Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH2:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1(=O)[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CC(C)=O.CN(C)C=O>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([N:16]3[C:22](=[O:23])[CH2:21][CH2:20][C:19]3=[O:24])[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCC(=O)O1
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CC1(C)CC(N2C(=O)CCC2=O)CC(C)(C)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.64 g of 1-cyclohexyloxy-4-amino-2,2,6,6-tetramethylpiperidine in 10 ml of acetone is added to a solution of 1.0 g of succinic anhydride in 25 ml of acetone. After stirring the reaction mixture at room temperature for 8 hours and removal of the solvent under reduced pressure, 3.54 g of the intermediate amide acid are obtained. A solution of the above (3.0 g), 0.1 g of sodium acetate and 3.1 ml of acetic anhydride in 10 ml of dimethylformamide is heated at 90° C. for 3 hours to effect cyclization to the desired imide. The removal of solvents under reduced pressure followed by purification utilizing SiO2 flash chromatography [heptane:ethyl acetate (60:40)] and crystallization from ethyl acetate-heptane provide the desired succinimide as a white crystalline solid m.p. 133°-36° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.1 %

Procedure:
The resultant compound from Example 98 (11.76 g, 33.2 mmol) in methylene chloride (25 ml) was treated with trifluoroacetic acid (25 ml). After stirring at room temperature for 90 min the solvent was evaporated to afford 9.91 g (100%) of the desired product as a solid, m.p. 48°-51° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[CH3:16][C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:22]2[S:18][C:19](=[O:24])[NH:20][C:21]2=[O:23])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:12]=1[OH:13])([CH3:15])[CH3:17]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(C=C2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 26.5 %

Procedure:
A mixture of 3,5-di-t-butyl-4-hydroxybenzaldehyde (6.5 g, 27 mmoles), 2,4-thiazolidinedione (3.0 g, 26 mmoles), sodium acetate (7.6 g, 93 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 78 hours the mixture is stirred into water (300 ml), and the precipitate is filtered off, rinsed three times with water, dried, and recrystallized from ethanol. The product is stirred in 1N NaOH (50 ml) and extracted several times with dichloromethane. The aqueous solution is acidified with acetic acid, stirred for 1-2 hours, and the precipitate is filtered off, rinsed three times with water and dried to afford the pure product (2.3 g), mp 238°-240° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:1][C@H:2]2[CH2:3][C@H:4]([NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13])[CH2:5]2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of racemic (2:1) in favor of trans tert-butyl (3-hydroxycyclobutyl)carbamate (16.8 g, 90 mmol) and 4-nitrobenzoic acid (10.97 ml, 102 mmol) in THF (300 mL) were added triphenyl phosphorus (30.0 ml, 130 mmol) and (E)-diisopropyl diazene-1,2-dicarboxylate (25 ml, 124 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 18 h. The reaction was concentrated and the crude material purified by flash silica gel chromatography on ISCO eluting with 0-40% EtOAc/hexanes to give a mixture cis and trans products. The mixture of isomers was purified by chiral separation to give the desired trans isomer trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-nitrobenzoate (17.4 g, 51.7 mmol, 87% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=1)[CH:14]=[CH:13][O:12]2.[OH:25]OS([O-])=O.[K+]>CO.C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23]([CH3:24])=[O:25])[N:18]=1)[CH:14]=[CH:13][O:12]2
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3F)nc3occn23)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2c(-c3ccc(F)cc3F)nc3occn23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A round bottom flask was charged with 6-(2,4-difluorophenyl)-5-(2-(methylthio)pyrimidin-4-yl)imidazo[2,1-b]oxazole (0.16 g, 0.47 mmol) and OXONE® (0.312 g, 0.508 mmol). The reaction mixture was diluted with MeOH (10.0 mL), DCM (10.0 mL) and water (2.0 mL). The reaction mixture was stirred at ambient temperature for about 8 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (2×200 mL). The organic phase was washed with H2O (100 mL) then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography using a gradient of 10-100% EtOAc in heptane and then a gradient of 0-20% MeOH in DCM to give the title compound (0.16 g, 96%). LC/MS (Table 1, Method o) Rt=2.63 min; MS m/z 361.1.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[C:15]([S:19][S:20][CH2:21][C@H:22]1[C:26](=[O:27])[O:25][CH2:24][N:23]1[C:28]([O:30][CH2:31][CH:32]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[CH:34]1[C:33]2[CH:32]([CH2:31][O:30][C:28]([N:23]([CH3:24])[C@@H:22]([CH2:21][S:20][S:19][C:15]([CH3:17])([CH3:16])[CH3:18])[C:26]([OH:27])=[O:25])=[O:29])[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)SSC[C@H]1C(=O)OCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](CSSC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.4 %

Procedure:
Triethylsilane (6.04 ml, 37.8 mmol) and trifluoroacetic acid (9 ml) were added to a solution of (R)-(9H-fluoren-9-yl)methyl 4-((tert-butyldisulfanyl)methyl)-5-oxooxazolidine-3-carboxylate (Compound 2b-B) (1.68 g, 3.78 mmol) in dichloromethane (18 ml), and the mixture was stirred at room temperature for one day. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=70/30→20/80→0/100) to afford (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(tert-butyldisulfanyl)propanoic acid (Compound 2c-B) (1.22 g, 72%).
Reaction SMILES: F[C:2]1[C:20]([CH3:21])=[C:19]([F:22])[C:18]([F:23])=[CH:17][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F-].[Na+]>CN(C=O)C>[CH:14]1([N:13]2[C:2]3[C:3](=[CH:17][C:18]([F:23])=[C:19]([F:22])[C:20]=3[CH3:21])[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12]2)[CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(C)c1F
Agent: [F-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
A mixture of ethyl 2-(2,4,5-trifluoro-3-methylbenzoyl)-3-cyclopropylaminoacrylate (300 mg) and sodium fluoride (70 mg) in anhydrous DMF (2 ml) was stirred at 130° to 140° C. for 6 hours. To the reacting mixture was added ice-water (3 ml), the resulting precipitate was collected by filtration, washed with water and recrystallized from methanol to give the title compound (220 mg) as white needles, mp 220°-221° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:62])[C:56]4[CH:57]=[N:58][NH:59][C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1>CN(C=O)C>[F:1][C:2]1[C:3]([C:8]([NH:62][C:55]2[CH:54]=[C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[C:52]4[C:47]=3[CH:46]=[CH:45][NH:44]4)[CH:61]=[C:60]3[C:56]=2[CH:57]=[N:58][NH:59]3)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1F
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ncccc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
To 3-fluoro-2-pyridinecarboxylic acid (available from Fluorochem, 63 mg, 0.44 mmol) was added O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (172 mg, 0.45 mmol), DIPEA (0.106 ml) and DMF (1 ml). The reaction was stirred for 20 mins at 25° C. 6-(1H-indol-4-yl)-1H-indazol-4-amine (50 mg, 0.20 mmol) was added and the reaction was stirred for a further 20 h at 25° C. The solvent was dried under a stream of nitrogen to give the crude product. This sample in DMF was loaded onto an aminopropyl cartridge (5 g) and after standing for 3 h, the column was washed with 10% methanol in dichloromethane. The appropriate fractions were combined and dried under a stream of nitrogen to give the crude product which was purified by Mass Directed Automated Preparative HPLC (Method B). The solvent was dried under a stream of nitrogen to give the title compound (23 mg).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:19]([F:22])([F:21])[F:20])[O:18][CH:13]2C(OC)=O)=[CH:8][CH:7]=1)[CH3:4]>C(O)C.O>[CH2:3]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:19]([F:20])([F:21])[F:22])[CH:13]=[O:18])=[CH:10][CH:11]=1)[CH3:4]
Reactant: CCOc1ccc(C2(C(F)(F)F)OC2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(C(C=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
Into a solution of 11.41 g of potassium hydroxide in 80 ml of ethanol and 20 ml of water, 29.55 g of methyl 3-(4-ethoxyphenyl)-2,3-epoxy-4,4,4-trifluorobutyrate was added with ice-cooling. The reaction solution was stirred at room temperature for 17 hours. Thereafter, the reaction solution was poured into ice water. The resulting solution was washed with diethyl ether and adjusted to pH 3 with 10% HCl and extracted twice with diethyl ether. The ether layers were combined and washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure and the residue was subjected to distillation under a reduced pressure by heating in an oil bath (130°-140° C.) to obtain 14.66 g of the desired aldehyde (b.p. 100°-105° C./0.3 mmHg).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:40](=[O:41])[N:12]2[C:13]([C:34]([O:36]CC=C)=[O:35])=[C:14]([CH2:17][N:18]3[C:22]4=[CH:23][C:24]5[C:29]([CH:30]=[C:21]4[N:20]([CH3:31])[S:19]3(=[O:33])=[O:32])=[CH:28][CH:27]=[CH:26][CH:25]=5)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+:71].C(OCC)(=O)C.C(C(CCCC)C(O)=O)C>ClCCl.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:7][C@@H:8]([C@H:10]1[C:40](=[O:41])[N:12]2[C:13]([C:34]([O-:36])=[O:35])=[C:14]([CH2:17][N:18]3[C:22]4=[CH:23][C:24]5[C:29]([CH:30]=[C:21]4[N:20]([CH3:31])[S:19]3(=[O:33])=[O:32])=[CH:28][CH:27]=[CH:26][CH:25]=5)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9].[Na+:71]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4cc5ccccc5cc4N(C)S3(=O)=O)[C@H](C)[C@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(CN3c4cc5ccccc5cc4N(C)S3(=O)=O)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product from step 1 (52 mg, 0.089 mmol), triphenylphosphine (7 mg, 0.0267 mmol), 0.5M sodium 2-ethyl-hexanoate in ethyl acetate (0.178 mL, 0.089 mmol), 2-ethyl-hexanoic acid (0.014 mL, 0.089 mmol) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.0089 mmol) were combined in dichloromethane (1.5 mL). The mixture was stirred at room temperature for 15 minutes, then diluted with ethyl ether (20 mL) and centrifuged. The solid pellet was washed with ether (5 mL) and dried under vacuum to afford the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([C:17]([CH:20]([CH3:22])[CH3:21])([CH3:19])[OH:18])([CH2:10]3)[CH2:8]1)[CH2:14]2.C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:18][C:17]([C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([OH:6])([CH2:14]3)[CH2:8]1)[CH2:10]2)([CH3:19])[CH:20]([CH3:22])[CH3:21])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: CC(C)C(C)(O)C12CC3CC(CC(O)(C3)C1)C2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OC(C)(C(C)C)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A total of 10 mmole of acrylyl chloride was added dropwise to a mixture of 10 mmole of 3-hydroxy-α-isopropyl-α-methyl-1-adamantanemethanol thus obtained, 10 mmole of triethylamine and 40 ml of tetrahydrofuran over about 30 minutes. After the completion of addition, the resulting mixture was stirred at room temperature for 6 hours. After adding water, the reaction mixture was concentrated, and the concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound in a yield of 67%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[N:41][CH:42]=1.[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([CH2:57]O)[CH:53]([C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)[CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([CH2:57][O:43][C:40]2[CH:39]=[CH:38][C:37]([Cl:36])=[CH:42][N:41]=2)[CH:53]([C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)[CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: OCC1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: Oc1ccc(Cl)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(C2CN(Cc3ccccc3)CCC2COc2ccc(Cl)cn2)cc1
Reaction time: 0.33 h

Procedure:
In a 100 mL four necked round bottom flask with a magnetic stirrer and inert atmosphere 1.3 g polymer bound triphenylphosphine was stirred in 15 mL THF. At 0-5° C. a solution of 514 mg (2.23 mmol) di-tert-butyl azodicarboxylate in 8 mL THF and a solution of 271 mg (2.1 mmol) 5-chloro-2-hydroxypyridine in 10 mL THF was added. The mixture was stirred for 20 min at 0° C.-5° C. 441 mg (1.4 mmol) [(3RS, 4RS)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-methanol in 8 mL THF was added. The ice bath was removed and the brownish mixture was stirred for 2 h at room temperature. The mixture was filtrated over decalite and washed with ethyl acetate. The solvents were evaporated and the residue purified by column chromatography on silica gel eluting with ethyl acetate/toluene to yield after evaporation of the product containing fractions 0.3 g (50%) of the title compounds as white solid. MS (m/e): 298.3/427.1 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:10])[CH3:2].C(N(CC)CC)C.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:10][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:2]
Reactant: CCOC(=O)CCNC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC(=O)[C@H](Cc1ccccc1)NCC(=O)OCC
Temperature: 60 °C
Yield: 80.4 %

Procedure:
Phenylalanyl-β-alanine ethyl ester (10 g, 0.038 mol) and triethylamine (10.3 g, 0.1 mol) were suspended in toluene (45 g), and the suspension was heated to 60° C. To the resultant suspension, ethyl bromoacetate (9.3 g, 0.057 mol) suspended in toluene (5 g) was added dropwise over 0.5 hours, and then the resultant mixture was stirred for three hours. After completion of reaction, the resultant reaction mixture was subjected to extraction with ethyl acetate (20 g). The organic layer was washed with a 2.5% aqueous solution of citric acid. Subsequently, the solvent was removed, to thereby obtain N-(carboethoxymethyl)phenylalanyl-β-alanine ethyl ester (10.7 g, yield: 80.3%). The compound was dissolved in methanol, and a 48% aqueous solution of sodium hydroxide (6.6 g, 0.08 mol) was added to the methanol solution, and the resultant mixture was stirred for three hours. After completion of reaction, the solvent was removed, and the resultant residue was dissolved in water (20 mL), and then washed with ethyl acetate (10 g). Subsequently, hydrochloric acid was added to the aqueous layer, so as to attain a pH of 3.5. After being cooled, the resultant solution was subjected to filtration, to thereby obtain crude crystals. The crystals were recrystallized from a 20% aqueous solution of isopropyl alcohol, to thereby obtain compound 1 (6.0 g, yield: 67%).
Reaction SMILES: C=CC(=O)C.C1(=O)NC(=O)C2=CC=CC=C12.[Br:17][CH2:18][C:19](=[O:33])[CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>C(O)C>[Br:17][CH2:18][C:19](=[O:33])[CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].[N:34]1[C:19]([CH2:20][CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[CH:18][N:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=12
Reactant: Nc1ccccn1
Agent: C=CC(C)=O
Agent: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Agent: O=C1NC(=O)c2ccccc21
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCc1cn2ccccc2n1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
2-(4-Bromo-3-oxo-butyl)-isoindole-1,3-dione is prepared by condensation of but-1-en-3-one with phthalimide followed by bromination according to known procedures (J. Med. Chem., 35:3239, 1992. A solution of 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (8.9 g, 30.06 mmol) and 2-aminopyridine (2.8 g, 29.75 mmol) in ethanol is heated at reflux for 4 hours. The mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica gel, dichloromethane/ethanol 95:5); to give 4.23 g of 2-[2-(imidazo[1,2-a]pyridin-2-yl)ethyl]-isoindole-1,3-dione (49%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].O>C1(C)C=CC=CC=1>[CH2:10]([NH:14][C:1]([CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1)=[O:8])[CH2:11][CH2:12][CH3:13]
Reactant: O=C(Cl)c1ccncc1
Reactant: CCCCN
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCNC(=O)C1CCNCC1
Reaction time: 8 h
Yield: 14.4 %

Procedure:
Isonicotinoyl chloride (100.0 g) was added over 1 hour to a solution of n-butylamine (51.6 g) in toluene (600 ml) at 0°. The mixture was allowed to stand overnight, heated on a steam bath for 1/2 hour, then water was added. The aqueous layer was separated, basified to about pH 12 (NaOH), and extracted with ethyl acetate (2 times). The combined organic extracts were dried (MgSO4), evaporated and the resulting residue (36.0 g) dissolved in acetic acid (400 ml) and hydrogenated at 50 p.s.i./30° in the presence of platinum oxide. The catalyst was removed by filtration, the solution evaporated to dryness, the residue basified to about pH 12 (Na2CO3), and extracted with chloroform. The chloroform extracts were dried (Na2SO4) and evaporated to give 4-(N-n-butylcarbamoyl)piperidine, (18.7 g), m.p. 75°-79°. The oxalate salt was prepared in isopropanol from the free base and oxalic acid and was recrystallised from isopropanol/ethyl acetate, m.p. 143°-144° .
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O)[CH3:2].[NH2:15][C@H:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1.NC1C2CCN(CC2)C1>>[N:18]12[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19]1)[CH:16]([NH:15][C:5](=[O:7])[C:4]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:3]=1[CH2:1][CH3:2])[CH2:17]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: CCOC(=O)c1cccc(C)c1CC
Agent: NC1CN2CCC1CC2
Product: CCc1c(C)cccc1C(=O)NC1CN2CCC1CC2

Procedure:
Proceeding as in Example 1, Method B, but replacing methyl 3-methoxy-2-methylbenzoate with ethyl 2-ethyl-3-methylbenzoate and (S)-3-amino-1-azabicyclo[2.2.2]octane with (RS)-3-amino-1-azabicyclo[2.2.2]octane gave (RS)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-ethyl-3-methylbenzamide, m.p. 125° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([CH3:12])([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:18])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2([CH3:12])[CH2:9][O:10][C:16]([CH3:18])([CH3:15])[O:11]2)=[CH:13][CH:14]=1
Reactant: CC(C)=O
Reactant: CC(O)(CO)COc1ccc(Br)cc1
Product: CC1(COc2ccc(Br)cc2)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61 %

Procedure:
3-(4-Bromophenoxy)-2-methylpropane-1,2-diol (261 mg, 1.00 mmol), acetone (10 mL), and a boron trifluoride diethyl ether complex (3 drops) were mixed. The mixture was then stirred at room temperature for 14 hours. A residue was obtained by concentrating the mixture under reduced pressure, and ethyl acetate and water were added thereto, followed by extraction. The organic layer was washed with a saline solution twice. A residue was obtained by concentrating the organic layer under reduced pressure, and the resulting residue was then subjected to chromatography refining (methylene chloride) using silica gel, obtaining 183 mg of the objective compound (yield: 61%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.C[O:11][CH:12](OC)[CH2:13][CH:14](OC)OC.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH:12]([CH:13]=[CH:14][NH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:11]
Reactant: COC(CC(OC)OC)OC
Reactant: Cc1cccnc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccnc1NC=CC=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-amino-3-methylpyridine (53.9 g) and anhydrous hydrogen chloride (40 g) in anhydrous ethanol (960 ml) was treated with 1,1,3,3-tetramethoxypropane and heated at reflux for 6 hours. The solution was then concentrated to dryness under reduced pressure and the residue was triturated with diethyl ether, to give crude 9-methylpyrido[1,2-a]pyrimidinium chloride (76 g). This crude salt was dissolved in water (300 ml) and treated with sodium bicarbonate (35.4 g). The mixture was stirred at room temperature for one hour and then it was filtered, washed with water and recrystallised from water, to give 1-formyl-2-(3-methylpyrid-2-ylamino)ethene (32.7 g), m.p. 129°-131° C. (with decomposition).