Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1([Mg]Cl)[CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1.C(OCC)C.C(OCC)(=O)C>[CH:14]1([C:7]([OH:13])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: Cl[Mg]C1CCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(O)(c1ccccc1)C1CCCC1
Reaction time: 0.5 h

Procedure:
To a solution of 23.5 g of ethyl phenylglyoxylate in 200 ml of tetrahydrofuran, 70 ml of 2.0 M cyclopentylmagnesium chloride solution in diethyl ether was added dropwise under cooling with ice, followed by stirring for 30 minutes at the same temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off-under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=30/1-20/1) to provide 11 g of ethyl 2-cyclopentyl-2-hydroxy-2-phenylacetate, which was dissolved in 40 ml of methanol. To the solution 20 ml of 4N aqueous sodium hydroxide solution was added at room temperature, followed by stirring for 2 hours at the same temperature and further for 1 hour at 50° C. Distilling the methanol off under reduced pressure, the aqueous layer was made weakly acidic with 4N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and then brine and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was washed with 1:1 mixture of diethyl ether and hexane. Thus, 8.7 g of the title compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([S:30]([N:33](CC4C=CC(OC)=CC=4OC)[C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[CH:36][C:35]=4[F:51])(=[O:32])=[O:31])[CH:26]=3)[CH2:21]2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([S:30]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)=[CH:36][C:35]=4[F:51])(=[O:31])=[O:32])[CH:26]=3)[CH2:21]2)=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1ccc(CN(c2ccc(OCCCCc3ccccc3)cc2F)S(=O)(=O)c2ccc3c(c2)CCN(CCc2ccc(C(C)(C)C)cc2)C3)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(CCN2CCc3cc(S(=O)(=O)Nc4ccc(OCCCCc5ccccc5)cc4F)ccc3C2)cc1
Reaction time: 21 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a turbid solution of 2-[2-(4-tert-butylphenyl)ethyl]-N-(2,4-dimethoxybenzyl)-N-[2-fluoro-4-(4-phenylbutoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (440 mg) in anisole (5 mL) and chloroform (5 mL) while cooling in ice, and the mixture was stirred for 21 hr while cooling in ice. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture while cooling in ice and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=3:1→ethyl acetate only) to afford the title compound as a colorless amorphous substance (240 mg).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])[CH2:42][CH2:41]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3ccccc3Cl)noc2N)CC1
Yield: 69 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (523 mg, 1.27 mmol, 69%) was obtained.
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2C/C(/O[C@H]2C[C@H]1O)=C/CCCC(O)=[O:21].[O:26]=[CH:27][C@@H:28]([C@H:30]([C@@H:32]([C@@H:34]([CH2:36][OH:37])[OH:35])[OH:33])[OH:31])[OH:29]>>[CH2:36]([OH:37])[C@@H:34]([OH:35])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@@H:28]([OH:29])[CH:27]=[O:26].[OH2:21]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2C/C(=C/CCCC(=O)O)O[C@H]2C[C@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O
Reaction time: 8 h

Procedure:
The epoprostenol degraded in 5% Dextrose solution (D5W) more than in the saline. The 6-keto PGF levels were very low, yet no other peaks were observed. Here, approximately 84% of the drug degraded after 8 hours, but no other peaks were detected as a degradation product.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:20].N1CCCCC1.O>CN(C)C=O>[C:1]1(=[C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:12]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1Cc2ccccc2C1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2C1=C1CCc2ccccc21
Temperature: 130 °C
Yield: 21.4 %

Procedure:
A mixture of 0.4 g indan-2-one, 1.33 g oxindole and 0.5 ml piperidine in 3 ml dimethylforamide was heated in a sealed tube at 130° C. for 60 hours. Enough water was added to cause precipitation of an oily solid. The mixture was decanted and the remaining oily solid heated with 5 ml of ethanol using a heat gun. Upon cooling, the solid was filtered off. The solid was slurried with 3 ml of ethanol and filtered to give 160 mg of 3-indan-1-ylidene-1,3-dihydroindol-2-one as an orange solid.
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:54]=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][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:64]=[C:63]([F:65])[CH:62]=[CH:61][C:57]=1[C:58](Cl)=[O:59]>>[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:54]=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][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:58](=[O:59])[C:57]2[CH:61]=[CH:62][C:63]([F:65])=[CH:64][C:56]=2[F:55])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccc(F)cc2F)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 42 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using N-[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-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2,4-difluorobenzoyl chloride as starting materials in 42% yield. LCMS for C31H29ClF2N7O2 (M+H)+: m/z=604.2.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[OH:34][CH:35]([CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)[CH3:36]>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([CH:35]([OH:34])[CH3:36])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CC(O)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)C1CCN(c2ccc3c(C(=O)NC[C@@]4(O)CCC[C@@H](C)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-(1-hydroxyethyl)-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.69 (m, 1H), 4.16 (s, 1H), 3.89 (m, 1H), 3.70 (m, 2H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.15 (m, 3H), 1.03 (m, 1H), 0.83 (d, 3H), 0.74 (m, 1H). m/z: 446 [M+H]
Reaction SMILES: [NH2:1][C:2]1([C:8]#[N:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[ClH:10]>C(O)C.[Pt]=O>[ClH:10].[ClH:10].[NH2:9][CH2:8][C:2]1([NH2:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N#CC1(N)CCCCC1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: NCC1(N)CCCCC1
Yield: 89 %

Procedure:
A mixture of 1-aminocyclohexanecarbonitrile (48.5 g, 391 mmol) and platinum oxide (5.0 g) in 4.2 M HCl in ethanol (200 mL) and 2.7 M HCl in ethanol (300 mL) was hydrogenated at 50 psi (3.4×105 Pa) for 20 h on a Parr apparatus. The reaction mixture was filtered through CELITE filter agent and the filtrate was concentrated to yield a clear oil. The oil was triturated with isopropanol to yield a white solid that was isolated by filtration, washed with ether, and dried to provide 1-(aminomethyl)cyclohexanamine dihydrochloride (70.0 g, 89%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[C:8]([N:11]1[CH:16]([CH3:17])[CH2:15][N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][C:28](F)=[CH:29][C:30]=4[O:35][CH3:36])[N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH:12]1[CH3:38])(=[O:10])[CH3:9].O>CS(C)=O.C(O)(=O)C>[C:8]([N:11]1[C@@H:16]([CH3:17])[CH2:15][N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][C:28]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:29][C:30]=4[O:35][CH3:36])[N:25]=3)=[CH:20][CH:19]=2)[CH2:13][C@H:12]1[CH3:38])(=[O:10])[CH3:9]
Reactant: COc1cc(F)cc2nc(-c3ccc(N4CC(C)N(C(C)=O)C(C)C4)cc3)[nH]c(=O)c12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4C[C@@H](C)N(C(C)=O)[C@@H](C)C4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-methoxy-ethanol (1.00 g, 13.4 mmol) in dimethyl sulfoxide (4 mL), sodium hydride (60% suspension in mineral oil, 0.50 g, 12.5 mmol) was added in portions, and the reaction mixture was stirred at room temperature for 20 minutes. To this reaction mixture was added 2-[4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-phenyl]-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.57 g, 1.34 mmol) and the reaction mixture was stirred at 85° C. for 24 hours. Water was added. The mixture was acidified to pH approximately 4-5 with acetic acid, and the precipitated solid was filtered to give crude product, which was purified by column chromatography (silica gel 230-400 mesh; eluting with 2% methanol in dichloromethane). The resulting mixture was purified by preparative HPLC to obtain the title compound as a white solid. Yield: 0.140 g (23.2%). MP 225-227° C. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.8 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.50 (bs, 1H), 4.23 (m, 2H), 4.14 (bs, 1H), 3.84 (s, 3H), 3.81 (m, 2H), 3.69 (m, 2H), 3.32 (s, 3H), 2.99 (bs, 2H), 2.07 (s, 3H), 1.25 (bs, 6H). MS (ES) m/z: 481.11 (M++1).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:40]=[C:41]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH:42]=1)[NH2:39].Cl[C:50]1[C:59]2[C:54](=[CH:55][C:56]([F:61])=[CH:57][C:58]=2[F:60])[N:53]=[C:52]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=2)[C:51]=1[CH3:68].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:35][C:36]1[CH:37]=[C:38]([NH:39][C:50]2[C:59]3[C:54](=[CH:55][C:56]([F:61])=[CH:57][C:58]=3[F:60])[N:53]=[C:52]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=3)[C:51]=2[CH3:68])[CH:40]=[C:41]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[CH:42]=1
Reactant: Nc1cc(Cl)cc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Cl)cc(N2CCOCC2)c1

Procedure:
The Buchwald coupled products were prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.026 g, 0.055 mmol), 3-chloro-5-morpholinoaniline (0.088 g, 0.413 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.1 g, 0.344 mmol) and Pd2dba3 (0.013 g, 0.014 mmol) and sodium tert-butoxide (0.063 g, 0.66 mmol) in toluene (3.4 mL) at 100° C. for 45 mins. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc in hexanes) to give the desired product N-(3-chloro-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.72 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 7.89 (1H, td, J=7.4, 1.8 Hz), 7.80-7.85 (1H, m), 7.67 (1H, br. s.), 7.38 (1H, ddd, J=7.5, 4.8, 1.2 Hz), 7.02 (2H, ddd, J=13.7, 8.6, 2.5 Hz), 6.51 (1H, s), 6.36 (1H, s), 6.27 (1H, s), 3.83 (4H, app t, J=4.9 Hz), 3.15 (4H, app t, J=4.9 Hz), 2.17 (3H, s). Mass Spectrum (ESI) m/e=467.2 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([OH:30])=[CH:25][C:24]=3[Cl:31])=[O:15])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][O:30][C:26]1[CH:25]=[C:24]([Cl:31])[C:23]([O:22][C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:14]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH2:5][CH2:6]2)=[O:15])=[CH:28][C:27]=1[Cl:29])[CH3:40]
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of 0.15 g (0.33 mmol) (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone (Example 57) in 2 mL N,N-dimethylformamide was added 0.016 g (0.37 mmol) sodium hydride (60% dispersion in mineral oil, Aldrich, CAS RN 7646-69-7). The reaction mixture was stirred for 15 min. at room temperature before 0.04 mL (0.36 mmol) ethyl bromoacetate (commercially available, CAS RN 105-36-2) were added. After stirring at room temperature for 3 hours the solution was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 30:70) to give 0.144 g (81%) of the desired compound as a light yellow foam. MS (ESI): m/z=542.123 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([Cl:16])=[CH:12][N:11]([CH3:17])[CH:10]=1)C1C=CC=CC=1>Cl.C(O)C>[Cl:16][C:13]1[C:14](=[O:15])[C:9]([OH:8])=[CH:10][N:11]([CH3:17])[CH:12]=1
Reactant: Cn1cc(Cl)c(=O)c(OCc2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: Cn1cc(O)c(=O)c(Cl)c1
Yield: 76.6 %

Procedure:
3-(Benzyloxy)-5-chloro-1-methylpyridin-4(1H)-one (2.70 g, 10.8 mmol) was mixed in 6N HCl (15 mL) and ethanol (10 mL). After being refluxed for 2 hours, the reaction mixture was concentrated by rotary evaporator. The residue was mixed with water (5 mL) and basified to pH 8-9 with concentrated ammonia. An off-white precipitate came out, and the mixture was again concentrated in vacuo to remove volatiles. The off-white solid was collected by suction filtration and dried to give 3-chloro-5-hydroxy-1-methylpyridin-4(1H)-one (1.32 g). Yield=76.6%; 1H NMR (DMSO-D6, 90 MHz) δ(ppm): 7.98 (s, 1H), 7.47 (s, 1H) and 3.67 (s, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][C@@H:7]([C@@H:9]1[C@@H:12]([C@H:13]([C:15]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:16])[CH3:14])[NH:11][C:10]1=[O:24])[CH3:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:34](=[O:41])[C:35]([O:37][CH2:38][CH:39]=[CH2:40])=[O:36]>ClCCl>[CH2:38]([O:37][C:35](=[O:36])[C:34]([N:11]1[C@H:12]([C@H:13]([C:15]([S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:16])[CH3:14])[C@@H:9]([C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:26])[CH3:25])[CH3:8])[C:10]1=[O:24])=[O:41])[CH:39]=[CH2:40]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)Sc1ccccc1
Reactant: C=CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=S)Sc1ccccc1
Reaction time: 2 h

Procedure:
To a mixture of (3S,4S)-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl] -4-[(1R)-1-{(phenylthio)thiocarbonyl}ethyl]-2-oxoazetidine (5.12 g) in dichloromethane (50 ml) were added pyridine (1.8 ml) and allyl chloroglyoxylate (2.3 ml) successively at 0° C. After stirring for 2 hours at the same temperature, to the solution were added pyridine (0.9 ml) and allyl chloroglyoxylate (0.75 ml). After stirring for 1 hour at 0° C., the solution was washed with water, 1N hydrochloric acid and brine, and dried. The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane=1:9) to afford (3S,4S)-1-(allyloxyoxalyl)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(phenylthio)thiocarbonyl}ethyl]-2-oxoazetidine (4.77 g).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[OH:25][C:19]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:24][CH2:23][CH2:22][N:21]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)=[O:7])[CH2:20]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1ccc(I)cc1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(I)cc3)C2)c1

Procedure:
The compound of Example 31 was prepared according to the general preparation protocol A from 4-iodobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:9][C:10](=[O:37])[C@@H:11]([C@@H:16]([C:26](=[O:36])[NH:27][O:28]CC1C=CC=CC=1)[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:7])=[O:6].[H][H]>CO.[Pd]>[NH2:1][CH2:2][CH2:3][CH2:4][S:5]([N:8]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:9][C:10](=[O:37])[C@@H:11]([C@@H:16]([C:26](=[O:36])[NH:27][OH:28])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:12][CH:13]([CH3:14])[CH3:15])(=[O:7])=[O:6]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCCN)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(=O)(=O)CCCN)[C@H](CCCc1ccccc1)C(=O)NO
Yield: 69 %

Procedure:
A solution of 0.15 g of (E)-2′-(3-aminopropanesulphonyl)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of methanol was hydrogenated in the presence of 60 mg of 10% palladium-on-charcoal until uptake of hydrogen was complete. The catalyst was removed by filtration and the solvent was evaporated. The residue was triturated with diethyl ether and there was obtained 0.088 g of 2′-(3-aminopropanesulphonyl)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a pale pink solid.
Reaction SMILES: OC[CH:3]([C:6]1[N:7]=[C:8]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][CH:10]=[CH:9]2)CO.[Se](=O)=[O:21]>C(OCC)(=O)C>[CH:3]([C:6]1[N:7]=[C:8]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=[CH:11][CH:10]=[CH:9]2)=[O:21]
Reactant: O=[Se]=O
Reactant: OCC(CO)c1nc2ccccc2c2ccccc12
Solvent: CCOC(C)=O
Product: O=Cc1nc2ccccc2c2ccccc12
Yield: 42 %

Procedure:
In the next step, a mixture of 6-(2-hydroxy-1-hydroxymethyl)-phenanthridine (24) (6 g, 31 mmoles) and finely powdered selenium dioxide (3.8 g, 34 mmoles) is refluxed in ethyl acetate (125 ml) for 10 hours. The deep red solution that form is then filtered while hot through celite, before evaporating to dryness. The resulting solid is digested in warm 1M hydrochloric acid (125 ml), filtered and partially neutralized with sodium bicarbonate. The initial red precipitate is filtered off before completely neutralizing the solution. The resulting pale yellow solid is filtered off and recrystallized from acetone/petroleum ether to give 2.7 g of 6-formylphenanthridine (yield=42%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[NH:4][N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].[OH-].[Na+].[H][H]>[Pd].C(Cl)Cl.O>[F:17][C:15]([F:16])([F:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:6]=[N:5][NH:4][C:3](=[O:19])[CH:2]=1
Reactant: O=c1[nH]ncc(Oc2ccccc2C(F)(F)F)c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=c1cc(Oc2ccccc2C(F)(F)F)cn[nH]1
Reaction time: 96 h
Yield: 70.1 %

Procedure:
A pressure vial containing a mixture of 4-chloro-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (3.66 g, 12.59 mmol), water (70 mL), and a 2N aqueous sodium hydroxide solution (7 mL, 14 mmol) was treated with 10% palladium on carbon (0.37 mg, 10% weight of 4-chloro-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one). The reaction was then pressurized with hydrogen (50 psi), where it shook for 4 d. The resulting reaction mixture was diluted with methylene chloride (100 mL) and water (100 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo. The aqueous residue was acidified with a 2N aqueous hydrochloric acid solution and was then extracted with a 90/10 methylene chloride/methanol solution. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (ISCO, 120 g, 50%-70% ethyl acetate/hexanes) afforded 5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (2.26 g, 70%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 5.79 (d, J=2.7 Hz, 1H), 7.52-7.60 (m, 2H), 7.82 (t, J=8.5 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 8.00 (d, J=2.7 Hz, 1H), 13.04 (br. s., 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-])=O)[CH:3]=1>[Zn]>[NH2:16][C:4]1[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: [Zn]
Product: CC(C)(C)OC(=O)Nc1ccc(I)cc1N

Procedure:
The title compound was prepared from the tert-butyl 4-iodo-2-nitrophenylcarbamate (Example A3; 3 mmol) by reduction with zinc according to the general procedure B. Obtained as a yellow solid (44%), MS (EI) 335 [(M+1)+].