Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH2:12]O.[CH:20]([NH:23][CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>>[CH:20]([N:23]([CH2:12][CH2:11][CH:10]([C:4]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(C)cc1C(CCO)c1ccccc1
Product: COc1ccc(C)cc1C(CCN(C(C)C)C(C)C)c1ccccc1

Procedure:
U.S. Pat. No. 6,822,119 provides another alternate method for the preparation of tolterodine. The process involves reacting 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one with dimethyl sulphate in the presence of sodium hydroxide, and a phase transfer catalyst to obtain methyl-3-(2-methoxy-5-methylphenyl)-3-phenyl propionate. Reducing the ester thus obtained with a reducing agent in the presence of a Lewis acid to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol. Protecting the hydroxy group of the alcohol to followed by aminating with diisopropylamine to give N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropylamine and removing the hydroxy protecting group to obtain N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine of Formula I.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([Br:18])[CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.CCN(CC)CC>C(Cl)Cl>[Br:18][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:17]=[CH:16][C:6]=1[O:7][CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)COc1ccc(CN)cc1Br
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
To a solution of t-butyl 2-(4-(aminomethyl)-2-bromophenoxy)acetate (6) (88 mg, 1 eq, 0.28 mmol) in DCM (15 mL) was added 4-fluoro-benzenesulfonyl chloride (65 mg, 0.33 mmol, 1.2 eq) and Et3N (56 mg, 0.56 mmol, 2 eq). The mixture was stirred at room temperature for 2 h, filtered, concentrated in vacuo and purified by preparative TLC to give 64 mg (48%) of t-butyl 2-(2-bromo-4-((4-fluorophenylsulfonamido)methyl)phenoxy)acetate (7).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]([N:19]=[C:20]=[S:21])([CH3:18])([CH3:17])[CH3:16].O>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[S:21])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)N=C=S
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NC(=S)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
24.93 g of 4-amino-1-benzylpiperidine are dissolved in 300 ml of dichloromethane and then 16.7 ml of tert-butylisothiocyanate are added dropwise and at room temperature. The reaction mixture is stirred at room temperature for 5 hours and then water is added and the mixture is allowed to settle. The organic phase is separated, dried over sodium sulphate and evaporated. The residue obtained is crystallized from petroleum ether in order to give white crystals which melt at 137° C.; yield: 88%.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[SH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>O>[S:21]1[C:2]2=[CH:3][N:4]=[CH:5][CH:6]=[C:7]2[CH:8]=[C:22]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: O=Cc1ccncc1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2ccncc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a 50-mL round-bottom flask was added 3-fluoro-4-pyridinecarboxaldehyde (0.8 mL, 8.02 mmol) and N,N-dimethylformamide (14 mL) and the solution was cooled to 0° C. To this solution was added potassium carbonate (1.22 g, 8.828 mmol) and methyl 2-mercaptoacetate (0.754 mL, 8.427 mmol). The solution turned to a clear yellow solution after stirring for 10 min. After 30 min at 0° C., the reaction was warmed to room temperature and stirred over the weekend by which time a solid precipitate was formed. Water was added provide a homogeneous solution, which was cooled to 0° C., the solid was collected via vacuum filtration, and washed with cold water until clear and colorless affording methyl thieno[2,3-c]pyridine-2-carboxylate (1.55 g, 82%) as a white solid. LCMS: (FA) ES+ 194; 1H NMR (d6-DMSO, 300 MHz) δ9.37 (s, 1 H), 8.56 (d, J=5.4 Hz, 1 H), 8.26 (d, J=0.6 Hz, 1 H), 7.97 (dd, J=5.4 Hz, 1.2 Hz, 1 H), 3.92 (s, 3 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+]([O-])(O)=O.[C:11]1([NH:17][C:18]([NH2:20])=[NH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:21][C:22]1[O:29]C(=O)[CH:26]([C:30]([CH3:32])=O)[C:24](=O)[CH:23]=1.Cl>CN(C)C=O>[NH:17]([C:18]1[N:20]=[C:30]([CH3:32])[CH:26]=[C:24]([CH2:23][C:22]([CH3:21])=[O:29])[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Reactant: N=C(N)Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CN(C)C=O
Product: CC(=O)Cc1cc(C)nc(Nc2ccccc2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
Into a 500 ml reaction flask equipped with a stirrer, a thermometer and a condenser, 200 ml of dimethylformamide, 13.8 g (0.1 mol) of potassium carbonate, 39.6 g (0.2 mol) of phenylguanidine nitrate and 33.6 g (0.2 mol) of dehydroacetic acid were charged, and the reaction was conducted at 140° C. for 3 hours. After completion of the reaction, the reaction solution was cooled and put into ice water. Then, the reaction solution was extracted with toluene and washed with water. Then, 21 g (0.2 mol) of concentrated hydrochloric acid was dropwise added thereto. Precipitated crystals were collected by filtration, washed with toluene, then neutralized with an aqueous sodium carbonate solution and again extracted with toluene. This toluene layer was washed with water and concentrated to obtain 24.1 g of 2-anilino-4-methyl-6-acetonyl-pyrimidine having a melting point of from 77° to 80° C. The yield was 50%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:16][CH:15]=3)=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH:32]([CH2:36]CO)[CH2:33]CO.O>CN(C)C=O>[CH3:33][N:32]([CH3:36])[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:16][CH:15]=3)=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccnc(Cl)c2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: OCCNCCO
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cc(-c2cn(C)nc2-c2ccc(OCc3ccc4ccccc4n3)cc2)ccn1
Temperature: 130 °C

Procedure:
To a solution of 2-{4-[4-(2-Chloro-pyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline (100 mg) in dimethyl formamide (1 ml) was added diethanolamine (0.035 ml) and the reaction mixture heated at 130° C. for 72 h. The reaction mixture was poured into water and extracted with ethyl ether, dried magnesium sulfate, filtered and concentrated. Prep TLC eluting with 60% ethyl acetate/hexane provided the title compound as a Free base. The product was stirred in ethyl acetate and 1 eq. of succinic acid was added. After 18 h, the white precipitate was filtered to provide the succinate salt (24 mg). 1H NMR (400 MHz, DMSO) δ 8.40 (d, J=8.3 Hz, 1 H), 8.03 (s, 1 H), 7.98 (m, 2 H), 7.90 (d, J=5.4 Hz, 1 H), 7.77 (m, 1H), 7.65 (d, J=8.3 Hz, 1 H), 7.59 (m, 1 H), 7.31 (d, J=6.6 Hz, 2H), 7.04 (d, J=9.1 Hz, 2 H), 6.37 (m, 2 H), 5.35 (s, 2H), 3.84 (s, 3H), 2.80 (s, 6H) 2.37 (s, 4H); MS: M+H m/z=436.0).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([C:12]([O:14]C)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH:7]1([C:12](=[O:14])[CH2:25][C:24]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=2)=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C1CCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C1CCCC1)c1ccc(C(F)(F)F)cc1
Yield: 66.3 %

Procedure:
1.97 kg of potassium tert-butoxide, 2.26 kg of methyl cyclopentanecarboxylate, 1.66 kg of p-trifluoromethylacetophenone and 36 g of 18-crown-6 ether were refluxed in 18 litres of tetrahydrofuran for 4 hours. Quenching of the reaction was carried out using 16 litres of 10% strength hydrochloric acid at room temperature. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution. After distilling off the solvent, the residue was distilled in an oil-pump vacuum at 1.5 mbar. 1.664 kg of 1-cyclopentyl-3-(4-trifluoromethylphenyl)propane-1,3-dione resulted as an oil, which crystallized completely on allowing to stand.
Reaction SMILES: Cl.[CH2:2]([C:4]1([C:10]([O:12]CC)=[O:11])[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:3].[CH3:15][N:16]1[CH:20]=[C:19]([S:21](Cl)(=[O:23])=[O:22])[N:18]=[CH:17]1>>[CH2:2]([C:4]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][N:6]([S:21]([C:19]2[N:18]=[CH:17][N:16]([CH3:15])[CH:20]=2)(=[O:23])=[O:22])[CH2:5]1)[CH3:3]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)C1(CC)CCCNC1
Agent: Cl
Product: CCC1(C(=O)O)CCCN(S(=O)(=O)c2cn(C)cn2)C1

Procedure:
The title compound was synthesized as in Production Example 1, using the compound synthesized in (1) and 1-methyl-1H-imidazole-4-sulfonyl chloride as the raw material.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[C:10](I)[C:5]=2[S:4][CH:3]=1.[CH2:13]([O:15][CH:16]([O:28][CH2:29][CH3:30])/[CH:17]=[CH:18]/B1OC(C)(C)C(C)(C)O1)[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[C:10](/[CH:18]=[CH:17]/[CH:16]([O:28][CH2:29][CH3:30])[O:15][CH2:13][CH3:14])[C:5]=2[S:4][CH:3]=1
Reactant: Nc1ncc(I)c2scc(Br)c12
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(/C=C/c1cnc(N)c2c(Br)csc12)OCC
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of Example 21A (200 mg, 0.56 mmol), 2-[(1E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (175 mg, 0.67 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol) and Na2CO3 (120 mg, 1.13 mmol) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was heated in an 85° C. oil bath for 15 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted with dichloromethane and the extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide the desired product (150 mg, 75%). 1H NMR (DMSO-d6, 400 MHz) δ 8.02 (s, 1H), 7.88 (s, 1H), 6.74 (d, 1H), 6.09 (dd, 1H), 5.09 (d, 1H), 3.62 (m, 2H), 3.48 (m, 2H), 1.15 (t, 6H); MS m/e 357.1, 359.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])=[CH:17][CH:16]=2)[C@H:10]([O:35][CH2:36][C@H:37]2[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:45][C:46]1[CH:47]=[C:48]([O:56][CH3:57])[C:49]2[C:54]([CH:55]=1)=[CH:53][CH:52]=[CH:51][CH:50]=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:45][C:46]2[CH:47]=[C:48]([O:56][CH3:57])[C:49]3[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:55]=2)[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])=[CH:17][CH:16]=2)[C@H:10]([O:35][CH2:36][C@H:37]2[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)[C@H](OC[C@H]2COC(C)(C)O2)C1
Reactant: COc1cc(CCl)cc2ccccc12
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(OCCCOc3ccccc3[N+](=O)[O-])cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (f) the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reacted with 3-chloromethyl-1-methoxy-naphthalene [example 1) (α)]to yield the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 773 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-:3])=[O:2].[Cl:15]N1C(=O)CCC1=O.C(OCC)(=O)C>C(#N)C>[Cl:15][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:11]([F:12])([F:13])[F:14])[C:7]=1[NH2:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Yield: 75 %

Procedure:
4-Nitro-2-trifluoromethyl-phenylamine (5.6 g) and N-chlorosuccinimide (4.0 g) were suspended in acetonitrile (15 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. Ethyl acetate (80 mL) was added and the organic phase was washed with 5% aqueous NaOH (2×50 mL), water (2×50 mL) and brine (2×50 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 4.9 g (75% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, CDCl3): 5.35 (b, 2H), 8.35 (b, 1H), 8.37 (b, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])=O.[Na+].Cl.[NH2:15]O>C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:15])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1ccc(Cl)cc1

Procedure:
The compound (I) may be synthesized by reacting 4-chlorobenzaldehyde, sodium formate, hydroxylamine hydrochloride and formic acid to form 4-chlorobenzonitrile, which may be nitrated to form 4-chloro-3-nitrobenzonitrile. Finally, this compound is reacted with the appropriate amine to obtain the desired compound (I) of the present invention.
Reaction SMILES: [Cl-:1].[NH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][O:11][CH3:12])([CH3:8])[CH3:7].C(O[Cl:20])(C)(C)C>CO>[Cl-:20].[Cl:1][N:2]([Cl:20])[C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][O:11][CH3:12])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OCl
Reactant: COCC[N+](C)(C)CCC(C)(C)N
Agent: [Cl-]
Solvent: CO
Product: COCC[N+](C)(C)CCC(C)(C)N(Cl)Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 168.4 %

Procedure:
A solution of 3-amino-N-(2-methoxyethyl)-N,N,3-trimethylbutan-1-aminium chloride (830 mg, 3.5 mmol) in methanol (14 ml) was cooled to 0° C. tert-Butylhypochlorite (984 μl, 2.5 mmol) was added. The resulting solution was stirred for 45 minutes at 0° C. and then concentrated under reduced pressure. The residue was purified by reverse phase high pressure liquid chromatography eluting from a C18 column with a gradient of 5 to 95% CH3CN in water (with 0.01% acetic acid) to give 618 mg of a clear oil. 1H NMR (D2O, 400 MHz) δ 1.33 (s, 6H), 2.15-2.20 (m, 2H), 3.08 (s, 6H), 3.40 (s, 3H), 3.40-3.44 (m, 2H), 3.49-3.51 (m, 2H), 3.80-3.82 (m, 2H). 13C NMR (D2O, 100 MHz) δ 73.1, 65.5, 62.9, 62.9, 62.8, 60.8, 60.8, 60.7, 58.2, 51.5, 51.4, 51.4, 31.3, 22.8; LRMS (ESI/APCI) m/z 257 [M]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:27](O)=[O:28]>>[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:33]([F:38])([F:34])([F:35])([F:36])[F:37])[CH:32]=1)[C:27]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:28]
Reactant: O=C(O)c1cc(F)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2cc(F)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
Analogously to the process described in Example 26, 100 mg (0.346 mmol) of the compound of Example 6A and 97 mg (0.363 mmol) of 3-fluoro-5-(pentafluoro-λ6-sulphanyl)benzoic acid (JRD Fluorochemicals Ltd., United Kingdom) gave 165 mg (89% of theory) of the title compound. In this case, the reaction time was about 15 h.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][N:39]=1.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:44][C:42]2[CH:41]=[CH:40][N:39]=[C:38]([O:37][CH3:36])[CH:43]=2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: COc1cc(N)ccn1
Reactant: O=C(O)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccc(Cl)cc2F)ccn1
Yield: 38.6 %

Procedure:
A solution of 4-chloro-2-fluoro-benzoic acid (7.0 g, 40.10 mmol), HATU (15.25 g, 40.10 mmol), 2-methoxypyridin-4-amine (4.98 g, 40.10 mmol) and Et3N (22.4 mL, 160.4 mmol) in dichloromethane (63.0 mL) was stirred at room temperature overnight. The crude mixture was purified by column chromatography eluting with a gradient of ethyl acetate in hexanes (0-50%) to yield 4-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (4.35 g, 39%), as a white solid. ESI-MS m/z calc. 280.04, found 281.3 (M+1)+; Retention time: 1.31 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.09 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.66 (dd, J=10.1, 1.9 Hz, 1H), 7.46 (dd, J=8.3, 1.9 Hz, 1H), 7.21 (m, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)=[C:9]([F:25])[CH:8]=1.[N+:26]([O-])([OH:28])=[O:27]>>[Cl:6][C:7]1[C:12]([N+:26]([O-:28])=[O:27])=[CH:11][C:10]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:18]=2)=[C:9]([F:25])[CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(Cl)cc2F)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To 3.3 ml of concentrated sulfuric acid was added 0.50 g of 3-(4chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-11) at 5° C. Furthermore, 0.17 ml of 61% nitric acid was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was added to ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.55 g (yield, 95%) of 3-(4-chloro-2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-17; m.p., 98.3° C.).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:22][CH3:23])(=O)=O.O>C(#N)C>[CH2:22]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])[CH3:23]
Reactant: CCOS(=O)(=O)OCC
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(C=O)cc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Vanillin (10 g., 66 mmol) in acetonitrile (100 ml) was treated with finely-powdered, anhydrous potassium carbonate (12 g., 87 mmol) with vigorous stirring to yield a mobile suspension. Diethyl sulfate (11 ml, 84 mmol) was added at room temperature. The suspension was brought to reflux, becoming quite thick after 10 minutes, but thinning again after 20 minutes. Refluxing was continued for 48 hours, at which point water (5 ml) was added. After an additional 2 hours of reflux, the mixture was cooled and treated with 500 ml ice water. Stirring at 0° for several hours produced a granular precipitate which was filtered off and washed with water. Air drying afforded 11.5 g. of the product (97%) as an off-white solid melting at 61°-62.5° C. NMR and IR data are listed in Tables 3 and 7. ##STR25##
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[CH3:22][C@@H:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1.CN1C(=O)CCC1>CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][C@H:23]2[CH3:22])[N:3]=1
Reactant: C[C@@H]1COCCN1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCOC[C@H]2C)nc(Cl)c1C(=O)NCc1ccc(F)cc1
Temperature: 180 °C
Yield: 19.3 %

Procedure:
A mixture of 6.0 g (19.2 mmol) 2,6-dichloro-N-(4-fluorobenzyl)-4-methyl-pyridine-3-carboxylic amide (synthesized according to the methods described in section a) of example 2), 3.9 g (28.7 mmol) (R)-3-methylmorpholine hydrochloride, 13.0 ml (76.6 mmol) and NMP (18.4 ml) was heated in the MW to 180° C. for 16 h. After cooling to RT the mixture was partiotionated between EtOAc and a 2M aq. NaOH sol. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1) provided 1.4 g (3.7 mmol, 20%) 2-chloro-N-(4-fluorobenzyl)-4-methyl-6-[(3R)-3-methylmorpholino]-pyridine-3-carboxylic amide.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>N1CCCCC1>[CH2:10]([C:16]1[CH:23]=[CH:22][C:19](/[CH:20]=[C:2](/[C:3](=[O:4])[CH3:5])\[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCc1ccc(C=O)cc1
Solvent: C1CCNCC1
Product: CCCCCCc1ccc(/C=C(/C(C)=O)C(=O)OCC)cc1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
Ethyl acetoacetate (3.9g, 0.03 moles), parahexylbenzaldehyde (3.8g, 0.02 moles) and piperidine (3 drops) were stirred at room temperature for 20 hrs. and then stirred for 4 days at 70° C. Products A and B were separated and purified by silica gel chromatography. Structure assignments were supported by NMR, infrared and uv spectra and elemental analysis (302.4).