Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][C:25]1[S:29][CH:28]=[N:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:30]([C:33]1[S:34][CH:35]=[C:36]([CH2:38][O:39][C:40]([NH:42][C@H:43]([C:47](O)=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[N:37]=1)([CH3:32])[CH3:31].CO>ClCCl>[CH:30]([C:33]1[S:34][CH:35]=[C:36]([CH2:38][O:39][C:40]([NH:42][C@H:43]([C:47]([NH:1][C@H:2]([CH2:24][C:25]2[S:29][CH:28]=[N:27][CH:26]=2)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]2[S:22][CH:21]=[N:20][CH:19]=2)=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[N:37]=1)([CH3:32])[CH3:31]
Reactant: CC(C)c1nc(COC(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@H](Cc1cncs1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc(COC(=O)N[C@H](C(=O)N[C@H](Cc2cncs2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U but replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-1-phenyl-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-6-(5-thiazolyl)-3-hydroxyhexane and replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((2-isopropyl-4-thiazolyl)methoxycarbonyl)valine provided, after silica gel chromatography using 10% methanol in dichloromethane, 25 mg (76%) of the desired compound (Rf 0.47, 10% methanol in dichloromethane). Mass spectrum: (M+H)+ =715.
Reaction SMILES: O[CH:2](C)CN(CC(O)C)CC(O)C.[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].COS(OC)(=O)=O>CC(C)=O.O.Cl>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][C:16]=1[C:17]([O:19][CH3:2])=[O:18]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: CC(O)CN(CC(C)O)CC(C)O
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(C(F)(F)F)ccc1Cl
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A sample of 620 g (3.25 moles) of tris-(2-hydroxypropyl)amine was melted on a steam bath. This was added slowly to a solution of 615 g (2.75 moles) of 2-chloro-5-trifluoromethylbenzoic acid and 375 g (282 ml, 2.98 moles) of dimethylsulfate in 750 ml of acetone in a 5 liter flask. (The solution began to boil during the course of the addition and was kept at 30° C. to 40° C. by intermittant cooling in an ice bath.) After addition was complete the solution was boilded on a steam bath for 30 minutes. The hot solution was diluted first with 250 ml water and, after 10 minutes, with 250 ml of 2N HCl and 750 ml of water and allowed to stir overnight. The solution was extracted with two 2 liter portions of dichloromethane and the organic extract was washed with saturated K2CO3 and water, dried over Na2SO4 and evaporated to afford 630 g (96%) of methyl 2-chloro-5-trifluoromethylbenzoate as a yellow liquid. TLC (silica gel, 10% CH2Cl2 -hexane) showed 1 spot (ester at Rf 0.4; this material was pure enough to be used in the next step without distillation. IR (NaCl, neat) 3080, 3000, 2960 (C--H), 1735 (C=O); NMR [CDCl3, (CH3)4Si] 3.78 (s, 3H, CH3 --), 7.27 (d, 1H, H-3, J3,4 =9), 7.43 (d of d, 1H, H-4, J3,4 =9, J4,6 -2.4), 7.80 (d, 1H, J4,6 -2.5); Mass Spectrum: m/e 240, 238 (1:3, M+), 209, 207 (1:3, M--OCH3), 181, 179 (1:3, M--CO22CH3). B.p. 95° C. at 4.5 torr.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:15][C@H:14]2[C:16]([O:18]CC)=[O:17])=[CH:9][CH:8]=1)[CH:4]=[CH2:5]>CO.C1COCC1>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:15][C@H:14]2[C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1)[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc([C@@H]2C[C@H]2C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
NaOH (6 N aqueous solution, 10 mL) was added to a solution of (trans)-ethyl 2-(4-(allyloxy)phenyl)cyclopropanecarboxylate (Intermediate F, 11.15 g, 45.27 mmol) in methanol (30 mL) and THF (25 mL) and stirred at room temperature for 18 h. After removal of the solvent, the residue was dissolved in CH2Cl2 (200 mL), acidified with HCl (10% aqueous solution, 30 mL), and washed with brine (2×200 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. Removal of the solvent afforded 9.13 of (trans)-2-[4-(allyloxy)phenyl]cyclopropanecarboxylic acid [Rf=0.25 (5% MeOH/CH2Cl2), white solid, 92% yield]
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].Cl.CN.[CH2:21]([N:23](CC)CC)C>CN(C)C=O>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:23][CH3:21])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.65 ml) was added to a solution containing 4-chloro-3-nitrobenzoic acid (1.50 g) in N,N-dimethylformamide (15 ml) and stirred for 30 minutes at room temperature. Methylamine hydrochloride (1.21 g) and triethylamine (3.11 ml) were added to the reaction mixture. After being stirred for 1 hour at room temperature, the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with water, 1N sodium hydroxide aqueous solution, 1N hydrochloric acid aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The yellow solid residue was purified by silica gel column chromatography (silica gel 10 g, chloroform:methanol=1:0-10:1), thereby yielding the entitled compound (0.97 g) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH2:14][OH:15])=[N:10]1.[H-].[Na+].CS([C:22]1[N:23]([CH3:33])[C:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[N:25][N:26]=1)(=O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH2:14][O:15][C:22]2[N:23]([CH3:33])[C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:10]1
Reactant: Cc1ccc(F)c(-n2nnc(CO)n2)c1
Reactant: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(F)c(-n2nnc(COc3nnc(-c4ccncc4)n3C)n2)c1

Procedure:
The title compound is prepared from [2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium hydride (1.5 mmol) and 4-(5-methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:19]([O:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC1C=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)N1C(OCC)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:19]([O:26][C:27]([NH:29][CH2:30][C:31]([N:1]1[CH2:18][CH2:17][N:16]([C:31](=[O:33])[CH2:30][NH:29][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH2:15][CH2:14][N:13]([C:31](=[O:33])[CH2:30][NH:29][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH2:12][CH2:11][N:10]([C:31](=[O:33])[CH2:30][NH:29][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH2:9][CH2:8][N:7]([C:31](=[O:33])[CH2:30][NH:29][C:27]([O:28][CH2:45][C:44]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:26])[CH2:6][CH2:5][N:4]([C:31](=[O:33])[CH2:30][NH:29][C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:28])[CH2:3][CH2:2]1)=[O:33])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1CNCCNCCNCCNCCNCCN1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCC(=O)N1CCN(C(=O)CNC(=O)OCc2ccccc2)CCN(C(=O)CNC(=O)OCc2ccccc2)CCN(C(=O)CNC(=O)OCc2ccccc2)CCN(C(=O)CNC(=O)OCc2ccccc2)CCN(C(=O)CNC(=O)OCc2ccccc2)CC1)OCc1ccccc1
Reaction time: 8 h

Procedure:
516 mg (2 mmol) of 1,4,7,10,13,16-hexaazacyclooctadecane (hexacyclene; Fluka) is azeotropically dehydrated with toluene. A solution of 3.14 g (15 mmol) of benzyloxycarbonyl-glycine (Fluka) in tetrahydrofuran (THF) as well as 3.71 g (15 mmol) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ; Fluka) are added to the cooled solution of hexacyclene in toluene at room temperature and stirred overnight. After completion of the reaction, the product is precipitated by adding hexane, and the precipitate is chromatographed with dichloromethane/hexane/isopropanol (20:10:1) on silica gel.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([O:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[C:33](Cl)=[O:34])[CH3:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:31]=[CH:32][C:23]=3[O:22][CH2:20][CH3:21])=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: CCOc1ccc2ccccc2c1C(=O)Cl
Product: CCOc1ccc2ccccc2c1C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-ethoxy-1-naphthoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-ethoxy-1-naphthamide as a white powder, m.p. 219° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ 8.33 (t, J=5.8 Hz, 1H), 8.22 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.91 (d, J=8.7 Hz, 11H), 7.87-7.84 (m, 1H), 7.64-7.56 (m, 2H), 7.47-7.22 (m, 5H), 6.60 (s, 2H), 4.69 (t, J=7.2 Hz, 2H), 4.09 (q, J=7.2 Hz, 2H), 3.37 (m, 2H), 2.01 (m, 2H), 1.64 (m, 2H), 1.18 (t, J=7.2 Hz, 3H); MS (EI) m/e 453.2157 (453.2165 calcd for C27H27N5O2).
Reaction SMILES: [CH:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=1[O:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.C(Cl)(Cl)Cl.[I-].[K+]>[CH:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][C:27]=3[O:35][CH3:36])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Fc1ccc(C(C2CCCCC2)C2CCNCC2)cc1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCO
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(c2ccc(F)cc2)C2CCCCC2)CC1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A mixture of 4-[cyclohexyl(4-fluorophenyl)methyl]piperidine (5.71 g, 0.0207 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.03 g, 0.207 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction mixture was cooled to room temperature and filtered. The 1-butanol was removed by rotary evaporation to give a brown oil. This oil was dissolved in chloroform and the chloroform layer was extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a brown oil. This oil was subjected to flash chromatography on silica gel. Elution was performed using ethyl acetate, 5% methanol-ethyl acetate, and 10% methanol-ethyl acetate. Separate fractions of similar purity were combined and solvent was removed to give a yellow oil. This oil was dried in vacuo overnight at 80° C. to give 7.36 g (73.8%) of title compound.
Reaction SMILES: [C:1]1([P:7](Cl)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([OH:12])[CH3:11].C(N(CC)CC)C.C([O:22]CC)C>>[CH2:10]([O:12][P:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:22])[CH3:11]
Reactant: ClP(Cl)c1ccccc1
Reactant: CCO
Reactant: CCOCC
Solvent: CCN(CC)CC
Product: CCOP(O)c1ccccc1

Procedure:
To a solution of 270 ml of phenyldichlorophosphine in 1000 ml of diethylether is added with stirring and cooling with ice a solution of 280 ml of ethanol and 280 ml of triethylamine in 500 ml of diethylether. After stirring for 14 hours at 20° the precipitate is filtered off and the filtrate is fractionally distilled. There is obtained phenylphosphonous acid-ethylester as a colorless liquid, b.p. 83-85°/6 Pa.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.021 mole) and 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (84 ml of 1M solution, 0.042 mole) was added dropwise at room temperature to the stirred solution and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated and the solid was triturated with water. The solid was collected and dried under high vacuum overnight. The solid was dissolved in tetrahydrofuran and acidified with ethereal hydrogen chloride to produce a crystalline precipitate, which was collected, washed with tetrahydrofuran, and dried under high vacuum overnight at room temperature to give 5.3 g, (73%), mp 216°-219.5° C.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:6]=1[O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:4].C(O)(=O)C>CN(C=O)C>[CH3:20][O:19][C:15]1[C:6]2[O:7][C:8]([CH3:14])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3](=[O:4])[C:5]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)Oc1c(C=O)cccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C1(C)Oc2c(OC)cccc2C1=O
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 6.61 g) was added to DMF (250 ml). To this solution, a solution of ethyl 2-(2-formyl-6-methoxyphenoxy)-propionate (34.56 g) in DMF (150 ml) was added dropwise at room temperature for 1 hour, and the resulting solution was stirred for another 30 minutes. Acetic acid (12 ml) was added to the reaction solution and the solution was concentrated. The solution was poured into water layer (300 ml) and the resultant was extracted twice with ethyl acetate (150 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed under reduced pressure and the obtained residue was dissolved in dichloromethane (600 ml). To this solution, Celite (105 g) and pyridinium chlorochromate (44.52 g) were added and the solution was stirred at room temperature for 21 hours. Isopropyl alcohol (20 ml) was added to the reaction solution and the resulting solution was stirred for 15 minutes. One liter of hexane was added to the reaction solution and the resultant was filtered through Celite, followed by washing the precipitate with one liter of ether. The filtrate was washed with water (500 ml) and the aqueous layer was extracted with ether (200 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1-3/1) using silica gel to obtain the desired compound (20.39 g, yield: 60%).
Reaction SMILES: C(OC([NH:11][CH2:12][C@H:13]([OH:33])[CH2:14][C:15]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[O:16][PH2:17]=[O:18])=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:11][CH2:12][C@H:13]([OH:33])[CH2:14][C:15]([O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])([CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[O:16][PH2:17]=[O:18]
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)OC(CC1CCCCC1)(C[C@@H](O)CNC(=O)OCc1ccccc1)O[PH2]=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)OC(CC1CCCCC1)(C[C@@H](O)CN)O[PH2]=O
Yield: 94.9 %

Procedure:
2,2-Dimethyl-propionic acid ((R)-3-benzyloxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinoyloxymethyl ester (0.90 g, 0.39 mmol) was dissolved in ethanol (35 mL) and was hydrogenated via a hydrogen par shaker for 3 h at 50 psi with 10% Pd/C (0.09 g) as a catalyst. The reaction was filtered through celite and concentrated in vacuo to give 2,2-dimethyl-propionic acid ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinoyloxymethyl ester (130 mg, 0.37 mmol). 1H NMR (CDCl3, 300 MHz): δ 5.65 (m, 1H), 4.2 (m, 1H), 3.8 (m, 1H), 3.60 (m, 1H), 2.01-1.55 (m, 14H), 1.40-0.95 (m, 11H). 31P NMR (CDCl3, 300 MHz): 60.65, 59.20. LC/MS m/z: [M+H]+=350.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C([O-])([O-])=O.[K+].[K+].[CH2:15](I)[CH:16]([CH3:18])[CH3:17]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CI
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CSc1ccccc1Br
Temperature: 40 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-bromobenzene thiol (10.0 g, 52.8 mmol, 1.0 eq.) in DMF (250 mL) was added K2CO3 (17.5 g, 126.7 mmol, 2.4 eq.) and isobutyl iodide (7.3 mL, 63.36 mmol, 1.2 eq). The reaction was warmed to about 40° C. and stirred overnight. The mixture was diluted with EtOAc (300 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was extracted with EtOAc(2×). The combined organic extracts were dried (Na2SO4), filtered and concentrated to afford 1-bromo-2-isobutylsulfanyl-benzene (12.94 g, 52.8 mmol, 100%), which is then taken to the next step without any further purification. GCMS (EI): 244.0
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)=[CH:6][C:5]([F:13])=[CH:4][N:3]=1.C(OCC)(=[O:16])C.[OH2:20]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([C:8]2([C:11]([OH:16])=[O:20])[CH2:10][CH2:9]2)=[CH:6][C:5]([F:13])=[CH:4][N:3]=1
Reactant: N#CC1(c2cc(F)cnc2Cl)CC1
Reactant: CCOC(C)=O
Reactant: O
Agent: O=S(=O)(O)O
Product: O=C(O)C1(c2cc(F)cnc2Cl)CC1
Temperature: 105 °C
Yield: 92 %

Procedure:
1-(2-chloro-5-fluoropyridin-3-yl)cyclopropanecarbonitrile (intermediate 16, 0.400 g, 2.034 mmol) was dissolved in a mixture of water (6 mL) and concentrated sulfuric acid (6 mL). The reaction was heated at 105° C. and stirred for 3½ hours. The reaction was cooled and ice (˜200 mL) and ethyl acetate (200 mL) were added. The pH was carefully adjusted to about 9 and the phases separated. The organic was discarded and the aqueous was reacidified to about pH 1 using 5 N hydrochloric acid. It was extracted with ethyl acetate (2×300 mL). The combined organic layers were dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude 1-(2-chloro-5-fluoropyridin-3-yl)cyclopropanecarboxylic acid (0.402 g, 1.864 mmol, 92% yield) was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=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].[Br:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30]>CCOC(C)=O.C(#N)C>[Br-:27].[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][CH:9]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N+:15]([CH2:28][C:29](=[O:30])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([CH2:20][CH2:19]2)[CH2:14]1)=[O:11])=[O:7]
Reactant: O=C(CBr)c1ccccc1
Reactant: COCCOC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCCOC(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.6 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-((2-methoxyethoxy)-carbonylamino)-2-phenylacetate (C36) (73.0 mg, 0.20 mmol) in EtOAc (3 ml) and acetonitrile (1 ml), was added 2-bromo-1-phenylethanone (44.1 mg, 0.22 mmol). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated, and the resulting crude was purified by flash chromatography (DCM/MeOH=95/5 to 93/7). The product was triturated with i-Pr2O to obtain (3R)-3-(2-((2-methoxyethoxy)carbonylamino)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (61.3 mg; 54% yield).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])O.C(=O)(O)[O-].[NH4+].[NH2:18]C1C=C(C(O)=O)C(O)=CC=1.C(Cl)(Cl)Cl>N1C=CC=CC=1.CO>[C@@H:11]1([NH2:18])[O:12][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
Beta-D-glucosylamine is prepared by the reaction of D-(+)-glucose with ammonium bicarbonate as described by Likhosherstov, L. M. et al. (Carbohydr. Res. 146: C1, 1986). A reaction mixture containing the glycosylamine and a 1- to 2-fold excess by weight of 5-aminosalicylic acid is allowed to react overnight in pyridine at 50° C. The reaction is monitored by thin-layer chromatography (TLC) (silica gel; eluent: CHCl3:MeOH, 1:1, by volume). The solvent is removed, and the reaction mixture is purified by chromatography on silica gel or BIOGEL-F2™ (BioRad, Richmond, Calif.), using absorbance at 254 nm as detection. The products are characterized by TLC on silica gel, electrospray mass spectrometry, and 1H- and 13C-NMR analysis. The transamination reaction is indicated by a downfield shift of resonance of the anomeric proton (observed at δ=4.1 ppm by analysis of the unsubstituted glycosyl-1-amine) to δ=4.3–4.7 ppm in the 1H-NMR spectrum of the β-anomer of the synthetic glycoconjugate product. (This anomer is the major product of the transamination reaction.)
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH2:18]([NH:25][C:9]1[C:8](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:12][C:11](=[O:13])[C:10]=1[N:14]=[O:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC1=C(N=O)C(=O)NC1=Cc1ccccc1
Reactant: NCc1ccccc1
Solvent: CO
Product: O=NC1=C(NCc2ccccc2)C(=Cc2ccccc2)NC1=O
Yield: 60 %

Procedure:
A solution of 0.11 g (0.5 mmol) 5-benzylidene-4-methoxy-3-nitroso-1,5-dihydropyrrol-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in methanol was boiled under reflux with 0.25 ml (0.25 mmol) benzylamine for two minutes. The compound 4-benzylamino-5-benzylidene-3-nitroso-1,5-dihydropyrrol-2-one was obtained as red-violet crystals in a yield of 60% after recrystallization from methanol. The compound decomposes at 220° C.