Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[Cs+].[Cs+].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[C:17]#[CH:18]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:21]([O:20][C:16](=[O:19])[C:17]#[C:18][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=1)[CH3:22]
Reactant: Fc1cc(I)ccc1Cl
Reactant: C#CC(=O)OCC
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(Cl)c(F)c1
Temperature: 35 °C
Reaction time: 38 h
Yield: 88.7 %

Procedure:
To a mixture of 4-chloro-3-fluoroiodobenzene (74.27 g, 284 mmol) and cesium carbonate (185.0 g, 568 mmol) in tetrahydrofuran (730 mL) was added under an argon atmosphere cuprous iodide (2.16 g, 11.4 mmol) and bis(triphenylphosphine)palladium (II) chloride (3.98 g, 5.7 mmol). Ethyl propiolate (57.0 g, 575 mmol) was added dropwise over a period of 20 min. The resulting dark brown suspension was stirred for 38 h at 35° C., then filtrated over Hyflo® and the residue was washed with tetrahydrofuran (285 ml). The filtrate was evaporated and purification of the residue by chromatography (SiO2, heptane: ethyl acetate=90:10) afforded the title compound (57.1 g, 89%) as a yellow liquid. MS m/e: 226.0 [M]+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=[CH:11][C:10]=1[CH:25](C(OC(C)(C)C)=O)[C:26]([O:28]C(C)(C)C)=[O:27]>ClCCl.C(OCC)(=O)C.O>[F:8][C:9]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=[CH:11][C:10]=1[CH2:25][C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2ccccc2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1F
Temperature: 45 °C
Yield: 110.5 %

Procedure:
Trifluoroacetic acid (3 mL, 38.9 mmol) was added to a solution of bis(1,1-dimethylethyl) [2-fluoro-4-nitro-3-(phenyloxy)phenyl]propanedioate (2.210 g, 4.94 mmol) in dichloromethane (20 mL). The mixture was heated at 45° C. overnight. The reaction mixture was diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate and the solvent was evaporated to give the crude product (1.59 g, 89% yield) as a gummy solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.70-7.80 (m, 1H), 7.20-7.33 (m, 3H), 7.07 (t, 1H), 6.89 (d, 2H), 3.78 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].[O-]CC.[Na+].[C:18](OC)(=[O:23])[CH2:19][C:20]([CH3:22])=O>C(O)C>[CH3:22][C:20]1[N:7]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:12])([F:13])[F:1])[NH:6][C:18](=[O:23])[CH:19]=1
Reactant: COC(=O)CC(C)=O
Reactant: N=C(N)c1ccccc1C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(=O)[nH]c(-c2ccccc2C(F)(F)F)n1
Yield: 50.2 %

Procedure:
A mixture of 2-trifluoromethyl-benzamidine (2.13 g, 4 mmol) and sodium ethoxide (0.83 g, 12 mmol) in ethanol (20 mL) was treated with methyl acetoacetate (0.44 mL, 4 mmol) and heated at for 24 hours. The reaction was cooled, concentrated, diluted with water and acidified with 2 N hydrochloric acid. The resulting solution was extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by flash chromatography [SiO2, methanol:dichloromethane (3:97)] provided the title compound (0.51 g, 50% yield) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) δ 12.7 (br s, 1H), 7.9 (m, 1H), 7.8 (m, 2H), 7.7 (m, 1H), 6.3 (s, 1H), 2.21 (s, 3H) ppm; MS (FIA) 255.0 (M+H); Rt (Method A) 2.578 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[N+:21]([CH3:24])([O-])=O>[Zn]>[NH2:21][CH2:24][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([OH:13])[C:9]([F:11])([F:12])[F:10]
Reactant: O=C(c1ccc(Cl)cc1)C(F)(F)F
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: O
Product: NCC(O)(c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
1-(4-Chlorophenyl)-2,2,2-trifluoroethanone (2.00 g, 9.59 mmol) in nitromethane (10 mL) was stirred with potassium carbonate (1.32 g, 9.59 mmol) at room temperature for 1 hour. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue (pale yellow amorphous, 3.3 g) was dissolved in ethanol (52 mL), then 6 M hydrochloric acid was added dropwise under cooling with ice, and zinc powder (3.13 g, 48.0 mmol) was gradually added. The reaction mixture was stirred for one day while the temperature was gradually raised to room temperature, and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was mixed with 28 wt % aqueous ammonia and extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/1 (v/v)) to give the title compound as a colorless solid (609 mg, yield 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1.CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)c1cc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)ccc1O[Si](C)(C)C(C)(C)C

Procedure:
3,5-Dichloro-4-(3'-isopropyl-4'-hydroxyphenoxy)-nitrobenzene (10.2 g), 6.75 g. of t-butyldimethylsilyl chloride, 4.06 g of imidazole, and 2 mg of N,N-dimethylaminopyridine in 10 ml dimethylformamide are stirred 18 hours at room temperature. The solution is poured into ether and extracted six times with water. The ether is dried, filtered and stripped to afford 3,5-dichloro-4-(3'-isopropyl-4'-t-butyldimethylsiloxyphenoxy)-nitrobenzene. NMR (CDCl3): δ 0.2 (6H,s), 1.1 (9H,s), 1.2 (6H,d), 3.3 (1H,m), 6.5 (1H,d of d), 6.7 (1H,d), 8.3 (2H,s).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:18])=[C:9]([S:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:18])=[C:9]([S:11]([NH:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])[CH:10]=1
Reactant: [N-]=[N+]=NCc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Cl)c(S(=O)(=O)NC2CC2)c1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 5-(azidomethyl)-2-chloro-N-cyclopropylbenzenesulfonamide (1.40 g, 4.87 mmol), THF (40 mL), triphenylphosphine (1.6 g, 6.43 mmol) and water (0.11 mL, 6.43 mmol) at 0° C. and the reaction was stirred at room temperature over night. The solvents were removed and the residue was dissolved in MTBE and 20% HCl in dioxane was added dropwise at 0° C. The resulting salt was collected and washed with EtOAc. The salt was then neutralized with 6N NaOH and extracted with CH2Cl2. The combined organic phases were concentrated under reduced pressure to get the title product as a very thick oil. 1H NMR (400 MHz, DMSO-d6): 8.00 (s, 1H), 7.58 (s, 2H), 3.78 (s, 2H), 2.18 (m, 1H), 0.50-0.35 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=[C:4]([Cl:9])[N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc(Br)cc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1cc(-c2ccccc2)cc(Cl)n1
Temperature: 80 °C
Yield: 26.8 %

Procedure:
A round-bottomed flask was charged with 4-bromo-2,6-dichloropyridine (Combi-Blocks Inc., 553 mg, 2.437 mmol), phenylboronic acid (446 mg, 3.66 mmol) and trans-dichlorobis(triphenylphosphine)palladium (ii) (27.8 mg, 0.04 mmol). The vial was placed under nitrogen atmosphere using two evacuation/backfill cycles. 1,4-dioxane (12 ml) and sodium carbonate (775 mg, 7.31 mmol) in water (4.1 ml) were added. The reaction mixture was sealed under nitrogen and heated at 80° C. for 1.5 h. The reaction mixture combined with that on pp14 was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined EtOAc layers were dried (Na2SO4) and concentrated. The crude material was dissolved in DCM, and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 20% EtOAc in hexane, to provide 2,6-dichloro-4-phenylpyridine (146 mg, 0.652 mmol, 26.7% yield) as light-yellow oil. MS m/z=224.0 [M]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=[O:12])[CH:7]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=1
Reactant: CCOC(=O)c1cc(Cc2cccc(F)c2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Cc2cccc(F)c2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Ethanol (3 mL) was added to the mixture of ethyl 5-(3-fluorobenzyl)isoxazole-3-carboxylate (0.688 g; 2.82 mmol) and 1M sodium hydroxide (10.5 mL; 10.5 mmol). The mixture was stirred overnight at room temperature and was concentrated under reduced pressure to remove ethanol. The aqueous solution was acidified by addition of 6N hydrochloric acid to pH 0-1. The formed precipitate was collected by filtration and was dried. 0.5026 g (82%) of 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid was obtained as a white solid which was directly used in the next step.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].C(N(CC)C(C)C)(C)C>N1C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:22])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)Nc4ccc(Cl)c(Cl)c4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
A mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.0 mmol), 3,4-dichlorophenyl isocyanate (0.56 g, 3.0 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol) in pyridine (20 mL) was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was suspended in a biphasic mixture of CH2Cl2 (150 mL) and water (150 mL) and stirred for 2 hours. The solid was filtered, washed with additional water (50 mL), and dried. The resulting solid was stirred in methanol (200 mL) at room temperature for 1 hour, filtered, and dried. This material was refluxed in methanol (2×200 mL) for 3 hours, filtered, and dried. The resulting solid was chromatographed using a methanol-CH2Cl2 (with 0.1% of triethylamine) gradient, eluting 0.23 g of the product at 7:93 methanol-CH2Cl2 (with 0.1% of triethylamine), in 16% yield; mp 290-292° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 10.50 (97.00%); 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H), 2.56-2.62 (m, 2H), 2.82-2.94 (m, 1H), 4.47 (d, J=5.9 Hz, 2H), 5.15 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 7.05 (t, J=6.1 Hz, 1H), 7.29 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.77-7.91 (m, 4H), 9.11 (s, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 42.7, 49.0, 117.9, 118.9, 121.7, 122.4, 123.5, 129.7, 130.4, 130.9, 131.6, 133.3, 140.6, 148.4, 155.0, 167.0, 167.2, 169.8, 172.7; Anal. Calcd for C21H16N4O5Cl2+0.25H2O: C, 52.57; H, 3.47; N, 11.68. Found: C, 52.22; H, 3.25; N, 11.56.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1>[OH-].[Na+].C(OCC)(=O)C>[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[CH:10]([NH:13][C:22](=[O:23])[CH2:21][C:20](=[O:24])[CH3:19])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:1]
Reactant: C=C1CC(=O)O1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Reaction time: 1 h
Yield: 61.8 %

Procedure:
5.44 g of 7-aminocephalosporanic acid were dissolved in 20 ml of a 1N aqueous solution of sodium hydroxide, and 1.68 g of diketene were added, with ice-cooling, to the resulting solution. The mixture was stirred at the same temperature for 1 hour, after which it was diluted with 20 ml of ethyl acetate and then acidified. The mixture was extracted twice with ethyl acetate and the combined extracts were washed with an aqueous solution of sodium chloride, dehydrated over anhydrous magnesium sulphate and then concentrated by evaporation under reduced pressure, giving 4.4 g of the title compound as crystals melting at 150° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][CH:23]([CH2:26][C:27](OCC)=[O:28])[CH2:24][N:25]=1)[NH:6]2.[BH4-].[Li+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:28][CH2:27][CH2:26][CH:23]1[S:22][C:21]([C:5]2[NH:6][C:7]3[C:3]([CH:4]=2)=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=3[N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[N:25][CH2:24]1
Reactant: CCOC(=O)CC1CN=C(c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CCO)S3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a mixture of ethyl (2-{4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.12 g), lithium borohydride (20 mg) and tetrahydrofuran (10 mL) was added methanol (2 mL), and the mixture was stirred at room temperature for 3 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (103 mg, yield: 94%) as pale-yellow crystals. MS: 436 (MH+). melting point 168-169° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][N:11]=[C:12]=[O:13].[H-].[Na+].[NH4+].[Cl-].[Na+].[Cl-]>C1COCC1>[CH:1]1([N:7]2[CH2:9][CH2:10][NH:11][C:12]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C=NCCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1NCCN1C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
A solution of cyclohexylamine (1.00 g, 10.08 mmol) and 2-chloro ethylisocyanate (1.064 g, 10.08 mmol) in THF (30 mL) was stirred at RT for 4 h, treated with sodium hydride (60% in mineral oil, 0.403 g, 10.08 mmol) and stirred at RT for 16 h. The mixture was poured into satd. NH4Cl, treated with solid NaCl until saturated, extracted with THF (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The material was suspended in 30% EtOAc/Hex, stirred and the resulting solid collected via filtration to afford 1-cyclohexylimidazolidin-2-one (650 mg, 38%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.14 (s, 1 H), 3.46-3.37 (m, 1 H), 3.27-3.21 (m, 2 H), 3.19-3.13 (m, 2 H), 1.75-1.68 (m, 2 H), 1.60-1.50 (m, 3 H), 1.37-1.18 (m, 4 H), 1.09-0.98 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.C(S)[CH2:11][S:12]([O-])(=O)=O.[Na+]>CC(O)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[S:12][CH3:11]
Reactant: Nc1nccc(Cl)c1I
Reactant: O=S(=O)([O-])CCS
Agent: [Cu]I
Agent: [Na+]
Solvent: CC(C)O
Product: CSc1c(Cl)ccnc1N
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution 4-chloro-3-iodopyridin-2-amine (400 mg, 1.57 mmol), CuI (30 mg, 0.157 mmol) in i-PrOH (3 mL) and glycol (10 mg, 0.157 mmol) was added MeSNa (110 mg, 1.57 mmol). The resulting mixture was allowed to stir at 100° C. for 24 h. The reaction mixture was concentrated and the resulting residue was purified by column chromatography to afford the title compound as oil. LC/MS m/z=175.19 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10]1([CH:16]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:16]/[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=CC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/C1CCCCC1
Yield: 106.5 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with cyclohexanecarbaldehyde (Aldrich) (0.6 g, 5 mmol) in CH2Cl2 at room temperature for 20 h to give {[1-cyclohexyl-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester as a colorless oil (1.2 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:23]3[NH:27][N:26]=[N:25][CH:24]=3)=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[C:12]=2[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.C(Cl)Cl.N1C=CC=CC=1.[C:37](OC(=O)C)(=[O:39])[CH3:38].CO.O.C(=O)(O)[O-].[Na+]>>[C:13]([C:12]1[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[C:10]([C:23]2[NH:27][N:26]=[N:25][CH:24]=2)[S:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:37](=[O:39])[CH3:38])[CH:7]=1)#[N:14]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1c(-c2ccnc(N)c2)sc(-c2cnn[nH]2)c1-c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-c2sc(-c3cnn[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
To a solution of 2-(2-aminopyridin-4-yl)-4-(2,4-dichlorophenyl)-5-(1H-1,2,3-triazol-5-yl)thiophene-3-carbonitrile (0.048 g, 0.12 mmol) in DCM (4 mL, 60 mmol) was added Pyridine (0.470 mL, 5.81 mmol) and Acetic anhydride (329 uL, 3.48 mmol) and the mixture was stirred at rt overnight. The mixture was concentrated and the residue was dissolved in MeOH (2.0 mL, 49 mmol) and Water (0.3 mL, 20 mmol). Sodium bicarbonate (0.5 g, 6 mmol) was added to the above mixture. The mixture was stirred at rt for 30 min. The reaction mixture was concentrated and the residue was dissolved in EtOAc and MeOH. The solid was filtered out. The organic solution was evaporated to dryness, purified by column chromatography and then further by HPLC to afford pure title compound (27 mg, 52%). LC/MS (FA) ES+ 455, 457; ES− 453, 455. 1H-NMR (400 MHz, DMSO-d6) δ: 8.59 (1H, d, J=0.75 Hz), 8.51 (1H, d, J=5.29 Hz), 7.93 (1H, d, J=1.09 Hz), 7.54 (1H, dd, J=5.25, 1.76 Hz), 7.23 (1H, s), 7.64 (2H, d, J=1.92 Hz), 10.80 (1H, s), 2.13 (3H, s), 2.07 (1H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13](O)=[O:14])=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.[CH3:39][N:40]1[CH2:45][CH2:44][CH:43]([NH:46]C)[CH2:42][CH2:41]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([NH:46][CH:43]1[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]1)=[O:14])=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Reactant: CNC1CCN(C)CC1
Product: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)NC3CCN(C)CC3)cnc12

Procedure:
8-Methoxy-N-(1-methyl-4-piperidinyl)-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxamide was prepared by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and commercially available 1-methyl-4-(methylamino)piperidine as described for Example 17, Step 5: mp 230°-232 ° C.; 1H NMR (Me2SO-d6, 400 MHz), 3:1 mixture of amide rotamers, a:b) δ 9.09 (s, 1Ha), 8.84 (s, 1Hb), 8.58 (s, 1Hb), 8.51 (s, 1Ha), 7.98 (d, J=7.9 Hz, 1Ha), 7.93 (d, J=7.9 Hz, 1Hb), 7.78 (d, J=8.7 Hz, 2Hb), 7.71 (d, J=8.7 Hz, 2Ha), 7.65 (d, J=8.3 Hz, 1 H), 7.51 (t, J= 8.5 Hz, 1 H), 7.43 (m, 5Hb), 7.30 (m, 5Ha), 7.24 (d, J=7.5 Hz, 1 H), 6.91 (d, J=8.7 Hz, 2Ha), 6.77 (d, J=8.7 Hz, 2Hb), 3.96 (s, 3 H), 3.74 (m, 2 H), 3.46 (s, 2 H), 3.32 (b, 2 H), 2.80 (d, J=11.6 Hz, 4Ha), 2.69 (s, 3Hb), 2.64 (d, J=12.2 Hz, 4Hb), 2.58 (s, 3Ha), 2.06 (s, 3Ha), 2.00 (t, J=13.9 Hz, 2 H), 1.97 (s, 3Hb), 1.72 (m, 4 H), 1.56-1.59 (m, 4 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15]COC)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])[CH:2]=1
Reactant: COCOc1ccc(C(=O)c2cccnc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(O)cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 2.01 g of the thus obtained 4-methoxymethyloxyphenyl 3-pyridyl ketone which has been dissolved in 35 ml of methylene chloride and cooled down to 0° C. was added dropwise 2.01 g of titanium tetrachloride dissolved in 35 ml of methylene chloride. After 2 hours of stirring at room temperature, the resulting reaction mixture was neutralized with saturated sodium hydrogencarbonate solution and mixed with 200 ml of ethyl acetate to separate the organic layer and to extract the water layer with ethyl acetate. Thereafter, the organic phases were combined, washed with saturated sodium chloride aqueous solution and dried using anhydrous magnesium sulfate, followed by the removal of solvents by distillation under a reduced pressure to obtain 1.32 g of 4-hydroxyphenyl 3-pyridyl ketone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:22]([F:23])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(Cl)cc2)cc1

Procedure:
To a solution of 2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanamine obtained by Example 53 (400 mg) and triethylamine (0.46 ml) in dichloromethane (20 ml) was added dropwise methanesulfonyl chloride (0.25 ml) at room temperature.