Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([I:14])=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]([C:16]([O:18]CC)=O)=[CH:5]2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.ClCCl.Cl>CO>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:16]([C:6]2[C:7](=[O:15])[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=2)=[O:18])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2ccc(I)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(I)cc2c1=O
Temperature: 180 °C

Procedure:
To a flask containing ethyl 1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate from Preparation No. 19 (0.19 g) is added p-chlorobenzylamine (1.0 mL). The reaction is tightly capped and heated to 180° C. for 1 hour. The reaction is cooled to room temperature and partioned between dichloromethane containing methanol and dilute hydrochloric acid. The aqueous layer is extracted with dichloromethane and the combined organic layers are washed with brine, dried and concentarted under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% to 6% methanol in dichloromethane. The product containing fractions are evaporated to give 0.10 g of the title compound as a tan solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I-].C[N+:15](C)(C)N.CCC([O-])(C)C.[Na+]>CS(C)=O>[NH2:15][C:9]1[C:2]([OH:1])=[C:3]([CH:6]=[CH:7][C:8]=1[N+:10]([O-:12])=[O:11])[C:4]#[N:5]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Reactant: C[N+](C)(C)N
Agent: CCC(C)(C)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc([N+](=O)[O-])c(N)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 2-hydroxy-4-nitro-benzonitrile [1.0 g, 6.1 mmol, prepared as described in Yasubiro Imakura et. al. Chem. Pharm. Bull. 40 (7), 1691-1696 (1992)] in DMSO (60 mL) was added trimethylhydrazinium iodide (1.23 g, 6.09 mmol), followed by sodium tert-pentoxide (2.01 g, 6.09 mmol). The mixture was stirred at rt overnight, and then partitioned between 10% HCl and ether. The separated ether layer was washed with H2O, brine, dried (Na2SO4), and concentrated under reduced pressure to furnish the title compound (0.78 g) as a brown solid.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[C:6]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>N1C=CC=CC=1>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:11][CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(OP(=O)(Cl)Cl)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a mixture of 225 g. phosphoryl chloride and 1.6 g. pyridine there is added 150 g. p-tert-butylphenol over a period of two hours at a temperature of 100°C. The temperature is then raised to 110°C. and held for two hours, stripped and cooled. Distillation of the reaction mixture affords 94.3 percent p-tert-butylphenyl phosphorodichloridate and 2.5 percent di-p-tert-butylphenyl phosphorochloridate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.CN.[C:19]([BH3-])#[N:20].[Na+]>>[CH3:19][NH:20][CH:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[CH:8]1[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: [BH3-]C#N
Reactant: O=C1C2CCN(CC2)C1Cc1cccnc1
Agent: CN
Agent: [Na+]
Product: CNC1C2CCN(CC2)C1Cc1cccnc1

Procedure:
Another illustration of derivatization of saturated ketone intermediates is the reductive amination to give amines. Thus, 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one reacts with ammonium formate, zinc chloride and sodium cyanoborohydride to give 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as predominantly the cis diastereomer. Likewise, reaction of 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one with methylamine and sodium cyanoborohydride provides 3-(methylamino)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane. These amine derivatives can be used as a template for library formation by reacting them with a variety of acylating agents (e.g., acid chlorides, acid anhydrides, active esters, and carboxylic acids in the presence of coupling reagents) and isocyanates to produce 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes with amide and urea substituents in the 3-position of the 1-azabicyclo[2.2.2]octane, both of which classes are compounds of the present invention. Commercially unavailable isocyanates can be prepared in situ from corresponding amines and tiphosgene in the presence of triethylamine. Such derivtatives can be produced as single enantiomers, using the single enantiomers of 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane and 3-(methylamino)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as starting materials. For instance, the (2R,3R)- and (2S,3S)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanes can be produced by resolution of the cis 3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane, for example, using diastereomeric amides. Thus, when the cis amine is reacted with a chiral acid such as (S)—N-(tert-butoxycarbonyl)proline using a suitable coupling agent such as diphenylchlorophosphate, a pair of diastereomeric amides, separable by reverse phase chromatography, is produced. The separated proline amides can then be deprotected, for example, by treatment with trifluoroacetic acid (to remove the tert-butoxycarbonyl protecting group) and then the proline can be cleaved from the desired amine, for example, using Edman degradation conditions (i.e., phenylisothiocyanate, followed by trifluoroacetic acid).
Reaction SMILES: [CH:1]1[C:11](=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH:10]=[CH:9][C:3](=[C:4]([C:7]#[N:8])[C:5]#N)[CH:2]=1.[CH2:17]([N:21]([CH2:30][CH2:31][CH2:32][CH3:33])[C:22]1[CH:27]=[CH:26]C=[C:24]([O:28][CH3:29])[CH:23]=1)[CH2:18][CH2:19][CH3:20]>CN(C)C=O>[C:7]([C:4]([C:5]1[CH:26]=[CH:27][C:22]([N:21]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][C:24]=1[O:28][CH3:29])=[C:3]1[CH:2]=[CH:1][C:11](=[C:12]([C:15]#[N:16])[C:13]#[N:14])[CH:10]=[CH:9]1)#[N:8]
Reactant: N#CC(C#N)=c1ccc(=C(C#N)C#N)cc1
Reactant: CCCCN(CCCC)c1cccc(OC)c1
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C(C#N)=c2ccc(=C(C#N)C#N)cc2)c(OC)c1
Yield: 25.8 %

Procedure:
In 8 ml of N,N-dimethylformamide, 460 mg (2.25 mmol) of 7,7,8,8-tetracyanoquinodimethane was dissolved. With stirring under ice cooling, 500 mg (2.12 mmol) of dibutyl(3-methoxyphenyl)amine was dissolved in 2 ml of N,N-dimethylformamide and added dropwise. The mixture was stirred for 1.5 hours. After the ice bath was removed, the mixture was further stirred for 3.5 hours. After the reaction mixture was poured into 100 ml of water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography and washed with chloroform to give 226 mg of an off-white crystal having a mp of 215-238° C. (yield: 25.6%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][OH:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:26]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]=1[OH:39])[C:33](Cl)=[O:34])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:40]([C:37]1[CH:36]=[C:32]([CH:31]=[C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:38]=1[OH:39])[C:33]([O:19][CH2:18][CH2:17][S:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=1)=[O:34])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(SCCO)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(SCCOC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
A solution of 9.8 g of 2-(3,5-di-tert-butyl-4-hydroxyphenylthio) ethanol and 3.1 g of pyridine in 40 ml of toluene was added at 15°-20° C. over five minutes to a solution of 9.4 g of 3,5-di-tert-butyl-4-hydroxybenzoyl chloride in 50 ml of toluene. The reaction mixture was stirred at room temperature for 15 hours and then the resultant precipitate of triethylamine hydrochloride was removed by filtration. The solvent was removed in vacuo and the residue was recrystalized from n-heptane to give 15 g (84%) of a white solid, mp 136°-139° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].Cl[S:15]([C:18]1[CH:19]=[CH:20][C:21]([OH:28])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:17])=[O:16]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([N:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[S:15]([C:18]2[CH:19]=[CH:20][C:21]([OH:28])=[C:22]([CH:27]=2)[C:23]([O:25][CH3:26])=[O:24])(=[O:17])=[O:16])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(NCC(C)C)cc1
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Solvent: c1ccncc1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(O)c(C(=O)OC)c2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of 4-ethyl-N-isobutylaniline (598 mg, 3.37 mmol) in pyridine (10 mL) stirred in air at 20° C., was added methyl 5-(chlorosulfonyl)-2-hydroxybenzoate (845 mg, 3.37 mmol) portionwise, over 1 hour. The reaction mixture was then stirred at 20° C. for 30 minutes. The solvent was evaporated in vacuo to give the crude product as a yellow sticky solid. This was triturated with methanol then filtered and dried to give the title product as a white solid, 907 mg. LCMS [LCMS1] Rt 1.38 min, m/z (ES+) 392 (M+H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C:11](=O)[CH:10]([CH2:16][C:17]([OH:19])=O)[CH2:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:21][NH2:22]>C(O)C>[N:1]1([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C:11]2=[N:21][NH:22][C:17](=[O:19])[CH2:16][CH:10]2[CH2:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)CC1Cc2cc(-n3ccnc3)ccc2C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CC2Cc3cc(-n4ccnc4)ccc3C2=NN1
Yield: 48 %

Procedure:
A solution of 1.48 g of 2,3-dihydro-5-(1H-imidazol-1-yl)-1-oxo-1H-indene-2-acetic acid and 0.38 g of 85% hydrazine hydrate in 15 ml of ethanol is heated to reflux for three hours. The reaction mixture is filtered, the residue is washed with ethanol and purified by crystallization from ethanol to give 0.7 g of the product, 2,4,4a,5-tetrahydro-7-(1H-imidazol-1-yl)-3H-indeno[1,2-c]pyridazin-3-one, mp 263°-264° dec.
Reaction SMILES: C1(O[C:8](=[S:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[S:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=S)N1CCN(c2cccc(Cl)c2)CC1
Yield: 69 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C.O>[Cl:1][C:2]1[N:6]([CH3:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CI
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-1H-benzimidazole (5.03 g, 33.0 mmol) in anhydrous DMF (33 mL) at 0° C. was added portion-wise 95% NaH (871 mg, 36.3 mmol). The ice bath was removed and the resulting mixture was stirred at room temperature for 1 h. Iodomethane (4.68 g, 33.0 mmol) was added and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then diluted with water, and the resulting precipitate was collected by filtration and purified by recrystallization from hexane to yield 2-chloro-1-methyl-1H-benzimidazole. MS 167 (M+1)+
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:5]OS(C1C=CC(C)=CC=1)(=O)=O)#[N:2].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CS(C)=O>[C:1]([CH2:3][CH:4]([CH2:5][S:31][C:29](=[O:32])[CH3:30])[CH2:17][S:31][C:29](=[O:32])[CH3:30])#[N:2]
Reactant: Cc1ccc(S(=O)(=O)OCC(CC#N)COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)SCC(CC#N)CSC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 62 g of 2-cyanomethyl-1,3-bis(tosyloxy)propane in 250 ml DMSO is added dropwise to a stirred solution of 36 g potassium thioacetate in 200 ml of DMSO. After stirring for one hour and adding additional DMSO, the mixture is poured into ice/water. Extraction with diethylether yields a colored organic layer which is washed successively with aqueous NaOH, water and saturated NaCl solution until neutral. Drying and evaporating yields the desired 2-cyanomethyl-1,3-bis(acetylthio)propane as a slightly yellow liquid; b.p. 146°-150° C./0.50.1 mm Hg; yield 20 g. Identification by IR and NMR.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: O=Cc1c(O)cc(O)cc1Br
Solvent: ClCCl
Product: O=Cc1c(O)cc(OC2CCCCO2)cc1Br
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a mixture of 2-bromo-4,6-dihydroxybenzaldehyde (2.50 g, 11.5 mmol) in dichloromethane was added 3,4-dihydro-2H-pyran (1.45 g, 17.3 mol) and PPTs (0.58 g, 2.3 mmol) at room temperature. The resulting mixture was stirred for 2 h and quenched by saturated aqueous NaHCO3 (35 mL). The organic layer was washed with water (20 mL), brine (20 mL) and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=2:1) on silica gel to afford the title compound as a colorless oil (2.93 g, yield: 85%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:32].[K+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:7][CH:8]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:32])=[O:24])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C=O)cc2)cc1)NC(=O)OC(C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 91.4 %

Procedure:
Amide compound 10 (2.0 g, 4.85 mmol) was dissolved in THF (50 mL) and the solution stirred at 70° C. Potassium permanganate (3.06 g, 19.4 mmol) dissolved in water (50 mL) was added slowly through a dropping funnel (5 mL/min) over 2 hours. After addition was complete, reaction mixture was stirred at 70° C. for 30 min and cooled to room temperature. The brown precipitate was filtered over a Celite® bed and the filtrate was concentrated under reduced pressure. The residual oil was taken up in EtOAc (100 mL) and acidified with 2.0 M HCl. The organic layer was separated and washed with water (1×50 mL) and brine (1×50 mL), dried, and concentrated under reduced pressure to yield the desired acid compound 11 (1.9 g, 91%). 1H NMR (DMSO-d6): 12.7 (br, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.56 (ddd, J=13.6, 9.2, and 6.0 Hz, 1H), 2.93 (s, 3H), 2.74-2.91 (m, 5H), 1.31 (s, 9H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9][C:8]2=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:18]>ClCCl>[CH:1]1([N:7]2[CH2:11][CH:10]([CH2:12][O:13][CH3:18])[CH2:9][C:8]2=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC(CO)CN1C1CCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COCC1CC(=O)N(C2CCCCC2)C1
Temperature: 0 °C
Yield: 71 %

Procedure:
Dissolve 1-cyclohexyl-4-hydroxymethyl-pyrrolidin-2-one (preparation 2) (280 mg, 1.4 mmol) in dichloromethane (30 mL) and cool to 0° C. Add sodium hydride (57 mg, 1.4 mmol) and stir for 20 minutes. Add iodomethane (302 mg, 2.1 mmol) and stir for 24 hours. Quench reaction with water and extract with dichloromethane. Combine extracts, dry over sodium sulfate, filter, and concentrate. Purify by silica gel (1% methanol in ethyl acetate) to give 210 mg (70%) of the title compound. NMR (CDCl3) δ 3.90 (m, 1H), 3.40 (m, 1H), 3.31 (m, 4H), 3.25 (m, 1H), 3.11 (m, 1H), 2.50 (m, 2H), 2.12 (m, 1H), 1.75 (m, 2H), 1.65 (m, 3H), 1.33 (m, 4H), 1.05 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23].C(O)(=O)C(O)=O>CO.C(#N)C>[CH2:23]([N:11]1[CH2:12][CH2:13][C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)([OH:14])[CH2:10]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: C=CCN1CCC(O)(c2cc(F)cc(F)c2)C1

Procedure:
Preparation according to Example 51: Enantiomer E1 of 3-(3,5-difluorophenyl)-pyrrolidin-3-ol (0.18 g, 0.92 mmol), acetonitrile (6 mL), potassium carbonate (0.25 g, 1.84 mmol) and allyl bromide (0.077 mL, 0.92 mmol). Flash chromatography on silica gel (ethyl acetate/methanol, 10:1). Yield: 0.1 g. [α]D=+22.4° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 104-105° C.; MS m/z (relative intensity, 70 eV) 239 (M+, 40), 83 (bp), 198 (84), 82 (13), 14 (33), 127 (31).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[NH+]1C=CC=CC=1.[F:14][C:15]([F:19])([F:18])[CH2:16]O.FC(F)(F)C(Cl)=O>>[F:1][C:2]([F:7])([F:6])[C:3]([O:5][CH2:16][C:15]([F:19])([F:18])[F:14])=[O:4]
Reactant: O=C([O-])C(F)(F)F
Reactant: OCC(F)(F)F
Agent: O=C(Cl)C(F)(F)F
Agent: c1cc[nH+]cc1
Product: O=C(OCC(F)(F)F)C(F)(F)F
Yield: 566.8 %

Procedure:
30 g (0.16 mole) of pyridinium trifluoroacetate in 355 g (3.55 mole) of 2,2,2-trifluoroethanol were introduced as an initial charge into a laboratory circulating reactor apparatus (one-liter four-necked flask fitted with KPG stirrer, a Prominent pump, and a 30 cm column packed with Raschig rings), and the initial charge was circulated at an internal temperature of 54° C. 134 g (1.01 mole) of trifluoroacetyl chloride were subsequently metered into the flask via an immersed inlet tube over a period of 100 minutes. After the trifluoroacetyl chloride addition was complete, the mixture was allowed to react for a further 10 minutes. Subsequent fractional distillation of the reaction mixture via a Vigreux column (temperature at the distillation head: from 54° to 56° C.) yielded 177.8 g of trifluoroethyl trifluoroacetate, corresponding to 89.8% of the theoretical yield. The trifluoroethanol/pyridinium salt mixture remaining in the reservoir flask can be used again for esterification with equal effectiveness.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][OH:6].CCN(CC)CC.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][O:6][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: COc1cc(Cl)cc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)cc(COS(C)(=O)=O)c1
Yield: 93.1 %

Procedure:
To a solution of 3-chloro-5-methoxybenzyl alcohol (14.7 mmol, 2.54 g) in DCM (20 ml) was added Et3N (22 mmol, 2.23 g, 3.1 ml) and the solution was cooled to −10° C. on an acetone-ice batch. Methanesulfonic chloride (17.7 mmol, 2.03 g, 1.4 ml) was added dropwise under stirring. After 45 min the mixture was separated between DCM and H3PO4 (5% v/v in water, cold). The organic phase was washed with H3PO4 (5% v/v in water, cold), NaHCO3 (10% in water, cold), brine and dried (MgSO4). Filtration and removal of solvents under reduced pressure yielded the title compound (3.43 g, 93%) as a white solid. The product was used in the next step without further purification. 1H NMR (CDCl3, 500 MHz) δ 2.97 (s, 3H), 3.82 (s, 3H), 5.16 (s, 2H), 6.82 (s, 1H), 6.90 (s, 1H) and 6.98 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH:7]1([NH2:10])[CH2:9][CH2:8]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:7]1([NH:10][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])[CH2:9][CH2:8]1
Reactant: NC1CC1
Reactant: O=C(O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NC1CC1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of cyclopropanecarboxylic acid (1.00 g, 11.6 mmol) and cyclopropylamine (0.995 g, 1.5 eq) in 8 mL of methylene chloride was added DMAP (4-dimethylaminopyridine, 2.13 g, 1.5 eq) followed by EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.34 g, 1.5 eq). The reaction was stirred at room temperature for 2 h after which time it was diluted with 50 mL of methylene chloride and washed twice with 0.5 N aqueous HCl followed by water, saturated aqueous sodium bicarbonate, then brine. The solvent was removed under reduced pressure and the residue was purified by silica chromatography eluting with 1:1 hexane/ethyl acetate to afford N-cyclopropylcyclopropanecarboxamide (2-A).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[S:13][C:4]=2[CH:3]=1
Reactant: COC(=O)CS
Reactant: O=Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2ccc(Br)cc2s1

Procedure:
Starting from 6.54 g (32.2 mmol) of 4-bromo-2-fluorobenzaldehyde, by general method A with 1.93 g (48.3 mmol) of sodium hydride (60% in liquid paraffin) and 3.76 g (35.5 mmol) of methyl mercaptoacetate, 4.06 g (46% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1([C:5](=[O:12])[CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(OC(=O)C)(=O)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:6]([N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[O:12])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1(C(=O)Cn2cncn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CC1(C(=O)C(=Cc2ccc(Cl)cc2)n2cncn2)CC1
Temperature: 100 °C

Procedure:
1-(1-Methylcyclopropyl)-2-(1,2,4-triazole-1-yl)ethane-1-one (10 g, 0.06 mole), 4-chlorobenzaldehyde (9 g, 0.06 mole), anhydrous potassium carbonate (8 g, 0.06 mole) and acetic anhydride (100 ml) were mixed, and the mixture was heated to 100° C. for 6 hours with stirring. Precipitates in the reaction solution was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain an oily product. The oily product was extracted with chloroform (300 ml), and the extract was washed with a sodium hydrogen carbonate-saturated water (300 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. One drop of the residue was dissolved in acetone, and the acetone solution was gas-chromatographed under the conditions described below. Then, a peak corresponding to the II-A isomer was found at a retention time of 250 sec, and that corresponding to the II-B isomer at a retention time of 300 sec. The ratio of the both isomers was 19.1/63.5, i.e. about 1/3, as calculated from the percentage of each area.