Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14]3[CH:15]=[C:16]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:18][C:13]=3[C:12]3[C:7](=[CH:8][N:9]=[CH:10][CH:11]=3)[C:6]2=[O:34])[CH2:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]2[C:12]3[C:7](=[CH:8][N:9]=[CH:10][CH:11]=3)[C:6](=[O:34])[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:14]=2[CH:15]=1
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(CC3CC3)c2c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)COc1ccc2c3ccncc3c(=O)n(CC3CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
To a solution of (S)-tert-butyl (1-((6-(cyclopropylmethyl)-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.08 g, 0.172 mmol) in anhydrous methanol (5 mL) was added a 4M solution of HCl in 1,4-dioxane (2 mL, 65.8 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure to afford crude compound which was purified by preparative HPLC (10 mM ammonium acetate in water:acetonitrile) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-6-(cyclopropylmethyl)benzo[c][2,7]naphthyridin-5(6H)-one (22 mg, 0.060 mmol, 35% yield) as a yellow gum. LC/MS (ESI) m/e 366.2 [(M+H)+, calcd for C22H28N3O2 366.2]; LC/MS retention time (method A): tR=1.47 min; HPLC retention time (method A): tR=9.470 min; HPLC retention time (method B): tR=5.250 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.47 (d, J=0.50 Hz, 1H), 8.78 (d, J=5.77 Hz, 1H), 8.46 (d, J=9.04 Hz, 1H), 8.26 (d, J=5.52 Hz, 1H), 7.28 (d, J=2.26 Hz, 1H), 7.14 (dd, J=9.03, 2.26 Hz, 1H), 4.39 (d, J=6.78 Hz, 2H), 4.31 (dd, J=9.79, 3.76 Hz, 1H), 4.13 (dd, J=9.79, 6.78 Hz, 1H), 3.53 (dd, J=7.15, 3.64 Hz, 1H), 1.87 (m, 1H), 1.59 (q, J=13.72, 7.03 Hz, 2H), 1.36-1.45 (m, 1H), 1.04 (dd, J=7.28, 6.78 Hz, 6H), 0.57-0.63 (m, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:18])([CH3:17])[CH:9]([C:11](=[O:16])[NH:12][CH:13]1[CH2:15][CH2:14]1)[OH:10])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]([CH3:18])([CH3:17])[CH:9]([OH:10])[C:11]([NH:12][CH:13]1[CH2:14][CH2:15]1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(O)C(=O)NC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(O)C(=O)NC1CC1

Procedure:
A solution of (2-cyclopropylcarbamoyl-2-hydroxy-1,1-dimethylethyl)-carbamic acid tert-butyl ester in CH2Cl2 (10 mL) and TFA (5 mL) was stirred at room temperature for 4 h. The reaction mixture was then concentrated and chased with toluene to yield 3-amino-N-cyclopropyl-2-hydroxy-3-methylbutyramide.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.[C:9](Cl)(=[O:25])[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][CH3:24]>>[C:9]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1)(=[O:25])[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][CH3:24]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: NC1CCCC(=O)C1
Product: CCCCCCCCCCCCCCCC(=O)NC1CCCC(=O)C1

Procedure:
2-Cyclohexenone is reacted with benzylamine to give 3-benzylaminocyclohexanone. Hydrogenolysis of the benzylamino group then gives 3-aminocyclohexanone. Reaction with hexadecanoyl chloride affords 3-hexadecanamidocyclohexanone, which is then reduced with sodium borohydride to produce a cis/trans mixture of 3-hexadecanamidocyclohexanol. Separation by column chromatography then gives the pure isomers. Reaction with bromoethylphosphodichloridate, then with trimethylamine will produce 3-hexadecanamido-cyclohexylphosphocholine.
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH3:24])[C:18](=[O:23])[CH2:19][S:20](=[O:22])(=[O:21])[C:15]=2[CH:14]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.Cl>CN(C)C=O>[Cl:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH3:24])[C:18](=[O:23])[CH:19]([C:35](=[O:36])[NH:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[S:20](=[O:22])(=[O:21])[C:15]=2[CH:14]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CN1C(=O)CS(=O)(=O)c2cc(Cl)ccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN1C(=O)C(C(=O)Nc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 1,8-diazabicyclo-[5,4,0]undec-7-ene (14.12 g) in dimethylformamide (111 ml) was added, dropwise in 10 minutes, a solution of 7-chloro-4-methyl-2H-1,4-benzothiazin-3(4H)one 1,1-dioxide (22.8 g) and 4-fluorophenylisocyanate (12.82 g) in dimethylformamide (111.4 ml) at room temperature. After being stirred for one hour, the mixture was poured into 1% hydrochloric acid (1 l). The separated solids were collected by filtration and washed with water. The wet solids were dissolved in ethyl acetate. The mixture was washed with 1% hydrochloric acid, with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from diethyl ether to yield 24.3 g of 7-chloro-2-(4-fluorophenylcarbamoyl)-4-methyl-2H-1,4-benzothiazin-3(4H)one 1,1-dioxide.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 96.4 %

Procedure:
A mixture of 3-(trifluoromethyl)benzaldehyde (25 g, 144 mmol), malonic acid (28.8 g, 277 mmol), anhydrous pyridine (100 ml) and piperidine (2 ml) was heated under reflux for 4 hours. The mixture was poured onto fresh ice (300 g) and concentrated hydrochloric acid (78 ml). The solid product was collected, dried and recrystallised (1:1 IMS/water) to give 30 g (96% of theory) of 3-(trifluoromethyl) cinnamic acid as off-white needles.
Reaction SMILES: CO[C:3]1([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([CH3:7])([CH3:6])[O:4]1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>ClCCl>[CH3:6][C:5]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([CH3:7])[C:3]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)=[O:4]
Reactant: COC1(c2ccc(SC)cc2)OC1(C)C
Reactant: C1CNCCN1
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(C)(C)N2CCNCC2)cc1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
Further, in a 500 mL four-neck flask provided with a stirrer, a condenser, and a thermocouple, the compound (c) and 31 g of piperazine were added, followed by stirring at 130° C. for 6 hours. After cooling, 80 mL of dichloromethane was added, and an organic layer was washed three times with 70 mL of water. The organic layer was dried with anhydrous sodium sulfate and concentrated to produce 60.7 g of 2-methyl-1-(4-methylsulfanylphenyl)-2-piperazin-1-yl-propan-1-one (12).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH2:7])[CH2:2]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)([O-:17])=[O:16]
Reactant: NC1CCCOC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NC1CCCOC1
Temperature: 135 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A solution of tetrahydropyran-3-ylamine (0.43 g, 4.05 mmol) in DMF (2 mL) was added to a mixture of 1-fluoro-2-nitrobenzene (0.57 g, 4.05 mmol) and potassium carbonate (1.68 g, 12.1 mmol) in DMF (10 mL). The reaction mixture was heated for 1 h at 135° C. under microwave irradiation. Additional tetrahydropyran-3-ylamine (40 mg) was added and microwave irradiation at 135° C. was continued for further 30 min. Volatiles were then removed in vacuo and the resulting residue was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc (×2) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-2% MeOH in DCM) affording (2-Nitrophenyl)(tetrahydropyran-3-yl)amine as an orange oil (0.73 g, 81%). LCMS: RT 3.31 min [M+H]+ 223.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:13])[C:8](OCC)=[O:9])=[CH:3][CH:2]=1.[NH3:14]>>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:13])[C:8]([NH2:14])=[O:9])=[CH:3][CH:2]=1
Reactant: N
Reactant: CCOC(=O)C(C)c1ccncc1
Product: CC(C(N)=O)c1ccncc1
Temperature: 70 °C
Yield: 38.8 %

Procedure:
Methanolic ammonia (20 ml) was added to ethyl 2-(pyridin-4-yl)propanoate (140 mg, 0.78 mmol) in a steel bomb. The reaction mixture was heated to 70° C. for 18 h, then the temperature of the reaction was brought down to room temperature and the volatiles were evaporated. The reaction mixture was washed with n-pentane to afford 45 mg (38.8%) of 2-(pyridin-4-yl)propanamide as an orange color solid.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:54][C:55]1[C:60]([F:61])=[CH:59][CH:58]=[CH:57][C:56]=1[C:62]1[CH:67]=[CH:66][C:65]([C:68](O)=[O:69])=[CH:64][CH:63]=1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:68]([C:65]1[CH:64]=[CH:63][C:62]([C:56]2[CH:57]=[CH:58][CH:59]=[C:60]([F:61])[C:55]=2[F:54])=[CH:67][CH:66]=1)=[O:69]
Reactant: O=C(O)c1ccc(-c2cccc(F)c2F)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2cccc(F)c2F)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 49.1 %

Procedure:
DIPEA (273 mg, 0.37 mL, 2.1 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (198.2 mg, 0.56 mmol) in DMF (3 mL). HOBT (69.7 mg, 0.51 mmol) and EDCI (225 mg, 1.1 mmol) were then added at room temperature. After 2 minutes, 2′,3′-difluoro-biphenyl-4-carboxylic acid (110 mg, 0.46 mmol) (prepared by the method as described above) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 120 mg (48.07% yield) of 2′,3′-difluoro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 82.25%. 1H NMR (DMSO-d6): δ 8.8 (s, 1H), 8.2-8.0 (d, 2H), 7.9-7.64 (m, 5H), 7.62-7.1 (m, 4H), 4.2 (d, 2H), 3.8-3.54 (m, 4H), 3.52-3.4 (m, 2H), 3.2-3.08 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][C:9]([CH:11]2[S:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:28]([Si](C)(C)C)[C:29](=[O:34])C(F)(F)F)(C)C.ClC(Cl)(Cl)C(N=C=O)=O>ClCCl>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]([CH:11]2[S:16][CH2:15][CH2:14][N:13]([C:29](=[O:34])[NH2:28])[C:12]2=[O:17])=[O:10])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Reactant: O=C1NCCSC1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: NC(=O)N1CCSC(C(=O)OC(c2ccccc2)c2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a mixture of 2-diphenylmethoxycarbonyl-3-oxothiomorpholine (327 mg, 1 mM), dichloromethane (8 ml), and bistrimethylsilyltrifluoroacetamide (0.53 ml). After 30 minutes' stirring from addition of trichloroacetyl isocyanate (0.18 ml), another trichloroacetyl isocyanate (0.06 ml) is added. After another 30 minutes' stirring, the mixture is concentrated and subjected to silica gel chromatography. Fractions eluted with dichloromethane and a mixture of dichloromethane and ethyl acetate (9:1) are combined and concentrated to give 2-diphenylmethoxycarbonyl-4-carbamoyl-3-oxothiomorpholine (332 mg). Yield 89.6%.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[O:27]([CH2:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:35](=[O:36])[CH2:34][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)COc1ccccc1
Product: CC(C)CN([C@@H](CCCCNC(=O)COc1ccccc1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 88 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with phenoxyacetyl chloride under the conditions described in example 2 to yield 88% of the desired product.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([NH:13][CH2:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)(=[O:16])=[O:15])=[CH:22][CH:21]=2)=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Reaction time: 18 h

Procedure:
416.5 mg (1.85 mmol) of tin(II) chloride dihydrate are added to a solution of 136 mg (0.37 mmol) of N-benzyl-4′-nitrobiphenyl-4-sulfonamide (Example 9A) in 2.0 ml of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated in vacuo and dried under high vacuum. 117 mg (84.3% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([SH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][C:30](Cl)=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=2)=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:30]3[CH:31]=[CH:32][C:27]([C:26](=[O:37])[NH:25][C:22]4[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=4)=[CH:28][C:29]=3[N+:34]([O-:36])=[O:35])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(S)ccc21
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ccc2cc(Sc3ccc(C(=O)Nc4ccc(Br)cc4)cc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of the product of Example 59C (39.9 mg, 0.160 mmol) in anhydrous ethanol (2 mL) under a nitrogen atmosphere was treated with the product of Example 49A (56.8 mg, 0.160 mmol) and anhydrous sodium acetate (66 mg, 0.800 mmol) at room temperature, then heated at reflux for 2 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation under vacuum. The residue was taken up in ethyl acetate (50 mL) and washed with water (2×25 mL) and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel flash chromatography using methylene chloride as eluent afforded the title compound as a yellow solid (77 mg, 85%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[NH:20][CH2:21][CH2:22][N:23]=2)=[CH:14][CH:13]=1.CC(C)([O-])C.[K+].CC(C)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[N:23]3[CH2:22][CH2:21][NH:20][C:19]=23)=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Clc1ccc(CC2=NCCN2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=c1c2cccnc2c(-c2ccc(Cl)cc2)c2n1CCN2
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Add a solution of 2-chloro-3-pyridinylcarbonyl chloride (4.4 g) in tetrahydrofuran (55 ml) to a stirred, cooled mixture of 2-(4-chlorophenyl)methylimidazoline (4.9 g), potassium tert.-butoxide (2.8 g) and tetrahydrofuran (200 ml). Use a bath of ice and acetone for cooling. Keep the reaction mixture in the bath for 15 minutes, and then allow it to warm to 20° C. over another 15 minutes. To the warmed mixture, add a second portion (2.8 g) of potassium tert.-butoxide; allow the reaction mixture to stir at 20° C. overnight. Evaporate solvent, partition the residue between chloroform and water, and dry the chloroform solution Use sodium sulfate as a drying agent. Filter the dried solution, evaporate the solvent, and crystallize the residue from acetonitrile to obtain 10-(4-chlorophenyl)-2,3-dihydro-imidazo[1,2-g]-[1,6]naphthyridin-5(1H)-one, mp 260°-262° C.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:29][S:28](=[O:31])(=[O:30])[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:11]=3[N:12]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:32][OH:33]>CCO>[OH:33][N:32]=[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([N:12]2[C:11]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[S:28](=[O:30])(=[O:31])[CH2:29][C:10]=3[C:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])=[N:13]2)[CH:15]=1)[NH2:18]
Reactant: NO
Reactant: N#Cc1cccc(-n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)c1
Solvent: CCO
Product: NC(=NO)c1cccc(-n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)c1
Temperature: 85 °C
Yield: 46.5 %

Procedure:
To a solution of 3-[3-(morpholin-4-ylcarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1(4H)-yl]benzonitrile (0.3 g, 0.69 mmol) in EtOH (20 mL) is added 50% aq. hydroxylamine solution (0.14 mL, 2.07 mmol). The reaction mass is heated to 85° C. for 12 h. The solvent is removed completely under reduced pressure to afford 150 mg (89%) of the title compound as a white solid. MS (ESI+): 468.0.
Reaction SMILES: [O:1]([C:8]1[CH:25]=[CH:24][C:11]([C:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1C=CC(C(CCC(OC(C)C)=O)=O)=CC=1)C1C=CC=CC=1>>[O:1]([C:8]1[CH:25]=[CH:24][C:11]([C:12]([CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCOC(=O)CCC(=O)c1ccc(Oc2ccccc2)cc1
Agent: CC(C)OC(=O)CCC(=O)c1ccc(Oc2ccccc2)cc1
Product: CCCCCOC(=O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Yield: 94.5 %

Procedure:
The procedure in Example 14(1) was followed, except that 6.80 g of pentyl 3-(4-phenoxybenzoyl)propionate were used in place of isopropyl 3-(4-phenoxybenzoyl)propionate, to give 6.39 g of pentyl 3-(4-phenoxybenzoyl)acrylate in the form of an oil.
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[O:10])=CC=1)([O-])=O.C(#N)C.Cl.Cl.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[CH2:38][CH2:37]2)[N:31]=1>CCOC(C)=O>[CH3:29][C:30]1[N:31]=[C:32]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][N:47]([C:9]([O:11][C:12]4[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=4)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[CH2:46][CH2:45]3)[CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: Cc1cccc(N2CCC(CCC3CCNCC3)CC2)n1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCC3CCN(c4cccc(C)n4)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (505 mg) was added to an acetonitrile (10 ml) solution of 2-methyl-6-[4-(2-piperidin-4-ylethyl)piperidin-1-yl]pyridine dihydrochloride (520 mg) and TEA (0.50 ml), followed by stirring at room temperature for 3 hours. The reaction liquid was diluted with EtOAc, washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=98:2 (v/v)) to obtain methyl 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate (424 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:15][C:14]2[C:9](=[C:10]([Cl:16])[CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:5])[CH3:2]>ClC1C=CC=CC=1.O=[Mn]=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2cccnc2)Nc2c(Cl)cccc2C1
Agent: O=[Mn]=O
Solvent: Clc1ccccc1
Product: CCOC(=O)c1cc2cccc(Cl)c2nc1-c1cccnc1
Temperature: 60 °C
Yield: 79 %

Procedure:
A suspension of 8-chloro-2-(pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (10.7 g, 34 mmol) in chlorobenzene (60 mL) was treated with MnO2 (10 g) and the mixture was heated to 60° C. for 3 h. The mixture was filtered through a celite plug and concentrated in vacuo. The residue was washed with diethyl ether to give 8-chloro-2-(pyridin-3-yl)quinoline-3-carboxylic acid ethyl ester (8.4 g, 79%) as a white solid. δH (CDCl3) 8.96 (d, J 1.7 Hz, 1H), 8.83 (s, 1H), 8.75 (dd, J 5.0, 1.1 Hz, 1H), 8.27 (dt, J 7.9, 1.7 Hz, 1H), 8.00 (dd, J 7.5, 1.0 Hz, 1H), 7.92 (dd, J 8.2, 1.0 Hz, 1H), 7.60 (m, 2H), 4.32 (q, J 7.1 Hz, 2H), 1.24 (t, J 7.1 Hz, 3H). LCMS (ES+) 313.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH3:24])[CH:22]=2)[CH:3]=1.[Br-].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Zn+]>O1CCCC1.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>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[CH:3][C:4]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH3:24])[CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCNC(=O)Nc1nc2cc(-c3cncc(OC)c3)cc(Br)c2s1
Reactant: [Zn+]c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cncc(OC)c3)cc(-c3ccccn3)c2s1
Temperature: 60 °C
Yield: 28 %

Procedure:
To a stirred solution of 1-[7-Bromo-5-(5-methoxy-pyridin-3-yl)-benzothiazol-2-yl]-3-ethyl-urea (90 mg, 0.22 mmol), and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.015 mmol), in tetrahydrofuran (4 ml), was added 2-pyridylzinc bromide (3.1 ml, 1.5 mmol, 0.5 M solution in THF). The reaction was purged with nitrogen then heated at 60° C. for 16 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution followed by brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to give 1-Ethyl-3-[5-(5-methoxy-pyridin-3-yl)-7-pyridin-2-yl-benzothiazol-2-yl]-urea as a white solid (25 mg, 27%)