Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])=[CH:22][C:21]=1[OH:40].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[N:29]([CH3:38])[C:28]2=[O:39])=[CH:22][C:21]=1[O:40][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)n3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A mixture of 5.29 g of 6-chloro-2-benzyloxy-3-nitropyridine, 6.77 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, 3.32 g of potassium carbonate and 30 ml of N,N-dimethylformamide was stirred for 30 minutes at room temperature, then at 50° C. for 2.5 hours. The resulted residue was added to ice water, extracted with ethyl acetate, and organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was recrystallized from ethyl acetate and hexane to obtain 9.11 g of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-benzyloxy-3-nitropyridine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[S:11])=[CH:8][N:7]=1.Br[CH2:16][C:17](=O)[CH2:18][CH3:19].C(N(CC)CC)C>CCO>[CH2:18]([C:17]1[N:12]=[C:10]([C:9]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH2:3][CH2:2][OH:1])=[N:7][CH:8]=2)[S:11][CH:16]=1)[CH3:19]
Reactant: CCC(=O)CBr
Reactant: NC(=S)c1ccc(OCCCO)nc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1csc(-c2ccc(OCCCO)nc2)n1
Temperature: 70 °C
Yield: 91 %

Procedure:
To a solution of 6-(3-hydroxy-propoxy)-thionicotinamide (Example 72, 8.8 g, 41.46 mmol) in EtOH (205 mL) at rt was added 1-bromo-2-butanone. The reaction mixture was then heated at 70° C. for 3 h. Upon completion, triethylamine was added and the volatiles were removed under reduced pressure. The crude material was suspended in CH2Cl2 and purified by flash chromatography. The column was eluted with a mixture of EtOAc/hexanes (30 to 50% EtOAc) to give the title compound as a white solid (10.04 g, 91%) after concentration of the chromatography fractions. 1H NMR (400 MHz, acetone-d6) δ 8.70 (s, 1H), 8.19 (dd, 1H), 7.15 (s, 1H), 6.86 (d, 1H), 4.48 (t, 2H), 3.74-3.71 (m, 3H), 2.83 (q, 2H), 2.01-1.98 (m, 2H), 1.32 (t, 3H). LC/MS m/z 265.3 (M+H)+; RT 2.12 min.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:15][CH2:14][C:13]2=[O:29])[CH2:8][CH2:7]1)=O)C.S1CCCC1.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CCOCC>[C:23]1([C:16]2[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[C:13](=[O:29])[CH2:14][N:15]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)N1CCC(N2C(=O)CN=C(c3ccccc3)c3ccccc32)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCSC1
Solvent: CCOCC
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1C1CCNCC1
Temperature: 110 °C
Yield: 106.1 %

Procedure:
To a solution of 1 g (2.6 mmol) of 12 in 1.1 ml (2.6×5 mmol) of tetrahydrothiophene is added 2 ml of methanesulfonic acid, and the mixture is heated at 110° C. (bath temperature) for 50 minutes. The reaction mixture is poured into ice water and shaken with ether. The aqueous layer is besified with aqueous potassium carbonate and extracted with methylene chloride. The methylene chloride layer is concentrated, and the residue is dissolved in 1 ml of methanol and mixed with 0.27 ml of 48% hydrobromic acid. The resultant crystals are recrystallized from methylene chloride-methanol to give 881 mg of 13 as crystals melting at 281°-283° C. (dec.). The yield is 86%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:15]C)[C:13]=1[OH:14])[CH:9]=[O:10].N1C=CC=CC=1.Cl>ClCCl>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([OH:15])[C:13]=1[OH:14])[CH:9]=[O:10]
Reactant: COc1cc(C=O)cc(F)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1cc(O)c(O)c(F)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
Anhydrous aluminum chloride (1.11 g, 8.2 mmol) was added to a solution of 3-fluoro-4-hydroxy-5-methoxy benzaldehyde (1.2 g; 6.8 mmol) in dry dichloromethane (16 ml) under an atmosphere of nitrogen. The reaction mixture was cooled down to 0° C., pyridine (2.5 ml; 31 mmol) was slowly added and the solution was heated to reflux and stirred for 24 h. The solution was cooled to 0° C. and 4M aqueous hydrochloric acid was added to the mixture until the pH was approximately 2. The organic phase was discarded and the water phase was extracted with ethyl ether (3×15 ml). The organic extracts were combined then dried over sodium sulfate and concentrated under vacuum to give 3-fluoro-4,5-dihydroxybenzaldehyde (0.904 g; 85% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 9.68 (d, 1H), 7.17 (dd, 1H), 7.16 (br. s, 1H). MS (EI) for C7H5FO3: 157 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:14]#[N:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:34][CH2:35][CH2:36][N:37]=[C:38]=[O:39]>C1COCC1>[NH2:1][CH:2]1[CH2:3][CH2:4][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:14]#[N:15])(=[O:10])=[O:9])[CH2:6][CH2:7]1.[Cl:34][CH2:35][CH2:36][NH:37][C:38]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([S:8]([C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)(=[O:10])=[O:9])[CH2:6][CH2:7]1)=[O:39]
Reactant: O=C=NCCCl
Agent: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(N)CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2cc(Cl)cc(Cl)c2)c(S(=O)(=O)N2CCC(NC(=O)NCCCl)CC2)c1
Reaction time: 1 h

Procedure:
3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile was prepared following the procedure of Example 1. The final product was prepared by dissolving 3-(4-aminopiperidin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile (1.00 g) in THF (30 mL) followed by the addition potassium carbonate (975 mg, 3.0 eq.), then 2-chloroethyl isocyanate (496 mg, 2.0 eq.) dropwise. After stirring for 1 hour, the starting material was consumed (confirmed by HPLC), and the mixture was filtered to remove potassium carbonate. The resulting filtrate was concentrated in vacuo, the solid triturated with dichlormethane and isopropyl ether, and fitted to obtain a white powder (838 mg, 67% yield, 97% purity).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1(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)C=CC=CC=1>[C:10]([CH:9]([S:8][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:13])(=[O:11])[NH2:12]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(Sc1cccc(Br)c1)C(N)=O
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(Sc1cccc(-c2ccc(C(=O)O)cc2)c1)C(N)=O

Procedure:
3.0 g 2-(3-Bromo-phenylsulfanyl)-propionamide, 1.95 g of 4-carboxybenzene-boronic acid, and 8.05 g potassium carbonate were stirred in a mixture of 25 ml dioxane and 25 ml water. 1.35 g tetrakis-triphenylphosphino-palladium were added under nitrogen atmosphere and the mixture was heated 85 C for 14 hrs. The mixture was diluted with 40 ml water and filtered. The filtrate was adjusted to pH 2 with conc. HCl and the precipitated product isolated by filtration.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]2[N:34]3[C:30]([S:31][CH:32]=[CH:33]3)=[N:29][C:28]=2[CH3:35])=[O:26])[CH2:19]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]3[N:34]4[C:30]([S:31][CH:32]=[CH:33]4)=[N:29][C:28]=3[CH3:35])=[O:26])[CH2:19]2)=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)c(F)c2)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccc(F)c(F)c2)s1

Procedure:
prepared by reaction of 5-(3,4-difluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:37]=[CH:36][C:35]([O:38]C)=[CH:34][C:7]=1[O:8][CH:9]1[CH2:12][N:11]([C:13]([CH3:33])([CH3:32])[CH2:14][CH2:15][C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([NH2:19])=[O:18])[CH2:10]1>ClCCl>[Cl:5][C:6]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:7]=1[O:8][CH:9]1[CH2:10][N:11]([C:13]([CH3:33])([CH3:32])[CH2:14][CH2:15][C:16]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([NH2:19])=[O:18])[CH2:12]1
Reactant: COc1ccc(Cl)c(OC2CN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC(Oc2cc(O)ccc2Cl)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Boron tribromide (1M in dichloromethane, 1.42 mL, 1.42 mmol) was added to an ice-cooled solution of the product of example 117 (70 mg, 0.142 mmol) in dichloromethane (5 mL) and the mixture was stirred at 0° C. for 1 hour. The reaction was then quenched with 0.88 ammonia (20 mL) and the solution stirred at room temperature for 18 hours. The organic layer was separated. The aqueous layer was extracted with dichloromethane (20 mls). The combined organic solution was washed with saturated sodium hydrogen carbonate solution (10 mL) and dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate:methanol:0.88 ammonia (90/10/1), 85:15 to 50:50. The resulting gum was dissolved in methanol (5 mls) and 1N hydrochloric acid in diethyl ether (0.5 ml) added. The solution was evaporated and the solid recrystallised from ethyl acetate/methanol to give the title compound hydrochloride salt as a purple solid in 30% yield, 22 mgs.
Reaction SMILES: C([NH:9][CH2:10][C@@H:11]([C@H:16]([OH:18])[CH3:17])[C:12]([O:14]C)=[O:13])(=O)C1C=CC=CC=1.[ClH:19]>>[ClH:19].[NH2:9][CH2:10][C@@H:11]([C@H:16]([OH:18])[CH3:17])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)[C@@H](CNC(=O)c1ccccc1)[C@@H](C)O
Agent: Cl
Product: C[C@@H](O)[C@H](CN)C(=O)O
Temperature: 25 °C
Yield: 93 %

Procedure:
10.65 g (42.43 mmol) of methyl (2S,3R)-2-[(N-benzoylamino)-methyl]-3-hydroxybutyrate was added to the 70 ml of 10% aqueous HCl solution at room temperature. The mixture was refluxed for 4.5 hours, then cooled to room temperature. Precipitated benzoic acid was filtered out, the filtrate was washed twice with 100 ml toluene, and the aqueous layer was taken and concentrated under reduced pressure to obtain 6.67 g of the title compound (yield: 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[NH:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Product: O=C(Nc1ccc2[nH]c(=O)[nH]c2c1)C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-chloro-phenoxy)-piperidin-1-yl]-oxo-acetic acid (Example 29d) and 5-amino-1,3-dihydro-benzimidazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and chloroform:methanol=10:1 as eluent. Melting Point: 286-288° C. (isopropanol)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14](=[CH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[S:8]([CH:11]1[CH2:13][CH2:12]1)(=[O:10])=[O:9].[CH:27]1(B(O)O)[CH2:29][CH2:28]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.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.C(OCC)(=O)C>[CH:27]1([C:2]2[CH:3]=[C:4]([C:14](=[CH:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=2[S:8]([CH:11]2[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH2:29][CH2:28]1
Reactant: CCOC(=O)C(=CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(Br)c1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(=CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 81.3 %

Procedure:
Ethyl 2-[3-bromo-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)acrylate (4.72 g), cyclopropylboronic acid (1.37 g), and tetrakis(triphenylphosphine)palladium (615 mg) were dissolved in toluene (142 mL), and to this solution were added tripotassium phosphate (4.07 g, 19.2 mmol) and water (7.1 mL). The mixture was stirred at 100° C. for 20 hours. It was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain ethyl 2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)acrylate (3.50 g) as an (E)/(Z)-mixture of olefin.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[OH2:7]>[O-2].[O-2].[Mn+4]>[OH:5][C:2]([CH3:6])([CH3:1])[C:3]([NH2:4])=[O:7].[CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4]
Reactant: O
Agent: [Mn+4]
Agent: CC(C)(O)C#N
Agent: [O-2]
Product: CC(C)(O)C(N)=O

Procedure:
It is publicly known that manganese dioxide is used as a solid catalyst in the hydration reaction of acetone cyanohydrin. According to any of the conventional processes, α-hydroxyisobutyramide is obtained by the reaction of acetone cyanohydrin with water as shown by the following reaction equation at a temperature of 40° to 100° C. in the presence of manganese-based catalyst and preferably an acetone-based solvent in a yield of 60 to 95%.
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[C:17]([C:19](=O)[NH:20]C(C)(C)C)[CH:16]=[C:15]([C:26](=O)[NH:27]C(C)(C)C)[CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)=O>>[F:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([C:26]#[N:27])[CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)NC(=O)c1cc(Oc2c([N+](=O)[O-])ccc(F)c2F)cc(C(=O)NC(C)(C)C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1

Procedure:
In another embodiment of the present invention there is provided a process for the preparation of a compound according to formula III wherein R2 is 3,5-dicyano-phenyl which process further comprises (i) contacting sodium 3,5-bis-tert-butylcarbamoyl-phenolate with 2,3,4-trifluoronitrobenzene in an appropriate solvent at temperatures from about −30° C. up to about 40° C. to afford a 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene; and (ii) contacting 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene with phosphorus oxychloride or a similar dehydrating agent to afford 3,4-difluoro-2-(3,5-dicyano-phenoxy)nitrobenzene 111 (R2=3,5-dicyanophenyl). The ether can be convert to IV (R2=3,5-dicyanophenyl) as described below.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:8]([O:26][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCCOC(=O)/C=C\C(=O)O

Procedure:
Into an autoclave, were charged 295 parts of maleic anhydride and 825 parts of stearyl alcohol. A mixture was reacted at 60° C. for 5 hours under sealed condition, to obtain maleic acid monostearyl ester, containing 1.5% unreacted maleic anhydride. After adding to the mixture, 11.2 parts of toluene, 275 parts of allyl chloride and 530 parts of tri-n-propyl amine, an atmosphere was substituted with nitrogen. The mixture was reacted at 80° C. for 8 hours, and cooled to a room temperature. The mixture was rinsed by 90 parts of 10% hydrochloric acid aqueous solution, followed by distillation of toluene, to obtain 1,200 parts of stearyl allyl maleate of 94.5% purity and of Gardner Color 9. A molar ratio of maleic anhydride:stearyl alcohol was 1:1.02, and maleic acid monostearyl ester:allyl chloride:tri-n-propyl amine was 1:1.19:1.23.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[CH2:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21]>>[CH2:23]([N:22]([CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)[CH2:20][CH3:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ICCCC1c2ccccc2C=Cc2ccccc21
Reactant: CCNCc1ccccc1
Product: CCN(CCCC1c2ccccc2C=Cc2ccccc21)Cc1ccccc1

Procedure:
5-(3-Iodopropyl)-5H-dibenzo[a,d]cycloheptene is added gradually to an excess of N-ethyl benzylamine in absolute alcohol with stirring and cooling. The reaction mixture then is heated to refluxing for 30 minutes and the alcohol distilled under reduced pressure. The residue is warmed with dilute acid and the acid-insoluble material separated. The aqueous layer then is rendered alkaline with sodium hydroxide and the liberated bases extracted into ether. The ether is evaporated and the product isolated by vacuum distillation.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@@H:15]([O:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C@H:16](O)[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:33])[C@@H:15]([O:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](Oc1ccc(F)cc1)[C@H](O)c1ccc(O)cc1
Agent: CC[SiH](CC)CC
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H](Cc1ccc(O)cc1)Oc1ccc(F)cc1

Procedure:
The target compound (1.21 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 20(d) using (S)-4-benzyl-3-[(2S,3R)-2-(4-fluorophenoxy)-3-hydroxy-3-(4-hydroxyphenyl)propionyl]oxazolidin-2-one (1.89 g) obtained from Reference example 22(c) and triethylsilane (5.4 ml).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([C:26]2[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([NH2:33])[N:27]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:33][C:28]4[N:27]=[C:26]([C:23]5[CH:24]=[N:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=5)[C:31]([CH3:32])=[CH:30][N:29]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(-c2nc(N)ncc2C)cn1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ncc2C)cn1
Temperature: 90 °C

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (369 mg, 1.42 mmol) and 4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-amine (153 mg, 0.71 mmol), pyridine (4 mL) was added. The reaction was heated at 90° C. for three and a half hours. The pyridine was evaporated under reduced pressure. The resulting mixture was dissolved in ethyl acetate and filtered. The filtrate was washed with saturated aqueous NaHCO3 (×3). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 440.13. Found 441.5 (M+1)+. Retention time 1.72 minutes.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH3:33])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)[CH3:33])=[O:26])[CH3:23]
Reactant: CCOC(=O)C1CCCC1NC
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCCC1N(C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1665 g, 0.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-Methylamino-cyclopentanecarboxylic acid ethyl ester (0.0856 g, 0.5 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1003 g, 0.525 mmol). Then N-methylmorpholine (115 μL, 1.05 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-methyl-amino}-cyclopentanecarboxylic acid ethyl ester, as a yellow oil. LC-MS (ESI) calcd for C19H26N4O7S2 486.12, found 487.2 [M+H+].