Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([S:9]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20]C(C)(C)C)=O)[CH2:14][CH2:13]3)(=[O:11])=[O:10])[NH:8][C:4]=2[CH:3]=1.Cl.[N:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:42]=[CH:41][C:37](C(O)=O)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([S:9]([N:12]3[CH2:13][CH2:14][N:15]([C:18](=[O:20])[C:37]4[CH:36]=[CH:35][C:34]([C:31]5[CH:30]=[CH:29][N:28]=[CH:33][CH:32]=5)=[CH:42][CH:41]=4)[CH2:16][CH2:17]3)(=[O:10])=[O:11])[NH:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2nc3ccc(Cl)cc3[nH]2)CC1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2nc3ccc(Cl)cc3[nH]2)CC1
Reaction time: 4 h
Yield: 35.7 %

Procedure:
A solution of 1-(5-chlorobenzimidazol-2-ylsulphonyl)-4-(t-butyloxycarbonyl)piperazine (860 mg, 2.15 mmol) in dichloromethane/methanol (15 ml of 1:1) was treated with an excess of hydrogen chloride gas as a saturated solution in ethyl acetate. After stirring for 4 hrs. the solvent was removed in vacuo and the residue dried under high vacuum. This was then suspended in DMF and treated sequentially with 4-(4-pyridyl)benzoic acid (428 mg, 2.15 mmol), triethylamine (0.6 ml, 4.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC, 495 mg, 2.68 mmol). After stirring overnight the solvent was removed in vacuo and the residue taken up in dichloromethane (50 ml). This was washed sequentially with water, saturated sodium bicarbonate solution, water and brine. Evaporation of the solvent gave a residue which was purified by chromatography (MPLC on Merck Art 9385 silica, gradient eluting with ethyl acetate containing 0-8.0% methanol) to give 1-(5-chlorobenzimidazol-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine as colourless crystals (370 mg) from ethanol, m.p. 242-244° C., 1H NMR (d6DMSO) 3.0-3.4 ppm (broad s, 4H), 3.4-3.8 ppm (broad s, 4H), 7.4 ppm (d, 1H), 7.5 ppm (d, 2H), 7.6-7.8 ppm (m, 4H), 7.85 ppm 2H), 8.6 ppm (d, 2H), 14.0 ppm (broad s, 1H); MS (M+H)+ 482/484.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[N:12][C:24](=[O:25])[CH2:23][O:22][CH3:21])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 78.6 %

Procedure:
100 mg (0.5 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulphoximide (Example 1b) are dissolved in 3.33 ml dichloromethane, cooled in the ice-bath and treated with 0.1 ml (0.75 mmol) triethylamine. 0.068 ml (0.75 mmol) 2-methoxy-acetyl chloride are added dropwise with ice cooling. The mixture is stirred for 30 minutes in the ice-bath and for 15 hours at room temperature. After chromatographic purification (silica gel, hexane/ethyl acetate (0-50% ethyl acetate)), 107 mg (79%) of the desired product is obtained.
Reaction SMILES: CN(C)C=O.[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:9].S(Cl)(Cl)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:24][C:23]=1[O:33][CH3:34]>O>[CH3:34][O:33][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:22]=1[O:21][CH3:20])[CH:28]=[CH:29][C:30]([NH:9][C:8]1[C:7](=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:15])=[O:14])=[O:31]
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Solvent: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 38.5 %

Procedure:
To 15 ml of dimethylformamide was dissolved 2.06 g (0.015 mol) of anthranilic acid. To 10 ml of dimethylformamide were added in order 0.78 ml of thionyl chloride and 2.08 g (0.01 mol) of 3',4'-dimethoxycinnamic acid, during which the reaction system was stirred and cooled with ice and water. The resulting mixture was added dropwise to the above solution, with stirring at room temperature. After the completion of the dropping, the reaction mixture was stirred for additional 1.5 hours, and then treated in the same manner as in Example 1. There was obtained 1.26 g (yield: 38.5%) of N-(3',4'-dimethoxycinnamoyl)-anthranilic acid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1I.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.[Cu]I>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1
Reactant: Fc1ccc(I)c(F)c1
Reactant: O=Cc1c[nH]cn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=Cc1cn(-c2ccc(F)cc2F)cn1
Temperature: 110 °C
Yield: 74.5 %

Procedure:
To 1H-imidazole-4-carbaldehyde (3.01 g, 31.3 mmol), 2,4-difluoro-1-iodobenzene (1.008 g, 4.20 mmol), Cs2CO3 (2.281 g, 7.00 mmol) in DMF (50 mL) was added copper(I) iodide (0.033 g, 0.175 mmol) and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.100 g, 0.700 mmol). The reaction was heated to 110° C. for 18 hours. The reaction mixture was then cooled to room temperature and filtered, and washed with EtOAc (100 mL). The organic was washed with water (2×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel chromotography to give 1-(2,4-difluorophenyl)-1H-imidazole-4-carbaldehyde (651 mg), to which was added (S)-2-methylpropane-2-sulfinamide (0.424 g, 3.5 mmol), CuSO4 (0.798 g, 5 mmol) and DCE (10 mL). The reaction was heated to 65° C. for 18 hours. The reaction was cooled to rt, filtered and concentrated to give (S,E)-N-((1-(2,4-difluorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide, to which was added DCM (20 mL). The reaction mixture was cooled to −70° C. and methylmagnesium bromide (1.667 ml, 5 mmol) was added dropwise to the solution. The reaction was stirred for two hours and the cold bath was then removed, and the reaction was allowed to warm to rt and stir for 30 minutes. The reaction was cooled to 0° C. and HCl (1M) was added cautiously to quench until aqueous pH=8. The phases were separated and the aqueous layer was extracted with DCM (2×30 mL). Combined organic was dried (Na2SO4) and concentrated to give (S)—N—((S)-1-(1-(2,4-difluorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (230 mg), which was then dissolved in MeOH (5 mL) and HCl (0.5 mL, 4M) was added. The reaction was stirred for one hour and concentrated to give product (212 mg). LCMS m/z 224.1 (M+H)+; Rt-0.39 min.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([CH:16]2[CH2:21][CH2:20][O:19][C:17]2=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>C1COCC1>[N:7]1([CH:16]([CH2:21][CH2:20][OH:19])[CH2:17][OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: O=C1OCCC1n1ccc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC(CO)n1ccc2ccccc21
Temperature: 0 °C

Procedure:
To an ice cooled suspension of LAH (0.84 g, 0.022 mol) in dry THF (60 mL) was added 2-(indol-1-yl)butyrolactone {4 g, 0.02 mol). After 1 hour the mixture was quenched successively with water (0.84 mL), 15% aqueous sodium hydroxide (0.84 mL), and water (2.5 mL). The reaction was filtered and the filtrate was dried, and evaporated. The material obtained, 2.5 g of colorless oil (61% of theory), was used directly in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.[CH2:28]([N:35]1[CH2:39][C@@H:38]2[C@@H:40]([NH2:43])[CH2:41][CH2:42][C@@H:37]2[CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:28]([N:35]1[CH2:39][C@@H:38]2[C@@H:40]([NH:43][C:14](=[O:16])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:41][CH2:42][C@@H:37]2[CH2:36]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-L-leucine (0.374 g, 1.617 mmol), 1-hydroxybenzotriazole hydrate (0.248 g, 1.617 mmol), and (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 (0.318 g, 1.470 mmol) were combined in dichloromethane (3.0 mL). After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.286 mL, 1.617 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane (2×2 mL), and the extracts were applied directly to a 25 g silica gel cartridge and purified with a gradient of 5-40% acetone/hexanes over 30 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.61-8.64 (m, 1H), 7.96-7.99 (m, 1H), 7.42-7.44 (m, 2H), 7.36 (t, J=7.4 Hz, 2H), 7.28 (d, J=7.3 Hz, 1H), 4.65-4.73 (m, 1H), 4.37-4.45 (m, 1H), 3.59 (d, J=13.1 Hz, 1H), 3.43 (d, J=13.1 Hz, 1H), 2.81-2.84 (m, 1H), 2.55-2.58 (m, 1H), 2.44-2.54 (m, 2H), 2.24-2.36 (m, 2H), 2.02-2.13 (m, 1H), 1.78-1.94 (m, 4H), 1.53-1.66 (m, 1H), 1.50 (s, 9H), 1.26-1.43 (m, 1H), 0.87 (d, J=5.5 Hz, 3H), 0.83-0.85 (m, 3H); MS (ESI+) m/z 430 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O)([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[O:30][CH:27]([CH3:29])[CH3:28])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccccc1B(O)O
Reactant: O=C(Nc1cc(Cl)ncn1)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)Oc1ccccc1-c1cc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)ncn1
Temperature: 110 °C
Yield: 34.2 %

Procedure:
To a stirred mixture of 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (0.830 g, 2.22 mmol), 2-isopropyloxyphenylboronic acid (0.400 g, 2.22 mmol) in saturated sodium carbonate solution (10 ml) and 1,4-dioxane (10 ml) was added palladium(II) acetate (0.1 g, 0.44 mmol) followed by triphenylphosphine (0.11 g, 0.42 mmol) at room temperature under an atmosphere of nitrogen. The resulting mixture was heated to reflux at 110° C. for one hour and monitored by TLC. The reaction mixture was filtered through a celite bed and the filtrate was extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, elution with 50% ethyl acetate/n-hexanes) to afford 4-[6-(2-isopropoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XIII) (0.36 g, 37%) as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:23][N:7]2[C:8](=[O:22])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH2:10][C@@H:6]2[CH2:5]1.[CH2:24]([CH:27]1[CH2:29][O:28]1)[CH2:25][CH3:26].O>C1COCC1>[OH:28][CH:27]([CH2:24][CH2:25][CH3:26])[CH2:29][O:3][C@H:4]1[CH2:23][N:7]2[C:8](=[O:22])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=3)[CH2:10][C@@H:6]2[CH2:5]1
Reactant: CCCC1CO1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](O)CN12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(O)CO[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
NaH (25 mg, 70% in oil, 0.7 mmol) was added to a solution of (6R,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step e) (300 mg, 1 mmol) in anhydrous THF (10 mL), the mixture was stirred at room temperature for 0.5 hour, then 2-propyloxirane (300 mg, 3.5 mmol) was added to the solution, the mixture was stirred at 75° C. overnight in a sealed tube. The mixture was cooled and poured into water (50 mL), extracted with ethyl acetate (3×30 mL), the organic layers was combined and washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate=4:1) to yield 100 mg (26%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.62 (d, 2H, J=8.7 Hz), 7.19 (d, 2H, J=8.7 Hz), 4.20 (t, 1H, J=5.7 Hz), 4.09-4.00 (m, 3H), 3.82-3.74 (m, 2H), 3.52-3.43 (m, 1H), 3.37-3.18 (m, 2H), 2.26-2.10 (m, 2H), 1.60-1.38 (m, 5H), 0.96 (t, 3H, J=6.9 Hz); LC-MS: 389.1 [M+1]+.
Reaction SMILES: C[O-].[Na+].[ClH:4].[CH3:5][S:6]([NH:9][C:10]1[CH:23]=[CH:22][C:13]([C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1)(=[O:8])=[O:7].Cl.[Cl:25][CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:25].[ClH:4].[CH3:5][S:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:22][CH:23]=1)(=[O:7])=[O:8]
Reactant: ClCc1ccncc1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc(C(=O)C2CCN(Cc3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.4 %

Procedure:
1.13 g (18.8 mmol) of sodium methoxide was added to a suspension of 3.0 g (9.4 mmol) of 4-(4-methylsulfonylaminobenzoyl)piperidine hydrochloride and 1.55 g (9.4 mmol) of 4-chloromethylpyridine hydrochloride in 90 ml of acetonitrile. The mixture was stirred at room temperature for 10 min. 2.88 g of potassium carbonate was added to the mixture and the obtained mixture was refluxed for 3 h. After cooling, the liquid reaction mixture was filtered and the filtrate was concentrated, while the residue was purified according to silica gel chromatography (chloroform:methanol=95:5). The product was converted into its hydrochloride with ethanolic hydrogen chloride and recrystallized from methanol/isopropanol to obtain 1.4 g of the intended compound:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4](=[CH:16][NH:17][CH2:18][CH3:19])[C:5](=[O:15])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[C:5](=[O:15])[CH2:6][CH:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:17]([CH2:18][CH3:19])[CH:16]=1
Reactant: CCNC=C(C(=O)C=Cc1ccc(Cl)cc1)C(=O)OC
Solvent: CN(C)C=O
Product: CCN1C=C(C(=O)OC)C(=O)CC1c1ccc(Cl)cc1

Procedure:
5.2 g. of 2-(ethylaminomethylene)-5-(4-chlorophenyl)-3-oxo-4-pentenoic acid methyl ester in 50 ml. of dimethylformamide were held at 140°-150° C. for 3 hours. After removal of the solvent, there were obtained 1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid methyl ester in the form of a uniform oily residue.
Reaction SMILES: Br.[Br:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:4]=1N.Br.N([O-])=O.[Na+].[C:17](#[N:20])[CH:18]=[CH2:19]>O.C1CCCCC1.CC(C)=O>[Br:2][C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:4]=1/[CH:19]=[CH:18]/[C:17]#[N:20]
Reactant: Cc1cc(C)c(N)c(Br)c1
Reactant: C=CC#N
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCCCC1
Product: Cc1cc(C)c(/C=C/C#N)c(Br)c1
Temperature: 15 °C

Procedure:
A 5 1, 3-necked round-bottom flask, equipped with an overhead stirrer, thermometer and addition funnel was charged with 2-bromo-4,6-dimethylaniline hydrobromide (713 g, 2.54 mol) and acetone (1.9 1). The slurry was cooled to 15° C. and 48% aqueous hydrobromic acid (450 ml, 4.0 mol), was added. The mixture was cooled to -4° C. then a solution of sodium nitrite (219 g, 3.17 mol) in 400 ml of water was slowly added with vigorous stirring while maintaining an internal temperature of 0° C. Acrylonitrile (550 ml) was charged and the reaction mixture was degassed under vacuum then purged with nitrogen. Cuprous bromide (3.0 g, 0.021 mol) was charged and the mixture stirred with gradual warming to ambient temperature over 6 hours. The mixture was aged with stirring, for 6 additional hours. The mixture was concentrated under vacuum, collecting 3 1 of solvent. The residue was diluted with toluene (3 1), the organic extract was washed with 3×500 ml of water, dried over sodium sulfate, filtered, and concentrated to a volume of 1 1. The dark concentrate was charged with triethylamine (1.2 1) and heated at 80°-90° C. under nitrogen for 6.5 hours. The mixture was concentrated under vacuum to a thick slurry then diluted with toluene (2.5 1). The organic phase was extracted 2×500 ml with 3 N aqueous hydrochloric acid, 2×500 ml with water, then dried over sodium sulfate. After filtration the toluene extract was treated with activated charcoal (10 g) at ambient temperature then filtered through super-cel. Removal of the solvent in vacuo yielded a yellow oil which solidified on standing. The crude nitrile was dissolved in a solution of cyclohexane (525 ml) and hexanes (840 ml) with heating. The mixture was gradually cooled to 3° C., filtered, washed with 500 ml of cold hexane and dried in vacuo to yield the Compound 2a as a light yellow solid (mp 95°-96° C.). The crystallization mother liquors contained an additional product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([N+:25]([O-])=O)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([NH2:25])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ncc([N+](=O)[O-])cc3OC)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCC(c2ccc(-c3ncc(N)cc3OC)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of {4-[4-(3-Methoxy-5-nitro-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.14 g) in 10 Ml EtOAc was added 30 mg Pd/C. The reaction vessel was purged with hydrogen, then stirred overnight under a balloon atmosphere of hydrogen. Filtration through Celite followed by removal of solvent in vacuo afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.02 (m, 1 H) 1.01 (s, 3 H) 1.31 (td, J=12.57, 9.98 Hz, 2 H) 1.64 (d, J=11.37 Hz, 4 H) 2.09 (d, J=6.82 Hz, 2 H) 3.44 (s, 3 H) 3.59 (s, 3 H) 5.25 (s, 2 H) 6.52 (d, J=2.02 Hz, 1 H) 7.02 (d, J=8.34 Hz, 2 H).7.47 (d, J=2.02 Hz, 1 H) 7.54 (d, J=8.34 Hz, 2 H); (M+H)+ 355.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:20].[I-].[Na+].Cl[CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH3:41].[H-].[Na+].OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:25][C:26]2[S:30][C:29]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=3)=[N:28][C:27]=2[CH3:41])=[CH:8][C:7]=1[CH3:20]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: COC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1C
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N(Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C(=O)OC(C)(C)C)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 114.7 %

Procedure:
To an ice-cooled and stirred solution of (4-tert-butoxycarbonylamino-2-methyl-phenoxy)-acetic acid methyl ester (1.00 g, 3.39 mmol, example 17.3), sodium iodide (0.51 g, 3.39 mmol) and 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (1.09 g, 3.72 mmol, WO02/28433) in DMF (10 ml) was added within 10 min NaH (0.19 g, 55% in oil, 4.40 mmol). The reaction was stirred at 0° C. for 2 h, 30 min at RT and then neutralized with chilled aqueous 10% KHSO4 and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to give 2.14 g of (4-{tert-butoxycarbonyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2-methyl-phenoxy)-acetic acid methyl ester, MS: 551.3 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24].C(O)(=O)C(C(C(O)=O)O)O.C(C(C(C([O-])=O)O)O)([O-])=O.[NH4+].[NH4+]>>[CH3:1][N:2]([CH2:4][CH2:5][C@H:6]([O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:23]([C@H:26]([C@@H:28]([C:30]([O-:32])=[O:31])[OH:29])[OH:27])([O-:25])=[O:24]
Reactant: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Product: CN(C)CC[C@H](Oc1cccc2ccccc12)c1cccs1

Procedure:
first by converting it to a mixture of diastereoisomeric salts of N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate via reaction with optically active tartaric acid in the molar ratio 1:2 relative to the substance of formula III or with optically active alkali metal tartrate or ammonium tartrate, or an alkylammonium tartrate, of formula IV, in the molar ratio 1:1, followed by isolating the salt (S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate (2:1) (Scheme 2) from the mixture of the diastereoisomeric salts in an organic solvent, water or a mixture thereof
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(OC(C)C)(=O)C.[F:21][CH:22]([F:25])[CH2:23][OH:24].C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([O:24][CH2:23][CH:22]([F:25])[F:21])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: OCC(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)C
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OCC(F)F)c1
Temperature: 2.5 °C
Yield: 97.4 %

Procedure:
194 g 3-nitro-benzenesulfonyl chloride (1.13 equiv.) were charged in the reaction vessel followed by 1.3 l isopropyl acetate and the solution was cooled to 0-5° C. A solution of 65 g 2,2-difluoroethanol (753 mmol, 1 equiv.), 163 ml triethylamine (1.55 equiv.) and 325 ml isopropyl acetate was added dropwise over 30 min, keeping the temperature between 0-5° C. After 4 h reaction (HPLC in process control), the reaction mixture was washed with 650 ml water. The water phase was re-extracted with 650 ml isopropyl acetate. The organic phases were washed with 650 ml 1M HClaq and 650 ml 10% NaClaq solution. The organic phases were combined, dried over MgSO4, filtered and concentrated to dryness under reduced pressure to give 196 g 2,2-difluoroethyl 3-nitrobenzenesulfonate (97% yield) as a viscous oil which crystallized on standing. The product can also be crystallized from isopropanol (seeding at 30° C., concentration: ca 13 L/kg product).