Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([OH:16])[CH3:15])=[CH:9][CH:8]=[C:7]([Cl:17])[CH:6]=2.CC(C)([O-])C.[K+]>CN(C)C=O.O>[Cl:17][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[NH:12][CH2:13][CH:14]([CH3:15])[O:16][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(O)CNc1c(Br)cnc2cc(Cl)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CNc2c(cnc3cc(Cl)ccc23)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.6 %

Procedure:
A solution of 11 g of 3-bromo-7-chloro-N-(2-hydroxypropyl)-4-quinolinamine in 33 ml of dimethylformamide was stirred and to it was added 4.3 g of potassium t-butoxide. The mixture was stirred at 130°-140° C. for three hours and then allowed to cool to room temperature. The reaction mixture was diluted with water and the organics were extracted into dichloromethane. Washing with water, drying over anhydrous magnesium sulfate and evaporation of solvents resulted in a crude oil which was purified by HPLC using 2:1 hexane/ethyl acetate as the eluent. Recrystallization from acetone yielded 2.5 g of solid with a melting point of 239°-241° C.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[N:28]=[N:29][NH:30][N:31]=4)=[CH:17][CH:16]=3)=[C:12]([C:32]([OH:34])=[O:33])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[Li][Li].[C:37]1([C:43](Cl)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>CC(C)=O>[CH:1]1([C:4]2[C:13]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[N:31]=[N:30][N:29]([C:43]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[N:28]=4)=[CH:17][CH:16]=3)=[C:12]([C:32]([OH:34])=[O:33])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1c(Oc2ccc(-c3ccccc3-c3nn[nH]n3)cc2)c(C2CC2)nc2ccccc12
Agent: [Li][Li]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12

Procedure:
A mixture containing the title compound of Example 6, 2-cyclopropy-3-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]oxy]-4-quinolinecarboxylic acid, dilithium salt (906 mg, 2.02 mmol), triphenylmethyl chloride (590 mg, 2.11 mmol), and triethylamine (0.309 mL, 224 mg, 2.22 mmol) in acetone (10 mL) was stirred at room temperature in a stoppered flask for four days (reaction time beyond two days was unnecessary). The reaction mixture was next filtered and re-dissolved into 40 mL total volume with acetone. Yield was assumed to be 100% and appropriate aliquots were used in subsequent reactions.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:5](=[CH:7][C:8]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][CH:10]=1)[OH:6].[CH2:17]([NH:24][CH:25]([CH3:38])[CH2:26][O:27][C:28]1[CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]([OH:37])=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(C)C>[C:33]([C:32]1[CH:36]=[C:28]([CH:29]=[CH:30][C:31]=1[OH:37])[O:27][CH2:26][CH:25]([N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:14][CH:13]([OH:15])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]([C:3]([O:2][CH3:1])=[O:16])=[C:5]([OH:6])[CH:7]=1)[CH3:38])(=[O:34])[NH2:35]
Reactant: CC(COc1ccc(O)c(C(N)=O)c1)NCc1ccccc1
Reactant: COC(=O)c1ccc(OCC2CO2)cc1O
Solvent: CC(C)O
Product: COC(=O)c1ccc(OCC(O)CN(Cc2ccccc2)C(C)COc2ccc(O)c(C(N)=O)c2)cc1O
Reaction time: 40 h

Procedure:
After 40 hours' boiling and working up analogously to Example (4a), 22.4 g of 4-(2,3-epoxypropoxy)salicylic acid methyl ester and 30 g of 5-(2-benzylaminopropoxy)salicylamide in 200 ml of isopropanol yield crude 1-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethyl]benzylamino]-3-(3-hydroxy-4-methoxycarbonylphenoxy)propan-2-ol as a light-coloured foam which is further processed as a crude product.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[CH3:8][C@@H:9]1[N:12]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)[C:11](=[O:18])[C@H:10]1[NH:19][C:20](=[O:59])/[C:21](/[C:34]1[N:35]=[C:36]([NH:39]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:37][CH:38]=1)=[N:22]\[O:23][C:24](C(C)(C)C)([CH2:26]C(O)=O)[CH3:25].ClCCl>C1(C)C=CC=CC=1>[CH3:8][C@@H:9]1[N:12]([C:13]2[NH:14][N:15]=[N:16][N:17]=2)[C:11](=[O:18])[C@H:10]1[NH:19][C:20](=[O:59])/[C:21](/[C:34]1[N:35]=[C:36]([NH2:39])[S:37][CH:38]=1)=[N:22]\[O:23][C:24]([C:3]([OH:5])=[O:4])([CH3:25])[CH3:26]
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@H]1[C@H](NC(=O)/C(=N\OC(C)(CC(=O)O)C(C)(C)C)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)N1c1nnn[nH]1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1c1nnn[nH]1
Reaction time: 1 h
Yield: 16 %

Procedure:
Trifluoroacetic acid (0.50 ml) was added to a -15° solution of 39 (0.047 g, 0.065 mmol) and 0.5 ml dichloromethane. After one hour, the solution was warmed to 23° and stirred for an additional hour before 2 ml toluene was added and volatiles were removed under a stream of nitrogen. Dilution with 10 ml water and washing with 20 ml of 1:1, ethyl acetate: diethyl ether was followed by evaporation under vacuum and chromatography by reverse phase preparative TLC (10% ethanol in water). Elution of a band of Rf 0.9 with 80% acetonitrile in water gave 0.0043 g (16%) 40 as a white solid after lyophilization:
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH:7]([C:19]([OH:21])=[O:20])[CH:8]([O:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH2:9][CH:3]1[CH2:4][CH2:5]2.ON1C(=O)CC[C:24]1=O>O1CCCC1>[CH3:1][N:2]1[C@H:6]2[C@@H:7]([C:19]([O:21][CH3:24])=[O:20])[C@@H:8]([O:10][C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])[CH2:9][C@@H:3]1[CH2:4][CH2:5]2
Reactant: CN1C2CCC1C(C(=O)O)C(OC(=O)c1ccccc1)C2
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
For example, and not by way of limitation, 10 mg of benzoyl ecgonine in 5 ml tetrahydrofuran (“THF”) may be added to 1.1 equivalent N-hydroxysuccinimide (NHS) and 1.1 equivalent of Ethyl 3-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The reaction mixture may be stirred at room temperature for about 30 min. The solvent may then be removed under reduced pressure and the resultant cocaine activated ester, cocaine-NHS (a cocaine pre-hapten), may be dissolved in 0.2 ml of DMF and mixed with 5 mg of carrier Self protein in 1 ml PBS. The mixture may then be stirred for about 3 hour at about 4 C.° to provide cocaine/Self protein conjugate. The foregoing amounts may be varied depending on the desired yield of conjugate. In preferred non-limiting embodiments, the carrier Self protein may be HSA or MSA or TSA.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([CH2:16][NH2:17])=[CH:3][CH:2]=1.[Cl:18][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:20][C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27].N1C=CC=CC=1.O>C1C=CC=CC=1>[CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([CH2:16][NH:17][C:24]([C@H:23]2[C@@H:21]([CH:20]=[C:19]([Cl:18])[C:29]([F:32])([F:30])[F:31])[C:22]2([CH3:28])[CH3:27])=[O:25])=[CH:3][CH:2]=1
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: NCc1cccc2c1CCCc1ccccc1-2
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)NCc1cccc2c1CCCc1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
A solution containing 6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-methanamine (0.5 gram, 0.0022 mole) and benzene (40 ml) was added dropwise to a stirred solution of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (0.75 gram, 0.0029 mole) and pyridine (1.0 gram, 0.013 mole) in benzene (20 ml). The resulting mixture was stirred at room temperature for approximately 16 hours, poured into water and the total extracted with three 100 ml portions of diethyl ether. The combined extracts were washed with a 10% aqueous sodium carbonate solution (100 ml) followed by two 50 ml portions of water. The washed extracts were dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under reduced pressure leaving a yellow residue. This residue was purified by column chromatography on silica gel, elution with benzene:diethyl ether (3:1), to yield N-(6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxamide as a colorless solid (0.85 gram, mp 65°-70°).
Reaction SMILES: [BH4-].[Li+].[CH3:3][C@@H:4]([C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:5][C:6](OC)=[O:7].[Cl-].[NH4+]>C1COCC1.CO>[OH:7][CH2:6][CH2:5][C@@H:4]([CH3:3])[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11]
Reactant: COC(=O)C[C@@H](C)C(=O)Nc1ccn(C)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](CCO)C(=O)Nc1ccn(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of lithium borohydride (97 mg) in THF (5.0 mL) was added a solution of methyl (3R)-3-methyl-4-((1-methyl-1H-pyrazol-3-yl)amino)-4-oxobutanoate (240 mg) in methanol (1.0 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (208 mg).
Reaction SMILES: [OH:1][P:2]([CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[OH-].[Na+:23]>O>[Na+:23].[Na+:23].[OH:3][P:2]([CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([O-:18])=[O:17])=[O:13])([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:1].[OH:3][P:2]([CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([O-:18])=[O:17])=[O:13])([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:1]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CP(=O)(O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])[C@@H]1CCCN1C(=O)CP(=O)(O)Cc1ccccc1

Procedure:
1-[[Hydroxy(phenylmethyl)phosphinyl]acetyl]-L-proline is dissolved in water and treated with two molar equivalents of aqueous sodium hydroxide. The resulting solution is lyophilized to give the product, 1-[[hydroxy(phenylmethyl) phosphinyl]acetyl]-L-proline disodium salt.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:3][CH2:4][C:5](OCC)=[O:6].[H-].C([Al+]CC(C)C)C(C)C.CCCCCCC.CO>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C.[Na+].[Cl-]>[CH3:1][C:2]([CH3:18])([CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:3][CH2:4][CH:5]=[O:6]
Reactant: CCOC(=O)CCC(C)(C)COC1CCCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(CCC=O)COC1CCCCO1
Reaction time: 1 h

Procedure:
To a solution of ethyl 4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pentanoate (11.3 g, 43.7 mmol) in toluene (300 mL) cooled to −78° C. under nitrogen was added diisobutylaluminum hydride 1.0M in heptane (53 mL, 52.5 mmol) slowly, keeping the internal temperature below −70° C. The mixture was allowed to stir in the cold for 15 minutes (TLC: 20% EtOAc in hexane). The reaction was quenched with MeOH (3.00 mL, 161 mmol) allowed to warm to −10 C, diluted with 500 mL of ethyl acetate and 500 mL of saturated NaCl. The mixture was allowed to warm and stir for 60 minutes forming a gel. The gelatinous mixture was filtered through diatomaceous earth and washed with 750 mL of ethyl acetate. The organic layer was separated, dried over MgSO4 and concentrated. Drying under vacuum gave 4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pentanal as a clear oil: 1H NMR (400 MHz, CDCl3) δ 9.8 (s, 1H), 4.6 (t, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.5 (d, 1H), 3.0, (d, 1H), 2.4 (m, 2H), 1.8 (m, 1H), 1.7-1.5 (m, 6H), 0.93 (s, 3H), 0.92 (s, 3H).
Reaction SMILES: C([O:3][C:4]([CH:6]([CH3:18])[C:7]([N:9]1[CH2:17][C@H:15]([OH:16])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=[O:5])C>CO.[OH-].[Na+]>[C:4]([CH:6]([CH3:18])[C:7]([N:9]1[CH2:17][C@H:15]([OH:16])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)C(=O)N1C[C@H](O)C[C@H]1C(=O)O

Procedure:
1-(2-Ethoxycarbonylpropanoyl)-L-hydroxyproline is dissolved in a mixture of methanol (20 ml.) and N sodium hydroxide (20 ml.). After 6 hours the solvent is concentrated in vacuo to half volume and applied to a column of resin Dowex 5 (50 ml.) and eluted with water to obtain 1-(2-carboxypropanoyl)-L-hydroxyproline.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[CH2:25][N:24]([C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][CH:12]4[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]4)=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCN(C(=O)OC(C)(C)C)CC1)C3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNCC1)C3
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.2 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (6.6 mL; 26.4 mmol; 5 eq.) was added to a solution of 4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (2.78 g; 5.28 mmol; 1 eq.) in 1,4-dioxane (30 mL) and the reaction mixture was stirred at room temperature for 18 hours then concentrated in vacuo. The residue was partitioned between DCM and sat. aq. Na2CO3 and the two phases separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (1.78 g, 79%) as a yellow solid. 1H NMR (DMSO-d6) δ 7.46-7.39 (m, 1H), 7.33-7.29 (m, 1H), 7.21-7.19 (m, 1H), 7.07-7.01 (m, 1H), 4.85 (s, 1H), 4.82 (s, 1H), 4.58-4.49 (m, 3H), 2.92-2.76 (m, 2H), 2.84 (s, 1.5H), 2.80 (s, 1.5H), 2.69-2.58 (m, 2H), 2.62 (s, 1.5H), 2.55 (s, 1.5H), 1.93-1.68 (m, 2H), 1.54-1.43 (m, 2H). HPLC (max plot) 92.5%; Rt 2.69 min. UPLC/MS: (MS+) 426.4 ([M+H]+).
Reaction SMILES: C([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]([Cl:17])[CH:6]=1)(=O)C.O=S(Cl)Cl.[CH3:22]O>>[Cl:17][C:7]1[CH:6]=[C:5]([OH:4])[C:10]([O:11][CH3:12])=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:22])=[O:15]
Reactant: COc1cc(CC(=O)O)c(Cl)cc1OC(C)=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(OC)c(O)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of [4-(acetyloxy)-2-chloro-5-methoxyphenyl]acetic acid (670 mg, 2.587 mmol) in 30 mL of MeOH was added dropwise SOCl2 at 0° C. The resulting mixture was stirred at 50˜60° C. overnight and concentrated to dryness. The residue was dissolved in EtOAc (50 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated to give methyl (2-chloro-4-hydroxy-5-methoxyphenyl)acetate. 1H-NMR (400 MHz, CDCl3) δ ppm 6.94 (s, 1H), 6.75 (s, 1H), 3.86 (s, 3H), 3.70 (s, 3H), 3.68 (s, 2H).
Reaction SMILES: [C:1]([O:5]C(N1C[C@@H](N(C)C)C[C@H]1CO)=O)(C)(C)C.O[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:23]([O:25][O:5][CH3:1])(=[O:24])[C:22]1[CH:27]=[CH:28][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COOC(=O)c1ccccc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
To a stirred solution of cis-1-tert-butoxycarbonyl-4-dimethylamino-(2S)-hydroxymethylpyrrolidine (555 mg, 2.27 mmol), methyl 4-hydroxybenzoate (380 mg, 2.5 mmol), and Ph3P (1.07 g, 4.09 mmol) in THF (10 ml) was added DIAD (826 mg, 4.09 mmol) at 0° C. The reaction mixture was stirred at 70° C. for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1/2, v/v) MeOH—CH2Cl2(5/95, v/v) as eluent to give methyl 4cis-1-tert-butoxycarbonyl diethylamino-(2S)-pyrrolidinyl)methoxy benzoate (260 mg, 30%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.45 (s, 9H), 1.70-1.90 (m, 1H), 2.26 (s, 6H), 2.33 (m, 1H), 2.57 (m, 1H), 3.06 (m, 1H) 3.85-4.23 (m, 4H), 388 (s, 3H), 6.93 (m, 2H), 7.95 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH:9]1[CH2:18][O:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].O.CCCCCC.C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:21]=[N+:22]=[N-:23])[CH2:10][CH:9]1[CH2:18][O:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1CC(OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
The 4-methanesulfonyloxy-2-methoxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester (172.26 mg, 0.56 mmol) was taken up in dry DMF under argon and sodium azide (182.00 mg, 2.80 mmol) was added. The reaction was then heated to 60° C. for 48 h. The reaction was poured into water and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with sat NaHCO3 and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (3:1 hexane-ethyl acetate) Yield 122.00 mg. C11H22N2O3 MS m/e=257.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=[O:12])[CH:10]2[CH2:13][CH:14]=[C:15]([Cl:17])[CH:16]=[C:9]2[NH:8][C:7](=[O:18])[CH2:6]1)=[O:4].[H-].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH3:24].Cl>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=2[N:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:7](=[O:18])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(=O)NC2=CC(Cl)=CCC2C1=O
Reactant: CCCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)CC(C(=O)OC)C(=O)c2ccc(Cl)cc21

Procedure:
The starting material is prepared as follows: -chloro-2,3,4,5 suspension of 6.0 g of 8-chloro--tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester in 125 ml of dimethyl formamide is added portion-wise to that of 2.1 g of a 57% mineral oil suspension of sodium hydride in 300 ml of dimethylformamide while stirring under argon. After stirring for 3 hours at room temperature 4.6 g of n-butyl iodide are added dropwise and stirring is continued over night at said temperature. The pH of the mixture is adjusted to 2 with 3N hydrochloric acid and the whole evaporated. The residue is partitioned between water and chloroform, the organic solution separated and the aqueous solution extracted with chloroform. The combined extract is washed with water, dried, evaporated and the residue taken up in diethyl ether. The mixture is treated with charcoal, filtered hot and the filtrate concentrated, to yield the 8-chloro-1-n-butyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester, melting at 89°-90°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:40]([O:41][CH3:42])=[O:43])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:28])([CH3:29])[NH:14]2
Reactant: COC(=O)Cl
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
5-(5-Fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 25.0 mg, 0.058 mmol) was dissolved in tetrahydrofuran (0.5 mL), triethylamine (23 μL, 0.17 mmol) and methyl chlorocarbonate (6.8 μL, 0.088 mmol) were added thereto, and then the mixture was stirred at room temperature for 20 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (28.0 mg) as a colorless amorphous product. (Yield 99%)
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.CO[CH:13](OC)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:15]=1>>[N:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:16]2[CH:15]=[C:14]([CH:13]3[C:3]4[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=4[NH:1][C:2]4[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]3=4)[CH:19]=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: COC(OC)c1cccc(OCc2ccncc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(OCc2ccncc2)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen-1-one with 3-(4-pyridylmethoxy)-benzaldehyde dimethyl acetal in an analogous manner to that described in Example 1 gave 9-[3-(4-pyridylmethoxy)-phenyl]-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from methanol/water gave a yellow crystalline solid of melting point 156-158° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]1[O:15][C:14]2[C:9](=[N:10][CH:11]=[C:12](Br)[CH:13]=2)[CH:8]=1.[CH3:17][C:18]1[CH:19]=[C:20]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[N:22][CH:23]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[C:7]1[O:15][C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:20]3[CH:21]=[N:22][CH:23]=[C:18]([CH3:17])[CH:19]=3)[CH:13]=2)[CH:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(C)c1
Reactant: CN1CCC[C@@H]1c1cc2ncc(Br)cc2o1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cncc(-c2cnc3cc([C@H]4CCCN4C)oc3c2)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(1-methyl-2-(R)-pyrrolidinyl)-6-(bromo)-furo[3,2-b]pyridine from Example 47 in toluene are added (5-methyl3-pyridyl)tributyltin and tetrakis(triphenylphosphine)palladium(O). After being refluxed overnight, the resulting mixture is cooled to room temperature. Solvent is removed, and the residue is chromatographed on a silica gel column.