Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:9]3([C:15]([OH:17])=[O:16])[CH2:11][CH:12]=[CH:13][CH2:14][CH:8]3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[CH:1]1[C:10]2[C:9]3([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C12CC=CCC1CSc1ccccc12
Agent: [Pd]
Solvent: CO
Product: O=C(O)C12CCCCC1CSc1ccccc12
Yield: 79.8 %

Procedure:
To a solution of the product from Example 19 (4.35 g) in methanol (100 ml) was added palladium on charcoal 5%, 0.5 g). The solution was hydrogenated (50 psi) and the suspension filtered through Hyflow. Evaporation of solvent gave the title compound as a colorless crystalline solid (3.5 g). Treatment of the catalyst residue with hot methanol afforded the remaining of the title compound (0.8 g), mp 200°-203° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][N:26]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][N:26]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3ccc(-c4ccccc4)cn3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (700 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(5-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (620 mg, yield: 94%). This was recrystallized from acetone-hexane. Melting point: 127–128° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([O:10]C)[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)[CH:20]=3)=[C:14]([CH3:31])[N:13]=2)=[CH:6][N:5]=1)[CH3:2].Br>>[CH2:1]([NH:3][C:4]1[NH:9][C:8](=[O:10])[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)[CH:20]=3)=[C:14]([CH3:31])[N:13]=2)=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(-n4cnc(C)c4)c3)c(C)n2)c(OC)n1
Agent: Br
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-n4cnc(C)c4)c3)c(C)n2)c(=O)[nH]1
Yield: 51.3 %

Procedure:
Using the procedure of Example 1, N-ethyl-4-methoxy-5-(6-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (0.12 g, 0.29 mmol) and 48% HBr (0.63 mL, 11.5 mmol) were combined to afford 2-(ethylamino)-5-(6-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one as a white solid (0.06 g, 51%). 1H NMR (400 MHz, DMSO-d6): δ 10.60 (br s, 1H), 8.68 (s, 1H), 8.40 (d, J=1.3 Hz, 1H), 8.31-8.30 (m, 2H), 7.64 (s, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.39 (d, J=2.2 Hz, 1H), 6.93 (br s, 1H), 6.73 (dd, J=5.8, 2.2 Hz, 1H), 3.35-3.33 (m, 2H), 2.35 (s, 3H), 2.13 (s, 3H), 1.12 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 404.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[C:16]1([O:24][CH3:25])[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:18][CH3:19]>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:11][C:12]([C:22]2[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:16]([O:24][CH3:25])[CH:23]=2)=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: COc1ccccc1OC
Solvent: O
Product: COc1ccc(CC(=O)c2ccc(OC)c(OC)c2)cc1OC
Reaction time: 24 h
Yield: 60 %

Procedure:
A warm solution of 3,4-dimethoxyphenylacetic acid (10 g) in veratrole (15 ml) was added to 200 g of polyphosphoric acid (PPA). After 24 hrs. at room temperature the acid mixture was added to cold water (800 ml) and the product was collected and recrystallized from aqueous ethanol. The recrystallized intermediate (9.5 g, 60% yield) had a melting point of 104°-105°.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.OS(O)(=O)=O>C1COCC1>[O:11]1[C:10]2[CH:14]=[CH:15][C:7]([B:16]([OH:21])[OH:17])=[CH:8][C:9]=2[O:13][CH2:12]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Butyl lithium (BuLi) (5.6 mL, 1.40 equiv) was added dropwise to a solution of 5-bromobenzo[d][1,3]dioxole (2 g, 9.95 mmol, 1.00 equiv) and triisopropyl borate (1.96 g, 14.00 mmol, 1.40 equiv) in THF (20 mL) at −78° C. in a 100-mL 3-necked round-bottom flask under an inert atmosphere of nitrogen. The mixture was stirred at room temperature for 4 hr, quenched with water (10 mL), and acidified with H2SO4 (4.9 g, 50.00 mmol, 5.00 equiv). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux. The solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting solid material was washed with 3×3 mL of ethyl acetate. This resulted in 0.5 g (30%) of benzo[d][1,3]dioxol-5-ylboronic acid as a white solid.
Reaction SMILES: [CH2:1]1[C@@H:5]([OH:6])[C@H:4](/[CH:7]=[CH:8]/[C@@H:9]([OH:22])[CH2:10][O:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][CH:13]=2)[C@@H:3]([CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C@H:2]1[OH:32].[NH2:33][C@H:34]([C:43]([OH:45])=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([NH2:42])=[NH:41]>CO.O>[CH3:35][CH:34]([O:30][C:29]([CH2:28][CH2:27][CH2:26]/[CH:25]=[CH:24]\[CH2:23][C@@H:3]1[C@@H:4](/[CH:7]=[CH:8]/[C@@H:9]([OH:22])[CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=2)[C@H:5]([OH:6])[CH2:1][C@@H:2]1[OH:32])=[O:31])[CH3:43].[NH2:33][C@H:34]([C:43]([OH:45])=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([NH2:42])=[NH:41]
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Agent: N=C(N)NCCCC[C@H](N)C(=O)O
Solvent: O
Solvent: CO
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Reaction time: 0.5 h

Procedure:
To travoprost free acid ((+)-fluprostenol free acid) 3 in MeOH/H2O is added L-Homoarginine and the solution is stirred for 30 minutes. The solvents are evaporated then azeotroped with Et2O and hexanes to give white crystalline travoprost-L-Homoarginine salt 5 (quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[N:10][C:11]([NH:14][CH2:15][CH2:16][N:17]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][C:18]3=[O:25])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]([N:39]([CH2:41][C:42](O)=[O:43])[CH3:40])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[Cl:31][C:28]1[S:27][C:26]([C:9]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:42](=[O:43])[CH2:41][N:39]([CH3:40])[C:32](=[O:33])[O:34][C:35]([CH3:37])([CH3:38])[CH3:36])[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:12]=[C:11]([NH:14][CH2:15][CH2:16][N:17]3[C:21]([CH3:22])([CH3:23])[C:20](=[O:24])[NH:19][C:18]3=[O:25])[N:10]=2)=[CH:30][CH:29]=1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(N)c2)c(-c2ccc(Cl)s2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)Nc1cccc(-c2cnc(NCCN3C(=O)NC(=O)C3(C)C)nc2-c2ccc(Cl)s2)c1)C(=O)OC(C)(C)C

Procedure:
A solution of 50 mg (0.11 mmol) of 1-{2-[5-(3-aminophenyl)-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione, 31 mg (0.16 mmol) of N-Boc-sarcosine, 31 mg (0.16 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 0.1 mg (0.01 mmol) of 4-dimethylaminopyridine and 0.057 mL (0.33 mmol) of N,N-diisopropylethylamine in 1 mL of CH2Cl2 was stirred for 18 h at rt. The reaction solution was poured into 75 mL of EtOAc and washed thrice with 2% (w/v) aqueous HCl, once with a saturated aqueous solution of NaHCO3, then with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with a linear gradient of neat EtOAc to 10% MeOH in EtOAc to yield the title compound. MS (M+H)+ 628.
Reaction SMILES: C([Mg]Br)C.[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:19]([CH:21]=[CH2:22])=[O:20].[Cl-].[NH4+]>C(OCC)C.O>[CH2:22]=[CH:21][CH:19]([OH:20])[C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCCCCCCCCCCC
Reactant: C=CC=O
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: C=CC(O)C#CCCCCCCCCCCCC
Temperature: -10 °C

Procedure:
To freshly prepared ethyl magnesium bromide (from 58.95 mmoles of bromoethane and 49.36 mmoles of magnesium) in diethyl ether (125 ml) was added 1-tetradecyne (44.5 mmoles) in diethyl ether (25 ml) dropwise at ambient temperature. After 3 hours the reaction mixture was cooled to -10° C. and freshly distilled acrolein (59.86 mmoles) in diethyl ether (25 ml) was added dropwise. After 30 minutes saturated ammonium chloride (100 ml) and water (50 ml) were added. The organic phase was separated, washed with brine (100 ml) and dried over anhydrous magnesium sulfate. The desired compound was purified by flash chromatography on silica gel eluted with 90:10 hexane:ethyl acetate.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Br[C:7]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:17]>ClCCl>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:7]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:8](=[O:17])[NH:9]2)=[CH:14][CH:13]=1
Reactant: NCC1CC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)NCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of cyclopropanemethylamine (142 mg, 2.0 mmol) in dichloromethane (20 mL) was added rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (0.37 g, 0.99 mmol). After the mixture was stirred at room temperature for 1 h, another portion of dichloromethane (20 mL) was added. The mixture was washed with water (20 mL×2). The organic layer was separated, dried over Na2SO4 and concentrated to give 0.34 g of rac-6-chloro-3-(3-chloro-benzyl)-3-(cyclopropylmethyl-amino)-1,3-dihydro-indol-2-one as a white solid. MS: [M+H]+=361
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C([N:18]1[CH:22]=[CH:21]N=C1)(N1C=CN=C1)=O.O>CN(C)C=O>[CH3:4][C:3]1[CH:2]=[C:22]([NH:18][C:4]([C:3]2[C:2](=[S:1])[NH:10][CH:9]=[CH:8][CH:7]=2)=[O:6])[CH:21]=[C:8]([CH3:9])[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cccnc1S
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2-Mercaptonicotinic acid (90 g, 0.58 mol) was suspended in N,N-dimethylformamide (660 mL) under ice-cooling, then carbonyldiimidazole (110 g, 0.70 mol) was added thereto, and the whole was stirred for 2 hours at room temperature. Water (5.4 mL) was added thereto, and the whole was stirred for 40 minutes, and then 3,5-xylydine (76 mL, 0.61 mol) was added thereto and the resulting mixture was stirred at 60° C. for 16 hours. The mixture was allowed to stand, and then water (1.3 L) was added, and the precipitated solid was filtered off. The solid was dried at 45° C. under reduced pressure to give 130 g of the title Reference Compound as a yellow solid (Yield: 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH:20]([F:22])[F:21])=[CH:17][CH:16]=[C:15]([F:23])[C:14]=3[Cl:24])[CH3:12])=[CH:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.[CH2:32]1[C:35]2(OCC[O:36]2)[CH2:34][CH:33]1[N:40]1[C:44]([CH3:45])=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1.C([O-])([O-])=O.[K+].[K+].O.Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:24][C:14]1[C:15]([F:23])=[CH:16][CH:17]=[C:18]([O:19][CH:20]([F:21])[F:22])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:43]3[CH:42]=[N:41][N:40]([CH:33]4[CH2:34][C:35](=[O:36])[CH2:32]4)[C:44]=3[CH3:45])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: C[C@H](c1c(OC(F)F)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C1CC2(C1)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1C1CC(=O)C1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (41.1 mg, 0.0791 mmol), 1-(5,8-dioxaspiro[3.4]oct-2-yl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (38.0 mg, 0.119 mmol), Pd(PPh3)4 (4.57 mg, 0.00396 mmol), K2CO3 (32.8 mg, 0.237 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated to 95° C. for 1 h. The solution was allowed to cool to rt, and 2 M of HCl in H2O (2 mL, 4 mmol) was added. The mixture was heated at 45° C. overnight. The organic solvent was removed in vacuo, and the material was extracted with DCM and sat. NaHCO3. The organic layer was loaded onto silica gel for column chromatography, eluting with 1-3% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=489.09/491.09 (100/50) [MH+]. HPLC: tR=4.04 min (polar—5 min, ZQ3).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].O.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: Brc1c[nH]c2ncccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a 0° C. solution of Example 1a (25 g, 127 mmol) in N,N-dimethylformamide (200 mL) was slowly added sodium hydride (3.37 g, 133 mmol) over several minutes. After stirring for 30 minutes in the cold water bath, benzenesulfonyl chloride (17.18 ml, 133 mmol) was added via a syringe. The solution was allowed to warm to room temperature overnight, quenched slowly with 500 mL water, stirred for 30 minutes, and then filtered. The solid obtained was washed with water, followed by 300 mL of hexanes, dried over high-vacuum for 16 hours to give 34 g of the title compound which was used without further purification. MS (ESI+) m/z 338.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[N:17]1[C:26]2[C:21](=[N:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:27][C:23]2[CH:24]=[CH:25][C:26]3[C:21](=[CH:20][CH:19]=[CH:18][N:17]=3)[N:22]=2)[C:9](=[O:11])[N:10]=1
Reactant: Cc1cccc(Cl)c1CNC1=NC(=O)CS1
Reactant: O=Cc1ccc2ncccc2n1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1cccc(Cl)c1CNC1=NC(=O)C(=Cc2ccc3ncccc3n2)S1
Temperature: 130 °C
Yield: 52.1 %

Procedure:
To a suspension of 2-(2-chloro-6-methyl-benzylamino)-thiazol-4-one (40.8 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 15 min., then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 2-(2-chloro-6-methyl-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a brown solid (32.9 mg, 52.1%). HR-ES (+) m/e calcd. for C20H15ClN4OS: (M+H)+ 395.0728. Found: 395.0728.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:45]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH2:44].[O:46]=[C:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49](=[O:56])[N:48]1[CH2:57][CH2:58][S:59](Cl)(=[O:61])=[O:60]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:45]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][S:59]([CH2:58][CH2:57][N:48]1[C:47](=[O:46])[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]1=[O:56])(=[O:60])=[O:61]
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 20 %

Procedure:
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) and 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanesulfonyl chloride as the starting materials in 20% yield. LCMS for C27H23ClN7O4S (M+H)+: m/z=575.9.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:25][C:26]1[C:30]2[C:31](=[O:37])[NH:32][CH2:33]CC(=O)[C:29]=2[NH:28][CH:27]=1.CI>C1COCC1.CN(C=O)C>[CH3:29][N:28]1[C:3]2[C:2](=[O:4])[CH2:1][CH2:33][NH:32][C:31](=[O:37])[C:30]=2[C:26]([CH3:25])=[CH:27]1
Reactant: CC(C)(C)[O-]
Reactant: Cc1c[nH]c2c1C(=O)NCCC2=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cn(C)c2c1C(=O)NCCC2=O
Temperature: 25 °C

Procedure:
To a suspension of potassium t-butoxide (1.62 g, 14.4 mmole) and 18-crown-6 (317 mg, 1.2 mmole) in THF (20 ml), a suspension of 3-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione (2.12 g, 12 mmole) in THF (20 ml) and a solution of methyl iodide (2.55 g, 18 mmole) in THF (5 ml) were successively added dropwise, and the reaction mixture was stirred at room temperature. Twenty-four hours later, a solution of-potassium t-butoxide (0.81 g, 7.2 mmole) and methyl iodide (1.28 g, 9.0 mmole) in DMF (5 ml) was added, and 24 hours later, a solution of potassium t-butoxide (0.81 g, 7.2 mmole) and methyl iodide (1.28 g, 9 mmole) in DMF (5 ml) was added further. The reaction mixture was then stirred at room temperature for 3 hours.
Reaction SMILES: [CH2:1]([C@@:5]1([C:34]([OH:36])=[O:35])[CH2:9][C@H:8]([CH2:10][O:11][CH2:12][CH:13]=[CH2:14])[C@H:7]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:6]1[C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[C:23]([O:31][CH3:32])[CH:22]=1)[CH:2]([CH3:4])[CH3:3].[H][H]>C(O)C.[Pd]>[CH2:1]([C@@:5]1([C:34]([OH:36])=[O:35])[CH2:9][C@H:8]([CH2:10][O:11][CH2:12][CH2:13][CH3:14])[C@H:7]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[N:6]1[C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:28])([CH3:30])[CH3:29])=[C:23]([O:31][CH3:32])[CH:22]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: C=CCOC[C@H]1C[C@@](CC(C)C)(C(=O)O)N(C(=O)c2ccc(C(C)(C)C)c(OC)c2)[C@H]1c1nccs1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCOC[C@H]1C[C@@](CC(C)C)(C(=O)O)N(C(=O)c2ccc(C(C)(C)C)c(OC)c2)[C@H]1c1nccs1

Procedure:
A solution of Example 40 (10 mg) in ethanol (4 mL) was added to 10% palladium on carbon (50 mg) and stirred under 1 atmosphere pressure of hydrogen at 20 degrees for 4 h. Catalyst was removed by filtration and washed with ethanol (10 mL). Filtrate and washings were combined and solvent was removed to give the title compound.
Reaction SMILES: [Na].C[C@@H]1C[C@@H]([C@H](O)CC2CC(=O)NC(=O)C2)C(=O)[C@@H](C)C1.[CH3:22][CH2:23][N:24]1[C:30](=[O:31])[C:28](=[O:29])[N:27]([C:32]([NH:34][C@@H:35]([C:43]([NH:45][C@@H:46]2[C:49](=[O:50])[N:48]3[C:51]([C:63]([O-:65])=[O:64])=[C:52]([CH2:55][S:56][C:57]4[N:61]([CH3:62])[N:60]=[N:59][N:58]=4)[CH2:53][S:54][C@H:47]23)=[O:44])[C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)=[O:33])[CH2:26][CH2:25]1.[Na+]>CO>[CH3:22][CH2:23][N:24]1[C:30](=[O:31])[C:28](=[O:29])[N:27]([C:32]([NH:34][C@@H:35]([C:43]([NH:45][C@@H:46]2[C:49](=[O:50])[N:48]3[C:51]([C:63]([OH:65])=[O:64])=[C:52]([CH2:55][S:56][C:57]4[N:61]([CH3:62])[N:60]=[N:59][N:58]=4)[CH2:53][S:54][C@H:47]23)=[O:44])[C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)=[O:33])[CH2:26][CH2:25]1
Reactant: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(CSc4nnnn4C)CS[C@H]23)c2ccc(O)cc2)C(=O)C1=O
Agent: C[C@@H]1C[C@@H]([C@H](O)CC2CC(=O)NC(=O)C2)C(=O)[C@@H](C)C1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCN1CCN(C(=O)N[C@@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nnnn4C)CS[C@H]23)c2ccc(O)cc2)C(=O)C1=O
Reaction time: 0.25 h
Yield: 10.3 %

Procedure:
Media: The composition of Campy-Cefex, modified CCDA and Campy-BAP are provided in Table 1. All media were prepared in our laboratories and used immediately or stored in the dark at 4° C. no more than two weeks prior to use. The basal media components were autoclaved at 121° C. for 15 min. The sterilized agar was then tempered in a waterbath to 50°-55° C., and the lysed horse blood and filter-sterilized antibiotics were added and gently mixed before the plates were poured. Filter-sterilized sodium cycloheximide (200 mg/L) was added as a 10% solution in 50% methanol. One gram of sodium cefoperazone was dissolved in 10 ml of sterile, distilled water. Each ml of this solution provided 100 mg cefoperazone/3 L of Campy-Cefex agar. The unused portion of cefoperazone was held in storage at -20° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[C:2]#[C:3][CH3:4].Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(COCC[Si](C)(C)C)c(=O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 1.2 ml of N,N-dimethylformamide, and then 44 μl of (2-chloromethoxyethyl)trimethylsilane and 34 mg of potassium carbonate were added thereto. The mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by silica gel chromatography to give 55 mg of the title compound.