Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:11]N1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2C1=O.[C:23]([OH:26])(=O)[CH3:24]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.[OH:26][C:23]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:14][CH:15]([CH2:18]3)[C:16]1=[O:17])[CH2:1]2
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(=O)O
Product: O=C1C2CC3CC(C2)CC1(O)C3
Product: O=C1C2CC3CC(C2)CC1C3
Yield: 16 %
Yield: 32 %

Procedure:
To 25 ml of acetic acid were added 10 mmol of adamantane, 1 mmol of N-hydroxyphthalimide and 0.2 mmol of phosphovanadotungstic acid (PV4W8O40.30H2), and the resultant mixture (pH 1.9) was stirred under an oxygen atmosphere at a temperature of 75° C. for 6 hours. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, adamantane was converted into adamantanone (yield 32%) and 1-hydroxyadamantanone (yield 16%) with a conversion of 79%. Incidentally, excepting the above, 1-adamantanol (yield 15%), 1,3-adamantanediol (yield 8%) and other products (polyketone such as adamantanedione) (yield 8%) were formed.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]3[N:20]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:21](=[O:32])[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]#[N:31])[C:18]=3[C:17]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47](=[O:49])[NH2:48])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(C)C=CC=CC=1.[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60]>ClCCl>[F:57][C:58]([F:63])([F:62])[C:59]([OH:61])=[O:60].[CH2:33]([N:20]1[C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[C:17]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]([NH2:48])=[O:49])[C:18]=2[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:21]1=[O:32])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Oc3ccccc3C(N)=O)c3c2n(Cc2ccccc2)c(=O)n3Cc2ccccc2C#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#Cc1ccccc1Cn1c(=O)n(Cc2ccccc2)c2c(N3CCNCC3)ncc(Oc3ccccc3C(N)=O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[3-Benzyl-7-(2-carbamoylphenoxy)-1-(2-cyanobenzyl)-2-oxo-2,3-dihydro-1H-imidazo[4.5-c]pyridin-4-yl]-piperazine-1-carboxylic acid t-butyl ester (0.023 g) was dissolved in dichloromethane and trifluoroacetic acid (1 mL). After stirring this at room temperature for two hours, then toluene (5 mL) was added, and this was concentrated under reduced pressure. The residue was purified by reverse phase high performance liquid chromatography to give the title compound (0.016 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[CH2:19][CH2:18][C:17]2[S:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]([O:20][CH:21]4[CH2:26][CH2:25][CH:24]([N:27]([CH3:36])[CH2:28][C:29](=[O:35])[N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:23][CH2:22]4)[C:10]=3[C:9]1=2)(=O)=O.[C-:37]#[N:38].[Na+]>CS(C)=O.CN(C)C1C=CN=CC=1>[CH3:36][N:27]([CH2:28][C:29](=[O:35])[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH:24]1[CH2:23][CH2:22][CH:21]([O:20][C:11]2[C:10]3[C:9]4[C@@H:8]([CH2:7][CH2:6][C:37]#[N:38])[CH2:19][CH2:18][C:17]=4[S:16][C:15]=3[N:14]=[CH:13][N:12]=2)[CH2:26][CH2:25]1
Reactant: [C-]#N
Reactant: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCOS(C)(=O)=O)CC4)CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCC#N)CC4)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of 2-[(3R)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl methanesulfonate (107 mg, 0.20 mmol, 1.00 equiv) in DMSO (5 mL) were added NaCN (58.8 mg, 1.20 mmol, 6.00 equiv) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol, 0.10 equiv) at room temperature. The resulting solution was stirred for 2 h at 80° C. After cooling to room temperature, the reaction was then quenched by the addition of aqueous FeSO4 solution and extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (10:1) to give the desired 3-[(3S)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (80 mg, 86%) as a yellow solid. MS (ES): m/z 468 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6]C(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[CH:55]=[CH:54][C:53]([C:56]([OH:58])=O)=[CH:52][CH:51]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:56]([C:53]1[CH:54]=[CH:55][C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:51][CH:52]=1)=[O:58]
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Reactant: O=C(O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccc(-c2ccccc2CSCCOc2ccccc2)cc1
Yield: 74 %

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.80 g, 2.19 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.36g, 2.23 mmol, 1.02 eq.) followed by 3-(dimethylamino)propylamine (0.27 g, 2.63 mmol, 1.2 eq.) as described. When complete, the reaction was worked up leaving a yellow oil that later crystallized. The solid was purified via silica gel flash chromatography using 140:10:1 (CHCl3/MeOH/NH4OH) as the mobile phase. Fractions containing the product were pooled and the solvent removed leaving 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (3-dimethylamino-propyl)-amide (0.72 g, 74% yield) as a white solid.
Reaction SMILES: F[C:2](F)([O:12]C)[CH:3]([C:8]([F:11])(F)F)[C:4]([F:7])([F:6])[F:5].CN(C)C.[F:19][C:20]1[CH:39]=[CH:38][CH:37]=[CH:36][C:21]=1[CH2:22][N:23]1[C:27]([C:28]2[CH:32]=[CH:31][O:30][N:29]=2)=[CH:26][C:25]([C:33](=[NH:35])[NH2:34])=[N:24]1>CN(C=O)C.C(OCC)(=O)C.CO>[F:11][C:8]1[N:34]=[C:33]([C:25]2[CH:26]=[C:27]([C:28]3[CH:32]=[CH:31][O:30][N:29]=3)[N:23]([CH2:22][C:21]3[CH:36]=[CH:37][CH:38]=[CH:39][C:20]=3[F:19])[N:24]=2)[NH:35][C:2](=[O:12])[C:3]=1[C:4]([F:5])([F:6])[F:7]
Reactant: COC(F)(F)C(C(F)(F)F)C(F)(F)F
Reactant: N=C(N)c1cc(-c2ccon2)n(Cc2ccccc2F)n1
Agent: CN(C)C
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1[nH]c(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc(F)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To a cold solution of 2-(difluoro(methoxy)methyl)-1,1,1,3,3,3-hexafluoropropane (81 mg, 1 equiv.) in DMF (876 μl) at 0° C., was added, slowly, trimethylamine (98 μl, 2 equiv.). The mixture was stirred at 0° C. for 1 h. To this mixture, was added a solution of 1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide (Intermediate 8C, 100 mg, 1 equiv.) in DMF (876 μl). The mixture was stirred at room temperature for 1 h and heated to 70° C. for an additional 1 h. The mixture was cooled to room temperature. It was diluted in ethyl acetate (100 ml) and washed with water (50 ml×3). The organic layer was dried, filtered and evaporated to give solid. The resulting solid was dissolved in methanol and absorbed onto silica gel. Purification by column chromatography (0 to 100% ethyl acetate in hexanes) gave 6-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4(3H)-one (35 mg, 24% yield) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15]Br)=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].Cl.[CH3:26][NH:27][OH:28].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][N:27]([CH3:26])[OH:28])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CNO
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(O)CC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 6.9 %

Procedure:
A mixture of 6-nitro-2,2-dimethyl-3-bromomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.30 g, 7.7 mmol), N-methylhydroxylamine hydrochloride (0.64 g, 7.7 mmol) and potassium carbonate (0.97 g, 7.7 mmol) in ethanol (10 ml) was heated at reflux for 30 minutes. Water was added and the mixture extracted with dichloromethane. The organic phase was separated and the solvent evaporated under reduced pressure. The residue was washed with diethyl ether, affording 0.19 g of 6-nitro-2,2-dimethyl-3-(N-methyl-N-hydroxyamino)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 159° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)=[N:7][C:8]=1[OH:9])=O.N1CCCCC1.C(O)(=O)C.[CH3:34][C:35]1[N:36]=[C:37]([CH3:50])[C:38]2[N:39]([CH:41]=[C:42]([CH2:44][C:45](OCC)=[O:46])[N:43]=2)[CH:40]=1>CCO>[CH3:34][C:35]1[N:36]=[C:37]([CH3:50])[C:38]2[N:39]([CH:41]=[C:42]([C:44]3[C:45](=[O:46])[O:9][C:8]4=[N:7][C:6]([N:10]5[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]5)=[CH:5][CH:4]=[C:3]4[CH:1]=3)[N:43]=2)[CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(C=O)c(O)n2)CC1
Reactant: CCOC(=O)Cc1cn2cc(C)nc(C)c2n1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cn2cc(-c3cc4ccc(N5CCCN(C(=O)OC(C)(C)C)CC5)nc4oc3=O)nc2c(C)n1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(5-formyl-6-hydroxypyridin-2-yl)-1,4-diazepane-1-carboxylate (225 mg, 0.7 mmol) in 3 mL of EtOH were treated with piperidine (119.2 mg, 1.4 mmol), acetic acid (252 mg, 4.2 mmol) and ethyl 2-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)acetate (196 mg, 0.84 mmol) at room temperature. The reaction mixture was stirred in microwave reactor at 150° C. for 2 hours. The mixture was concentrated, quenched with a saturated NaHCO3 solution and extracted with dichloromethane three times. The combined organic layers were combined and concentrated. The residue was purified on silica gel to provide tert-butyl 4-(3-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate after concentration. MS m/z 491 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][NH2:16])[CH2:7][O:8]2.C(N(CC)CC)C.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][NH:16][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:7][O:8]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCN(CCN)C1COc2cccc(OC)c2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCNS(=O)(=O)c1ccc(C)cc1)C1COc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
4 mmol of the compound prepared in Example 14 are dissolved in 30 ml of dichloromethane cooled in ice. 11.4 mmol of triethylamine are added dropwise, followed by 4 mmol of tosyl chloride dissolved in dichloromethane. The mixture is left stirring for 30 minutes at room temperature. The solvent is then evaporated off and the expected product is obtained after purification by chromatography on a silica column (elution solvent: dichloromethane).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([Cl:14])[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[Cl:14][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)[N:3]=[CH:4][N:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1ncnc(Cl)c1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2ncnc(Cl)c2-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 63.2 %

Procedure:
To a mixture of 4,6-dichloro-5-phenylpyrimidine (675 mg, 3.0 mmol), 4-chlorophenylboronic acid (704 mg, 4.5 mmol) and tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) in toluene (10 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 3 mL, 6 mmol). The resulting reaction mixture was stirred at 100° C. under argon for 5 h, after which time analysis by HPLC/MS indicated that the the reaction was complete. After cooling the reaction mixture to room temperature, water (15 mL) was added. The resulting mixture was extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain 571 mg of the title compound as a white solid. HPLC/MS: retention time=3.85 min, [M+H]30 =301.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([N:45]4[CH2:46][CH2:47][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:49][CH2:50]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: OCC(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-[4-(methylsulfonyl)-1-piperazinyl]aniline (Example 232, step B) (51 mg, 0.18 mmol), and p-toluenesulfonicacid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (96 mg, 0.12 mmol, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 9.37 (s, 1H), 8.48 (s, 1H), 8.21 (d, J=5.13 Hz, 1H), 8.10 (d, J=1.83 Hz, 1H), 7.77 (dd, J=8.61, 2.02 Hz, 1H), 7.69 (d, J=8.80 Hz, 1H), 7.36-7.48 (m, 3H), 7.28 (d, J=8.43 Hz, 1H), 7.18 (t, J=8.07 Hz, 2H), 6.96 (t, J=6.78 Hz, 1H), 6.73 (d, J=2.20 Hz, 1H), 6.49-6.57 (m, 2H), 3.98 (s, 3H), 3.81 (s, 3H), 3.25 (br. s., 8H), 2.92 (s, 3H); MS (ESI): 741 [M+H]+.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:29][C:30](Cl)=[O:31].[OH-].[K+]>ClCCl>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C@@H:11]2[CH2:12][O:13][CH2:29][C:30](=[O:31])[N:9]([C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[CH2:10]2)=[CH:19][CH:18]=1
Reactant: C[C@@H](NCC(CO)c1ccc(Br)cc1)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)COCC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diastereopure 3-((R)-1-phenylethylamino)-2-(4-bromophenyl)propan-1-ol (2.40 g, 7.18 mmol) in dichloromethane (22.0 ml) was added triethylamine (0.799 g, 7.90 mmol) and chloroacetyl chloride (0.892 g, 7.90 mmol) at 0° C. The mixture was stirred at 0° C. for one hour. The reaction mixture was partitioned between 0.5N—HCl and dichloromethane, and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. To the residue dissolved into 2-propanol (48 ml) was added potassium hydroxide (805 mg, 14.4 mmol) at 0° C. The mixture was stirred at 0° C. for 3 hours and partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=7/3) to afford (S)-6-(4-bromophenyl)-4-((R)-1-phenylethyl)-1,4-oxazepan-3-one as white solid (2.42 g, 90 W. An analytical sample for X-ray was obtained by crystallization from dichloromethane-hexane and the absolute configuration of 6-position was found to be the (S)-configuration.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5](/[CH:6]=[N:7]/[C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][O:11][C:12]3=[O:17])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH:26]=O.[CH2:28]([OH:30])[CH3:29]>C(OCC)(=O)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[CH:26]([C:22]3[N:21]([CH3:20])[CH:25]=[CH:24][N:23]=3)[C:28](=[O:30])[C:29]3[C:13]([C:12]([O:11][CH2:10][CH3:9])=[O:17])=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7]2)=[CH:18][CH:19]=1
Reactant: O=C1OCc2c(/N=C/c3ccc(F)cc3)cccc21
Reactant: Cn1ccnc1C=O
Reactant: CCO
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(F)cc1)N2
Temperature: 0 °C
Reaction time: 2 h
Yield: 5.3 %

Procedure:
To a stirred mixture of 4-fluorobenzaldehyde (3 g, 20.4 mmol) and anhydrous sodium sulfate (29 g, 20.4 mmol) in anhydrous dichloromethane (200 mL) was added 4-aminoisobenzofuran-1(3H)-one (3.04 g, 24.5 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with dichloromethane (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (4.25 g, yield 81%); LC-MS (ESI) m/z: 256 (M+1)+. A mixture of (E)-4-(4-fluorobenzylideneamino)isobenzofuran-1(3H)-one (2.53 g, 10 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (1.21 g, 11 mmol) in ethyl propionate (50 mL) was cooled to 0° C. Then a solution of sodium ethanoxide in ethanol [sodium (1 g, 44 mmol) in ethanol (30 mL)] was added drop-wise. After the addition, the mixture was stirred at room temperature for 2 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=10:1 to 1:10) to give ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (210 mg, yield 5%). LC-MS (ESI) m/z: 394 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[C:13]1([C@@H:19]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:20]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOC(C)=O>[Br-:1].[C:8]([C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N+:25]23[CH2:26][CH2:27][CH:28]([CH2:29][CH2:30]2)[C@@H:23]([O:22][C:20](=[O:21])[C@@H:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24]3)[CH:12]=[CH:11][CH:10]=1)#[N:9]
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
3-(2-Bromoacetyl)benzonitrile (40.0 mg, 0.18 mmol) was added to a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (60 mg, 0.18 mmol) in EtOAc (2 ml). The reaction mixture was stirred at room temperature overnight (UPLC-MS: complete conversion). EtOAc was removed under vacuum, and the residue is triturated with Et2O. The solid was collected by suction filtration and dried at 40° C. for 48 hours to obtain the (R)-1-(2-(3-cyanophenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (61.1 mg, 61% yield).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:12]([NH2:14])=[O:13])[CH2:3][CH2:2]1.O>CN(C=O)C>[CH2:3]([N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:12]([NH2:14])=[O:13])[CH2:3][CH2:2]1)[CH:4]([CH3:12])[CH3:5]
Reactant: NC(=O)C1=Cc2ccccc2NCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CN1CCC(C(N)=O)=Cc2ccccc21
Temperature: 50 °C
Reaction time: 96 h
Yield: 38.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(1-trityl-1H-imidazol-4-yl)methyl]thio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.50 g) in DMF (10 ml), 2-iodinated ethanol (0.25 ml) was added at room temperature, and the mixture was stirred at 50° C. for 4 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:49→1:19), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[1-(2-hydroxyethyl)-1H-imidazol-5-yl]methyl]thio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 438) (124.6 mg) as yellow amorphous.