Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:26]2[C:17](=[C:18]3[C:23](=[CH:24][C:25]=2[N+:29]([O-])=O)[CH:22]=[CH:21][C:20]([CH2:32][N:33]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N:19]3)[N:16]=1)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].C([O-])=O.[NH4+]>O1CCCC1.C(O)C.O.[Pd]>[NH2:29][C:25]1[CH:24]=[C:23]2[C:18]([N:19]=[C:20]([CH2:32][N:33]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:21]=[CH:22]2)=[C:17]2[C:26]=1[CH:27]=[CH:28][C:15]([CH2:14][N:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:16]2
Reactant: CCOC(=O)CN(CC(=O)OCC)Cc1ccc2cc([N+](=O)[O-])c3ccc(CN(CC(=O)OCC)CC(=O)OCC)nc3c2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CN(CC(=O)OCC)Cc1ccc2cc(N)c3ccc(CN(CC(=O)OCC)CC(=O)OCC)nc3c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,9-Bis[N,N-di(ethoxycarbonylmethyl)aminomethyl]-5-nitro-1,10-phenanthroline (3.37 g, 5.4 mmol) was dissolved in a solution of 100 mL tetrahydrofuran and 200 mL absolute ethanol. A solution of 6.8 g (108 mmol) of ammonium formate in 22 mL of distilled H2O was added, followed by 5.72 g of palladium on carbon (10%) (50% wet with water for safety). The reaction was stoppered with a gas bubbler, stirred at room temperature for 30 minutes, and then filtered through a diatomaceous earth filter pad. The solvents were then removed on a rotary evaporator. The residue was dissolved in 300 mL of dichloromethane which was then extracted with 300 mL of distilled water. The organic phase was extracted with 300 mL of saturated sodium chloride, dried with a mixture of Celite diatomaceous earth and sodium sulfate, filtered, and then concentrated under high vacuum to a dark amber oil which weighed 2.90 g. The oil was treated with 9.0 mL of propionitrile to induce the crystallization of a yellow solid. The solid was filtered, washed with 13 mL of propionitrile, 15 mL of hexanes, and then air dried to a constant weight of 1.04 g (32%); mp 137°-139° C. FDMS (m/e) 598 MH+, 597 M. Anal. calcd. for C30H39N5O9.H2O: C, 58.52; H, 6.71; N, 11.38. Found: C, 58.28; H, 6.55; N, 11.53. The NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:17][CH2:18][CH3:19])[CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][N:3]=1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.CC(C)([O-])C.[K+].O>COCCOC.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-]C1C(Cl)=CC=CN=1)(C)C>[CH2:18]([O:17][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:27][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=2)=[N:3][CH:4]=1)[CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH3:19]
Reactant: CCOC(CC(OCC)c1ccc(Br)nc1)OCC
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-]c1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(CC(OCC)c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
2-Bromo-5-(1,3,3-triethoxypropyl)pyridine (328 mg, 0.987 mmol) produced in Example 17 (17B) and 4-trifluoromethylbenzylamine (346 mg, 1.98 mmol) were dissolved in 1,2-dimethoxyethane (10 mL), and potassium tert-butoxide (346 mg, 1.98 mmol) and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (34 mg, 5 mol %) were added thereto, and then, the resulting mixture was stirred under a nitrogen atmosphere at 100° C. for 3 hours. After the reaction solution was cooled to room temperature, water was added thereto, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 50:50 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (25 mg, yield: 6%).
Reaction SMILES: OO.[F:3][CH2:4][CH2:5][O:6][CH:7]1[C:16]2[C:11](=[C:12]([CH3:21])[CH:13]=[C:14]([C:18]([OH:20])=[O:19])[C:15]=2[CH3:17])S[CH2:9][CH2:8]1.[S:22]([O-:25])(O)=[O:23].[Na+]>C(O)(=O)C>[F:3][CH2:4][CH2:5][O:6][CH:7]1[C:16]2[C:11](=[C:12]([CH3:21])[CH:13]=[C:14]([C:18]([OH:20])=[O:19])[C:15]=2[CH3:17])[S:22](=[O:25])(=[O:23])[CH2:9][CH2:8]1
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCCC2OCCF
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2OCCF
Yield: 85 %

Procedure:
4 ml of acetic acid and 6.24 g (56.7 mmol) of a 30% hydrogen peroxide aqueous solution as an oxidizing agent were added to 5.37 g (18.9 mmol) of the 4-(2-fluoroethoxy)-5,8-dimethylthiochroman-6-carboxylic acid, and the mixture was allowed to react at 80° C. for2hours. After the reaction mixture was allowed to cool, a 2% sodium hydrogensulfite aqueous solution was added to the reaction mixture, excessive hydrogen peroxide was removed, and a precipitated crystal was recovered by filtration and dried to give 5.08 g (yield 85%) of 4-(2-fluoroethoxy)-5,8-dimethylthiochroman-6-carboxylic acid-1,1-dioxide (corresponding to compound of the formula (II-2)).
Reaction SMILES: CN(C=O)C.S(Cl)([Cl:8])=O.[CH2:10]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:28]=1)[CH2:24]O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N1C=CC=CC=1>ClCCl>[CH2:10]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:28]=1)[CH2:24][Cl:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCC)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCC)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94.5 %

Procedure:
Dry dichloromethane (5 mL), DMF (3.04 mL, 39.2 mmol), and a magnetic stir bar were placed into a 250 mL RBF and sealed with a rubber septum. N2 inlet and outlet needles were inserted into the septum. The flask was then cooled to 0° C. in an ice bath. Thionyl chloride (2.86 mL, 39.2 mmol) was added to the RBF via a syringe. The RBF was placed into an ice bath and cooled to 0° C. 3,5-didecoxybenzyl alcohol (15.0 g, 35.7 mmol) was dissolved in a solution of dichloromethane (60 mL) containing pyridine (2.88 mL, 35.7 mmol). This solution was then drawn into a syringe and added cautiously to RBF over 20 minutes. The solution gradually changed from a transparent yellow color to an opaque yellow color. Dichloromethane was used to rinse the beaker which was used to dissolve 3,5-didecoxybenzyl alcohol and then added to the RBF. The RBF was removed from the ice bath and allowed to stir overnight. The solution was then concentrated using a rotary evaporation. A solution of 50/50 ether/hexanes (100 mL) was added to the RBF, changing the solution from deep yellow to opaque white. The liquid was decanted off leaving behind any solid. The RBF was rinsed in this manner 2 more times, saving the decanted liquid. The decanted liquid was run through a silica gel baseline filtration apparatus. Filtrate was then concentrated using rotary evaporation. A compound solidified after approximately 2 hours under a high vacuum. There was a 14.8 g yield or a 94.5% yield of the derivative. The NMR characterization data for this derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.6, 6H, CH2CH3), 1.27-1.43 (m, 28H, CH2(CH2)7), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.92 (t, J=6.6, 4H, OCH2), 4.50 (s, 2H, ArCH2Cl), 6.39 (t, J=2.2, 1H, ArH), 6.50 (d, J=2.5, 2H, ArH). 13C NMR (75 MHZ, CDCl3): 14.23, 22.78, 26.12, 29.30, 29.42, 29.47, 29.70, 32.00, 46.56, 68.18, 101.332, 106.97, 139.38, 160.52.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH3:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH3:27][O:28][C:29]1[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=1[C:31]([O:33][CH2:34]Cl)=[O:32].[C:40](OCC)(=O)C>CN(C=O)C.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:34]([O:33][C:31](=[O:32])[C:30]3[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=3[O:28][CH3:27])[CH3:40])=[O:22])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH3:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: COc1ccccc1C(=O)OCCl
Reactant: CSc1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: CCOC(C)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)OC(C)OC(=O)C1=C(c2cn3cnc(SC)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 2 h

Procedure:
Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol2-yl)-1-carbapen-2-em-3-carboxylate (170 mg) was dissolved in 2 ml of DMF. Triethylbenzylammonium chloride (193 mg) and 182 mg of 2-methoxybenzoyloxymethyl chloride were added to the solution in an argon atmosphere. The mixture was stirred under ice cooling for 2 hr and then stirred at room temperature for 5 hr. Ethyl acetate (30 ml) was added to the reaction solution. The mixture was washed twice with 20 ml of semisaturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated to a volume of 5 ml under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane: methanol=40: 1) to give 131 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=2)=CC=1)([O-])=O>C(Cl)Cl.CO.N.C(Cl)Cl>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][C:31]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:30])=[CH:38][CH:37]=2)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(N5CCOCC5)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.8 %

Procedure:
A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (111.4 mg, 408 μmol), prepared as described in Example 1d, but with purification by silica flash chromatography (9:1 DCM/MeOH saturated with NH3), (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester (147 mg, 429 μmol), prepared as described in the previous step, and DCM (700 μL) was treated with TEA (63 μL, 449 μmol) in one portion at rt. The homogeneous amber solution was stirred at rt for 3.5 h, diluted with DCM (1.3 mL), and washed with 2 M K2CO3 (2 mL). The aqueous layer was extracted with DCM (2×2 mL), the organic layers were combined, dried (Na2SO4), and concentrated, and the residue was purified with silica flash chromatography (1:1 DCM/acetone) to afford the title compound (167.1 mg, 86%). 1H-NMR (300 MHz, CDCl3): δ 9.08 (s, 1H), 7.34 (s, 1H), 7.31-7.24 (m, 3H), 6.88 (m, 2H), 6.31 (br s, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.86 (m, 4H), 3.59 (m, 1H), 3.23-3.07 (m, 6H), 2.24-2.07 (m, 2H), 2.05-1.93 (m, 2H). LC/MS (ESI): calcd mass 477.2, found 478.3 (MH+). Select fractions of this material were combined (112.5 mg) and submitted for combustion analysis: Anal. Calcd for C26H31N5O4: C, 65.39; H, 6.54; N, 14.67. Found: C, 65.26; H, 6.58; N, 14.51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH2:11])=[O:10])=[N:7][CH:8]=1.[Na].C(S)C.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](CCl)=[CH:19][CH:18]=1.ClC1C=CC(CCl)=CC=1.CN(C=O)C>CN(C=O)C.C(OCC)(=O)C>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:1][O:2][C:3]2[CH:4]=[CH:5][C:6]([C:9]([NH2:11])=[O:10])=[N:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(N)=O)nc1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCS
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCc2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 5-methoxy-2-pyridylcarboxamide (2 g, 13.2 mmol) in 5 ml of DMF at RT is added the sodium salt of ethanethiol (26.3 mmol) in DMF (61.5 ml). The slurry is heated to 110° with stirring for about 15 minutes. The reaction is cooled to 50° and 40 ml of DMF is added. After 0.5 hour, the reaction is cooled to 10° & 4-chlorobenzyl chloride (2.47 g, 15.4 mmol) is added. The reaction is allowed to warm to RT and is stirred for 3 days. About 0.5 ml of 4-chlorobenzyl chloride/DMF (0.21 g/l ml) is added. After 2 hours at RT, the reaction is poured into ice water and ethyl acetate. The ethyl acetate is separated off, and the water layer is extracted with ethyl acetate (4X). The combined organic layers are washed with water and with brine, dried, filtered and rotoevaporated. The residue is washed with 20% ether/hexane (4X). The liquid is pipetted off and the residue is rotoevaporated to give 5-(4-chlorobenzyloxy)-2-pyridylcarboxamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]([O-])=[CH:8][C:9]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=O)([CH3:4])([CH3:3])[CH3:2].[Li+].Cl.[F:20][C:21]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][C:22]=1[C:23]#[N:24]>C(O)(=O)C>[C:23]([C:22]1[CH:25]=[C:26]([N:29]2[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[N:30]2)[CH:27]=[CH:28][C:21]=1[F:20])#[N:24]
Reactant: N#Cc1cc(NN)ccc1F
Reactant: CC(C)(C)OC(=O)C([O-])=CC(=O)c1ccco1
Agent: Cl
Agent: [Li+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1cc(-c2ccco2)n(-c2ccc(F)c(C#N)c2)n1
Temperature: 25 °C
Yield: 95 %

Procedure:
Part A. To lithium 1-tert-butoxy-4-(2-furyl)-1,4-dioxo-2-buten-2-olate (13 g, 54 mmol; Example 74, Part A) was added 2-fluoro-5-hydrazinobenzonitrile hydrochloride (10 g, 54 mmol) and 250 mL of glacial acetic acid. The resulting orange mixture was maintained at rt for 20 h and then concentrated to dryness. The resulting residue was taken up in 30% chloroform in hexanes and filtered to afford tert-butyl 1-(3-cyano-4-fluorophenyl)-5-(2-furyl)-1H-pyrazole-3-carboxylate (18 g, 95%) as a light brown solid. LC/MS (ESI+): 354.2 (M+H)+. 1H NMR (CDCl3) δ 7.64-7.78(m, 3H), 7.42 (s, 1H), 7.05 (s, 1H), 6.45 (s, 1H), 6.30 (s, 1H), 1.61 (s, 9H).
Reaction SMILES: [IH:1].CS[C:4](=[N:8][C:9](=[NH:11])[NH2:10])[NH:5][CH2:6][CH3:7].[CH:12]([NH2:15])([CH3:14])[CH3:13]>O>[IH:1].[CH2:6]([NH:5][C:4]([NH:8][C:9]([NH2:10])=[NH:11])=[N:15][CH:12]([CH3:14])[CH3:13])[CH3:7]
Reactant: CCNC(=NC(=N)N)SC
Reactant: CC(C)N
Agent: I
Solvent: O
Product: CCNC(=NC(C)C)NC(=N)N
Reaction time: 2 h

Procedure:
9.2 g. (30 mmol) of 2-methyl-1-ethyl-3-guanyl isothiourea hydroiodide is agitated with 30 ml. of water and 11.8 g. (200 mmol) of isopropylamine for 48 hours at 30° C. and then for 2 hours at the boiling temperature. Excess isopropylamine, methyl mercaptan, and water are removed. To the oily residue, 2 ml. of concentrated aqueous sodium iodide solution and then water are added until a clear solution is obtained. The product is crystallized during standing in a refrigerator and is recrystallized from acetone-petroleum ether.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH3:14][NH:15][CH3:16].[CH2:17]=O.[OH-].[Na+]>C(O)(=O)C>[CH3:14][N:15]([CH2:17][C:3]1[C:4]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1)[CH3:16]
Reactant: C=O
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)c1cccc2[nH]cc(CN(C)C)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100 g of methyl indole-4-carboxylate were dissolved in 500 ml of glacial acetic acid. To the solution were added dropwise at room temperature a mixture of 86 ml of a 40% strength aqueous dimethylamine solution, 55 ml of a 37% strength aqueous formaldehyde solution and 250 ml of glacial acetic acid. The reaction mixture was subsequently stirred at room temperature for 20 hours. To work up the reaction mixture it was cooled in ice and 20% strength aqueous sodium hydroxide solution was added until pH 9 was reached. This was followed by extraction three times with dichloromethane, and the combined organic extracts were dried with sodium sulfate, filtered and concentrated. 127 g of crude methyl 3-dimethylaminomethylindole-4-carboxylate were obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([NH:30][C:31]2[CH:32]=[C:33]([CH:39]=[CH:40][CH:41]=2)[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:19](=[O:29])[O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[CH:14][CH:13]=1>CCOC(C)=O>[Cl-:1].[CH2:37]([O:36][C:34]([C:33]1[CH:32]=[C:31]([NH:30][CH:18]([C:15]2[CH:16]=[N:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:19]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N+:23]([CH2:2][C:3](=[O:4])[C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)([CH2:24][CH2:25]3)[CH2:22]2)=[O:29])[CH:41]=[CH:40][CH:39]=1)=[O:35])[CH3:38]
Reactant: O=C(CCl)c1cccs1
Reactant: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccc(OC)nc2)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2C[N+]3(CC(=O)c4cccs4)CCC2CC3)c2ccc(OC)nc2)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
2-Chloro-1-(thiophen-2-yl)ethanone (18.3 mg, 0.11 mmol) was added to a solution of ethyl 3-(1-(6-methoxypyridin-3-yl)-2-oxo-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (C65) (50 mg, 0.11 mmol) in EtOAc (2 ml). The reaction was stirred at room temperature overnight. The solvent was evaporated, and the residue was triturated with Et2O, filtered and dried. The product was purified by flash-chromatography (DCM/MeOH=97/3 to 9/1) to obtain (3R)-3-(2-(3-(ethoxycarbonyl)phenylamino)-2-(6-methoxypyridin-3-yl)acetoxy)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (41.6 mg, 60.9% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[C:24](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(OCC)(=O)C>[CH3:24][O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H](Cc1cccnc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of N-(t-butoxycarbonyl)-3-(3-pyridyl)alanine (5.0 g, 18.8 mmole) in methanol (100 mL) was added thionyl chloride (2M solution in dichloromethane, 66 mL, 132 mmole). The resulting solution was stirred overnight at ambient temperature. The methanol was removed under reduced pressure to a minimum volume and ethyl acetate (100 mL) was added. The resulting white precipitate was collected in a fritted funnel. To a solution of the collected precipitate in a mixture of tetrahydrofuran/water (40 mL each) was added di-tert-butyl dicarbonate (4.8 g, 21.99 mmole) and sodium carbonate (1.95 g, 18.4 mmole). After stirring for 12 hours at ambient temperature, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with a solution of saturated sodium bicarbonate (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give crude product. This product was subjected to flash column chromatography on silica gel (230-400 mesh) using a 8×54 cm column and eluting with a 10:90 mixture of ethyl acetate/hexane followed by a 60:40 mixture of ethyl acetate/hexane. 4 g (74%) of the title compound was obtained as an oil. Thin-layer chromatography gave a Rf=0.68 (silica gel; ethyl acetate).
Reaction SMILES: [CH:1]1([N:4]2[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:16]=O)[CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1.[CH2:18](O)[CH3:19].[OH-].[Na+].O1CCC[CH2:24]1>>[C:16]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[CH:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:13])[CH2:19][CH2:18][C:12]2([CH3:14])[CH3:15])#[CH:24]
Reactant: CC1(C)CN(C2CC2)Cc2ccc(C=O)cc21
Reactant: C1CCOC1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2N(C)C(C)C

Procedure:
Following general procedure I and using 4-[5-(iso-propyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)]-benzoic acid ethyl ester (Compound 25, 0.04 g, 0.01 mmol), ethanol (2 mL), tetrahydrofuran (1 mL) and 1M aqueous sodium hydroxide solution (1 mL) followed by recrystallization from diethylether-hexane, the title compound was obtained as an off-white solid (0.010 g, 27%).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:39])/[CH:21]([CH2:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:40][CH3:41])[C:15]([CH3:42])=[C:14]2[C:10]=1[C:11](=[O:43])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(#N)C>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:39])/[CH:21]([CH2:28][CH2:29][CH2:30][OH:31])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]([O:40][CH3:41])[C:15]([CH3:42])=[C:14]2[C:10]=1[C:11](=[O:43])[O:12][CH2:13]2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(CCCO[Si](C)(C)C(C)(C)C)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Solvent: CC#N
Product: CCOC(=O)CC(CCCO)/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Reaction time: 0.17 h
Yield: 87.7 %

Procedure:
Ethyl (E) 6-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy -7-methyl-3-oxo-isobenzofuran-5-yl)-3-(3-tert-butyldimethylsilyloxypropyl) -4-methylhex-4-enoate (2.92 g) was dissolved in acetonitrile (50 ml). To this was added a solution of 40% aqueous HF (5 ml) in acetonitrile (45 ml), and the reaction mixture stirred for 10 minutes. Most of the acetonitrile was then evaporated, and the remaining solution diluted with ether. The ether was washed with water, saturated sodium bicarbonate (3×), brine, and dried. Evaporation of the solvent gave an oil which was chromatographed on silica gel (40% ethyl acetate in hexanes) to give ethyl (E) 6-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo-isobenzofuran -5-yl)-3-(3-hydroxypropyl)-4-methylhex-4-enoate (2.10 g) , a compound of Formula 803, as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:24][CH:25]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc(CN2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1
Yield: 79.2 %

Procedure:
4-carboxyphthalic anhydride (0.5 g, 0.0026 mol) and 4-(aminomethyl)benzoic acid (0.39 g, 0.0026 mol) were refluxed as above overnight. Crystallisation of the product from 1,4-dioxane/H2O yielded 0.67 g (79%) of 108 as a white solid: mp=365–366° C.; Rf 0.76 (A): Rf 0.71 (C): Rf 0.50 (D): IR (cm−1): 2800–3100 (OH), 3071 (C═CH), 2678 (C—H), 1782 (C═O), 1712 (bs, C═O), 1611 (C═C), 1577 (C═C), 1428 (C═C), 1391 (C—O), 1300 (C—O), 1105 (C—O), 734 (C═CH); MS m/z (rel intensity) 325 (20), 324 (100).