Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:22])[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[OH-].[Li+].O>C(O)C>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:22])[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Temperature: 50 °C
Yield: 104.2 %

Procedure:
A mixture of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid methyl ester (380 mg, 1.21 mmol, Eq: 1.00) and lithium hydroxide (3.8 ml, 3.8 mmol, Eq: 3.14) in ethanol (7.6 ml) was heated to 50° C. for 72 h in a sealed tube. Then water was added and the mixture was extracted with diethylether (3×). The pH of the aqueous layer was then adjusted to 1 by addition of 1N HCl and the mixture was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were washed with brine, dried with Na2SO4 and evaporated to yield the title compound (378 mg) as off-white solid. MS (ESI): 300.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]([C:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[NH:23][N:22]=1)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+].[Li+].[Cl-]>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1[CH:25]=[C:24]([CH2:26][CH2:27][CH3:28])[N:23]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])=[CH:8][CH:9]=2)[N:22]=1)=[O:20])[CH3:17]
Reactant: CCCc1cc(C(=O)OCC)n[nH]1
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)OCC)nn1Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the recovered intermediate (19a) (1.4 g, 5 mmol, 1.0 eq) dissolved into 15 mL DMF, was added 5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (910 mg, 5.0 mmol, 1.0 eq) and potassium carbonate (0.8 g, 5.5 mmol, 1.1 eq) and the mixture was stirred at room temperature for 16 hours. The mixture was then added to 50 mL of 10% aq. LiCl solution and extracted with 50 mL EtOAc. The organic was dried over MgSO4, and concentrated under reduced pressure to yield intermediate (19b) and its regioisomer in a 1:1 ratio. The recovered regioisomers were dissolved into 25 mL MeOH. To this was added 10 mL of 1M NaOH and the mixture was stirred at room temperature over night.
Reaction SMILES: N1CCCCC1.[CH3:7][C:8]([CH3:10])=[O:9].C(O)C.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(O)(=O)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH:7][C:8](=[O:9])[CH3:10])=[CH:17][CH:16]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C=Cc1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
Piperidine (1.5 ml) was added to a mixed solvent of acetone (1.1 ml) and ethanol (5 ml). After the resulting mixture was stirred for 5 minutes, 4-chlorobenzaldehyde (700 mg, 5.0 mmol) was added. The thus-obtained mixture was stirred at room temperature for 30 minutes. Acetic acid (two droplets, 0.2 ml) was then added, followed by heating under reflux for 6 hours. The solvent was distilled off and the residue (879 mg) was separated and purified by chromatography on a silica gel column [silica gel 40 g, hexane/diethylether (10/1)], whereby the title compound was obtained as a pale yellow oil (375 mg, 41.7%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[N:23]=[C:22]([C:24]2[C:32]3[C:27](=[CH:28][N:29]=[C:30]([C:33]4[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=4)[CH:31]=3)[N:26]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)[N:25]=2)[CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH3:38][N:36]1[CH:37]=[C:33]([C:30]2[CH:31]=[C:32]3[C:24]([C:22]4[N:23]=[C:18]([O:1][C@@H:2]5[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]5)[CH:19]=[CH:20][CH:21]=4)=[N:25][N:26]([CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[C:27]3=[CH:28][N:29]=2)[CH:34]=[N:35]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: Cn1cc(-c2cc3c(-c4cccc(Cl)n4)nn(C4CCCCO4)c3cn2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3c(-c4cccc(O[C@@H]5CCCN(C(=O)OC(C)(C)C)C5)n4)nn(C4CCCCO4)c3cn2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 28.2 %

Procedure:
To (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (61.2 mg, 0.30 mmol) in anhydrous DMF (3 mL) was added sodium hydride (40.5 mg, 1.01 mmol, 60% in mineral oil), and the reaction mixture was stirred at 60° C. under N2 for 1 h. A solution of 3-(6-chloropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (40.0 mg, 0.10 mmol) in anhydrous DMF (˜1.0 mL) was then added, and the reaction mixture was stirred at 90° C. under N2 for 16 h. The reaction mixture was quenched with aqueous saturated NH4Cl solution and was extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified using flash chromatography (Si-PPC gradient elution, solvent: 0-60% MeOH/EA) to give (3R)-tert-butyl 3-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yloxy)piperidine-1-carboxylate as a foam (15.8 mg, 27.9%). LC/MS: m/z 560.4 [M+1].
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1.[B:14](OC)([O:17]C)[O:15]C.Cl>C1COCC1>[CH3:13][C:9]1[CH:8]=[C:7]([B:14]([OH:17])[OH:15])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
n-Butyllithium (15 mL, 2.5M in hexane, 37.4 mmol) was added dropwise to a solution of 3-bromotoluene (5.8 g, 34.0 mmol) in 50 mL of THF cooled to -78° C. The resulting suspension was stirred at -78° C. for 30 min, treated with trimethyl borate (10.6 g, 102.2 mmol), stirred -78° C. for 10 min, and allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 16 hours, then cooled in an ice bath and acidified to pH 6 with 2N HCl. The mixture was extracted with methylene chloride, and the organic extract was washed with bdne, dried over Na2SO4, and concentrated to yield 4.24 g of 3-methylphenyl boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:26](Br)([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[O:23][C:18]=4[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](Cc1ccc(O)c(O)c1)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)cc2O1

Procedure:
More specifically, the chiral synthesis may be carried out by performing the synthetic reaction sequence outlined in Scheme III. L-DOPA 19 is treated with di-t-butyl-dicarbonate in dimethylformamide, giving (S)-N-(1-(1,1-dimethylethoxy)carbonyl)-3-hydroxy-L-tyrosine 20 which is reacted with methyl iodide and anhydrous potassium carbonate in acetone, giving (S)-N-(1,1-dimethylethoxy)carbonyl)-3,4-dimethoxy-L-phenylalanine methyl ester 21 which is reduced with lithium borohydride giving (S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1-(hydroxymethyl)ethyl) carbonate 22, which is reacted with methanesulfonyl chloride and triethylamine in methylene chloride, giving (S)-1,1-dimethylethyl-(2-(3,4-dimethoxyphenyl)-1(((methylsulfonyl) oxy)methyl)ethyl)carbamate 23. Compound 23 is treated with trifluoroacetic acid and then is reduced using 10% Pd/C and hydrogen giving (R)-3,4-dimethoxy- -methylbenzeneethanamine 24. The compound 24 is treated with 3-chlorostyrene oxide 25 and N-(trimethylsilyl) acetamide giving a mixture of (R,S)- and (S,S)-3-chloro-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl) benzenemethanol 26. Reaction of 26 with carbonyl diimidazole and triethylamine in tetrahydrofuran, followed by chromatographic separation of the diastereomers gives cyclized derivative 27, which is reacted with boron tribromide in dichloromethane, giving (R,R)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxyphenyl)-1-methylethyl)-2-oxazolidinone 28. Compound 28 is then reacted with diethyl dibromomalonate and anhydrous potassium carbonate in acetone, giving (R,R)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester 29. Compound 29 is reacted with 5N sodium hydroxide in ethanol and then isolated by reverse phase chromatography to give (R,R)-1,3-benzodioxole-2,2-dicarboxylic acid, 5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-, disodium salt 15.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][CH2:17][CH2:18][N:19]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH3:20])[C:5]=2[CH:4]=[CH:3][CH:2]=1>CO.[OH-].[Na+]>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][CH2:17][CH2:18][N:19]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH3:20])[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCC=C1c2ccccc2C=Cc2ccccc21)CCC(=O)O
Yield: 73.7 %

Procedure:
To a solution of 1.81 g of ethyl 3-[N-[3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-N-methylamino]propionate in 19 ml of methanol, 5 ml of 2N sodium hydroxide aqueous solution was added and the mixture was refluxed for 30 minutes. The solvent was removed by distillation, and then the residue was dissolved in warm water and the solution was neutralized with 2N hydrochloric acid. The crystals precipitated were collected by filtration to give 1.23 g of colorless crystals. Recrystallization from aqueous ethanol gave colorless needles, mp 119°-120° C.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[N:10][CH:11]=1)[CH3:5])=[N+]=[N-]>C(O)C.O=[Pt]=O>[F:12][C:9]1[N:10]=[CH:11][C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][CH:8]=1
Reactant: CC(N=[N+]=[N-])c1ccc(F)nc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(N)c1ccc(F)nc1
Yield: 91.4 %

Procedure:
Hydrogenate 5-(1-azido-ethyl)-2-fluoro-pyridine (4.09 g, 24.59 mmol) under a 60 psi pressure in ethanol (200 mL) in the presence of PtO2 (6% w/w). Filter the mixture after 4 h, remove the solvent on a rotovap, and dry the resulting oil under vacuum to obtain the title compound (3.15 g). GCMS m/z 140 [M]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[OH:20][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][NH2:23]>>[OH:20][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][NH:23][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NCC(O)c1ccccc1
Product: CCc1cc(-c2cncc(C(=O)NCC(O)c3ccccc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (2-hydroxy-2-phenyl-ethyl)-amine to afford the title compound. MS: m/e=378 (M+H).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][C@H:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[C:13]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:23][CH2:22]3)[N:12]=2)[CH:7]=[CH:6]1)(=O)C.[OH-].[Na+]>CC(C)=O>[CH2:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][N:21]([C:13]2[N:12]=[C:11]([O:10][C@H:8]3[CH2:9][C@@H:5]([OH:4])[CH:6]=[CH:7]3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH2:26][CH2:25]1)=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(=O)O[C@H]1C=C[C@@H](Oc2nc(N3CCN(C(=O)OCc4ccccc4)CC3)nc3ccccc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)N1CCN(c2nc(O[C@@H]3C=C[C@H](O)C3)c3ccccc3n2)CC1
Yield: 59.9 %

Procedure:
A solution of 4-[(1S,4R)-(4-acetoxycyclopent-2-en-1-yl)oxy]-2-[4-(benzyloxycarbonyl)piperazin-1-yl]quinazoline (2.30 g) and 2N aqueous sodium hydroxide (4.9 ml) in acetone (20 ml) is stirred at room temperature for 18 hours. Acetone is distilled off from the reaction mixture under reduced pressure, and thereto is added ethyl acetate, and the mixture is washed with water, and then dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the resulting residue is purified by medium pressure liquid column chromatography [eluent, chloroform, (chloroform:methanol=200 1, v/v)] to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1S,4R)-(4-hydroxycyclopent-2-en-1-yl)oxy]quinazoline (1.26 g) as crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH:11]=[CH:12][C:13]2=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Rh].C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH2:12][C:13]2=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC2CN(Cc3ccccc3)CC12
Reactant: [H][H]
Agent: [Rh]
Solvent: CCOC(C)=O
Product: O=C1CCC2CN(Cc3ccccc3)CC12
Yield: 84.1 %

Procedure:
To an ethyl acetate (50 ml) solution of 7-benzyl-2-oxo-7-azabicyclo[3.3.0]oct-3-ene (1.45 g, 6.78 mmol) was added 5% rhodium-on-alumina (700 mg), and the mixture was stirred vigorously in a hydrogen atmosphere for 3.5 hours. The insoluble matter was removed by Celite filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give 1.22 g (5.70 mmol, 84%) of the title compound as a colorless oily substance. The TLC and 1H-NMR data of the product were in agreement with those of the product of Reference Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[Na+].[Cl-]>COC(C)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
A mixture of pyridine-3-sulfonic acid (10.3 g, 64.8 mmol), phosphorus pentachloride (20.82 g, 100 mmol) and phosphorus oxychloride (10 mL, 109 mmol) was heated to reflux for 3 h (according to J. Org. Chem. 1989, 54(2), 389.). Evaporated to dryness to give a yellow solid, dissolved in ice water and methyl-tert-butyl ether, added cautiously sat. NaHCO3-sol. until neutralized, saturated with solid NaCl, separated phases, dried organic layer over Na2SO4. Removal of the solvent in vacuum to give the title compound as an orange liquid (10.85 g, 94%). MS (ISP) 178.1 [(M+H)+] and 180.0 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[S:42]([NH2:45])(=[O:44])=[O:43].[C:46](Cl)(=[O:49])[CH2:47][CH3:48]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:11][CH2:12][C:13]([CH2:22][CH2:23][N:24]3[CH:29]4[CH2:30][CH2:31][CH:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)=[O:9])=[CH:4][C:3]=1[S:42]([NH:45][C:46](=[O:49])[CH2:47][CH3:48])(=[O:43])=[O:44]
Reactant: CCC(=O)Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Product: CCC(=O)NS(=O)(=O)c1cc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)ccc1Cl
Yield: 73 %

Procedure:
2-Chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo-[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-N-propionylbenzene-sulfonamide (16 mg, 73%) was obtained as amorphous solid from 2-chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl piperidin-1-yl)carbonyl]benzenesulfonamide and propionyl chloride following the procedure outlined in example 476. 1H NMR (300 MHz, DMSO-d6) δ 7.81-7.56 (m, 3H), 7.49 (d, J=8.4 Hz, 1H), 7.39-7.26 (m, 5H), 7.24-7.08 (m, 3H), 4.80 (br, 1H), 3.99-3.93 (m, 1H), 3.58-3.38 (m, 5H), 3.11-2.99 (m, 1H), 2.47 (m, 4H), 2.22-1.72 (m, 17H), 0.89-0.81 (m, 3H). HRMS m/z (M+H)+ calcd: 702.2881, obsd: 702.2885.
Reaction SMILES: [Br:1][C:2]1[CH:3]=C([CH:7]=[C:8]([Br:10])[CH:9]=1)C=O.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:24][O:25][C:26]([O:29][CH3:30])(C)[CH3:27]>>[Br:1][C:2]1[CH:3]=[C:27]([CH:26]([O:29][CH3:30])[O:25][CH3:24])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: COC(C)(C)OC
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(OC)c1cc(Br)cc(Br)c1

Procedure:
A mixture of 13.2 g (50 mmoles) of crude 3,5-dibromobenzaldehyde, 2 mL (50 mmoles) of methanol, and 100 mg of p-toluenesulfonic acid in 100 mL of 2,2-dimethoxypropane was heated to reflux 6 hrs. After cooling, solvent was removed in vacuo to give a brown oil. This was applied on silica gel and washed with 1:20 ethylacetate:hexane mixture. The filtrate was concentrated to orange brown oil of the desired acetal.
Reaction SMILES: C1(C)C=CC=CC=1.CN(C=O)C.[N:13]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C@@H:15]([OH:21])[CH2:14]2.CC([O:26][C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:30]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O)(C)C>CC(C)([O-])C.[Na+]>[CH:42]1[CH:43]=[CH:44][C:39]([C@@H:30]2[N:29]([C:27]([O:21][C@@H:15]3[CH:16]4[CH2:19][CH2:20][N:13]([CH2:18][CH2:17]4)[CH2:14]3)=[O:26])[CH2:38][CH2:37][C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]2=3)=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O[C@H]1CN2CCC1CC2)N1CCc2ccccc2[C@@H]1c1ccccc1
Yield: 3.9 %

Procedure:
In a mixture of 0.38 g of sodium tert-butoxide, 60 ml of toluene and 3 ml of DMF, 2.96 g of (R)-quinuclidin-3-ol was allowed to react with 6.00 g of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-methylpropan-2-yl ester for 8 hours while evaporating the solvent, thereby obtaining 0.274 g of a solifenacin-containing composition.
Reaction SMILES: Br[C:2]1[C:3]([Br:18])=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16]C)=[O:14])[C:5]([O:7][CH2:8]C)=[O:6].[CH:19]1[C:31]2[NH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1.N#N.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1Cl.[Cu].O>[Br:18][C:3]1[CH:2]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:11]([N:30]2[C:31]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:10][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cu]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: N#N
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc(-n2c3ccccc3c3ccccc32)c(C(=O)OC)cc1Br
Temperature: 170 °C

Procedure:
A degassed solution of 157.6 g (400 mmol) of diethyl dibromoterephthalate and 36.7 g (220 mmol) of carbazole in 1 l of 1,2-dichlorobenzene is saturated with N2 for 1 h. Then, firstly 20 g (314 mmol) of copper powder, then 18 g (67 mmol) of 18-crown-6 are added to the solution, and 177 g (850 mmol) of potassium carbonate as the solid are subsequently added. The reaction mixture is heated at 170° C. for 18 h. After cooling to room temperature, 1 l of water is carefully added. The organic phase is washed with 4×50 ml of H2O and dried over MgSO4, and the solvents are removed in vacuo. The pure product is obtained by recrystallisation. The yield is 83 g (177 mmol), corresponding to 81% of theory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:29]([C:31]1[CH:32]=[C:33]([CH3:40])[C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1)#[N:30].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:37]([C:34]3[C:33]([CH3:40])=[CH:32][C:31]([C:29]#[N:30])=[CH:36][N:35]=3)=[O:38])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C#N)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)c1

Procedure:
To a solution of [(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (step p Example 1) (2.2 g, 5.43 mmol) in DMF (20 ml) was added at 0-5° C. 5-cyano-3-methyl-pyridine-2-carboxylic acid (0.968 g, 5.97 mmol), EDC (1.095 g, 7.05 mmol), HOAt (1.182 g, 8.68 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was added to cold saturated NaHCO3 solution and the product was extracted with TBME. Combined TBME layers were washed with H2O and brine, dried over MgSO4, filtered and concentrated to obtain after crystallization from diisopropylether the title compound as colorless crystals: UPLC RtH5=1.472 min); ESIMS: 550; [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 11.11 (s, 1H), 10.11 (s, 1H), 8.79 (br s, 1H), 8.01 (s, 1H), 7.84 (m, 1H), 7.68 (dd, 1H), 7.21 (dd, 1H), 4.49 (d, 1H), 4.16 (d, 1H), 1.76 (s, 3H), 1.64 (s, 3H), 1.62 (s, 9H).
Reaction SMILES: O1CCCC1.CN(OC)[C:8](=[O:17])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH2:16].[C:20]([O:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C([Li])CCC>C(OC(=O)C)C.O.CCCCCC>[NH2:16][C:10]1[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=1[C:8]([C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH:33]=1)=[O:17]
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)c2cc(Cl)ccc2N)c1
Yield: 14.5 %

Procedure:
A tetrahydrofuran (30 ml) solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (4.3 g) and N-tert-butoxycarbonyl-3-bromoaniline (3.79 g) was cooled to −78° C. To the solution was gradually added dropwise a hexane solution of n-butyl lithium (1.6 mol/L) (42 ml). To the mixture were added water (100 ml) and acetic acid ethyl ester (300 ml). The organic layer was washed with water and dried over anhydrous MgSO4. The _solvent was then distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-amino-3′-tert-butoxycarbonylamino-5-chlorobenzophenone (0.7 g) as a yellow oily product.