Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].CO.[Fe:24]>C(O)(=O)C>[Fe:24].[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[NH2:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(OCc2ccccc2)cc1N

Procedure:
1-Acetamido-4-benzyloxy-2-nitrobenzene is treated with 100 ml. methanol with 1.5 g. iron powder and 1 ml. acetic acid at reflux, followed after one hour with a further addition of 1 ml. of acetic acid and 1.0 g. of iron powder to afford 1-acetamido-2-amino-4-benzyloxybenzene. This latter compound is treated in accordance with the third paragraph of Example I to afford 2-acetamido-5-benzyloxy-1-(3-methoxycarbonyl-2-thioureido)benzene.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[C:28]([Cl:30])[CH:29]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32](=[O:33])[N:3]([CH2:4][C:5]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:6]=2[CH2:7][N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:9]3=[O:14])[CH3:2])[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O)C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and 3,5-dichlorophenyl-isocyanate (0.42 g, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and filtered. The resulting solid was rinsed with CH2Cl2 (5 mL) to give 3-(3,5-dichloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.76 g, 86%): mp 285-287° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.97 (99%); 1H NMR (DMSO-d6): δ 2.00-2.05 (m, 1H), 2.33-2.40 (m, 1H), 2.57-2.64 (m, 1H), 2.85-2.94 (m, 1H), 2.98 (s, 3H), 4.37 (d, J=17.3 Hz, 1H), 4.45 (d, J=7.4 Hz, 1H), 4.65 (s, 2H), 5.10-5.18 (dd, J=4.9, 13.1 Hz, 1H), 7.13 (s, 1H), 7.45 (d, J=8.9 Hz, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.63-7.67 (m, 3H), 8.80 (s, 1H), 11.01 (s, 1H). 13C NMR (DMSO-d6) δ: 22.57, 31.19, 34.78, 46.26, 48.37, 51.61, 117.44, 120.77, 121.82, 128.51, 129.81, 131.95, 133.40, 133.65, 140.15, 143.05, 155.03, 167.98, 171.00, 172.83. Anal Calcd for C22H20Cl2N4O4+0.2 CH2Cl2: C, 54.16; H, 4.18; N, 11.38, Cl, 17.28. Found: C, 54.34; H, 3.95; N, 11.29, Cl, 17.13.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][Zn+].Cl.N>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:33][C:32]5[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[CH:31]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COc1cccc(C[Zn+])c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Agent: [Pd]
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5cccc(OC)c5)ccc(F)c43)ccc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (84 mg), 3-methoxy-benzylzinc chloride (0.5 mol/L in tetrahydrofuran, 1.2 mL) and tetrakis(triphenylphosphine)-palladium (23 mg). Degassed tetrahydrofuran (1 mL) is added under Ar atmosphere, and the mixture is heated to 60° C. and shaken at this temperature overnight. The mixture is acidified with 4 N aqueous hydrochloric acid (1 mL) and then neutralized with saturated aqueous ammonia solution. The organic phase is separated, diluted with N,N-dimethylformamide (1 mL), and purified by HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=1.17 min.
Reaction SMILES: C([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:42])[C@@H:30]([CH3:41])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:40])([CH3:39])[C@@H:35]([OH:38])[CH2:36][CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[C:22]([O:21][C:19]([N:14]1[CH2:13][C:12]2[C:11]3[O:26][C@@:27]45[CH2:37][CH2:36][C@H:35]([OH:38])[C:34]([CH3:40])([CH3:39])[C@@H:33]4[CH2:32][CH2:31][C@H:30]([CH3:41])[C@@:28]5([CH3:42])[CH2:29][C:10]=3[C:9]([OH:8])=[CH:17][C:16]=2[C:15]1=[O:18])=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(O)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reaction time: 2.5 h
Yield: 90.9 %

Procedure:
To a solution of Compound (39a) (Step-1 in Example 44) (303 mg, 0.53 mmol) in 10 ml of methanol containing 1% water was added 30 mg of 10% palladium-carbon, followed by catalytic reduction under atomospheric pressure for 2.5 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a column chromatography (silica gel 5 g; ethyl acetate) to give 234 mg (91%) of Compound (55a).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CN1CCc2cccc(Cl)c2CC1
Agent: O=S(=O)(O)O
Product: CN1CCc2c(Cl)ccc([N+](=O)[O-])c2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution of 67.2 g (0.34 mol, U.S. Pat. No. 4,265,890) of 6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 100 ml of sulfuric acid was added, dropwise over 2 hours, 40 ml of concentrated nitric acid. The mixture was stirred at room temperature overnight and quenched in ice. It was made basic with 10% sodium hydroxide solution and extracted with methylene chloride. The organic phase was washed, dried and evaporated to leave a residue, which was chromatographed over a "Waters prep 500" high pressure liquid chromatographic silica gel column, using isopropanol-hexane-diethylamine, to give pure 6-chloro-3-methyl-9-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:13][N:14]([CH3:18])[C:15](=[O:17])[CH3:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:22][C:21]1[CH:20]=[CH:19][C:12]([CH2:13][N:14]([CH3:18])[C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH2:9][OH:8]
Reactant: CC(=O)N(C)Cc1ccc(Cl)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-chlorobenzyl]-N-methylacetamide from the previous step (1 eq.) in THF (0.8M) was added tetrabutylammonium fluoride (1.0 M THF solution, 1.5 eq.). The resulting reaction mixture was stirred at RT for 1 h. After quenching the reaction with 10% aq. HCl, the mixture was extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) CH2Cl2:MeOH) afforded the title compound as a light yellow oil.
Reaction SMILES: O.[C:2]1([C:8]2[NH:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+].[CH3:19]O>C(OC(=O)C)C>[C:2]1([C:8]2[NH:9][CH:10]=[C:11]([C:13]([O:15][CH3:19])=[O:14])[N:12]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c[nH]c(-c2ccccc2)n1
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
2-Phenyl-1H-imidazole-4-carboxylic acid mono hydrate (2.00 g) was suspended in methanol (30 mL) and concentrated hydrochloric acid (10.0 mL) was added and the reaction mixture heated at reflux overnight. The reaction mixture was cooled to room temperature and diluted with ethylacetate and the aqueous basified with 1 N sodium hydroxide. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound. The title compound was used without further purification, having the following physical data.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([C:20](OC)=[O:21])=[CH:16][C:15]4=[O:24])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]4=[O:24])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccn(-c2ccc3nc(C4CC4)n(C)c3c2)c(=O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(CO)cc3=O)cc21
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a stirred solution of methyl 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate (800 mg) in DCM (20 ml) was added diisobutylaluminum hydride (1.0 M in toluene, 1.04 ml) at −78° C., and the mixture was stirred at same temperature for 2 h. The reaction mixture was then quenched with a mixture of MeOH (2 ml) and water (2 ml), filtered through celite and the resulting filtrate was concentrated in vacuo. The residue was purified by column chromatography (MeOH/DCM) to give the title compound (350 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Li]CCCC.[C:21](OC)(=[O:26])[C:22]([O:24][CH3:25])=[O:23].[NH4+].[Cl-]>C1COCC1.CCOCC>[CH3:1][O:2][CH2:3][N:4]1[C:8]([C:21](=[O:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:7][N:6]=[C:5]1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COCn1ccnc1Sc1ccccc1
Reactant: COC(=O)C(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCn1c(C(=O)C(=O)OC)cnc1Sc1ccccc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a cold (−78° C.), stirred solution of 1-methoxymethyl-2phenylthioimidazole (Ohta, S. et al. (1992) Chem. Pharm. Bull. 40:2681) (11) 340 mg, 1.55 mmol) in dry THF (8.0 mL) was added a solution of n-BuLi (1.47 M in hexanes, 1.26 mL, 1.85 mmol) and the mixture was stirred for 1 hour. A solution of dimethyl oxalate (540 mg. 4.58 mmol) in dry THF (2.0 mL) was added and the mixture was stirred at −78° C. for an additional 1.25 hours. The reaction mixture was treated with saturated aqueous NH4Cl (5.0 mL) and Et2O (20 mL). The phases were separated and the aqueous layer was extracted with Et2O (25 mL). The combined organic extracts were washed (brine, 10 mL), dried (MgSO4), and concentrated. Flash chromatography (35 g of silica gel, 1:1 petroleum ether-Et2O) of the crude material afforded 305 mg (66%) of 8 as a beige solid that exhibited mp 59-60° C.; IR (KBr) 1729, 1657, 1305, 1273, 1167, 1114, 784 cm−1; 1H NMR (CDCl3, 400 MHz) δ8.23 (s, 1H), 7.52-7.54 (m. 2H), 7.37-7.38 (m, 3H), 5.81 (s, 2H), 3.91 (s, 3H), 3.36 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ172.2, 161.6, 154.1, 145.4, 145.3, 133.2, 129.5, 129.2, 128.7, 75.8, 56.5, 53.0; HREIMS calcd for C14H14N2O4`S 306.0674, found 306.0674.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9].[CH3:15][C:16](=O)[CH3:17].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[NH:10][C:16]1([CH3:17])[CH3:15]
Reactant: CC(C)=O
Reactant: NC(=O)c1ccccc1NCCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC1(C)NC(=O)c2ccccc2N1CCCCl

Procedure:
A mixture of 10 parts of 2-[(3-chloropropyl)amino]benzamide, 16 parts of 2-propanone, 1 part of 4-methylbenzenesulfonic acid and 40 parts of ethanol is stirred and refluxed overnight. The reaction mixture is evaporated and the oily residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 10 parts of 1-(3-chloropropyl)-2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone.
Reaction SMILES: F[C:2]1[C:20](F)=[C:19](F)[C:18](F)=CC=1C(C(C(OCC)=O)C(OCC)=O)=O.[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:44])=[C:34]([N:38]4[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]4)[C:35]=3[F:37])[C:30](=[O:45])[C:29]([C:46]([OH:48])=[O:47])=[CH:28]2)[CH2:26][CH2:25]1.C1(CCl)CC1.[I-].[K+]>C(N(CC)CC)C>[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:44])=[C:34]([N:38]4[CH2:39][CH2:40][N:41]([CH2:18][CH:19]5[CH2:2][CH2:20]5)[CH2:42][CH2:43]4)[C:35]=3[F:37])[C:30](=[O:45])[C:29]([C:46]([OH:48])=[O:47])=[CH:28]2)[CH2:25][CH2:26]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Agent: ClCC1CC1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCN(CC4CC4)CC3)c(F)cc2c1=O
Temperature: 80 °C

Procedure:
A mixture of 3 5 g (0.01 mol) of 1-cyclopropyl-6,8-difluoro-7-(piperazin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 2.1 g of triethylamine, 1.8 g of cyclopropylmethyl chloride and 3.3 g of potassium iodide is heated to 80° C. for 6 hours. Thereafter, the mixture is evaporated down in vacuo, 30 ml of water are added, the mixture is adjusted to pH 5 and the precipitate is filtered off under suction, washed with water and methanol and recrystallised from glycol monomethyl ether. 1.8 g of 1-cyclopropyl-7-(4-cyclopropylmethylpiperazin-1-yl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid having a decomposition temperature of 246°-248° C. are obtained.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[NH2:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[C:1]1([S:7]([C:10]2[C:11]3[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:13][N:18]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=N[O-]
Reactant: Nc1ccccc1CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(c1ccccc1)c1n[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A stirred solution of 2-[(phenylsulfonyl)methyl]aniline (247 mg, 1.00 mmol) in 4N HCl (50 ml) is treated with a solution of NaNO2 (100 mg, 1.5 mmol) in water at ice-bath temperatures, stirred for 30 min., neutralized with 10% NaOH and filtered. The filtercake is dissolved in CH2Cl2, dried over MgSO4 and concentrated in vacuo to afford the title product as a tan solid, 240 mg (93% yield), mp 118° C., identified by mass spectral and HNMR analyses.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([O:20][CH3:21])[CH:4]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([S:34]([N:37](CC3C=CC(OC)=CC=3)[C:38]3[S:39][CH:40]=[CH:41][N:42]=3)(=[O:36])=[O:35])=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:22][CH:2]([F:1])[C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34]([NH:37][C:38]4[S:39][CH:40]=[CH:41][N:42]=4)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[C:5]([O:20][CH3:21])[CH:4]=1
Reactant: COc1cc(C(F)F)c(OC)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(F)F)c(OC)cc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Yield: 17.8 %

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (7.78 mg, 9.53 μmol), 2-(4-(difluoromethyl)-2,5-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate NNNNN; 0.078 g, 0.248 mmol), 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ; 0.085 g, 0.191 mmol), and potassium carbonate (0.079 g, 0.572 mmol) in 2 mL dioxane, 1 mL water was heated to 100° C. overnight. LC/MS showed mostly product, so the reaction mixture was allowed to cool to room temperature. The aqueous layer was then removed. The reaction mixture was treated with HCl (4N in dioxane) (0.953 ml, 3.81 mmol) and was heated to 100° C. for one hour. LC/MS showed mostly product, so the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18 30μ, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4-(difluoromethyl)-2,5-dimethoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.016 g, 0.034 mmol, 17.58% yield). 1H NMR (MeCN-d3) δ: 8.68 (d, J=5.7 Hz, 1H), 8.51 (s, 1H), 7.93 (d, J=6.0 Hz, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.32 (s, 1H), 7.10 (d, J=6.1 Hz, 1H), 6.99 (d, J=4.7 Hz, 1H), 6.61 (d, J=4.7 Hz, 1H), 3.81 (s, 3H), 3.65 (s, 3H); (M+H)+=478.0.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:20])=[O:19]
Reactant: OCCN1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN1CCCCC1

Procedure:
The 1-piperidineethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 33.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3,8-di-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (18 mg, 0.039 mmol), β-alanine (553 mg, 6.21 mmol) and NaOMe solution (9 mL, 4.66 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 6.8 mg of the title compound as a light yellow solid. MS: (+) m/z 522.29 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH2:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO[C:15]1(OC)[CH2:19][CH2:18][CH2:17]O1.O>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:19][CH:18]=[CH:17]2)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cc(F)c(C(=O)O)cc1F
Reactant: COC1(OC)CCCO1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(F)c(-n2cccc2)cc1F
Yield: 79.2 %

Procedure:
5.2 grams (0.03 mol) of 2,5-difluoro-4-aminobenzoic acid, melting at 250°-3°, are dissolved in 60 ml of glacial acetic acid, and 4 grams (0.03 mol) of dimethoxytetrahydrofuran are added. The mixture is heated at the boil for 10 minutes, 20 ml of water are added and the resulting mixture is left to cool. The precipitate formed is filtered off and washed with water to give 5.3 grams of a solid melting at 196°-8° C.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClC(Cl)C.C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Solvent: c1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R, 3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (1.0 g) in dichloroethane (50 ml) was added rhodium (II) acetate (2 mg) under refluxing. After refluxing for 1 hour, the reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in anhydrous benzene (10 ml) and then evaporated. This operation was repeated once again to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in anhydrous acetonitrile (20 ml) and cooled to 0° C. under an atmosphere of nitrogen. To this solution were added N,N-diisopropyl-N-ethylamine (0.59 ml) and diphenyl phosphorochloridate (0.61 ml) successively, and the solution was stirred at 0°-5° C. for 40 minutes. To the resulting solution were added a solution of (2S,4S)-2-(2-aminothiazol-4-yl)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.07 g) in acetonitrile and N,N-diisopropyl-N-ethylamine (0.59 ml) and the stirring was continued at the same temperature for 2 hours. The reaction mixture was poured into ethyl acetate (60 ml) and washed with 0.1N hydrochloric acid, saturated aqueous sodium bicarbonate and brine successively. The dried organic layer was evaporated and the oily residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (5:2 V/V) to give 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (900 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:3]1=[CH:4][CH2:5][C:6]1[C@H:7]3[C@:19]([CH3:29])([CH2:20][CH2:21][C:22]=12)[C@@H:10]([C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8]3>O1CCCC1>[CH3:30][C:2]1([CH3:1])[C@@H:26]([OH:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:3]1=[CH:4][CH2:5][C:6]1[C@H:7]3[C@:19]([CH3:29])([CH2:20][CH2:21][C:22]=12)[C@@H:10]([C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8]3
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C(C)(C)C1=CC3
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C(C)(C)C1=CC3
Reaction time: 1 h
Yield: 59.7 %

Procedure:
4,4-Dimethylcholesta-5,8-diene-3-one (100 mg) is reduced with lithiumaluminumhydride (5 mg) in 2 ml tetrahydrofuran at room temperature. The solution is stirred for one hour. After aqueous work-up and column chromatography 4,4-dimethylcholesta-5,8-diene-3β-ol (60 mg) is isolated.