Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH2:5][S:6][C:7]1[S:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:11]=1[N+:12]([O-])=O)=O>C(O)(=O)C.O.[Fe]>[CH3:18][O:17][C:15]([C:9]1[S:8][C:7]2[S:6][CH2:5][C:3](=[O:2])[NH:12][C:11]=2[CH:10]=1)=[O:16]
Reactant: COC(=O)CSc1sc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc2c(s1)SCC(=O)N2
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
To a solution of 2-methoxycarbonylmethylthio-5-methoxycarbonyl-3-nitrothiophene (26.1 g) in acetic acid (360 ml) and water (36 ml) was added portionwise iron (36.5 g) at 80° C. After stirring for 3 hours at 80° C., the hot reaction mixture was filtered and the filtrate was poured into ice-water. The resulting precipitate was collected by filtration and washed with water to give 2,3-dihydro-6-methoxycarbonyl-2-oxothieno[2,3-b][1,4]thiazine (11.12 g).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:15](#[N:17])[CH3:16]>>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH:8]=1)[CH2:16][C:15]#[N:17]
Reactant: CC(C)CCOc1cccc(C=O)c1
Reactant: CC#N
Product: CC(C)CCOc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-(isopentyloxy)benzaldehyde gave 3-hydroxy-3-(3-(isopentyloxy)phenyl)propanenitrile as a yellow oil. Yield (0.82 g, 54%): 1H NMR (400 MHz, CDCl3) δ 7.27-7.32 (m, 1H), 6.94-6.96 (m, 2H), 6.85-6.90 (m, 1H), 5.00-5.03 (m, 1H), 3.99 (t, J=6.4 Hz, 2H), 2.77 (d, J=6.0 Hz, 2H), 1.81-1.88 (m, 1H), 1.64-1.71 (m, 2H), 0.96 (d, J=6.4 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[S:3]([CH3:6])(=[O:5])=[O:4].II.[I:16](O)(=O)=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.O.C(OCC)(=O)C>[I:16][C:10]1[CH:11]=[CH:12][C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:4])=[O:5])=[CH:8][C:9]=1[CH3:13]
Reactant: Cc1cccc(N(C)S(C)(=O)=O)c1
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(N(C)S(C)(=O)=O)ccc1I
Yield: 340 %

Procedure:
A solution of N-methyl-N-(3-tolyl)methanesulphonamide (0.12 g), iodine (76 g) and iodic acid (35 mg) in glacial acetic acid (5 ml) and concentrated sulphuric acid (0.6 ml) was stirred at 80° C. for 2.5 hours. Ethyl acetate (40 ml) and water (40 ml) were then added and the mixture neutralised with solid sodium bicarbonate. The organic phase was washed with brine (30 ml), dried (MgSO4) and the solvent evaporated to leave N-(4-iodo-3-methylphenyl)-N-methylmethanesulphonamide (0.22 g, 90%), m.p. 85°-87° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:21]=[C:22]([CH2:25][C:26]#[N:27])[S:23][CH:24]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-:29].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:21]=[C:22]([CH2:25][C:26]([NH2:27])=[O:29])[S:23][CH:24]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCc1cc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cs1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)Cc1cc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of (4-(7-chloro-1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-thienyl)acetonitrile (69.4 mg) obtained in Example 152 and 2M aqueous potassium carbonate solution (0.431 mL) in DMSO (3 mL) was added 30% aqueous hydrogen peroxide (0.176 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 5 hr. The reaction mixture was allowed to be cooled to room temperature, water was added thereto under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was washed with ethyl acetate and diisopropyl ether to give the title compound (55.8 mg).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[C:26]([OH:27])=[CH:25][C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[CH:18]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC(C2(O)C3C(=CC=CC=3)N(CC3OC(C(F)(F)F)=CC=3)C2=O)=C(O)C=1>>[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[CH:18]=3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)CCCC2
Agent: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1ccc(Br)cc1O
Product: O=C1C(c2cc3c(cc2O)CCCC3)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations using 1-(diphenylmethyl)-3-hydroxy-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-one to replace 3-(4-bromo-2-hydroxyphenyl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-one was obtained (71%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.41 (s, 1H), 7.33-7.29 (m, 9H), 7.24-7.22 (m, 2H), 7.10-7.07 (m, 2H), 6.98 (s, 1H), 6.80 (s, 1H), 6.64 (s, 1H), 6.56-6.53 (m, 1H), 5.13 (s, 1H), 2.73 (br s, 2H), 2.60-2.56 (m, 2H), 1.74 (br s, 4H); MS (ES+) m/z 446.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[NH:5][S:6](=[O:9])(=[O:8])[N:7]=1.C([O-])(O)=O.[Na+:32]>O>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][C@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22](=[O:27])[CH2:23][CH:24]([CH3:25])[CH3:26])[CH2:17]3)=[CH:12][CH:11]=[CH:10][C:4]=2[N-:5][S:6](=[O:8])(=[O:9])[N:7]=1.[Na+:32]
Reactant: CC(C)CC(=O)N1CCC[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc3c2C(N)=NS(=O)(=O)[N-]3)C1
Yield: 99.5 %

Procedure:
To a suspension of (S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one (2.0 g, 5.07 mmol) (Example 5) in water (25 mL), was added NaHCO3 (425 mg, 5.07 mmol). The reaction was heated to reflux until complete dissolution of solid material occurred, and then concentrated under reduced pressure. The resulting residue was dissolved in water and lyophilized to give the title compound as a beige solid (2.1 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 0.78-0.96 (m, 6H), 1.21-1.50 (m, 2H), 1.55-1.75 (m, 1H), 1.78-2.07 (m, 3H), 2.10-2.25 (m, 2H), 2.60-2.78 (m, 1H), 2.88-3.15 (m, 2H), 3.65-3.97 (m, 3H), 4.00-4.41 (m, 1H), 5.97 (t, 1H, J=8.0 Hz), 6.21 (d, 1H, J=8.8 Hz), 6.57 (br. s, 2H), 6.95 (d, 1H, J=8.0, 3.2 Hz). MS 395 (MH+—Na).
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([CH:9]=[O:10])=[CH:7][N:8]=1.[CH3:11][Al](C)C.[NH4+].[Cl-].Cl>C(Cl)Cl.CCCCCCC>[Br:3][C:4]1[S:5][C:6]([CH:9]([OH:10])[CH3:11])=[CH:7][N:8]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: C[Al](C)C
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(O)c1cnc(Br)s1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 2-bromo-thiazole-5-carbaldehyde (1.80 g, 9.37 mmol) in CH2Cl2 (70.0 mL) was treated at 0° C. with trimethylaluminum (46.0 mL of a 1M solution in heptane, 46 mmol). The reaction mixture was then stirred at 0° C. for 45 min. CH2Cl2 (100.0 mL) followed by sat. aq. NH4Cl (100 mL) was then added. The mixture was then treated with 1N HCl (50 mL) and the aq. layer was extracted with CH2Cl2 (150 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC:rf (1:2 hept-EA)=0.40. LC-MS-conditions 02: tR=0.70 min; [M+AcCN+H]+=249.17.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.[N:20](OCCC(C)C)=O.[H+].[B-](F)(F)(F)F>C(O)C.[Pd]>[F:18][C:15]1[CH:14]=[N:13][C:12]([N:11]2[C:6]3[CH:5]=[C:4]([CH3:19])[N:3]=[CH:2][C:7]=3[N:8]=[N:20]2)=[N:17][CH:16]=1
Reactant: CC(C)CCON=O
Reactant: Cc1cc(Nc2ncc(F)cn2)c([N+](=O)[O-])c(Cl)n1
Agent: [Pd]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Product: Cc1cc2c(cn1)nnn2-c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 10 h
Yield: 40.9 %

Procedure:
To a slurry of N-(2-chloro-6-methyl-3-nitropyridin-4-yl)-5-fluoropyrimidin-2-amine (13 g, 45.8 mmol) in ethanol (300 mL) was added 10% Pd/C (100 mg). The reaction was stirred for 10 h under a hydrogen atmosphere after which time the reaction was filtered and the filtrate was concentrated. The residue was diluted with ethanol (200 mL) and cooled to 0° C. Isoamyl nitrite (4.0 g, 34.0 mmol) and HBF4 (5.5 g, 34.0 mmol) were added and the reaction was stirred for 30 min at 0° C. followed by rt for 10 h. Evaporation of the solvents followed by recrystallization afforded the product as a white solid (3.2 g, 48%). MS (ESI) mass calcd. C10H7FN6, 230.07. m/z found, 231.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.17 (s, 2H), 8.14 (s, 1H), 2.70 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C@@H:10]([CH2:27][OH:28])[CH2:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].S.[N:32]1C=CC=CC=1.CI.CC(C)=O>O.CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@@H:10]([CH2:27][OH:28])[CH2:11][C:12]2[CH:26]=[CH:25][C:15]([O:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[CH:29][CH:30]=1)(=[NH:32])[NH2:2]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)COc1ccc(C[C@H](CO)NC(=O)c2ccc(C#N)cc2)cc1
Agent: S
Solvent: CO
Solvent: CC(C)=O
Solvent: CI
Product: CC(C)(C)OC(=O)COc1ccc(C[C@H](CO)NC(=O)c2ccc(C(=N)N)cc2)cc1

Procedure:
3.14 g of t-butyl p-[(R)-2-(p-cyanobenzamido)-3-hydroxypropyl]phenoxyacetate were successively reacted with H2S/pyridine, CH3I/acetone and NH4OAc/methanol as described in Example 1. After chromatography on silica gel with water/methanol (100:0 1:1), 1.2 g of t-butyl p-[(R)-2-(p-amidinobenzamido)-3-hydroxypropyl]phenoxyacetate were obtained in the form of a white foam. MS: 428 (M+1).
Reaction SMILES: C(OC[N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[C:11]1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH:40]2[CH2:42][CH2:41]2)[CH:30]=1)C1C=CC=CC=1.C(OCN1C2C=NNC(=O)C=2C(CC2C=CC=CC=2F)=C1C1C=CC(OC(F)F)=C(OC2CC2)C=1)C1C=CC=CC=1>>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][C:12]1[C:13]2[C:18](=[O:19])[NH:17][N:16]=[CH:15][C:14]=2[NH:10][C:11]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:37])[F:38])=[C:31]([O:39][CH:40]2[CH2:41][CH2:42]2)[CH:30]=1)#[N:28]
Reactant: N#Cc1ccccc1Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c2cn[nH]c(=O)c12
Agent: O=c1[nH]ncc2c1c(Cc1ccccc1F)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Product: N#Cc1ccccc1Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Yield: 86.5 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 22-(b) except for using 548 mg (0.964 mmol) of 1-benzyloxymethyl-3-(2-cyanobenzyl)-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Example 25-(a) in place of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(2-fluorobenzyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 374 mg of the title compound was obtained as a white solid. (Yield: 87%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=2)[CH:11]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(F)c1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2)c(F)c1

Procedure:
The title compound was prepared by 2-(2-fluoro-4-methoxyphenyl)-6-methoxynaphthalene (1.12 g, 3.97 mmol) with boron tribromide (23.8 mL of 1.0 M solution in CH2Cl2, 23.8 mmol) according to method D to yield 0.92 g (91%) of a white solid: mp 208–209° C.; 1H NMR (DMSO-d6): δ 6.66–6.75 (2H, m), 7.08–7.13 (2H, m), 7.41 (1H, dd, J=9.37 Hz, J=8.57 Hz), 7.49–7.53 (1H, m), 7.72 (1H, d, J=8.64 Hz), 7.80 (1H, d, J=8.76 Hz), 7.86 (1H, s), 9.79 (1H, s), 10.01 (1H, s); MS (ESI) m/z 255 (M+H)+, MS (ESI) m/z 253 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[C:13]3[CH:18]([C:39]4[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=4)[N:19]([C:22]4[C:23](=[O:38])[N:24](CC5C=CC(OC)=CC=5)[CH:25]=[C:26]([Cl:28])[CH:27]=4)[C:20](=[O:21])[C:12]=3[CH:11]=2)=[CH:4][N:3]=1>C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[C:13]3[CH:18]([C:39]4[CH:40]=[CH:41][C:42]([C:43]#[N:44])=[CH:45][CH:46]=4)[N:19]([C:22]4[C:23](=[O:38])[NH:24][CH:25]=[C:26]([Cl:28])[CH:27]=4)[C:20](=[O:21])[C:12]=3[CH:11]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(Cn2cc(Cl)cc(N3C(=O)c4cc(-c5cnc(N)nc5OC)n(C(C)C)c4C3c3ccc(C#N)cc3)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(N)ncc1-c1cc2c(n1C(C)C)C(c1ccc(C#N)cc1)N(c1cc(Cl)c[nH]c1=O)C2=O

Procedure:
A solution of 4-{2-(2-amino-4-methoxy-pyrimidin-5-yl)-5-[5-chloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl}-benzonitrile (Step 125.1) (0.137 mmol) in TFA (1 mL) was stirred at 100° C. for 30 min and then the reaction mixture was concentrated. The residue was purified by flash chromatography to afford the title compound as a white solid. ESI-MS: tR=0.75 min, [M+]+516/518 (LC-MS 1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[C:9]([C:12]([O:14]C)=[O:13])[CH:8]=1)=[O:5].O[Li].O.O.Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=1)=[O:5]
Reactant: COC(=O)c1cc(NC(=O)c2ccccc2Cl)[nH]n1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(NC(=O)c2ccccc2Cl)[nH]n1

Procedure:
A solution of 1.0 eq. of 22 and 5.0 eq. of LiOH.H2O in THF, MeOH, and H2O (2:1:1) was stirred at rt. After a time sufficient for reaction completion, the reaction mixture was rotary evaporated. The mixture was acidified with concentrated HCl. As the pH of the solution reached about 2, a precipitate formed. The solid was collected by filtration and after drying under vacuum, product 23 was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]([O:21][C@@H:22]3[CH:27]4[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]4)[CH2:23]3)=[N:19][CH:20]=2)=[CH:11][C:10]=1[N+:30]([O-])=O)C1C=CC=CC=1>[Pd]>[NH2:30][C:10]1[CH:11]=[C:12]([C:15]2[CH:16]=[N:17][C:18]([O:21][C@@H:22]3[CH:27]4[CH2:26][CH2:25][N:24]([CH2:29][CH2:28]4)[CH2:23]3)=[N:19][CH:20]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)ccc1OCc1ccccc1
Agent: [Pd]
Product: Nc1cc(-c2cnc(O[C@H]3CN4CCC3CC4)nc2)ccc1O

Procedure:
The product of Example 37C (380 mg, 0.88) was hydrogenated under the catalysis of Pd/C (Aldrich, 10 wt. %, 100 mg) according to the procedure of Example 28E. The title compound was obtained as yellow solid (220 mg, yield, 92%). 1H NMR (300 MHz, CD3OD) δ 1.47-1.93 (m, 3 H), 1.95-2.35 (m, 2 H) 2.70-3.05 (m, 5 H), 3.33-3.48 (m, 1 H), 5.04-5.30 (m, J=8.8 Hz, 1 H), 6.72-6.88 (m, 2 H), 6.98 (d, J=1.7 Hz, 1 H), 8.70 (s, 2 H) ppm. MS (DCl/NH3): 313 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C@@:8]12[C:24](=O)[CH2:23][CH2:22][C@H:21]1[C@H:20]1[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=3[CH2:18][CH2:19]1)[CH2:10][CH2:9]2.Cl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O.C[C@H]1O[C@H]2[C@H](O)[C@@H](O)[C@H](OC3C4C(=CC5OCOC=5C=4)[C@@H](C4C=C(OC)C(O)=C(OC)C=4)[C@@H]4[C@@H]3COC4=O)O[C@@H]2CO1.C1COP(NCCCl)(=O)N(CCCl)C1.[NH2-].[NH2-].Cl[Pt+2]Cl>[CH2:1]=[C:24]1[CH2:23][CH2:22][C@H:9]2[C@H:10]3[C@H:11]([CH2:20][CH2:21][C@:8]12[CH3:7])[C:12]1[CH:13]=[CH:14][C:15]([OH:26])=[CH:16][C:17]=1[CH2:18][CH2:19]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[O-]
Agent: Cl[Pt+2]Cl
Agent: COc1cc([C@@H]2c3cc4c(cc3C(O[C@@H]3O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]3O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 74.5 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (100.03 g, 0.28001 mol) and potassium t-butoxide (31.42 g, 0.2800 mol) in anh. dimethylsulfoxide (DMSO, 320 mL) under argon was stirred in an oil bath (68-81° C.) 1 h, after which estrone (15.14 g, 55.99 mmol) in anh. DMSO (320 mL) was added via syringe. See FIG. 17. Stirring was continued 1 h and the reaction allowed to cool. The mixture was poured into 800 mL of ice-1 N hydrochloric acid and then extracted three times with 400 mL aliquots of ether. The combined organic extracts were washed with 350 mL of saturated sodium bicarbonate+400 mL of brine, dried over sodium sulfate, and flash filtered through a 58 mm high×84 mm dia. column of silica gel (200-40 mesh). Product continued eluting with additional ether. Concentration of appropriate fractions under reduced pressure and three-fold recrystallization from aqueous ethanol gave very fine white needles (11.47 g, 42.73 mmol, 76%), m.p. 134-136° C., homogeneous to TLC (20% ethyl acetate/hexanes on silica gel, Rf 0.45).
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]=[O:18])[C:9]2[C:8](=[O:19])[N:7]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:6](=[O:28])[N:5]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:4]=2[N:3]=1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C(Cl)(Cl)Cl>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:2]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:17]=[O:18])[C:9]3[C:8](=[O:19])[N:7]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])[C:6](=[O:28])[N:5]([CH2:29][O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:4]=3[N:3]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2c(nc(Cl)n2-c2ccccc2C=O)n(COC(=O)C(C)(C)C)c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2nc3c(c(=O)n(COC(=O)C(C)(C)C)c(=O)n3COC(=O)C(C)(C)C)n2-c2ccccc2C=O)CC1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
2,2-Dimethylpropionic acid [8-chloro-1-(2,2-dimethyl-propionyloxymethyl)-7-(2-formylphenyl)-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl ester (2.0 g) and piperazine-1-carboxylic acid tert-butyl ester (2.15 g) were mixed, and the mixture was stirred at 150° C. for 1 hour and 10 minutes. The reaction mixture was diluted with chloroform and purified by silica gel column chromatography to give 1.94 g of the title compound from the elution fraction of hexane-ethyl acetate (1:1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[N-:11]=[N+:12]=[N-:13].[Na+]>>[N:11]([CH:4]([CH2:3][CH3:2])[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[N+:12]=[N-:13]
Reactant: O=C(O)CCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCC(CCCC(=O)O)N=[N+]=[N-]

Procedure:
Reaction of 7-bromoheptanoic acid and NaN3, as described for the synthesis of 6, gave 5-azidoheptanoic acid 10. Saponification was not necessary. Used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].N1CCCCC1.Cl>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:16]2[NH:10][C:11](=[O:12])[NH:13][C:14]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc(O)cc2)N1
Temperature: 130 °C
Yield: 87.9 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (100 g, 0.819 M), hydantoin (90 g, 0.9 M) and piperidine (165 ml) was heated to 130° C. for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 60° C. and 3.21 water was added. The reaction mixture was acidified with 12N HCl. The precipitated solid was filtered and washed with cold water to yield the title compound of the formula (18) (147 g, 88%), (Org. Syn. Vol. V., pp627).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C@@H:12]([C:13](OC)=[O:14])[C@H:11]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(=O)C.[Cl-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:8][N:9]1[C@@H:12]([CH2:13][OH:14])[C@H:11]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@H]1CO
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
In 60 ml of tetrahydrofuran is dissolved 5.95 g (17 mmole) of trans-1-benzyloxy-3-(tert-butoxycarbonylamino)-4-methoxycarbonyl-2-azetidinone obtained in the same manner as the method described in The Journal of Organic Chemistry, 48 (1983), 3556-3559, and a solution of 965 mg (25.5 mmole) of sodium borohydride in 15 ml of water is added dropwise to the solution under cooling at -15° C. with stirring over the period of 10 minutes. After the addition is completed, the reaction solution is stirred at -5° to -10° C. for 40 minutes, and acetic acid is added to decompose excess sodium borohydride. 100 ml of ethyl acetate and 30 ml of aqueous sodium chloride solution are added, and the mixture is shaken, followed by separation of the ethyl acetate layer. The aqueous layer is extracted again with ethyl acetae, and the ethyl acetate layer are combined, washed with saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution successively, and dried over anhydrous megnesium sulfate. The solvent is distilled off under reduced pressure, and the residue i purified by column chromatography (silica gel, 250 g; n-hexabe-ethyl acetate =3:2, then 1:1). The fractions containing the objective compound are collected, and the solvent is distilled off under reduced pressure. Ether and petroleum ether (1:2) are added to the residue, and the resulting crystals are recovered by filtration to give 1.33 g (24.3%) of trans-1-benzyloxy-3-(tert-butoxycarbonylamino)-4-hydroxymethyl-2-azetidinone.