Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:15](O)[CH3:16]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CCO
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of 10 g (60 mmol) of 3-nitrophenylacetic acid in 120 ml of ethanol were added 20 ml of a saturated solution of hydrogen chloride in ethyl acetate and the mixture was heated at reflux for 4 hours, cooled and left to stand at room temperature for 18 hours. The mixture was evaporated and the residue was partitioned between 120 ml of diethyl ether and 100 ml of saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 10.3 g (82%) of ethyl 3-nitrophenylacetate as a pale yellow oil. [NMR spectrum (250 MHz) δ1.25(t) (3H), δ3.68(s) (2H), δ4.6(q) (2H), δ6.5-δ6.7(m) (3H), δ7.09(dd) (1H)].
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11](Cl)[C:10]([CH3:14])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)CCC1.[CH2:23]([Mg]Br)[CH:24]([CH3:26])[CH3:25].C[Mg]Br>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:10]([CH3:14])=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Reactant: CC(C)C[Mg]Br
Agent: C[Mg]Br
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)OC(C)(C)C)cc1CC(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
5-Chloro-6-methyl-nicotinic acid tert.-butyl ester (3.09 g, 13.5 mmol), Fe(acac)3 (719 mg, 2.04 mmol) and NMP (1.95 mL, 20 mmol) are dissolved in THF (3 M, 500 mL) and cooled at −78° C. A solution of isobutylmagnesium bromide in THF (2 M, 13.6 mmol) is slowly added at −75° C. The brown solution turns turbid and yellow. Stirring is continued for 1 h at −75° C. before it is slowly warmed to rt. The reaction is incomplete, further Fe(acac)3 (719 mg, 2.04 mmol) is added and the mixture is cooled again at −70° C. Further methylmagnesium bromide in THF (2 M, 13.6 mmol) is slowly added at −70° C. The dark green mixture is slowly warmed to rt and stirred for 15 h. The mixture is carefully quenched with 0.7 N aq. HCl (150 mL). The mixture is extracted with EA (6×60 mL). The combined org. extracts are dried over Na2SO4, filtered and evaporated. The residue is purified by reversed phase MPLC to give 6-methyl-5-isobutyl-nicotinic acid tert.-butyl ester as black oil (0.50 g); LC-MS: tR=0.84 min, [M+1]+=250.14.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+].ClCCl.[C:31]1([C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N+]=[N-])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.S(=O)(=O)(O)O>O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([O:14][CH:37]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 0.25 h
Yield: 123.2 %

Procedure:
To a solution of sodium (6R, 7R)-3-acetoxymethyl-7-(thien-2-ylacetamido)ceph-3-em-4-carboxylate (4.2 g, 10 mM) in water (50 ml) was added dichloromethane (30 ml) containing diphenyldiazomethane (2.1 g, 11 mM). The solution pH was adjusted to 3.0 over 15 minutes using 10% v/v sulphuric acid. The mixture was separated and the solvent phase washed with water (4 × 50 ml). The solvent was removed in vacuo to give the title compound (6.96 g).
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:11]([CH3:15])[C:12](=O)[CH3:13].C(=O)([O-])O.[Na+]>CC(O)C>[CH3:15][C:11]1[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[S:9][C:12]=1[CH3:13]
Reactant: NC(=S)N1CCCCC1
Reactant: CC(=O)C(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc(N2CCCCC2)sc1C
Yield: 99.2 %

Procedure:
A mixture of piperidine-1-carbothioamide (3.00 g), 3-chloro-2-butanone (4.43 g) and 2-propanol (30 mL) was heated under reflux for 15 hrs. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 1-(4,5-dimethyl-1,3-thiazol-2-yl)piperidine as a colorless oil (4.05 g, yield 99%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[N:3][C:2]=1[OH:8].C1C(=O)N([I:16])C(=O)C1>CC(O)=O>[I:16][C:5]1[C:4]([OH:7])=[N:3][C:2]([OH:8])=[N:1][CH:6]=1
Reactant: Oc1ccnc(O)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Oc1ncc(I)c(O)n1
Reaction time: 7 h
Yield: 95.2 %

Procedure:
A mixture of pyrimidine-2,4-diol (100 g, 0.892 mol) and NIS (220 g, 1.981 mol, 1.1 eq) in AcOH (900 mL) was stirred for about 7 h. Solid 5-iodopyrimidine-2,4-diol (202 g, 95%) was obtained by filtration, washed with ethyl acetate. LC-MS (m/z)=238.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][OH:12])=[CH:9][S:8][C:7]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[O:12])=[CH:9][S:8][C:7]=1[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CO)csc1NC(=O)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)c1c(C=O)csc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
2-t-Butoxycarbonylamino-4-hydroxymethyl-thiophene-3-carboxylic acid ethyl ester (2.83 g, 9.44 mmol) was dissolved in anhydrous CH2Cl2 (165 mL) and treated with manganese dioxide (16.41 g, 188.70 mmol). It was stirred at room temperature for 5 hr then it was filtered through a pad of Celite. The Celite was washed with copious amounts of acetone. The filtrate was concentrated in vacuo to give title compound (2.69 g, 95%). MS m/e (CI) 300.0 (M+H)+; 1H NMR (300 MHz, CDCl3): δ ppm 1.42 (t, 3H), 1.55 (s, 9H), 4.43 (q, 2H), 7.59 (s, 1H), 10.30 (s, 1H), 10.34 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C)C=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(F)cc1
Yield: 82.8 %

Procedure:
A mixture of 4-fluorobenzoic acid (0.15 mol), thionyl chloride (0.45 mol) and dimethylformamide (5 drops) in chloroform (200 ml) was heated at reflux for 16 hours. Volatiles were removed from the cooled solution in vacuo. The residue was diluted with carbon tetrachloride (100 ml) and the mixture evaporated in vacuo to remove residual thionyl chloride. The residue was distilled affording 19.7 g of a clear oil (83% yield); bp 110°-112° C. at 40 mm of Hg. Spectral data are consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:10]3([C:14](=[O:15])[NH:13][C:12](=[S:16])[NH:11]3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([N:13]1[C:14](=[O:15])[C:10]2([C:4]3[CH:3]=[C:2]([Br:1])[S:6][C:5]=3[CH2:7][CH2:8][CH2:9]2)[N:11]=[C:12]1[S:16][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:5]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(=S)NC12CCCc1sc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1N(Cc2ccccc2)C(SCc2ccccc2)=NC12CCCc1sc(Br)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 111.7 %

Procedure:
2-Bromo-2′-thioxo-6,7-dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazolidin]-5′-one (0.285 g, 0.9 mmol) was dissolved in THF (20 mL) and cooled to 0° C. in an ice bath. Sodium hydride (50% dispersion in oil, 26 mg, 1.08 mmol) was added and the mixture was stirred for 15 min. Benzyl bromide (0.13 ml, 1.08 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled to 0° C. again and a further portion of sodium hydride (50% dispersion in oil, 26 mg, 1.08 mmol) was added. The mixture was stirred for 15 min, benzyl bromide (0.13 mL, 1.08 mmol) was added and the reaction mixture was stirred at room temperature for 18 hr. Solvent was evaporated under reduced pressure. The residue was dissolved in water and extracted with dichloromethane (×3). The organic extracts were combined, dried (MgSO4), and concentrated in vacuo. The crude residue purified on silica gel using ethyl acetate in iso-hexane (1:1) to afford the title compound as a colourless oil (0.25 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@H:6]([CH3:13])[N:5]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:4]=2[N:3]=1.[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:25])[C:7](=[O:12])[C@H:6]([CH3:13])[N:5]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:4]=2[N:3]=1
Reactant: COc1c(C)cnc(CN2c3nc(N)ncc3NC(=O)[C@@H]2C)c1C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C)cnc(CN2c3nc(N)ncc3N(C)C(=O)[C@@H]2C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(7S)-2-amino-8-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7-methyl-7,8-dihydropteridin-6(5H)-one (Example 1)(164 mg, 0.5 mmol) was stirred in anhydrous THF (1 mL) and triphenylphosphine (400 mg, 1.53 mmol) and methanol (0.2 mL, 4.94 mmol) were added. DIAD (0.3 mL, 1.52 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was loaded onto a SCX cartridge and washed with THF and methanol, then eluting with methanolic ammonia (7M). The crude product was further purified by MPLC eluting with 0-15% methanol/DCM. The title compound was isolated as a colourless foam after trituration and re-concentration from ether (113 mg, 66%); 1H NMR spectrum (400 MHz, CDCl3) δ1.39 (3H, d), 2.17 (3H, s), 2.25 (3H, s), 3.26 (3H, s), 3.75 (3H, s), 4.03-4.15 (2H, m), 4.66 (2H, s), 5.71 (1H, d), 7.57 (1H, s), 8.18 (1H, s); Mass spectrum: (M+H)+ 343.
Reaction SMILES: CN(C)[CH:3]=[CH:4][CH:5]=[C:6]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:7]#[N:8].[ClH:16].C(=O)([O-])[O-].[K+].[K+].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(O)(=O)C.C(OCC)(=O)C.CCCCCC>[Cl:16][C:10]1[C:9]([C:6]2[CH:7]=[N:8][CH:3]=[CH:4][CH:5]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Cl
Reactant: CN(C)C=CC=C(C#N)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Clc1ncccc1-c1cccnc1
Temperature: 60 °C

Procedure:
A 3.0 g portion of α-[3-(dimethylamino)-2-propenylidene]-3-pyridineacetonitrile was dissolved in 100 ml of glacial acetic acid. Dry hydrogen chloride gas (about 2.5 g) was introduced and the solution was heated at 60° C. for 3 hours. The reaction was cooled to 20° C. and then poured onto 200 g of ice. The solution was basified with potassium carbonate and then extracted with four 100 ml portions of methylene chloride. The organic extracts were combined, dried and the solvent removed at reduced pressure, giving an oil. This oil was dissolved in ethyl acetate:hexane (1:1) and passed through a pad of hydrous magnesium silicate. The solid obtained was recrystallized from hexane, giving 2-chloro-3,3'-bipyridine as white needles, mp 92°-93.5° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH:18]=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[Si](C(F)(F)F)(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH:8]([NH:10][C:18](=[O:19])[CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: NC(=O)Cc1ccccc1
Agent: C[Si](C)(C)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC(Cc1ccccc1)NC(=O)Cc1ccccc1
Yield: 18.8 %

Procedure:
To a well stirred suspension of 2-phenylacetamide (540 mg, 4 mmol) in dry DCM (2 mL) was added the 2-phenylacetaldehyde (240 mg, 2 mmol) and trimethylsilyltrifluoromethane sulonate (22 mg, 0.1 mmol). The mixture was vigorously stirred for 12 h at room temperature, diluted with toluene (4 mL), and filtered. The precipitate was washed several times with toluene which was recrystallized with methanol and hexane to give the final product (140 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J=7.6 Hz, 2H), 7.14-7.28 (m, 15H), 5.55 (t, J=7.6 Hz, 1H), 3.39 (s, 4H), 2.93 (d, J=7.2 Hz, 2H). LC-MS (ESI): m/z 373.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[NH:15][C:14](=O)[N:13]=1.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:14]1[N:13]=[C:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[F:1])[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=1
Reactant: O=c1nc(-c2ccc(C(F)(F)F)cc2F)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (9.84 g, 0.03 mol) and phosphoroxychloride (50 ml) according to the general procedure I. Obtained as a light yellow solid (9.99 g, 96%). MS (ISN) 341.2 [(M−H)−]; mp 47° C.
Reaction SMILES: [CH3:1][N:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3](=O)[CH3:4].C1COCC1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].CCCCCCC>C(Cl)Cl>[CH3:1][N:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3](=[S:20])[CH3:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(=O)N(C)Cc1ccc(F)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=S)N(C)Cc1ccc(F)cc1
Yield: 91.3 %

Procedure:
Combine N-methyl-N-(4-fluorobenzyl)acetamide (364.8 g, 2.01 mol) and THF (9 L). Stir to dissolve and then add phosphorus pentasulfide (537.7 g, 1.21 mol). After 45 min heat to reflux for 3 h, then cool and stir overnight to give a solid. Collect the solid by filtration and rinse the cake with THF (4 L), evaporate the filtrate in vacuo to give a residue, dissolve the residue in methylene chloride (about 500 mL), and passed over a cake of silica gel 60 (1.2 kg) preconditioned with heptane. Elute with 4 L of heptane/methylene chloride (1:1) followed by 100% methylene chloride to afford 217.98 g of N-methyl-N-(4-fluorobenzyl)thioacetamide (55%): mp=99-104° C.; Rf=0.42 (methylene chloride); 1H NMR (CDCl3) 7.35-7.26 (m, 1), 7.14-6.96 (m, 3),5.28 (s, 1.2) and 4.79 (s, 0.8), 3.42 (s, 1.2) and 3.15 (s, 1.8), 2.72 (s, 1.2) and 2.69 (s, 1.8). Note: Partial protons are believed to be due to rotomers.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C1(C2CCC(=O)CC2)C=CC=CC=1.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:8]([CH:5]2[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: CNC
Reactant: O=C1CCC(c2ccc(C(=O)Cl)cc2)CC1
Agent: O=C1CCC(c2ccccc2)CC1
Product: CN(C)C(=O)c1ccc(C2CCC(=O)CC2)cc1
Reaction time: 2 h
Yield: 68 %

Procedure:
4-(4-Oxocyclohexyl)benzoyl chloride [obtainable by reacting 0.75 mol (130.7 g) of 4-phenylcyclohexanone with 1 mol of oxalyl chloride and 2 mol of AlCl3 in dichloromethane, followed by hydrolysis with ice-water/HCl] is added to an aqueous solution (15%) of 3 mol of dimethylamine and the mixture is stirred for 2 hours at 0 to 5°. It is worked up in conventional manner to give 125.2 g of N,N-dimethyl-4-(4-oxocyclohexyl)benzamide, m.p. 118°; yield: 68% based on 4-phenylcyclohexanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=2)=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH2:31][OH:32].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:29][CH2:30][CH2:31][OH:32])=[O:17])=[N:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)NCCO)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a solution of 5-[[(4-fluorophenyl)thio](2,3,6-trifluorophenyl)methyl]-4-m ethylpyridine-2-carboxylic acid (163 mg, 0.40 mmol) obtained in Example 34 in methylene chloride (5 ml), 2-aminoethanol (0.027 ml, 0.44 mmol), 1-hydroxybenzotriazole (60 mg, 0.44 mmol), 4-methylmorpholine (0.048 ml, 0.44 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (84 mg, 0.44 mmol) were added at room temperature. After stirring for 3 hours at room temperature, the reaction mixture was washed with water and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=2:3 was concentrated under reduced pressure to obtain the title compound (175 mg, 0.39 mmol, 97%) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])C)[CH:7]=1.[H-].[Na+].[CH3:15][O:16][C:17]([C:19]1OC(Cl)=[N:21][CH:20]=1)=[O:18]>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[O:11][C:9]([NH:8][C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=2[CH3:12])=[N:21][CH:20]=1)=[O:18]
Reactant: COC(=O)c1cnc(Cl)o1
Reactant: CC(=O)Nc1cc(N)ccc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(Nc2cc(N)ccc2C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of N-(5-Amino-2-methyl-phenyl)-acetamide (0.51 g, 3.1 mmol) in THF (12 mL) was added to a suspension of NaH (186 mg, 4.65 mmol, 60% dispersion in mineral oil) in THF (12 mL) at 0° C. under an atmosphere of argon. The mixture was stirred for 30 min. at room temperature and cooled to 0° C. A solution of 2-chloro-oxazole-5-carboxylic acid methyl ester (0.5 g, 3.1 mmol) in THF (12 mL) was added dropwise to the mixture. After 30 min., at 0° C., the reaction was poured into ice water (30 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and filtered. After removal of solvent the residue was silica gel column chromatographed (CH2Cl2/Ethanol:99/1) to give 0.54 g of 2-(5-Amino-2-methyl-phenylamino)-oxazole-5-carboxylic acid methyl ester (71%) as a Colorless syrup.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31]1[C:35]([C:36]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 1H, J=2.3 Hz), 7.48 (s, 1H), 7.4 (m, 1H), 7.39 (s, 1H), 7.37 (m, 2H), 7.24 (t, 1H, J=7.2 Hz), 6.92 (d, 1H, J=7.9 Hz), 6.06 (s, 1H), 3.31 (q, 2H, J=6.4 Hz), 2.94 (d, 2H, J=10.8 Hz), 2.79 (s, 3H), 2.53 (q, 1H, J=6.1), 2.47 (tt, 1H, J=4.2, 11.4 Hz), 2.29 (t, 2H, J=7.2 Hz), 1.99 (t, 2H, J=11.4 Hz), 1.81 (m, 2H), 1.69 (dt, 2H, J=2.4, 11.6), 1.59 (q, 2H, J=6.6 Hz), 1.24 (d, 6H, J=6.5 Hz); ESMS m/e: 557.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:27][CH2:28][CH2:29][CH3:30])[NH:11][C:5]=2[N:4]([CH2:31][CH2:32][CH3:33])[C:3]1=[O:34].[CH:35](=O)[CH2:36][CH3:37].[Na]>CO.C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:26][CH2:25][N:24]([CH2:35][CH2:36][CH3:37])[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:27][CH2:28][CH2:29][CH3:30])[NH:11][C:5]=2[N:4]([CH2:31][CH2:32][CH3:33])[C:3]1=[O:34]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCNCC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Reactant: CCC=O
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CCC)CC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
A mixture of the title compound of example 87 (50 mg, 0.1 mmol), propanal (0.073 mL, 1 mmol) and 3 Å molecular sieves (300 mg) in methanol (2 mL) and acetic acid (0.1 mL), was stirred at room temperature for 4 hours. Then sodium cianoborohydride (32 mg, 0.51 mmol) was slowly added and the mixture was stirred at room temperature overnight. The reaction mixture was purified by solid phase extraction using a Varian Bond Elut SCX cartridge (methanol for washing, methanol-ammonia for elution) to yield the title compound (40 mg, 72%).
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.F[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=4)[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[CH:7]=1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: Fc1ccccn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(c4ccccn4)CC3)cc2)cc1NCc1cccc(F)c1F
Temperature: 125 °C
Reaction time: 24 h

Procedure:
The mixture of 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (55 mg, 0.11 mmol), DIEA (0.1 mL, 0.55 mmol), 2-fluoropyridine (110 mg, 1.10 mmol) in 3 mL NMP was stirred in a sealed tube at 125° C. for 1 day. It was acidified with TFA and subjected to reverse phase preparative HPLC to isolate the title compound. MS found for C29H28F2N6O as (M+H)+ 515.4. UV: λ=249, 306 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 8.00-7.94 (2H, m), 7.39 (1H, d, J=9.2 Hz), 7.36 (2H, dt, J=8.0; 2.0 Hz), 7.25 (1H, m), 7.18 (1H, m), 7.14-7.07 (3H, m), 6.94 (1H, t, J=7.2 Hz), 5.79 (1H, s), 4.55 (2H, s), 4.36 (2H, m), 3.38 (2H, m), 3.03 (1H, m), 2.08 (2H, m), 1.87 (2H, m) ppm.