Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:12]([OH:14])=[O:13]>O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:4]2[C:5]([O:14][C:12](=[O:13])[C:3]=12)=[O:7]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1C(=O)O
Solvent: O
Product: O=C1OC(=O)c2c(Cl)cc(Cl)cc21

Procedure:
3,5-Dichlorophthalic acid (3.36 g, preparation given in Example 1 of U.S. Pat. No. 5,086,188) was refluxed with 10 mL of xylenes while the water generated from the cyclization was collected in a Barrett trap. After refluxing for 5 hours the reaction was cooled, and the xylenes were removed under vacuum. The resultant solids were dried overnight in a vacuum desiccator to give 2.32 g of 3,5-dichlorophthalic anhydride, mp 90° to 94° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[Cl-].[OH:34][NH3+:35].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:34][N:35]=[C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:15]([F:16])([F:17])[F:18])=[O:12])=[CH:5][C:4]=1[C:29]([F:30])([F:32])[F:31])[NH2:2]
Reactant: [NH3+]O
Reactant: N#Cc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F

Procedure:
1.17 g (2.51 mmol) of (2E)-3-[4-cyano-3-(trifluoromethyl)phenyl]-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}acrylamide from Example Ia-46 were initially charged in a mixture of 11.7 ml of ethanol and 2.9 ml of water and admixed with 209.6 mg (3.01 mmol) of hydroxylammonium chloride and 399.5 mg (3.77 mmol) of sodium carbonate. The reaction mixture was heated under reflux for 18 hours and then admixed with water. After extracting repeatedly with ethyl acetate, the combined organic phases were dried over magnesium sulphate, the solvent was distilled off under reduced pressure and the residue was chromatographed using silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 0% ethyl acetate to 100% ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]([CH2:15][C:16]([C:18]1[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]=1[CH3:27])=O)[C:12]([OH:14])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:28]1([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.ClC1C=CC(CN2C3C(=CC([N+]([O-])=O)=CC=3)C(C3C(=O)OC(C4C5C(=CC=C([N+]([O-])=O)C=5)N(CC5C=CC(Cl)=CC=5)C=4C)(C4C5C(=CC=C([N+]([O-])=O)C=5)N(CC5C=CC(Cl)=CC=5)C=4C)C=3)=C2C)=CC=1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[C:12](=[O:14])[O:13][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]=3[CH3:27])([C:42]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[NH:35][C:34]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:15]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: Cc1[nH]c2ccccc2c1C(=O)CC(C(=O)O)c1c(C)[nH]c2ccccc12
Agent: Cc1c(C2=CC(c3c(C)n(Cc4ccc(Cl)cc4)c4ccc([N+](=O)[O-])cc34)(c3c(C)n(Cc4ccc(Cl)cc4)c4ccc([N+](=O)[O-])cc34)OC2=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccc(Cl)cc1
Product: Cc1[nH]c2ccccc2c1C1=CC(c2c(C)[nH]c3ccccc23)(c2c(-c3ccccc3)[nH]c3ccccc23)OC1=O
Yield: 4.9 %

Procedure:
Following a procedure similar to that described in Example 3, part B above, 3.6 g (0.01 mole) of 2,4-bis(2-methyl-3-indolyl)-4-oxobutanoic acid (described above in Example 10, part A) and 2.12 g (0.01 mole) of 2-phenylindole were interacted to obtain 0.26 g of 3,5-bis(2-methyl-3-indolyl)-5-(2-phenyl-3-indolyl)-2(5H)-furanone (Formula III: R=R2 =Y=Y1 =H; R1 =CH3 ; R3 =C6H5), a pale blue-colored powder which melted in the range of 204°-215° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[C:11]([CH3:25])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O.NN>C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:25])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1onc(-c2cccc(F)c2)c1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of 2-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione (6.3 g, 19 mmol) in THF (252 mL) and ethanol (22 mL) at 0° C. was added hydrazine hydrate (7.0 g, 6.8 mL, 140 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was then filtered and the filtrate diluted with HCl (1 N) and extracted with ethyl acetate. The combined organic extracts were then washed with HCl (1 N) and the aqueous layer made basic with NaOH (6 N). The aqueous layers were extracted with ethyl acetate and the combined organic layers washed with brine and dried over sodium sulfate. Concentration and purification by chromatography (NH2—SiO2, dichloromethane) afforded the title compound (3.0 g, 77%) as a yellow oil. MS: m/e=207.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:11]([F:23])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH:24]1([C:27]([NH2:29])=[O:28])[CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:24]1([C:27]([NH:29][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:11]([F:23])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[O:28])[CH2:26][CH2:25]1
Reactant: NC(=O)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)c2)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1F
Temperature: 25 °C
Yield: 213.2 %

Procedure:
Dissolve tert-butyl N-[4-[(2-chloro-4-pyridyl)oxy]-2-fluoro-phenyl]carbamate (13 g, 14.7 mmol), cyclopropanecarboxamide (8.1 g, 36.7 mmol) in 1,4-dioxane (240 mL). Then add tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3, 1.75 g, 0.73 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP, 2.38 g, 1.47 mmol) and Cs2CO3 (24.8 g, 29.4 mmol) under N2. Stir the reaction at 100° C. for 12 hrs. Cool to room temperature, filter, and concentrate the filtrate to give the crude product. Purification by chromatography (silica gel, DCM:EtOAc-1:5) affords the title compound (12.14 g, 83.2%). MS: (M+1): 388.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1.[C:24]([C:32](O)=[O:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)CCl>C(Cl)Cl>[O:31]=[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:32]([N:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:8][CH:7]=1)[C:12]1[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)=[O:33]
Reactant: FC(F)(F)c1ccc(CCNc2ccc(C(F)(F)F)nc2)cc1
Reactant: O=C(O)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of [2-(4-trifluoromethyl-phenyl)-ethyl]-(6-trifluoromethyl-pyridin-3-yl)-amine (50 mg) in CH2Cl2 (3 mL) was added under a nitrogen atmosphere at 0° C. benzoyl formic acid (1.1 eq., commercially available) and EDC (1.1 eq). After stirring for 12 h a ambient temperature, the mixture was washed with aqueous Na2CO3 (saturated, 2.5 mL) and water (2.5 mL), the combined aqueous layers were extracted with CH2Cl2 (3×2.5 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (46 mg, 66%) as a light yellow solid. MS m/e: 467.2 [M+H]+.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21]([CH2:23][NH2:24])[OH:22].O>CCCCCC>[C:1]([NH:24][CH2:23][CH2:21][OH:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: O
Solvent: CCCCCC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCO

Procedure:
In an exemplary embodiment, 1 mmol oleic acid was reacted with 1 mmol ethanolamine in 1.5 mL hexane at 65° C. for 3 hours in the presence 30% lipase and 10 μL water. N-oleoyl ethanolamine with 96.6% purity was obtained and all oleic acid was consumed. In another exemplary embodiment, when the synthesis was conducted on a large scale (50 mmol of each of the reactants), the purity of N-oleoyl ethanolamine after crystallization purification was 96.1%. More examples of reacting the alkanolamine and the fatty acid to prepare the high-purity fatty acid N-acylalkanolamine in a high yield are described in Examples 9-18.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[Al](C)C.[N:23]1([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35](OC)=[O:36])=[CH:30][CH:29]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[O:10][CH2:11][CH2:12][N:13]([C:35](=[O:36])[CH2:34][C:31]4[CH:30]=[CH:29][C:28]([N:23]5[CH:27]=[CH:26][N:25]=[CH:24]5)=[CH:33][CH:32]=4)[CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)Cc1ccc(-n2ccnc2)cc1
Reactant: c1cn(-c2ccc3c(c2)OCCNCCO3)cn1
Agent: C[Al](C)C
Product: O=C(Cc1ccc(-n2ccnc2)cc1)N1CCOc2ccc(-n3ccnc3)cc2OCC1

Procedure:
In a manner similar to preparation 7, react 9-(1H-imidazol-1-yl)-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine, trimethylaluminum, and 4-(1H-imidazol-1-yl)benzeneacetic acid, methyl ester to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][CH:12]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(OCC)(=O)C>O>[C:21]([O:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([CH:13]=[O:14])=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc(-c2ccc(CO)s2)s1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCc1ccc(-c2ccc(C=O)s2)s1
Yield: 95 %

Procedure:
5-Hydroxymethyl-5'-formyl-2,2'-bithiophene (0.2 g) and pyridine (1 ml) were mixed together. Acetic anhydride (1 ml) was added slowly into the mixture with stirring. Ethyl acetate (200 ml) and water (50 ml) were added 2 hours later. The ethyl acetate layer was washed with weak base, weak acid and water. The product was concentrated and purified by column chromatography, eluted with ethyl acetate/n-hexane (1/9). Light yellowish crystals were obtained. The melting point of the crystal was 89°-91° C. The yield was 95%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 24 (t)] with benzyl bromide therer was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless, amorphous solid, which was used in the next step without characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]5[NH:26][CH:27]=[CH:28][N:29]=5)[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[Li+].[OH-]>C1COCC1.[Cl-].[Na+].O>[NH:26]1[CH:27]=[CH:28][N:29]=[C:25]1[CH2:24][N:20]1[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][C:15]2[C:14]([F:30])=[CH:13][N:12]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[NH:8][CH:9]=3)[N:16]=2)[CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(Cc5ncc[nH]5)C4)n3)c3cc(Cl)cnc32)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCN(Cc2ncc[nH]2)C1
Temperature: 120 °C

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-1-(1H-imidazol-2-ylmethyl)-3-piperidyl]pyrimidin-4-amine, 4a, (0.08 g, 0.13 mmol) in THF (2.5 mL) was added 1M LiOH (0.67 mL, 0.65 mmol) solution. The reaction mixture was heated in microwave at 120° C. for 10 minutes. The mixture was cooled to room temperature and diluted with brine. The aqueous phase was extracted with CH2Cl2, then twice with 20% isopropanol/CH2Cl2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to afford the desired product, 589, as a white solid.
Reaction SMILES: [NH2:1][C:2]1([C:10]#[N:11])[CH2:7][CH2:6][N:5]([O:8][CH3:9])[CH2:4][CH2:3]1.[CH2:12](ON1CCC(=O)CC1)C>>[NH2:1][C:2]1([C:10]#[N:11])[CH2:3][CH2:4][N:5]([O:8][CH2:9][CH3:12])[CH2:6][CH2:7]1
Reactant: CCON1CCC(=O)CC1
Reactant: CON1CCC(N)(C#N)CC1
Product: CCON1CCC(N)(C#N)CC1

Procedure:
4-Amino-1-ethoxy-piperidine-4-carbonitrile was prepared analogously to the synthesis of 4-amino-1-methoxy-piperidine-4-carbonitrile (preparation example P1, step P1.1) starting from N-ethoxy-4-piperidone (Journal of Organic Chemistry (1961), 26, 1867-74).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)nc1

Procedure:
To 7.88 g of 6-chloronicotinic acid were added 7.3 ml of thionyl chloride and a few drops of DMF. The mixture was heated under reflux for 2 hours, and then the excess of thionyl chloride was distilled off to give crystals of 6-chloronicotinoyl chloride. A solution of the crystals in 60 ml of tetrahydrofuran was added dropwise to a solution of 15.47 g of 5-aminopentanol in 200 ml of tetrahydrofuran at a temperature below 0° C. The mixture was stirred overnight while gradually raising the temperature to room temperature. The solvent was distilled off and to the residue was added water followed by extraction with ethyl acetate. Then, the extract was washed successively with water and a saturated brine solution, dried over magnesium sulfate. The solvent was distilled off and the residue was recrystallized from ethyl acetate to give 11.24 g of N-(5-hydroxypentyl)-6-chloronicotinamide (yield 93%).
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].C1(C)C=CC=CC=1.[NH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]>O>[O:20]=[C:16]1[CH2:17][CH2:18][CH2:19][N:15]1/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4]
Reactant: CCC(=O)C(=O)O
Reactant: O=C1CCCN1
Solvent: Cc1ccccc1
Solvent: O
Product: C/C=C(/C(=O)O)N1CCCC1=O
Temperature: 25 °C
Yield: 67.6 %

Procedure:
A1 l flask fitted with a magnetic stirring bar and a Dean-Stark trap was charged with 2-oxobutanoic acid (25 g, 245 mmol), toluene (500 ml, 20 vol) and 2-pyrrolidinone (37.2 ml, 490 mmol, 2 equiv). The reaction mixture was stirred under reflux with azeotropic removal of water via the Dean-Stark trap for 5.5 hours. The solution was then concentrated to ca. 90 ml (3.6 vol) and allowed to cool slowly to ambient temperature. Off-white solid started to come out of solution at around 55° C. The solid was filtered, the cake was washed with toluene (2×1 vol) followed by dichloromethane (3×1 vol) and dried on the filter under vacuum for 5 min to afford crude material (28 g, 70% yield). The crude product was dissolved in acetone (450 ml, 16 vol) at reflux, cooled slowly to ambient temperature and allowed to crystallise over 12 hrs at −15 to −20° C. Pure product was obtained as a white crystalline solid (21 g, 51% overall yield).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].FC(F)(F)C(O)=O.[C:17]1(=O)OC(=O)[CH2:20][C@@H:18]1O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(C)C>[CH:18]([O:8][C:1](=[O:9])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3])([CH3:20])[CH3:17]
Reactant: O=C1C[C@H](O)C(=O)O1
Reactant: O=C(O)C[C@H](O)C(=O)O
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)OC(=O)[C@@H](O)CC(=O)O
Yield: 97.7 %

Procedure:
By the use of the procedures and conditions described by Example 3A, L-malic acid was converted to L-malic anhydride trifluoroacetate with trifluoroacetic anhydride, and the anhydride allowed to react with isopropyl alcohol to provide in 97.7% yield L-malic acid monoisopropyl ester as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:4][OH:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Yield: 81 %

Procedure:
Was prepared from 1,4-dibenzyl-piperidine-4-carboxylic acid ethyl ester (J. Chem. Soc., Perkin Trans. 1 1996, 20, 2545-2551.) by lithium aluminium hydride reduction in tetrahydrofurane under standard conditions in 81% yield. MS 296(M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH2:9][O:10][CH3:11])([CH3:8])[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][N:46]([CH2:64][CH2:65][CH2:66][NH:67][CH3:68])[CH2:47][CH2:48][C:49]1([OH:63])[CH2:54][CH:53]2[CH2:55][CH2:56][CH:50]1[CH:51]=[C:52]2[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C(Cl)Cl>[OH:63][C@@:49]1([CH2:48][CH2:47][N:46]([CH3:45])[CH2:64][CH2:65][CH2:66][N:67]([CH3:68])[C:5](=[O:7])[C:4]([CH2:3][O:2][CH3:1])([CH3:8])[CH2:9][O:10][CH3:11])[CH2:54][C@H:53]2[CH2:55][CH2:56][C@@H:50]1[CH:51]=[C:52]2[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CNCCCN(C)CCC1(O)CC2CCC1C=C2c1ccccc1
Reactant: COCC(C)(COC)C(=O)O
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: ClCCl
Product: COCC(C)(COC)C(=O)N(C)CCCN(C)CC[C@]1(O)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 65 mg 3-methoxy-2-methoxymethyl-2-methyl-propionic acid in 0.5 mL DCM was added 0.14 mL DIPEA followed by 133 mg HATU. The resulting mixture was stirred at rt for 20 min before 88 mg of rac-(1R*,2R*,4R*)-2-{2-[methyl-(3-methylamino-propyl)-amino]-ethyl}-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol, dissolved in 1 mL DCM was added. After stirring overnight the reaction was quenched with water. The water phase was extracted with DCM, the combined organic phases were washed with brine, dried and concentrated in vacuo. The residue was purified by CC with EtOAc-MeOH (3:1) to obtain 115 mg of rac-N-(3-{[2-((1R*,2R*,4R*)-2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-methyl-amino}-propyl)-3-methoxy-2-methoxymethyl-2,N-dimethyl-propionamide as colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([O-:19])(=[O:18])=[O:17])([CH3:3])[CH3:2].[OH:20][C:21]1[CH:26]=[CH:25][C:24]([S+:27]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:40][CH:39]=2)[C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)CCN(C)C.[CH:62]([O:64][CH2:65][CH2:66]Cl)=[CH2:63]>CS(C)=O>[CH:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[S:16]([O-:19])(=[O:17])=[O:18])([CH3:14])[CH3:15].[CH:62]([O:64][CH2:65][CH2:66][O:20][C:21]1[CH:26]=[CH:25][C:24]([S+:27]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][CH:43]=2)[C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[CH2:63]
Reactant: CC(C)(C)c1ccc([S+](c2ccc(O)cc2)c2ccc(C(C)(C)C)cc2)cc1
Reactant: C=COCCCl
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)[O-])c(C(C)C)c1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: C=COCCOc1ccc([S+](c2ccc(C(C)(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
4-Hydroxyphenyldi(4-t-butylphenyl)sulfonium 2,4,6-triisopropylbenzenesulfonate salt (5.00 g), potassium carbonate (1.28 g), and N,N,N′,N′-tetramethylethylenediamine (0.10 g) were dissolved in dimethyl sulfoxide (15 g). Chloroethyl vinyl ether (0.83 g) was added to the solution, followed by heating to 80° C. The reaction mixture was stirred for 15 hours and cooled to 30° C. or lower. After removal of solid through filtration, water (75 g) and dichloromethane (44 g) were added to the filtrate, whereby the target substance was extracted to the dichloromethane layer. The organic layer was repeatedly washed with distilled water until the pH of the separated aqueous layer was shifted to 7. The solvent was removed by means of a rotary evaporator, to thereby yield 4.64 g of a brown oily substance. Through 1H-NMR and ion chromatography, the substance was identified to be 4-vinyloxyethoxyphenyldi(4-t-butylphenyl)sulfonium 2,4,6-triisopropylbenzenesulfonate salt.
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Br:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([NH:25][CH2:26][CH2:27][CH2:28][OH:29])=[C:17]([N+:22]([O-])=O)[CH:18]=[N:19]2)=[CH:14][CH:13]=1>O.C(O)C>[NH2:22][C:17]1[CH:18]=[N:19][C:20]2[C:15]([C:16]=1[NH:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:14][CH:13]=[C:12]([Br:11])[CH:21]=2
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCO
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cnc2cc(Br)ccc2c1NCCCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
A solution of sodium dithionate (27.5 g, 158 mmol) in water (60 mL) was added to a solution of 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol (10.3 g, 31.6 mmol) in ethanol (175 mL), and the mixture was stirred vigorously for four hours at ambient temperature. The solvent was removed under reduced pressure, and the residue was partitioned between dichloromethane/chloroform/methanol (500 mL) and saturated aqueous sodium bicarbonate (200 mL). The aqueous layer was separated and extracted with chloroform (5×200 mL), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 7.27 g of 3-[(3-amino-7-bromoquinolin-4-yl)amino]propan-1-ol.