Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH:11]3[CH2:13][CH2:12]3)=[CH:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>[OH-].[Na+]>[Br:1][C:2]1[C:10]2[O:9][CH:8]([CH:11]3[CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)c2oc(C3CC3)cc2c1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cc(Br)c2c(c1)CC(C1CC1)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.1 %

Procedure:
To a solution of the title compound from Step 1 (250 mg, 0.79 mmol) in Et3SiH (516 mg, 4.44 mmol) at 0° C. was added TFA (5.43 g, 47.59 mmol) in one portion. The reaction mixture was warmed up to rt and stirred for 48 hours. Aqueous NaOH solution (10 mL, 1 N) was added slowly to the above solution. The mixture was extracted with EtOAc (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE to PE/EA=2/1) to give the title compound (83 mg, 33%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.90 (s, 1H), 7.64 (s, 1H), 4.47-4.43 (m, 1H), 3.51-3.47 (m, 1H), 3.23-3.17 (m, 1H), 3.04 (s, 3H), 1.24-1.22 (m, 1H), 0.74-0.55 (m, 3H), 0.44-0.41 (m, 1H).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=O)=[CH:12][C:7]=2[N:6]=[C:5]1[NH:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:13]([C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH2:3][CH2:2][F:1])[C:5]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:30])[F:29])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:6][C:7]=2[CH:12]=1)=[O:15]
Reactant: COCCN
Reactant: O=C(O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCF
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CCF
Yield: 43.4 %

Procedure:
1-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (49.0 mg) was prepared by following General Procedure F starting from 1-(2-fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-methoxy-ethylamine (26.0 mg), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 499.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH2:13][CH3:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH3:3].[OH:15]O>[Pt]>[CH2:12]([N+:4]([O-:15])([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:13][CH3:14]
Reactant: CCCN(CCC)CCCCCCO
Reactant: OO
Agent: [Pt]
Product: CCC[N+]([O-])(CCC)CCCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.2 %

Procedure:
To 44 g of dipropyl-6-hydroxyhexyl amine was added slowly 11.0 g of 30% hydrogen peroxide. After stirring overnight at room temperature, the reaction mixture was stirred with 0.2 platinum black for several hours followed by filtration through Hyflo® filter-aid. After extraction with 50 ml ether, the aqueous phase was evaporated in vacuo to remove most of the water, leaving 2.0 g of dipropyl-6-hydroxyhexyl amine oxide. NMR analysis showed that there was 30% water present.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH2:12][OH:13].[OH-].[Na+].C(O)(=[O:18])C>O>[OH:13][CH2:12][CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:18])[NH:10][CH:9]=[N:8][C:7]1=2
Reactant: OCCn1cnc2c(Cl)ncnc21
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]cnc2c1ncn2CCO

Procedure:
6-Chloro-9-hydroxyethyl purine, III (4 g), was added slowly to warm N NaOH (30 ml) and refluxed for 2 hr. The reaction is cooled in ice and neutralized with glacial acetic acid. After filtration, portions of unreacted III are removed. The product is recrystallized from methanol and washed with acetone. Colorless crystals. Yield, 1 g. (28%); mp. 274°; uv (H2O, pH 5.5), λmax 250 nm.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH2:21]Br>>[F:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(F)ccc1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-difluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1.S(=O)(=O)(O)O.O>O1CCOCC1>[O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1
Reactant: CCOC(=O)C(C)c1ccc(C=C2CCSC2=O)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C(=O)O)c1ccc(C=C2CCSC2=O)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58 %

Procedure:
Ethyl 2-[4-(2-oxothiolan-3-ylidenemethyl)phenyl]propionate (124 mg) obtained in Example 34 was dissolved in 1,4-dioxane (4.0 ml), and then to the solution was added 30% aqueous sulfuric acid (4.0 ml). The reaction mixture was stirred at room temperature for 4 days, then added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to give the title compound (65 mg, 58%).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38]([OH:40])[CH3:39]>>[CH2:38]([O:40][C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9][C@H:8]([NH2:12])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:2][CH:3]=1)[CH3:39]
Reactant: CCO
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
1 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one (2-a, R1=H), 10 ml ethanol and 1.4 g para-toluenesulphonic acid were heated at about 80-120° C. for about 24 hours. The mixture was evaporated to dryness to obtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester (p-toluenesulfonate salt). Spectroscopic data as in Example 12.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:18][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCC(O)CCCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCC(Br)CCCCC
Yield: 86 %

Procedure:
The title compound (13.87 g) was prepared from Pentadecan-6-ol (Example 11, 12.65 g), carbon tetrabromide (22 g), triphenylphosphine (24.82 g) and dichloromethane (200 ml) using the procedure of Example 6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:22][CH:21]=2)=[O:19])=[O:10])=[N:6][CH:7]=1.Cl.[OH:35][NH2:36].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]=[N:33][NH:36][OH:35])=[CH:22][CH:21]=2)=[O:19])=[O:10])=[N:6][CH:7]=1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2ccccc2C=NNO)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 27.4 %

Procedure:
A mixture of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(2-cyanophenyl)phenyl]carboxamide (14 mg, 0.03 mmol, 1.0 equiv.), hydroxyamine hydrochloride (6.25 mg, 0.09 mmol, 3.0 equiv.) and triethyl amine (0.03 mL, 0.3 mmol, 10.0 equiv.) in ethanol (3 mL) was stirred at rt for 6 days, concentrated and HPLC (C18 reversed phase) eluting with 0.1% TFA in H2O/CH3CN to give N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}{4-[2-((hydroxyamino)iminomethyl)phenyl]phenyl}carboxamide (4 mg, 27.5%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.Cl.[NH2:9][CH2:10][C:11]1[CH:12]=[C:13]([B:17]([OH:19])[OH:18])[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:5]([NH:9][CH2:10][C:11]1[CH:12]=[C:13]([B:17]([OH:19])[OH:18])[CH:14]=[CH:15][CH:16]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cccc(B(O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCc1cccc(B(O)O)c1
Reaction time: 1 h
Yield: 23.3 %

Procedure:
Acetic anhydride (76 μL, 0.80 mmol) was added dropwise to a stirred solution of (3-aminomethylphenyl)boronic acid, hydrochloride (150 mg, 0.80 mmol) and DIEA (560 μL, 3.2 mmol) in CH2Cl2 (5 mL) at 0° C. After 1 h, the solution was concentrated in vacuo and purified by preparatory HPLC to give 36 mg (23%) of the title compound as a white solid. [M+H] calc'd for C9H12BNO3, 194; found, 194.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]3)=[CH:4][C:3]=2[O:2]1.Cl.[NH2:19][OH:20]>>[CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][C:10](=[N:19][OH:20])[CH2:9][CH2:8]3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
1-(3,4-Methylenedioxy)benzyl-4-piperidone oxime is prepared from 1-(3,4-methylenedioxy)benzyl-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][NH:10]1.F[C:21](F)(F)S(OC)(=O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]1[CH3:21]
Reactant: CCOC(=O)c1c[nH]n(-c2ccccc2OC)c1=O
Reactant: COS(=O)(=O)C(F)(F)F
Product: CCOC(=O)c1cn(C)n(-c2ccccc2OC)c1=O
Yield: 66 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 2-(2-methoxyphenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.6 g, 14 mmol) and methyl trifluoromethanesulfonate (3 mL) as starting materials, the title compound (2.5 g, 66%) was obtained as a pale-yellow solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1COCC1>[CH3:7][O:8][C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19](=[O:21])[CH3:20])=[CH:13][CH:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC(C)=O)cc1
Temperature: 44 °C
Reaction time: 1 h

Procedure:
41.5 g of K2CO3 are added to a solution of 40 g of methyl(4-hydroxyphenyl)acetate in 800 mL of anhydrous THF in a 2 L flask equipped with a magnetic stirrer, under nitrogen. 27 mL of acetic anhydride are then added at 9° C. After 1 hour of stirring at 44° C., the insoluble matter is filtered. It is washed with THF and the filtrate is concentrated to yield 53 g of expected product (white solid). The crude product is used directly for preparing the corresponding intermediate VII.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([CH2:9][CH3:10])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(Cn2cc(Br)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
5-Bromo-1H-pyridin-2-one (1.04 g) and 4-ethylbenzyl bromide (1.43 g) were dissolved in N,N-dimethylformamide (15 ml), and thereto was added potassium carbonate (1.66 g). The mixture was stirred at room temperature overnight, diluted with ethyl acetate, and washed successively with water and brine. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1-3:1) to give 5-bromo-1-(4-ethylphenylmethyl)-1H-pyridin-2-one (1.58 g) as colorless crystals. APCI-Mass m/Z 292/294 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](O)=[O:33]>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:32](=[O:33])[CH2:31][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[Cl:24])[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: O=C(O)Cc1ccccc1Cl
Product: O=C(Cc1ccccc1Cl)NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1

Procedure:
Using a procedure similar to that described in Example 6 except starting with 4-amino-1-[9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]piperidine and 2-chlorophenylacetic acid, the title compound was obtained as a pink solid (71%), mp 212.0°-14.0° C.; MS(CI): 457 (M+H); NMR (300 MHz,DMSO-d6): 1.38(m, 2H), 1.70(m, 2H), 2.28(m, 2H), 2.46(s, 2H), 2.93(m, 2H), 3.30(m, submerged, 2H), 3.54(m, 3H), 4.31(s, 1H), 6.87-6.96(m, 4H), 7.17-7.41(m, 8H), 7.96(d, 1H, J=7.7 Hz).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11]1[CH2:17][S:14](=[O:16])(=[O:15])[O:13][CH2:12]1>C(#N)C>[S:14]([CH2:17][CH2:11][CH2:12][N:1]1[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)([OH:16])(=[O:15])=[O:13]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=S1(=O)CCCO1
Solvent: CC#N
Product: O=S(=O)(O)CCCN1CCCC2CC=CC=C21
Yield: 60 %

Procedure:
In a round bottom flask fitted with a stirrer and reflux condenser were placed 50.0 g of tetrahydroquinoline, 48.8 g of 1,3-propanesultone and 500 ml of reagent grade acetonitrile solvent. The mixture was heated at reflux under a nitrogen blanket overnight. The reaction mixture was cooled to ice-bath temperature and the resulting white solid precipitate filtered and washed with cold acetonitrile. A yield of 58 g (60%) of crude product was obtained with a melting point over 200° . Nuclear magnetic resonance (NMR) and mass spectrometry analyses showed the product to be consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]#[N:14])=[CH:10][S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][C:27]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[CH2:37][N:36]([C:39]1[S:40][C:41]([CH2:49][CH2:50][CH2:51]I)=[C:42]([C:44]([O:46]CC)=[O:45])[N:43]=1)[CH2:35][CH2:34]2)=[O:28]>CN(C=O)C>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][C:27]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[CH2:37][N:36]([C:39]1[S:40][C:41]([CH2:49][CH2:50][CH2:51][O:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[C:9]([C:13]#[N:14])=[CH:10][S:11][CH:12]=4)=[CH:6][CH:7]=3)=[C:42]([C:44]([OH:46])=[O:45])[N:43]=1)[CH2:35][CH2:34]2)=[O:28]
Reactant: N#Cc1cscc1-c1ccc(O)cc1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reaction time: 0.17 h

Procedure:
To compound 51A (0.095 g, 0.015 mmol) in DMF (4 mL) was added 60% sodium hydride (0.036 g, 0.9 mmol) at 0° C. The solution was stirred for 10 minutes. To this solution was added compound 2C. The solution was stirred at rt for 2 hours. The reaction was quenched with MeOH (1 mL). Conc. HCl (0.5 mL) was added, and the solution was filtered through a syringe filter. The filtrate was then purified by Prep HPLC to provide the desired product 51: 1H NMR (DMSO-d6): δ 8.57 (d, J=3.38 Hz, 1H), 7.95 (d, J=7.98 Hz, 1H), 7.71-7.72 (m, 2H), 7.60 (d, J=7.36 Hz, 1H), 7.45-7.48 (m, 2H), 7.26-7.41 (m, 4H), 6.95-6.97 (m, 214), 4.77 (s, 2H), 3.97 (t, J=6.29 Hz, 2H), 3.66 (t, J=5.98 Hz, 2H), 3.11-3.14 (m, 2H), 2.96 (t, J=5.98 Hz, 2H), 1.93-2.00 (m, 2H); MS (ESI(+)): m/z 678 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:7][C:6]=1[O:5]2.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CS(C)=O>[OH:17][C:10]1[C:11]2[C:12](=[O:16])[C:13]3[C:4](=[CH:3][C:2]([O:31][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)=[CH:15][CH:14]=3)[O:5][C:6]=2[CH:7]=[C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: O=c1c2ccc(F)cc2oc2cc(N3CCOCC3)cc(O)c12
Reactant: OCc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c2ccc(OCc3cccnc3)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 80 °C
Reaction time: 60 h
Yield: 33.6 %

Procedure:
6-Fluoro-1-hydroxy-3-morpholin-4-yl-xanthen-9-one (16 mg. 0.05 mmol) and 3-pyridylmethanol (8 mg, 0.07 mmol) were dissolved in DMSO (0.25 mL), and KHMDS (0.5 M in toluene, 0.24 mL) was added. The reaction mixture was heated to 80° C. for 16 hours, then stirred at room temperature for 60 hours. The reaction was quenched with sat. NH4Cl/water (1:1, 2 mL) and the solids were filtered. The crude solid was purified via flash chromatography eluting with CH2Cl2/MeOH (98:2) to yield 6.8 mg (34%) of product. 1H NMR (CDCl3, 400 MHz) δ: 12.80 (s, 1H), 8.73 (s, 1H), 8.64 (d, 1H), 8.15 (d, 1H), 7.80 (d, 1H), 7.36 (dd, 1H), 6.97 (dd, 1H) 6.85 (s, 1H), 6.27 (s, 1H), 6.24 (s, 1H), 5.19 (s, 2H), 3.86-3.83 (m, 4H), 3.37-3.35 (m, 4H). LRMS (APCI, positive): Da/e 405.1 (m+1).
Reaction SMILES: [OH:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[N:5][C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:7].[BH4-].[Na+].Cl>C(O)C>[OH:1][C:2]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C@@H:6]([C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)[CH3:7]
Reactant: COc1cccc(C=N[C@H](C)c2ccc([N+](=O)[O-])cc2)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(CN[C@H](C)c2ccc([N+](=O)[O-])cc2)c1O
Reaction time: 2 h
Yield: 90.6 %

Procedure:
8.5 g (0.0283 mole) of (R)-(-)-N-(2-hydroxy-3-methoxybenzylidene)-1-(p-nitrophenyl)ethylamine were dissolved in 150 ml of ethyl alcohol. Then, 0.54 g (0.0143 mole) of sodium borohydride was added at room temperature to the reaction mixture, which was thereafter stirred at a temperature of from 30° to 35° C. for 2 hours, and then stirred at a temperature of from 55° to 60° C. for 2 hours. After the completion of the reaction, the reaction mixture was admixed with 30 ml of a 10% hydrochloric acid, and then concentrated under reduced pressure. The resulting residue was dissolved in 150 ml of water, washed with 100 ml of toluene, and separated into individual layers. The aqueous layer was neutralized or weakly alkalized with a 20% aqueous sodium hydroxide solution, and extracted twice with 100 ml of toluene. The toluene layer was washed with water, and concentrated under reduced pressure to give 7.75 g of (R)-(+)-N-(2-hydroxy-3-methoxybenzyl)-1-(p-nitrophenyl)ethylamine as crystalline substance. Yield: 90.6%. m.p. 112.5°-113.56° C.; a!D24 +64.0° (C 1.0, CHCl3) NMR-spectral data (δ ppm, CDCl3) 1.46 (d) 3H; 3.5-4.2 (m) 3H; 3.9 (s) 3H; 5.0-6.4 (broad) 1H; 6.4-6.9 (m) 3H 7.35-8.4 (m) 4H (s)
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([N:8]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4]1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>CN(C=O)C>[N:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:3]2[CH:7]=[CH:6][C:5]([NH2:8])=[N:4]2)=[CH:22][CH:23]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Reactant: ClCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccn(Cc2ccncc2)n1
Temperature: 50 °C
Yield: 83 %

Procedure:
NaH (0.9 g., 60% suspension in liquid paraffin) is dissolved in DMF (10 ml) and 2-(1H-pyrazole-3-yl)-isoindole-1,3-dione (11.7 mmol) is added at 0° C. To this solution is added 4-chloromethyl-pyridine (11.7 mmol) and the mixture is heated to 50° C. for 16 hours. The solvent is removed in vacuo. The residue is dissolved in ethanol (100 ml) and hydrazinium-hydroxide (70 ml) is added and the mixture is heated to 120° C. for 9 days. The solvent is removed in vacuo. 1-Pyridine-4-ylmethyl-1H-pyrazole-3-ylamine is obtained after column chromatography as colorless oil in a yield of 83%; LC-MS (method B): 0.44 min, 175.15 (M+H+);
Reaction SMILES: [CH:1]([O:14][C:15]([CH2:17][C:18]([NH:20][C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[C:29]1[S:33][C:32]([NH:34][C:35](=[O:38])[CH2:36][Cl:37])=[N:31][CH:30]=1)[CH:24]([S:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=1)[C:23]2=[O:48])=[O:19])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:57])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([O:14][C:15]([CH2:17][C:18]([NH:20][C:21]1[N:22]2[CH:25]([S:26](=[O:57])[CH2:27][C:28]=1[C:29]1[S:33][C:32]([NH:34][C:35](=[O:38])[CH2:36][Cl:37])=[N:31][CH:30]=1)[CH:24]([S:39][C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([Cl:47])[CH:41]=1)[C:23]2=[O:48])=[O:19])=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CC(=O)OC(c1ccccc1)c1ccccc1)NC1=C(c2cnc(NC(=O)CCl)s2)CSC2C(Sc3ccc(Cl)c(Cl)c3)C(=O)N12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CC(=O)OC(c1ccccc1)c1ccccc1)NC1=C(c2cnc(NC(=O)CCl)s2)CS(=O)C2C(Sc3ccc(Cl)c(Cl)c3)C(=O)N12
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A solution of 2-benzhydryloxycarbonyl-3-(2-chloroacetamido-thiazol-5-yl)-7-(3,4-dichlorophenylthio)-acetamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2 g) in methylene chloride (50 cc) is cooled to 0° C. and treated with an 85% strength solution of meta-chloroperbenzoic acid (0.45 g) in methylene chloride (10 cc). After 30 minutes at a temperature of between 0° and 5° C., the reaction mixture is diluted with methylene chloride (100 cc) and a saturated sodium bicarbonate solution (100 cc) is added. The solid which precipitates is filtered off and taken up in methylene chloride (200 cc). The decanted organic phase is added to this solution, after having been washed with water (100 cc) and then with a saturated sodium chloride solution (100 cc) and dried over sodium sulphate, and the mixture is then concentrated under reduced pressure to a residual volume of 10 cc. The solid is filtered off and washed with ethyl acetate (20 cc) and then with ethyl ether (20 cc). 2-Benzhydryloxycarbonyl-3-(2-chloroacetamido-thiazol-5-yl)-7-(3,4-dichlorophenylthio)-acetamido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (1.48 g) is obtained in the form of a cream solid.