Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:39][C:40]([F:55])([F:54])[C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[C:44](Cl)=[O:45].C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:17])=[O:18])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]([O:25][C:44](=[O:45])[C:43]1[CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=[C:41]([C:40]([F:39])([F:54])[F:55])[CH:42]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O[C@@H]1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 69.3 %

Procedure:
A solution of (1R*,2R*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 4; 0.98 g, 2.25 mmol), triethylamine (0.6 ml), N,N-dimethylaminopyridine (100 mg) and 3,5-bis(trifluoromethyl)benzoyl chloride (0.6 ml, 3.33 mmol) in dry dichloromethane (10 ml) was stirred at room temperature for 6 days. The reaction mixture treated with saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 5-30%) to give the title compound (1.05 g, 69%).
Reaction SMILES: CC1[N:3]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH:20]([C:22]([F:25])([F:24])[F:23])[N:19]=[C:18]3[C:26]3[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])C(C)=CC=1.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.O>[CH3:32][C:27]1[C:26]([C:18]2[N:17]([C:14]3[CH:15]=[CH:16][C:11]([S:8]([NH2:3])(=[O:10])=[O:9])=[CH:12][CH:13]=3)[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[N:19]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Cc1ncccc1C1=NC(C(F)(F)F)CN1c1ccc(S(=O)(=O)n2c(C)ccc2C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1-c1nc(C(F)(F)F)cn1-c1ccc(S(N)(=O)=O)cc1
Yield: 78.5 %

Procedure:
A mixture of 3-[1-[4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]phenyl]-4,5-dihydro-4-(trifluoromethyl)-1H-imidazol-2-yl]-2-methylpyridine (Step 4) (4.6 g, 0.01 mol) in 75 mL of TFA and 25 mL of water was heated at reflux for 2 hours. The solution was cooled, treated with 400 nL of water and basified with sodium bicarbonate to pH 8. The aqueous phase was extracted with ethyl acetate (400 mL). The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/acetone, 95:5) to afford 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide as a white solid (3.0 g, 78%): mp (DSC): 235–237° C. Anal. Calc'd. for C16H13F3N3O2S: C, 50.26; H, 3.43; N, 14.65; S, 8.39. Found: C, 50.06; H,3.29; N. 14.4; S, 8.52.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:16]([O-])([OH:18])=[O:17].OS(O)(=O)=O>>[N+:16]([C:10]1[CH:11]=[C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=[CH:8][C:9]=1[NH:12][C:13](=[O:15])[CH3:14])([O-:18])=[O:17]
Reactant: CC(=O)Nc1ccc(N2CCCC2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc(N2CCCC2)cc1[N+](=O)[O-]

Procedure:
N-(4-Pyrrolidin-1-ylphenyl)acetamide obtained in step III above was nitrated using nitric acid (1.2 eq)+H2SO4 (1.0 eq) at 0 to 5° C. for 2 hrs. After the completion of the reaction, reaction mixture was added to ice and pH was adjusted to 8, extracted with dichloromethane, which was evaporated to dryness to obtain N-(2-nitro-4-pyrrolidin-1-ylphenyl)acetamide
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C@@H:8]([CH2:13][N:14]3[CH2:30][CH2:29][C:17]4([N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:20][NH:19][C:18]4=[O:28])[CH2:16][CH2:15]3)[C@@H:9]2O)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(O)(=O)C.C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]([CH2:13][N:14]3[CH2:30][CH2:29][C:17]4([N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:20][NH:19][C:18]4=[O:28])[CH2:16][CH2:15]3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C[C@@H]1CCc3ccc(Cl)cc3[C@H]1O)CC2
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NCN(c2ccccc2)C12CCN(CC1=Cc3cc(Cl)ccc3CC1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
trans-8-[(7-Chloro-1,2,3,4-tetrahydro-1-hydroxy-2-naphthalenyl)methyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (4.0 g, see example 190) is added in portions to 25 ml of 20% v/v sulfuric acid/acetic acid and the resulting solution is stirred for 16 hours at room temperature protected from moisture by a drying tube. The acid solution is then warmed for 5 minutes on a steam bath, cooled, poured onto 200 g of ice, and basified with solid sodium bicarbonate. The resulting mixture is extracted with methylene chloride. Concentration of the dried methylene chloride solution provides 2.3 g of a crude solid. Crystallization of this material from absolute ethanol gives 1.6 g of the title compound, melting point 191°-192° C.
Reaction SMILES: C1(O)C=CC=CC=1.[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])[CH3:9].OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.C(C1C=CC(O)=CC=1)(C)=C.[CH3:45][NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.OC1C=CC(C(C2C=CC(N)=CC=2)(C)C)=CC=1>>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]([C:50]2[CH:51]=[CH:52][C:47]([NH:46][CH3:45])=[CH:48][CH:49]=2)([CH3:10])[CH3:9])=[CH:12][CH:13]=1
Reactant: CC(C)c1ccc(O)cc1
Reactant: CNc1ccccc1
Agent: C=C(C)c1ccc(O)cc1
Agent: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: Oc1ccccc1
Product: CNc1ccc(C(C)(C)c2ccc(O)cc2)cc1
Temperature: 170 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
N-methylaniline (20 g) was added to 50 g of a mixture of alkenyl phenols and phenol obtained by the alkali cleavage of bisphenol A (consisting of 47.7% of phenol, 1.4% of p-isopropyl phenol, 1.1% of bisphenol A, 21.4% of p-isopropyl phenol monomer, 4.8% of a linear dimer of p-isopropenyl phenol, 4.4% of a linear trimer and higher polymers of p-isopropenyl phenol, and 19.2% of other compounds) (1.62 moles of N-methylaniline per mole of the p-isopropenyl phenol monomeric unit). The mixture was stirred at 170° C. Then, 0.8 g of the catalyst solution prepared in Example 1 (0.0026 mole of catalyst per mole of the p-isopropenyl phenol monomeric unit) was added, and the reaction was performed for 3 hours. Gas-chromatographic analysis of the reaction mixture showed that 0.98 g of bisphenol A and 25.4 g (yield 92%) of 2-(4'-hydroxyphenyl)-2-(4'-methylaminophenyl)-propane having a melting point of 135.5° to 137° C. were formed.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]([OH:11])[CH3:10]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][O:11][CH:9]1[CH2:3][CH2:4][O:6][CH2:7][CH2:10]1)[CH3:8]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCO
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COC1CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of tetrahydro-4H-pyran-4-one (1.0 g, 10.0 mmol) in cold (0° C.) THF is added 1.0M lithium aluminum hydride in THF (5 mL, 5.0 mmol). The reaction mixture is stirred at 0° C. for 15 min. followed by the sequential addition of water (0.190 mL), 5M sodium hydroxide (0.190 mL), and water (0.190 mL) and Et2O. The mixture is filtered, and the filtrate is evaporated to give tetrahydro-4H-pyran-4-ol, which is dissolved in dichloromethane (30 mL). To the solution is added rhodium (II) acetate dimer (44 mg) followed by ethyl diazoacetate (1.25 g, 11.0 mmol). The reaction mixture is stirred at RT for 40 min. The reaction mixture is diluted with ethanol, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 1.67 g of the product 409. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.11 (s, 2H), 3.95 (dt, 2H), 3.59 (m, 1H), 3.42 (dt, 2H), 1.91 (m, 2H), 1.62 (m, 2H), 1.28 (t, 3H); MS: m/z 189 (M++1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=1[OH:19])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[O:4]=[C:3]1[CH2:2][O:19][C:7]2[CH:8]=[C:9]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:11][C:6]=2[NH:5]1
Reactant: CCOC(=O)C(C)c1ccc(NC(=O)CCl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)c1ccc2c(c1)OCC(=O)N2
Temperature: 25 °C

Procedure:
A solution of ethyl 2-(4-(2-chloroacetamido)-3-hydroxyphenyl)propanoate (110 mg, 0.385 mmol) in acetone (10 mL) was added potassium carbonate (61 mg). the reaction mixture was refluxed for 3 hrs then cooled to room temperature. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:2) as eluent.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([I:20])=[C:5]([C:7]([I:19])=[C:8]([C:11]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[O:12])[C:9]=1[I:10])[NH2:6].C(O[C:25](=[O:27])[CH3:26])(=O)C>N1C=CC=CC=1>[C:2]([O:1][CH2:2][C:3]1[C:4]([I:20])=[C:5]([C:7]([I:19])=[C:8]([C:11]([NH:13][CH2:14][CH:15]([O:18][C:25](=[O:27])[CH3:26])[CH2:16][O:17][C:11](=[O:12])[CH3:8])=[O:12])[C:9]=1[I:10])[NH2:6])(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(I)c(CO)c(I)c(C(=O)NCC(O)CO)c1I
Solvent: c1ccncc1
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Hydroxymethyl-5-(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodoaniline (1.32 g, 2.1 mmol) was dissolved in pyridine (10 ml) containing acetic anhydride (10 ml). The mixture was stirred at room temperature for 2 h and CH2Cl2 (100 ml) and the solution was washed with water (3×25 ml). The organic phase was washed with water (3×50 ml) and a saturated aqueous solution of NaHCO3 (2×50 ml). After drying (Na2SO4) and evaporation, the residue was purified by flash chromatography on a silica column using a mixture of CH2Cl2 and methanol (95:5) as the eluent. Yield: 1.30 g (82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.C(N(CC)C(C)C)(C)C>C(OCCO)C>[C:19]([O:18][C:16]([NH:15][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[CH:7][CH:6]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:17])([CH3:21])([CH3:20])[CH3:22]
Reactant: Clc1nccc2ccccc12
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Solvent: CCOCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3ccccc23)cc1)NC(=O)OC(C)(C)C

Procedure:
A stirred solution of ethyl (S)-3-(4-aminophenyl)-2-(N-t-butyloxycarbonylamino)propanoate (3.08 g, 10.0 mmol), 1-chloroisoquinoline (1.80 g, 11.0 mmol) and N,N-diisopropylethylamine (1.42 g, 1.91 ml, 11.0 mmol) in 2-ethoxyethanol (1.0 ml) was heated at 130° for 4 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (120 ml) and saturated aqueous NaHCO3 (50 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (80 ml). The combined organic extracts were washed with brine (30 ml), dried (MgSO4) and evaporated in vacuo. The obtained dark oil was chromatographed (silica; 20-30% EtOAc/hexane) to afford the title compound as a pink oil which crystallised on standing (2.78 g, 64%). δH (CDCl3) 8.07 (1H, d, J 5.8 Hz), 7.93 (1H, d, J 8.4 Hz), 7.72 (1H, d, J 7.5 Hz), 7.63 (1H, d), 7.61 (2H, d, J 8.5 Hz), 7.51 (1H, t, J 6.8 Hz), 7.23 (1H, br s), 7.10 (1H, br s), 7.10 (2H, d, J 6.8 Hz), 5.02 (1H, br d, J 8.0 Hz), 4.54 (1H, br m), 4.16 (2H, t, J 7.1 Hz), 3.05 (2H, br m), 1.43 (9H, s), 1.25 (3H, t, J 7.1 Hz); m/z (ES+, 60V) 436 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17](F)=[C:18]([CH:21]=1)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:17]2[CH:16]=[CH:15][C:14]([Br:13])=[CH:21][C:18]=2[CH:19]=[O:20])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
(3-Hydroxy-phenyl)-acetic acid methyl ester (1.44 g, 8.66 mmol), 5-bromo-2-fluorobenzaldehyde (1.76 g, 8.66 mmol), and potassium carbonate (2.39 g, 17.32 mmol) were combined in 1,4-dioxane (18 mL) and heated to 100° C. overnight. Some starting material was still observed by analytical LCMS, so additional potassium carbonate (0.6 g, 4.3 mmol) was added, and the reaction was stirred at 100° C. for 4 hours. The mixture was cooled to room temperature and partitioned between EtOAc and H2O. Brine was added to facilitate separation, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography (10-30% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[N:17]=[C:18]([CH3:21])[S:19][CH:20]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH2:25].Cl>CC(O)CCC.C(O)(C)C>[ClH:1].[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[N:17]=[C:18]([CH3:21])[S:19][CH:20]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1csc(C)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)cnnc2cc1OCc1csc(C)n1
Yield: 89.2 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline (150 mg, 0.46 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (78 mg, 0.56 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (3 ml) and a 5M solution of hydrogen chloride in isopropanol (105 μl) was heated at reflux for 90 minutes. The solid obtained was filtered off, washed with isopropanol followed by ether to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[(2-methylthiazol-4-yl)methoxy]cinnoline hydrochloride as a pale yellow solid (190 mg, 82%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1>O>[CH3:11][C:12]1[S:13][C:14]([CH3:17])=[CH:15][C:16]=1[CH:8]=[O:9]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C)s1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(C=O)c(C)s1
Temperature: 100 °C
Reaction time: 15 h
Yield: 10.1 %

Procedure:
Phosphorus oxychloride (10 ml) was slowly added dropwise to dimethylformamide (30 g) under ice-cooling, and 2,5-dimethylthiophene (11.2 g) was added. The mixture was stirred at 100° C. for 15 hours, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2,5-dimethyl-3-thiophenecarbaldehyde (1.41 g). 2,5-Dimethyl-3-thiophenecarbaldehyde (3.89 g) synthesized in this manner was dissolved in acetonitrile (30 ml), and sodium dihydrogen phosphate (1.2 g) in water (15 ml) and 30% aqueous hydrogen peroxide (3.5 ml) were added dropwise. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2,5-dimethyl-3-thiophenecarboxylic acid (4.09 g) as crystals.
Reaction SMILES: [CH:1]1([CH:4]([N:6]2[C:15](=[O:16])[C:14]3[C:9](=[N:10][C:11](F)=[C:12]([CH3:17])[CH:13]=3)[C:7]2=[O:8])[CH3:5])[CH2:3][CH2:2]1.[O-]C#[N:21].[K+].CN(C=O)C>O>[CH:1]1([CH:4]([N:6]2[C:15](=[O:16])[C:14]3[C:9](=[N:10][C:11]([NH2:21])=[C:12]([CH3:17])[CH:13]=3)[C:7]2=[O:8])[CH3:5])[CH2:3][CH2:2]1
Reactant: N#C[O-]
Reactant: Cc1cc2c(nc1F)C(=O)N(C(C)C1CC1)C2=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(nc1N)C(=O)N(C(C)C1CC1)C2=O

Procedure:
6.3 g (0.0254 mol) of N-1-(cyclopropyl)ethyl-6-fluoro-5-methylpyridine-2,3-dicarboximide and 4.1 g (0.051 mol) of potassium cyanate were introduced into a mixture of 50 ml of DMF and 1 ml of water at 25° C. with stirring and then stirred at 125° C. for 30 minutes. After concentrating the reaction mixture under reduced pressure, the residue was stirred in succession with methyl tert-butyl ether and with water. Insoluble matter was filtered off with suction, washed with methyl tert-butyl ether and dried under reduced pressure. 3.5 g (56% of theory) of the title compound of m.p. 219°-220° C. were obtained. A further 1.6 g (=26% of theory) of the title compound of m.p. 201°-219° C. were obtained from the organic phase after washing with water and drying over magnesium sulfate (active compound Example 1.059).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:11]([CH2:12][C:13]3[CH:19]=[CH:18][S:17][C:14]=32)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC(Cl)OC(Cl)=O>ClC(Cl)C>[CH:19]1[C:13]2[CH2:12][CH:11]3[CH:15]([C:14]=2[S:17][CH:18]=1)[CH2:16][NH:8][CH2:9][CH2:10]3
Reactant: c1ccc(CN2CCC3Cc4ccsc4C3C2)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: c1cc2c(s1)C1CNCCC1C2
Temperature: 22 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
The product from step f) (409 mg, 1.52 mmol) in dichloroethane (8 ml) was treated with K2CO3 (839 mg, 6.08 mmol) and Ace-Cl (658 μl, 6.08 mmol) at 80° C. for 16 hours. Next, the reaction mixture was filtered, concentrated and the residue was dissolved in anhydrous MeOH (25 ml) and stirred for 1 hour at 22° C. The MeOH was concentrated and triturated with ether producing to give 215 mg (66%) of the subtitle compound as its HCl salt. MS calculated for C10H13NS+H 180, observed 180.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH2:3][CH2:4][OH:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[CH2:3][CH2:4][O:5][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][O:31]1
Reactant: C1=COCCC1
Reactant: CN(CCO)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCOC1CCCCO1)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 4-[N-methyl--N-(2-hydroxyethyl)-amino]-3-nitrobenzotrifluoride (29.0 g, 110 mmol), p-toluenesulfonic acid monohydrate (2.09 g, 11.0 mmol), 3,4-dihydro-2H-pyran (18.5 g, 220 mmol) and tetrahydrofuran (600 ml) was stirred at room temperature for 4.5 hours. Sodium hydrogencarbonate (10 g) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 30 minutes, after which the insoluble materials were filtered off. The filtrate was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 5/95) to obtain an oil of 4-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl) oxyethyl]amino]-3-nitrobenzotrifluoride.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:10]=[O:11])=[C:4]([CH2:7][CH2:8][CH3:9])[S:5][CH:6]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([CH2:10][OH:11])=[C:4]([CH2:7][CH2:8][CH3:9])[S:5][CH:6]=1
Reactant: CCCc1scc(Br)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1scc(Br)c1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 850 mg (3.6 mmol) sample of the compound from step 43a was dissolved in 20 mL of ethanol and treated with 206 mg (5.4 mmol) of sodium borohydride. The mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with ether. The extract was washed with water, dried over MgSO4, and concentrated in vacuo to give 950 mg of an oil that was taken to the next step without further purification. NMR (CDCl3) δ:7.09 (s, 1H), 4.60 (s, 2H), 2.85 (t, J=7 Hz, 2H), 1.68 (m, 2H), 0.99 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([CH3:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)C(C)Cc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)Cc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step E was prepared from 2-methyl-3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester of Step δ and benzenesulfonyl chloride, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine and with a reaction time of 4 h. 1H NMR (400 MHz, CDCl3) δ 7.87 (m, 3H), 7.69 (m, 1H), 7.61 (m, 1H), 7.54 (m, 4H), 7.10 (m, 3H), 6.98 (d, 1H), 6.85 (d, 1H), 6.75 (s, 1H), 6.44 (m, 1H), 4.31 (s, 2H), 4.29 (s, 2H), 3.61 (s, 3H), 2.87 (dd, 1H), 2.61-2.47 (m, 2H), 1.06 (d, 3H); MS 504 (M+1).
Reaction SMILES: O[C@H:2]1[CH2:12][C@@:11]2([CH3:14])[O:13][C@@:3]31[C@@H:15]1[C@@H:7]([N:8]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=4)[C:9](=[O:16])[C@H:10]21)[O:6][CH2:5][CH2:4]3.Cl.[NH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>N1C=CC=CC=1.CCOC(C)=O>[CH3:14][C@:11]12[O:13][C@:3]3([C@@H:15]4[C@@H:7]([N:8]([C:17]5[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:26])([F:28])[F:27])[CH:18]=5)[C:9](=[O:16])[C@H:10]14)[O:6][CH2:5][CH2:4]3)/[C:2](=[N:30]/[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)/[CH2:12]2
Reactant: C[C@@]12C[C@H](O)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Reactant: NN1CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@@]12C/C(=N\N3CCOCC3)[C@]3(CCO[C@H]4[C@@H]3[C@@H]1C(=O)N4c1ccc(C#N)c(C(F)(F)F)c1)O2
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a stirring solution of Example 3 (85 mg, 0.216 mmol) in pyridine (2 mL) was added. N-aminomorpholine hydrochloride (0.287 mmol, 1.5 eq). The mixture was stirred at 50° C. for 1 h. The reaction was judged completed by LCMS. The reaction mixture was cooled to room temperature. It was then diluted with EtOAc (6 ml) and extracted with 1N HCl (2×10 ml). The ethyl acetate layer was then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified on Isco (12 g column) 0-5% MeOH-DCM to give Example 92 (59 mg, 58%, 0.133 mmol).