 ml). The resulting mixture was stirred at room temperature overnight. Further methanesulfonyl chloride (87 μl, 1.12 mmol) was added and stirring continued for 0.5 h. The mixture was concentrated in vacuo and the resulting orange residue was purified by flash column chromatography eluting with dichloromethane to afford 3-[2-(chloromethyl)thiazol-4-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole as a yellow oil (0.415 g). 3-[2-(Chloromethyl)thiazol-4-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (0.08 g, 0.214 mmol) and diethylamine (221 μl, 2.14 mmol) were dissolved in acetonitrile (2 ml). The resulting mixture was exposed to microwave irradiation at 100° C. for 5 min. The mixture was concentrated in vacuo and the resulting residue was purified by column chromatography eluting with 33% (v/v) ethyl acetate in n-heptane. The resulting product was taken up in diethyl ether and hydrogen chloride (1M solution in diethyl ether; 1 ml) was added. The solution was concentrated in vacuo and the resulting solid triturated with ether, then dried to afford the title compound as a 1:1 hydrochloride salt (0.034 g). 1H NMR (400 MHz, CD3OD) δ 0.99-1.25 (5H, m), 1.43 (6H, t, J 7.5), 1.56-1.90 (6H, m), 3.35-3.42 (4H, m), 3.96 (3H, s), 4.27 (2H, d, J 7.5), 4.75-4.80 (2H, s, masked by H2O peak), 6.75 (1H, d, J 8.0), 7.08 (1H, dd, J 8.0, 8.0), 7.64-7.68 (3H, m). EsIMS: m/z 412.1 [M+H]+, 339.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([Cl:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:28]3[CH:27]=[C:26]([Cl:25])[CH:31]=[C:30]([Cl:32])[CH:29]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cc(-c3cc(Cl)cc(Cl)c3)ccc2F)c1

Procedure:
The phenyl bromide (139)(50 mg, 0.13 mmol) was coupled to 3,5-dichloro-phenylboronic acid (24 mg, 0.13 mmol) using method E. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: O.[C:2]([C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[C:20](=C\OC)/[C:21]([O:23][CH3:24])=[O:22])[CH:8]=1)#[N:3].[Mn]([O-])(=O)(=O)=[O:33].[K+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC>[C:2]([C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](=[O:33])[C:21]([O:23][CH3:24])=[O:22])[CH:8]=1)#[N:3]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Reaction time: 16 h
Yield: 70.6 %

Procedure:
To a vigorously stirred mixture of water (20 ml) and a solution of (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (3.2 g, 7.94 mmol) in dichloromethane (20 ml) was added potassium permanganate (2.5 g, 15.9 mmol) in one portion and tetra-n-hexylammonium hydrogen sulphate (200 mg). The reaction mixture was stirred overnight (16 hours) and then filtered. The filter was washed through with ether and water and then the combined filtrates were extracted with ether (×3). The ether extracts were washed with water (×3) and brine (×1), dried, filtered and evaporated. The residue was chromatographed (eluent dichloromethaneacetone, 98:2). Recrystallisation (ether-pentane) of the major component afforded methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-ketoacetate (2.105 g, 71%) as a white crystalline solid; mp 96°-97° C.; 1H NMR (CDCl3) δ 3.83(3H,s), 6.61(1H,s), 7.27-7.47(4H,m), 7.67-7.76(3H,m), 8.02(1H,dd), 8.39(1H,s) ppm; IR maxima 2234(CN), 1743(CO, ester); 1688(CO, ketone)cm-1.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:32]([CH3:34])[CH3:33])[C:11]([N:13](CC1C=CC=CC=1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1CC2C(=CC=CC=2)C1.N[N:46]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47]1>>[C:1]([NH:9][C@@H:10]([CH:32]([CH3:33])[CH3:34])[C:11]([N:13]([N:46]1[CH2:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:47]1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN1Cc2ccccc2C1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1ccccc1
Agent: NC1Cc2ccccc2C1
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)N1Cc2ccccc2C1

Procedure:
Compound 756 was prepared by a method similar to the method used to prepare compound 724 and compound 706, except 2-aminoindane was replaced with 2-aminoisoindoline (prepared as described in Eloy, F., Moussebois, C., Bull. Soc. Chim. Belg., 68, pp. 409-421 (1959)). ##STR136##
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@@:9]2([OH:18])[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[NH:11][C@@H:10]2[CH3:17])[CH:6]=[CH:7][CH:8]=1.C(OCC)C.[OH-].[Na+]>O>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2([OH:18])[O:14][CH2:13][C:12]([CH3:15])([CH3:16])[NH:11][CH:10]2[CH3:17])[CH:6]=[CH:7][CH:8]=1
Reactant: C[C@H]1NC(C)(C)CO[C@]1(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC1NC(C)(C)COC1(O)c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
(+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-tiimethyl-2-morpholinol hydrochloride may be converted back to its free base by the following process. A 3.0 g sample of (+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol hydrochloride was dissolved in water (100 mL) and diethyl ether was added (200 mL). The mixture was chilled in an ice bath and the pH was adjusted to>10 with 1.0N aqueous sodium hydroxide. After stirring for 30 min., the phases were separated and the aqueous phase was extracted with diethyl ether. The combined diethyl ether extracts were dried (Na2SO4) and concentrated in vacuo to give 2.6 g of (+/−)-(2R*, 3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol as a white solid. This was used without further purification for the chiral chromatography described below.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:29](O)(C)C>[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])([CH3:29])[CH3:2]
Reactant: CC(C)O
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Oc4ccccc4)c3c2c1COC
Agent: [Ti+4]
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Reaction time: 2 h
Yield: 82 %

Procedure:
540 mg of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester in 30 ml of isopropanol is refluxed with 0.2 ml of titanium(IV) isopropylate for 2 hours. After concentration, it is mixed with 0.5N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is dried, filtered and concentrated and digested with diisopropyl ether. 450 mg (82% of theory) of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid isopropyl ester with a melting point of 207°-209° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Br:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[Br:16][C:17]1[N:18]=[CH:19][C:20]([NH:1][C:2]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:3]=2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:21][CH:22]=1
Reactant: Cc1ccc(N)c(C(=O)OC(C)(C)C)c1
Reactant: Brc1ccc(I)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2ccc(Br)nc2)c(C(=O)OC(C)(C)C)c1
Temperature: 120 °C
Yield: 40.2 %

Procedure:
In a schlenck tube, a mixture of tert-butyl 2-amino-5-methylbenzoate (2.89 mmol, 0.600 g), 2-bromo-5-iodopyridine (2.89 mmol, 0.822 g), BINAP (0.29 mmol, 0.096 g), Pd2(dba)3 (0.14 mmol, 0.132 g) and NaOtBu (5.79 mmol, 0.556 g) in toluene (15 ml) was heated at 120° C. for 3 hours. Water and ethyl acetate were added to the reaction crude. The aqueous phase was extracted again with more ethyl acetate. The organic phase was washed with water and brine, dried, filtered and concentrated in vacuo. The crude mixture was purified by chromatography (Biotage 40S, SiO2, Hexane:Ethyl acetate from 0% to 10%) affording 0.422 g (yield 40%) of the expected product.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]1([C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)Cl)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>N1C=CC=CC=1>[C:5]1([C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:3][CH2:2][CH2:1][OH:4])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCO
Solvent: c1ccncc1
Solvent: O
Product: OCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 2.4 %

Procedure:
Ethylene glycol (3.10 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) and triphenylchloromethane (1.39 g, 49.9 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in pyridine (6 mL) (Wako Pure Chemical Industries, Ltd.), and the solution was heated to 45° C. and stirred for 2 hours. Water (50 mL) was poured into the reaction solution, and mixture was extracted with toluene (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with an hydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled of funder reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=9:1), to thereby obtain the title compound (0.37 g, 24% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CN(C)CCO.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])O.[Na+]>[Cu]>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:4]=1
Reactant: C1CCCNCC1
Reactant: Ic1ccc(I)cc1
Agent: [Cu]
Agent: CN(C)CCO
Agent: O=C([O-])O
Product: Ic1ccc(N2CCCCCC2)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 16.4 %

Procedure:
Under an argon atmosphere, 1,4-diiodiobenzene (2 g), azepane (1.2 g), and 2-(dimethylamino)ethanol (5.3 g) were mixed, and tripotassium phosphate (2.8 g) and copper (77 mg) were added thereto, followed by stirring at 60° C. for 2 days. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 1-(4-iodophenyl)azepane (300 mg).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1.N([O-])=O.[Na+].[ClH:21]>O.[Cu]Cl>[Cl:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1
Reactant: CC(=O)N1CCC(c2ccccc2N)CC1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCC(c2ccccc2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-[4-(2-Amino-phenyl)-piperidin-1-yl]-ethanone (0.3 g, 1.38 mmol) was dissolved in a solution of hydrochloric acid (6 N, 6 mL) and cooled to 0° C. A solution of sodium nitrite (0.097 g, 1.4 mmol) in water (1 mL) was added drop wise and the mixture stirred for 1 hour. The resulting solution was added drop wise to a solution of copper (I) chloride (0.35 g, 3.5 mmol) in hydrochloric acid (6 N, 6 mL). The mixture was allowed to warm to room temperature, and was then diluted with water (20 mL) and the products extracted into ethyl acetate. The organic solution was washed with water (20 mL) then dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as an orange oil (0.2 g). LCMS m/z 238.2 [M+H]+. R.T.=4.30 min (Analytical Method 4).