Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[C:9]([O:11]CC)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O.[Cl-].[Na+].O>[CH:1]1([CH2:7][CH:8]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(CC1CCCCC1)C(=O)NCCc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CC1CCCCC1)C(=O)NCCc1ccccc1
Temperature: 0 °C
Yield: 40.7 %

Procedure:
A solution comprised of ethyl 2-cyclohexylmethyl-N-phenethylmalonamate (366 mg, 1.106 mmol) in ethanol (10 mL) was treated with 1N aqueous sodium hydroxide (1.3 mL) for 2.5 hours and then diluted with water (30 mL) and brine (10 mL). The dilution was extracted with diethyl ether (3×30 mL). The aqueous layer was cooled to 0° C., acidified with 1N hydrochloric acid (2 mL) and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate extracts were washed with brine, dried (MgSO4) and concentrated to provide 2-cyclohexylmethyl-N-phenethyhnalonamic acid (138 mg, 0.45 mmol).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)C.CC(C[AlH]CC(C)C)C.[Cl-].[NH4+].C(Cl)Cl>C1COCC1>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:6]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=[CH:5][CH2:4][OH:3]
Reactant: CCOC(=O)C=C(c1ccco1)c1ccco1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCC=C(c1ccco1)c1ccco1
Reaction time: 2 h

Procedure:
To a solution of 3,3-bis-(2-furanyl)-acrylic acid ethyl ester (1.31 g, 5.66mmol) in THF (15 ml) was added a solution of DIBAL-H (1 M in toluene, 25.5 ml, 25.5 mmol) at −10° C. The reaction mixture was stirred for a further 2 h. A solution of ammonium chloride (2 ml) was added followed by methylene chloride (250 ml) and decalite. The mixture was filtered and the filter was washed with additional methylene chloride (500 ml) and ethanol (100 ml). The combined organic phases were evaporated to give crude 3,3-bis-(2-furanyl)-prop-2-en-1-ol in 953 mg (88%) yield.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[OH:30])[CH2:23][CH2:22][CH2:21]4)[C:14]3=[O:31])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C.O>[Cl:36][CH2:35][CH2:34][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:20]1([NH:19][C:15]2[C:14](=[O:31])[N:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:32])[CH:18]=[CH:17][N:16]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: ClCCBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CCC2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Temperature: 90 °C

Procedure:
To N-cyclopropyl-3-(3-(1-(2-hydroxyphenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 268f, 0.874 g) in acetonitrile (17 mL) was added 1-bromo-2-chloroethane (1.68 mL) and cesium carbonate (6.61 g) and the reaction heated at 90° C. for 18 h. Ethyl acetate and water were added and the organic layer separated, washed with water, brine, dried (MgSO4), filtered and the solvent removed in vacuo. Purification (SiO2 chromatography eluting with 50-70% ethyl acetate/iso-hexane) gave the subtitle product (304 mg). The drying agent was re-washed with dichloromethane (2×50 mL) and the solvent removed to afford further subtitle product (472 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:25]([N:32]1[C:36](=[O:37])[C:35](=[C:38]2[N:42]([CH3:43])[C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[S:39]2)[S:34][CH2+:33]1SC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N:11]=[C:33]2[N:32]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:36](=[O:37])[C:35](=[C:38]3[N:42]([CH3:43])[C:41]4[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=4[S:39]3)[S:34]2)[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)c1ccc(O)c(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2ccccc2)c1

Procedure:
In a manner similar to Example 30, 4′-hydroxy-3′-nitroacetophenone was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 488 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[C:20]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:19][S:18][CH:17]=2)=[C:6]1[CH3:31].[OH-].[Li+]>O1CCCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:20]2[C:16]([CH2:15][C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]=3[CH3:31])=[CH:17][S:18][CH:19]=2)(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: COC(=O)Cn1c(C)c(Cc2cscc2S(=O)(=O)c2ccc(Cl)cc2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2cscc2S(=O)(=O)c2ccc(Cl)cc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A mixture of {3-[4-(4-chlorobenzenesulfonyl)thiophen-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}acetic acid methyl ester (0.35 g) and tetrahydrofuran (5.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (1.0 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 49:1 by volume) to afford the title compound as a white solid (0.30 g).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1>CC(=O)CC>[CH:5]([N:3]1[CH2:4][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:6]1)([CH2:7][CH3:12])[CH3:4]
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: Cl
Solvent: CCC(C)=O
Product: CCC(C)N1CC(c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1, with racemic 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride from Example 2, Step 1 and 2-butanone instead of acetone. The crude was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a mixture of diastereomers. LCMS calculated for C23H32ClN6O (M+H)+: m/z=443.2; Found: 443.1
Reaction SMILES: C(N(CC)CC)C.[N+](=[C:10]1[CH:19]=[CH:18][C:17]2[C:16](S(Cl)(=O)=O)=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=O)=[N-]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:12]12[CH2:11][CH:15]([CH2:14][CH2:13]1)[CH:16]1[CH:17]2[CH2:18][CH2:19][CH2:10]1
Reactant: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Cl)C1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C1CC2C3CCC(C3)C2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
To a solution of 1.86 g 4,8-Bis(hydroxyeth-1'-yl)tricyclo [5.2.1.02,6 ] decane, 0.93 g of 4-di-methylamino-pyridine, 4.7 ml of triethylamine and 30 ml of CH2Cl2 at 0° C. was added a solution of 7.8 g of 6-diazo-5,6-dihydro-5-oxo-1-naphthalene sulfonyl chloride and 80 ml of methylene chloride over 0.5 hr. The mixture was stirred 1/2 hour at 9° C. and 6 hours at 25° C. and then diluted with 100 ml of methylene chloride. The mixture was then filtered and the methylene chloride phase washed with 100 ml of 10% sodium bicarbonate solution, 100 ml of water, 100 ml of 2 N sulfuric acid solution 50 ml of 5% sodium bicarbonate solution and 50 ml of water. The solution was then dried over sodium sulfate and the solvent removed at reduced pressure to give 3.5 g of product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 50 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (40 mg, 0.08 mmol) in DCM (2.5 mL) at 0° C. was added BBr3 (1.0 M in DCM, 0.33 mL, 0.33 mmol) dropwise, a solid immediately precipitated from the solution. The resulting mixture was stirred at 0° C. for 100 min after which the reaction was quenched by addition of sat. aq. NaHCO3 (4 mL) solution and a white precipitate was observed. The aqueous layer was then extracted with 5% MeOH/EtOAc (4×12 mL) and the combined organic layers were passed through a phase separator to remove water and concentrated in vacuo to afford the crude product which was dissolved in MeOH (2 mL) and purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/HO) to afford (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (17.5 mg, 0.04 mmol, 53% yield). LC/MS (m/z, MH+): 405.0790.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([NH2:24])[C:17](=[CH:22][CH:23]=1)[C:18](OC)=[O:19].C[O-].[Na+].C(O)=O>C1(C)C(C)=CC=CC=1.CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]2[C:18](=[O:19])[C:17]3[C:16](=[CH:15][C:14]([Cl:13])=[CH:23][CH:22]=3)[NH:24][C:8]2=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: O=C=NCc1ccc(Br)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1Cc1ccc(Br)cc1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
A solution of 4-bromo-2-fluorobenzyl isocyanate (46.0 g, 0.20 mol) in xylene (100 ml) is metered, at room temperature, into a solution of methyl 4-chloroanthranilate (37.1 g, 0.20 mol) in xylene (250 ml). After the addition has ended, the batch is stirred at 110° C. for 2 hours. 3.60 ml of a 30% solution of methanolic sodium methylate (0.020 mol) are metered in and the mixture is stirred at 90° C. for 2 hours, during which process methanol is distilled off. 1.8 ml of 85% formic acid (0.040 mol) are subsequently added, and the mixture is stirred at 90° C. for a further hour. After cooling, the product is filtered off with suction, washed with 3×50 ml of xylene, 3×50 ml of ethanol and 3×100 ml of water, and dried. 66.1 g of 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4(1H,3H)-quinazolinedione (yield: 86.2% of theory) of melting point 288 ° to 289° C. (lit. >280° C.) are obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[N:9]=[C:8]2[C:3]=1[O:4][CH2:5][C@@H:6]1[CH2:15][CH2:14][CH2:13][N:7]12.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1([C:2]2[N:11]=[C:10]([C:37]3[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=3)[N:9]=[C:8]3[C:3]=2[O:4][CH2:5][C@@H:6]2[CH2:15][CH2:14][CH2:13][N:7]23)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2c(n1)N1CCC[C@H]1CO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Nc1ncc(-c2nc(N3CCOCC3)c3c(n2)N2CCC[C@H]2CO3)cn1
Temperature: 140 °C
Yield: 7.2 %

Procedure:
A mixture of (S)-6,8-dichloro-2,3,3a,4-tetrahydro-1H-5-oxa-7,9,9b-triaza-cyclopenta[a]naphthalene (290 mg, 1.18 mmol), morpholine (275 μL, 3.14 mmol) and triethylamine (242 μL, 1.74 mmol) in IMS (11 mL) was heated at 140° C. for 20 mins in a microwave reactor, then concentrated in vacuo. The resulting residue re-dissolved in acetonitrile (2 mL) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (500 mg, 2.26 mmol), PdCl2(PPh3)2 (88 mg, 0.125 mmol) and sodium carbonate (4 mL, 4.0 mmol, 1M aqueous solution) were added. The reaction mixture was degassed and heated at 120° C. for 30 mins in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water gradient acetonitrile 5-60%) affording 122 as a white solid (30 mg, 8%). LCMS (method B): RT=3.34 min, [M+H]+=356. 1H NMR (400 MHz, CDCl3): δ 9.15 (2H, s), 5.14 (2H, broad s), 4.48 (1H, dd, J=10.4, 3.5 Hz), 3.87-3.68 (10H, m), 3.62 (1H, m), 3.31 (1H, t, J=10.1 Hz), 2.21-1.94 (3H, m), 1.50 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[O:10]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1.[OH-].[K+]>O1CCOCC1.C(O)C.O>[O:10]1[C:14]2([CH2:19][CH2:18][N:17]([C:4]3[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[N:5]=3)[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: C1CC2(CCN1)OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1nc(N)nc(N2CCC3(CC2)OCCO3)n1

Procedure:
A mixture of 2,4-diamino-6-chloro-1,3,5-triazine (2 g, 14 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (3 g, 21 mmol), and KOH (100 mg, 1.8 mmol) in dioxane (10 mL) and ethanol (40 mL) was heated at reflux overnight, diluted with water, and filtered. The precipitate was rinsed with water and dried under vacuum to provide the title compound.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[CH3:30][N:31]([CH2:33][C:34]1[O:38][C:37]([CH2:39][OH:40])=[CH:36][CH:35]=1)[CH3:32]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:28][CH3:29])=[N:3][C:2]([O:40][CH2:39][C:37]2[O:38][C:34]([CH2:33][N:31]([CH3:32])[CH3:30])=[CH:35][CH:36]=2)=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: CN(C)Cc1ccc(CO)o1
Product: COc1nc(OCc2ccc(CN(C)C)o2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared as for Example 115b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.3 g) and (5-dimethylaminomethyl-2-furanyl)methanol (0.2 g). After removal of the SEM (2-[trimethylsilyl]ethoxymethyl) group the title compound was purified by silica gel chromatography eluting with methanol/dichloromethane mixtures Yield 0.23 g
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:31][CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>CCOC(C)=O>[Br-:31].[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N+:15]([CH2:32][C:33](=[O:34])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O[C@H]1CN2CCC1CC2
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 22 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)propanoate (95 mg, 0.23 mmol) in EtOAc (3 ml), was added 2-bromo-1-phenylethanone (54.9 mg, 0.28 mmol), and the reaction was stirred at RT for 15 hours. The solid was collected by filtration and purified by silica gel flash chromatography (DCM/MeOH=94/6) to obtain (3R)-3-(2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)propanoyloxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (31.0 mg, 22% yield).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([C:23]#[CH:24])[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:32][C:27]1[C:26]([C:24]#[C:23][C@H:13]2[O:12][CH2:11][C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14]2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Nc1ncccc1Br
Reactant: C#C[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H](C#Cc2cccnc2N)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (2R,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-ethynylmorpholine-4-carboxylate (1 eq) and 3-bromopyridin-2-amine (1.4 eq) in acetonitrile (0.1M) and triethylamine (25 eq) was flushed with nitrogen for 10 minutes. Then bis(triphenylphosphine)palladium(ii) chloride (0.1 eq) and copper(i) iodide (1.2 eq) were added and the mixture was flushed again with nitrogen for 10 minutes. The reaction mixture was stirred at 60° C. for 2 hours in the dark. It was concentrated to dryness and the residue was purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:29]4[CH2:28][CH2:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=5)([OH:32])[CH2:31][CH2:30]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Product: OC1(c2ccc(Cl)cc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Yield: 29 %

Procedure:
Using a procedure similar to that described in example 21 except starting with 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (described in example 1i) and 4-(4-chlorophenyl)-4hydroxypiperidine, the title compound hydrochloride salt was obtained in 29% yield as a white powder, mp 261°-263° C. elemental
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16]C)[C:13]([O:18]C)=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][CH:3]=1.O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([O:20][CH3:21])[C:13]([OH:18])=[C:14]([OH:16])[CH:15]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(CSc2ccc(O)cc2)cc(OC)c1OC
Solvent: ClCCl
Solvent: O
Product: COc1cc(CSc2ccc(O)cc2)cc(O)c1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
3,4,5-Trimethoxybenzyl 4-hydroxyphenyl thioether (3g, 9.8 mmol) prepared as described in Example 1 was dissolved in 60 ml of dry methylene chloride, and cooled to -78° C. Then 2.8 ml (29.5 mmol) of borontribromide in 10 ml of methylene chloride was added dropwise to the above solution. After stirring for 2 hr, the solution was warmed to room temperature, and stirred for another 2 hr (monitored by TLC). Then, the reaction mixture was cooled to 0° C., and added dropwise 50 ml of water. The methylene chloride layer was separated. The crude product, obtained after drying over magnesium sulfate and concentration, was purified on silica gel column chromatography (ethyl acetate/n-hexane=2:1). 3,4-Dihydroxy-5-methoxybenzyl 4-hydroxyphenyl thioether (2.1 g, 77% yield) was obtained as a light yellow solid.
Reaction SMILES: [CH2:1]=[C:2]1[S:6][C:5](=[N:7]C(=O)C)[N:4]([C:11]2[CH:24]=[CH:23][C:14]3[O:15][C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[O:18][C:13]=3[CH:12]=2)[CH2:3]1.CB(O)O.B(O[O-])=O.[Na+]>C(O)(=O)C>[CH2:1]=[C:2]1[S:6][C:5](=[NH:7])[N:4]([C:11]2[CH:24]=[CH:23][C:14]3[O:15][C:16]([F:22])([F:21])[C:17]([F:19])([F:20])[O:18][C:13]=3[CH:12]=2)[CH2:3]1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)C(=NC(C)=O)S1
Agent: CB(O)O
Agent: O=BO[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)C(=N)S1
Reaction time: 0.08 h

Procedure:
An alternative procedure for the preparation of the titled compound follows. The acetyl-imine (Example 22B, 725 mg, 2.0 mmol) was dissolved into acetic acid (5 mL) and treated with a solution of methylboronic acid (180 mg, 3.0 mmol) in acetic acid (2 mL). After the solution was stirred for 5 minutes, it was further treated with solid sodium perborate (491 mg, 6.0 mmol). The mixture was stirred at room temperature overnight, and then more sodium perborate (163 mg, 2.0 mmol) was added. After 2 hours, the solution was concentrated thrice from EtOAc (3×15 mL), partitioned between 2:1 EtOAc/hexanes (15 mL) and water (5 mL) with enough concentrated NH4OH to bring the aqueous pH to 8. The aqueous phase was separated and extracted with more 2:1 solution, and the combined organic phases were twice washed with a mixture of water (2 mL) and concentrated NH4OH (0.5 mL), washed with brine, dried (Na2SO4), concentrated, and chromatographed on silica (50% CH2Cl2/hexanes, then 0 to 4% EtOAc/CH2Cl2) to give the titled compound.