Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=2)[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[C:23]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24].[Cl:32][C:33]1[CH:38]=[C:37](Cl)[N:36]=[CH:35][N:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:32][C:33]1[N:34]=[CH:35][N:36]=[C:37]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]([CH3:21])[C:4](=[O:22])[C:3]([C:23]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])=[C:2]3[OH:1])[CH:38]=1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n(C)c1=O
Reactant: Clc1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(-c3cc(Cl)ncn3)ccc2n(C)c1=O
Temperature: 70 °C

Procedure:
To a 10 ml reaction vial was charged ethyl 2-(4-hydroxy-1-methyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydroquinoline-3-carboxamido)acetate (200 mg, 465 μmol) in 1,4-dioxane (5 ml), 4,6-dichloropyrimidine (69 mg, 465 μmol), tetrakis(triphenylphosphine)palladium(0) (27 mg, 23 μmol) and sodium carbonate (0.7 ml, 1395 μmol), and the reaction vial was heated to 70° C. After reaction was complete, the reaction mixture was concentrated on a roto-evaporator, extracted with EtOAc, washed with water and brine (3×ea.) then dried with MgSO4 and concentrated on a roto-evaporator. The yellow solid was washed with EtOH and filtered and the solid was washed with ether. Yield=55 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[Na].[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10])[CH3:13]
Reactant: COc1c(Cl)ccnc1C
Reactant: CCO
Agent: [Na]
Product: CCOc1ccnc(C)c1OC

Procedure:
4-Chloro-3-methoxy-2-methylpyridine (3.14 g) was added to a solution of sodium (2.0 g) in ethanol (30 ml), and the solution was refluxed by heating for 10 hours. The solvent was evaporated and the residue was added to ice water, which was extracted with chloroform, washed with water, dried and evaporated. The residue was purified by column chromatography on silica gel, to give 4-ethoxy-3-methoxy-2-methyl-pyridine (2.6 g) as a light brown oil.
Reaction SMILES: [Cl-].[Li+].CS(C)=O.[CH2:7]([C:10]([CH:21]([CH2:23][CH3:24])[CH3:22])(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH2:9]>O>[CH:21]([CH:10]([CH2:7][CH:8]=[CH2:9])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:23][CH3:24])[CH3:22]
Reactant: C=CCC(C(=O)OCC)(C(=O)OCC)C(C)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCC(C(=O)OCC)C(C)CC
Temperature: 185 °C
Reaction time: 6 h

Procedure:
Lithium chloride (9.67 g, 228.1 mmol) and water (2.05 mL, 113.9 mmol) were added to a dimethyl sulfoxide (60 mL) solution of diethyl allyl(sec-butyl)malonate (30.90 g, 120.5 mmol), and the mixture was stirred at 185° C. for 6 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a brown oil substance. This compound was used in the next reaction without being purified.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[C@H:14]([NH2:18])([CH2:16][CH3:17])[CH3:15]>O>[C@H:14]([NH:18][C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1)([CH2:16][CH3:17])[CH3:15]
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: CC[C@@H](C)N
Solvent: O
Product: CC[C@@H](C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide and (R)-(-)-sec-butylamine by a procedure analogous to the procedure described in example 1Bb; mp 215°-220° C. (water), 1H-NMR (DMSO-d6): δ 0.88 (t. 3H), 1.11 (d, 3H), 1.48 (m, 2H), 3.69 (m, 1H), 7.07 (s, 1H), 7.14 (br. s, 1H), 10.75 (br. s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CI.[C:18](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Br)cc1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1Br

Procedure:
5.8 g of 2-bromo-4-fluoro-5-methylsulphonylbenzoic acid are stirred, at room temperature for 12 h, in 20 ml of DMF together with 3.7 ml of methyl iodide and 8.3 g of potassium carbonate. The reaction mixture is then concentrated and 50 ml of water are added to it. The resulting precipitate is filtered off with suction and dried. Methyl 2-bromo-4-fluoro-5-methylsulphonylbenzoate is obtained, m.p. 126°.
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.O[N:9]=[C:10]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[S:12][C:11]1=[CH:20][C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1>N1C=CC=CC=1>[C:5]([O:4][N:9]=[C:10]1[NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[S:12][C:11]1=[CH:20][C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: ON=C1Nc2ccccc2SC1=Cc1ccc[nH]1
Solvent: c1ccncc1
Product: CC(=O)ON=C1Nc2ccccc2SC1=Cc1ccc[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (1.3 ml, 13.78 mmol) was added to a solution of 3-hydroxyimino-2-[(pyrrol-2-yl)methylene]-2H-1,4-benzothiazine (0.27 g, 1.05 mmol) (Compound 273) in dry pyridine (1.5 ml). The reaction mixture was stirred for 30 minutes at room temperature, poured into ice water and extracted with ethyl acetate. The organic layer was washed with 10% HCl and brine, dried over magnesium sulfate and brought to dryness in vacuo. The residue was purified by silica gel chromatography using (9:1) dichloromethane:ethanol as the mobile phase.
Reaction SMILES: [C:1]([C:3](=[C:8](SC)[S:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH2:13]([NH2:16])[CH:14]=[CH2:15]>C(COC)OC>[C:1]([C:3](=[C:8]([S:9][CH3:10])[NH:16][CH2:13][CH:14]=[CH2:15])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)C(C#N)=C(SC)SC
Reactant: C=CCN
Solvent: COCCOC
Product: C=CCNC(SC)=C(C#N)C(=O)OC
Yield: 101.5 %

Procedure:
To a suspension of 2-cyano-3,3-bis(methylthio)-2-propenoic acid, methyl ester (8.12 g) in dimethoxyethane (13 mL) was added (2-propenyl)amine (2.51 g). The mixture dissolved. After about 15 min the solvent was evaporated under nitrogen and the solid residue was filtered with diethyl ether to give 2-cyano-3-methylthio-3-(2-propenyl)amino-2-propenoic acid, methyl ester (8.61 g).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[NH:5][C:6]=1I.CN(C)C=O.S([O-])([O-])=O.[Na+].[Na+]>O>[I:1][C:2]1[NH:3][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:5][CH:6]=1
Reactant: Ic1nc(-c2ccccn2)[nH]c1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cnc(-c2ccccn2)[nH]1
Temperature: 120 °C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of 2-(4,5-diiodo-1H-imidazol-2-yl)pyridine (18.6 g) in a mixed solvent of N,N-dimethylformamide (200 mL) and water (100 ml) was added sodium sulfite (35.4 g), and the mixture was stirred at 120° C. for 24 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:99-20:80, volume ratio) to give the title compound (11.2 g, yield 88%) as colorless crystals. melting point 175-179° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:12]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].[ClH:27]>CO>[ClH:27].[ClH:27].[OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:6])[C:7]1[C:12]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C(=O)NCCO
Agent: Cl
Solvent: CO
Product: O=C(NCCO)c1ncccc1OC[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
(R)-tert-butyl 2-((2-(2-hydroxyethylcarbamoyl)pyridin-3-yloxy)methyl)pyrrolidine-1-carboxylate (330 mg, 0.90 mmol, EXAMPLE 33 Step 3) was dissolved in 10% hydrogen chloride in methanol (8 mL) at room temperature. After being stirred at room temperature for 4 days, the volatile was evaporated to afford 304 mg (quant.) of the title compound that was used directly in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:26]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)[CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
Prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a yellow solid (270 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([F:19])=[CH:12][C:5]=1[O:6][CH2:7][C:8](OC)=[O:9])([O-])=O>C(O)(=O)C.CCOC(C)=O.[Fe]>[NH2:16][C:14]1[C:13]([F:19])=[CH:12][C:5]2[O:6][CH2:7][C:8](=[O:9])[NH:1][C:4]=2[CH:15]=1
Reactant: COC(=O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc2c(cc1F)OCC(=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.7 %

Procedure:
To a suspension of 12.2 g (0.22 mol) of iron powder in 100 ml of 5% aqueous acetic acid was added dropwise a solution of 10.0 g (36.5 mmol) of methyl 2,4-dinitro-5-fluorophenoxyacetate in 100 ml of EtOAc and 100 ml of glacial acetic acid. The reaction mixture was stirred at room temperature for 18 hours. The iron was removed by suction filtration through a small pad of Celite® and the filter pad was rinsed with 50 ml of EtOAc. The filtrate was transferred to a separatory funnel and the phases were separated. The aqueous layer was extracted with EtOAc (3×50 ml) and the combined organic phases were washed with sodium bicarbonate (2×50 ml), dried over Na2SO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 3.9 g (60% yield) of 6-amino-7-fluoro-2H-1,4-benzoxazin-3(4H)-one as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([C:10]([NH:12][C:13]2[CH:25]=[CH:24][C:16]3S[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:15]=3[CH:14]=2)=[O:11])[CH3:9])=[CH:3][CH:2]=1.[S:26](=[O:30])(=O)(O)[OH:27].OO.C([O-])(O)=O.[Na+]>C(O)(=O)C.CN1C(=O)CCC1.O>[O:27]=[S:26]1(=[O:30])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:18][C:19]=2[C:15]2[CH:14]=[C:13]([NH:12][C:10]([CH:8]([CH3:9])[CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:11])[CH:25]=[CH:24][C:16]1=2
Reactant: CC(Cc1ccncc1)C(=O)Nc1ccc2sc3ccccc3c2c1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(Cc1ccncc1)C(=O)Nc1ccc2c(c1)-c1ccccc1S2(=O)=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2-[(2-Pyrid-4-yl-1-methylethyl)carbonylamino]dibenzothiophene (Example 11; 0.39 g, 1.13 mmol) was dissolved in glacial acetic acid (10 ml) and concentrated sulphuric acid (0.5 ml) at 60° C. 30% aqueous hydrogen peroxide (1.3 ml) was added in one portion and the solution was stirred at 60° C. for two hours. The mixture was allowed to cool and then poured into water (50 ml). The mixture was made basic by the addition of solid NaHCO3 and extracted with DCM (2×50 ml). The combined organic layers were washed with brine (50 ml), dried and evaporated in vacuo to leave a pale yellow solid. NMP: 8.45 (d, 2H), 8.3 (d, 1H), 8.0 (d, 1H), 7.95 (d, 1H), 7.9 (d, 1H), 7.8 (t, 1H), 7.7 (dd, 1H), 7.65 (t, 1H), 7.25 (d, 2H), 3.0 (m, 2H), 2.7 (m, 1H), 1.15 (d, 3H); m/z 379.
Reaction SMILES: [C:1]1([CH2:7][S:8][CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([C:23](=O)[CH3:24])[CH:20]=[CH:21][CH:22]=1.[K+].[Br-]>>[OH:15][C:13]1[CH:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[CH:18]=2)[O:12][C:10](=[O:11])[C:9]=1[S:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1cccc(C)c1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: [Br-]
Agent: [K+]
Product: Cc1cccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)c1
Yield: 65 %

Procedure:
This compound was prepared by the condensation of the diethyl ester of [(phenylmethyl)thio]-propanedioic acid (1 g, 3.54 mmol) with the corresponding trimethylsilyl enol ether of 3'-methyl acetophenone (7.09 mmol, 1.46 g) as described in general procedure A. Isolated Yield: 65% m.p. 137-138° C. 1H NMR (400 MHz, DMSO-d6) δ11.9 (brs, 1 H), 7.6 (m, 2 H), 7.39 (t, 1 H), 7.35 (d, 1 H), 7.25 (d, 4 H), 7.2 (m, 1 H), 6.7 (s, 1 H), 4.0 (s, 2 H), 2.38 (s, 3 H); IR (KBr) 3030, 2585, 1617, 1536, 1402, 1100, 787, 696 cm-1; MS (CI) m/e 325 (65), 291 (2), 233 (4), 119 (9), 91 (100).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[CH2:23]([NH:22][C:20]1[CH:19]=[CH:18][C:17]([S:30][C:31]2[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(NCc2ccccc2)ccc1Sc1ccc(O)cc1
Product: CCCc1ccc2c(Nc3cc(NCc4ccccc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (105 mg, 0.50 mmol) was reacted with the product from Example 44c (161 mg, 0.50 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (68 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.83 (sext, J=7.35 Hz, 2H) 2.97 (dd, J=7.35 Hz, 2H) 4.29 (m, 2H) 6.15 (d, J=6.99 Hz, 1H) 6.51 (d, J=8.46 Hz, 2H) 6.93 (d, J=8.46 Hz, 2H) 7.22-7.38 (m, 8H) 7.78 (d, J=8.83 Hz, 1H) 8.95 (d, J=8.46 Hz, 1H) 9.66 (s, 1H) 10.90 (br s, 1H) 14.21 (br s, 1H); MS (ESI+) m/z 493 (M+H−TFA)+.
Reaction SMILES: Cl[C:2]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.Cl.[NH2:20][OH:21].[H-].[Na+].O>N1C=CC=CC=1.CN(C=O)C>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:2]=2[O:21][N:20]=1
Reactant: COc1ccc(C(=O)c2ccccc2F)c(Cl)c1
Reactant: NO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccccc3F)noc2c1
Temperature: 60 °C

Procedure:
2-chloro-2'-fluoro-4-methoxybenzophenone (15.5 g) is refluxed for three hours in 150 ml of pyridine containing 10.0 g of hydroxylamine hydrochloride. The pyridine is removed in vacuo and the residue is distributed between ether and 5% HCl. Drying and evaporation of the organic phase gives an isomeric mixture of oximes. The mixture is dissolved in 50 ml of DMF and is added to a suspension of 1.5 g NaH in 30 ml of DMF. After warming at 60° C. for 30 minutes the reaction mixture is poured into H2O and extracted with ether. Concentration under reduced pressure gives a solid. Recrystallization from ether gives 3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 101°-103° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:13])[CH2:11][OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[C:16](OC)([CH3:18])[CH3:17].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:17][C:16]1([CH3:18])[O:13][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][O:12]1
Reactant: O=[N+]([O-])c1ccc(C(O)CO)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OCC(c2ccc([N+](=O)[O-])cc2)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.8 %

Procedure:
A mixture of 1-(4-nitrophenyl)ethane-1,2-diol (7.0 g, 38.3 mmol), 2,2-dimethoxypropane (16 g, 153.2 mmol) and 4-methylbenzenesulfonic acid (2.6 g, 15.32 mmol) in acetone (100 mL) was stirred at 25° C. for 12 h. The reaction mixture was concentrated and then dissolved in ethyl acetate (300 mL). The organic layer was separated, washed by water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to afford the title compound (4.0 g, 40%) as a yellow oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)CNC(=O)[C@@H](N)CC(C)C

Procedure:
3.12 Grams of Z-Leu-Gly-OC2H5 was dissolved in 50 ml of methanol and 8.90 ml of 1N hydrochloric acid and the solution was catalytically reduced by using palladium as the catalyst to obtain H-Leu-Gly-OC2H5.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:15][CH2:16][N:17]1[N:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[OH-].[Na+]>Cl>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][N:3]([CH2:15][CH2:16][N:17]2[N:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:27])[CH3:2])=[CH:11][CH:10]=1
Reactant: CN(CCc1ccc([N+](=O)[O-])cc1)CCn1ncc2ccccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(CCc1ccc(N)cc1)CCn1ncc2ccccc2c1=O
Temperature: 55 °C
Yield: 96.5 %

Procedure:
Stannous chloride dihydrate (13.05 g) was dissolved in concentrated hydrochloric acid and stirred at 55° C. N-Methyl -N-(4-nitrophenethyl)-2-(2H-phthalazin-1-on-2-yl)ethylamine hydrochloride (7.5 g) was added portionwise over 1 hour and the solution was then heated a further 4 hours at 100° C. The partly cooled solution was poured onto crushed ice containing 500 ml of a 20% aqueous solution of sodium hydroxide and then extracted three times with methylene chloride. The resultant organic extracts were combined, dried (MgSO4), filtered and evaporated to give a pale yellow oil (6.0g). Chromatography of the oil on silica [Merck "Kieselgel 60" (Trade Mark)] eluting with methylene chloride gave, after collection and evaporation of appropriate fractions, the title compound as a pale yellow oil (3.5 g) which was used in part (C) without further purification.
Reaction SMILES: Br[C:2]1[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]=1[O:8]C.[CH3:11][C:12]([C:15]([NH2:17])=[NH:16])([CH3:14])[CH3:13].Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH3:11][C:12]([C:15]1[NH:17][C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]=2[N:16]=1)([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=N)N
Reactant: COC1=C(Br)C(=O)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1nc2c([nH]1)CCCC2=O
Temperature: 100 °C
Yield: 36.8 %

Procedure:
To a stirred solution of 2-bromo-3-(methyloxy)-2-cyclohexen-1-one (0.957 g) in anhydrous N,N-dimethylformamide (20 mL) at ambient temperature was added solid tert-butylcarbamidine hydrochloride (0.638 g) and potassium carbonate (1.613 g, 11.67 mmol). The reaction was then heated to 100° C. under an atmosphere of nitrogen for 2.5 h. The reaction was diluted with dichloromethane (50 mL) the resultant solid was removed by filtration. The filtrate was concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-25% methanol-dichloromethane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (330 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([Mg]Cl)(C)C.[Li]CCCC.[CH3:35][S:36]SC>C1COCC1>[CH3:18][C:15]1[CH:14]=[C:13]([C:6]2[C:7](=[O:12])[NH:8][C:9]3[C:4]([C:5]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][C:2]([S:36][CH3:35])=[CH:11][CH:10]=3)[O:17][N:16]=1
Reactant: CSSC
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(Br)ccc3[nH]c2=O)on1
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc2[nH]c(=O)c(-c3cc(C)no3)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 6-bromo-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (30 mg, 0.079 mmol)(example 39), 1 mL of THF and cooled to 0° C. A 2M solution of i-PrMgCl in THF (0.39 mL, 0.077 mmol) was added and the reaction stirred for 5 minutes at 0° C. and then cooled to −78° C. and a 2M solution of n-BuLi in hexanes (0.06 mL, 0.12 mmol) was added. After stirring for 15 minutes dimethyldisulfide (15 mg, 0.16 mmol) was added and the reaction allowed to attain RT and stirred for 30 minutes. The reaction was diluted with EtAc (10 mL) and washed with brine (2×10 mL). The organic layer was concentrated and the title product (14 mg, 50%) eluted from a 5 g SPE with 50% EtOAc/hexanes. 1H NMR (400 MHz, CD3OD) δ 7.54 (dd, 1H), 7.48 (m, 3H), 7.48 (d, 1H), 7.24 (m, 2H), 7.06 (d, 1H), 6.36 (s, 1H), 2.34 (s,3H), 2.24 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C20H16N2O2S 348.1, found 349.1 (M+H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:49](=[O:50])[N:13]2[C:14]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])=[C:15]([S:18]([CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=O)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:51][N:52]([CH3:74])[C:53]([C@@H:55]1[CH2:59][C@H](S)CN1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:54]>>[CH3:51][N:52]([CH3:74])[C:53]([C@@H:55]1[CH2:59][C@H:20]([S:18][C:15]2[C@H:16]([CH3:17])[C@@H:12]3[C@@H:11]([C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH3:10])[C:49](=[O:50])[N:13]3[C:14]=2[C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH2:21][N:22]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])=[O:54]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)CCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 18, but using 101 mg of 4-nitrobenzyl (1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-[2-(4-nitrobenzyloxycarbonyl)aminoethylsulfinyl)-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 48) and 61 mg of (2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine, the title compound was obtained in a yield of 83%.