Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1.CCCCC.C([Li])(C)(C)C.CN([CH:30]=[O:31])C.C(OCC)(=O)C>C(OCC)C.O>[CH3:15][Si:13]([CH3:14])([CH3:16])[C:12]#[C:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[C:6]([CH:7]=1)[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(C#C[Si](C)(C)C)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: O
Product: COCOc1ccc(C#C[Si](C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(2-trimethylsilylethynyl)phenol methoxymethyl ether (6.08 g) in diethyl ether (450 ml) was cooled to -78° C., to which was added dropwise, under argon atmosphere, a 1.7M t-butyl lithium pentane solution (18 ml), and the mixture was stirred for one hour at the same temperature. To the reaction mixture was then added dropwise DMF(5 ml), followed by warming up to room temperature and stirring overnight. To the reaction mixture were added ethyl acetate and water, which was subjected to extraction. The organic layer was washed (a saturated aqueous saline solution) and dried (anhydrous magnesium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 5-(2-trimethylsilylethynyl)-2-methoxymethoxybenzaldehyde (5.29 g) (Compound B-27). The physical properties are shown in Table 8.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[NH2:27][C@H:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[OH:33].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[OH:33][C@H:29]1[CH2:30][CH2:31][CH2:32][C@@H:28]1[N:27]1[CH2:21][C:14]2[C:15](=[CH:20][C:11]([CH2:10][C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:25][CH:24]=3)=[C:12]([CH3:23])[CH:13]=2)[C:16]1=[O:17]
Reactant: N[C@H]1CCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)N([C@H]1CCC[C@@H]1O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.16 g), (1S,2S)-2-aminocyclopentanol hydrochloride (0.06 g), triethylamine (0.07 mL) and anhydrous magnesium sulfate (0.11 g) in THF (3.10 mL) was stirred at room temperature for 3 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (3.10 mL) and THF (3.10 mL), sodium triacetoxyborohydride (0.20 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (71 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14][C@H:13]1[C:26]1[O:30][N:29]=[C:28]([CH3:31])[N:27]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:18][C@@H:15]1[CH2:16][CH2:17][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:13]([C:26]2[O:30][N:29]=[C:28]([CH3:31])[N:27]=2)[CH2:14]1
Reactant: Cc1noc([C@@H]2C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]2NC(=O)OCc2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc([C@@H]2C[C@H](N)CC[C@@H]2NC(=O)OCc2ccccc2)n1
Reaction time: 5 h

Procedure:
To absolution of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexylcarbamate (250 mg) in CH2Cl2 (10 mL) was added TFA (3 mL) at RT. The reaction was stirred for 5 h and concentrated in vacuo. The residue was partitioned between 1N NaOH (30 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the organic phases were combined, washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give benzyl (1S,2R,4R)-4-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)cyclohexylcarbamate. MS found: (M+H)+=331.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]([NH:5][C:6]1[C:7]([C:26]([O:28][CH3:29])=[O:27])=[C:8]([C:12]#[C:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:9]=[CH:10][CH:11]=1)=[O:4]>C(O)C.[Pd]>[CH3:1][C:2]([CH3:31])([CH3:30])[C:3]([NH:5][C:6]1[C:7]([C:26]([O:28][CH3:29])=[O:27])=[C:8]([CH2:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: COC(=O)c1c(C#CC2CCCN2C(=O)OC(C)(C)C)cccc1NC(=O)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1c(CCC2CCCN2C(=O)OC(C)(C)C)cccc1NC(=O)C(C)(C)C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
A solution of tert-butyl 2-[3-(2,2-dimethylpropionylamino)-2-methoxycarbonylphenylethynyl]-pyrrolidine-1-carboxylate (Intermediate 38, 3.71 g) in ethanol (100 mL) was treated with 10% palladium on carbon (0.50 g) and stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give tert-butyl 2-{2-[3-(2,2-dimethylpropionylamino)-2-methoxycarbonyl-phenyl]-ethyl}-pyrrolidine-1-carboxylate (3.21 g) as a colourless gum.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[C:22]([C:24]4[NH:25][C:26](=[N:29]C(OC(CC)(C)C)=O)[S:27][CH:28]=4)=[O:23])[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1>C(O)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:38])[C:22]([C:24]4[N:25]=[C:26]([NH2:29])[S:27][CH:28]=4)=[O:23])[C:18](=[O:39])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:4][N:3]=1
Reactant: CCC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)cs1
Solvent: O=CO
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A solution of 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-7-[2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-tert-pentyloxycarbonylimino-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylamido]-3-cephem-4-carboxylic acid, (8.56 g.) in formic acid (180 ml.) was stirred for 5.5 hours at room temperature. After the reaction, the reaction mixture was post-treated in the similar manners as in Examples 16 to 17 to give 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-amino-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-7-[2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylamido]-3-cephem-4-carboxylic acid, (2.6 g.), mp. 156° to 160° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CN(C)C(=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1nc2ccc(N)cc2o1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: Cc1nc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2o1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-1,3-benzoxazol-6-amine (1.00 g, 6.74 mmol) and pyridine (1.64 ml, 20.2 mmol) in N,N-dimethylacetamide (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.39 ml, 10.1 mmol) under ice-cooling, and the mixture was stirred for 2 hours under ice-cooling. The reaction mixture was poured into ice-water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate, and 1.45 g (66.5%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:5]([C:6]([C:8]2[C:16]3[C:11](=[C:12]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[N:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[C:4]([Cl:26])[CH:3]=1.N1C=CC=CC=1.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([Cl:26])[C:5]([C:6]([C:8]2[C:16]3[C:11](=[C:12]([NH:17][C:18]([CH:20]4[CH2:21][CH2:22]4)=[O:19])[N:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[C:23]([Cl:25])[CH:24]=1)(=[O:35])[CH3:34]
Reactant: Nc1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
To a solution of N-[3-(4-amino-2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (0.2 g, 0.5 mmol) in dichloromethane (10 mL), pyridine (0.081 g, 1 mmol) was added followed by addition of acetyl chloride (0.044 g, 0.56 mmol) at 0° C. After stirring at 0° C. for about 0.5 hour, the reaction was kept at room temperature for about 2 hours. Dichloromethane was evaporated; water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (2×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel (100-200 mesh) column chromatography. Elution with 2.5% methanol in dichloromethane afforded N-{3-[4-(acetylamino)-2,6-dichlorobenzoyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}cyclopropanecarboxamide (0.06 g, 27%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:14][C:15]1([CH3:27])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[O:16]1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[N:25]1[CH:26]=[C:22]([B:17]2[O:16][C:15]([CH3:27])([CH3:14])[C:19]([CH3:21])([CH3:20])[O:18]2)[CH:23]=[N:24]1
Reactant: C1=COCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2cnn(C3CCCCO3)c2)OC1(C)C
Temperature: 90 °C

Procedure:
3,4-Dihydro-2H-pyran (5.6 g, 67 mmol) and trifluoroacetic acid (1.17 g, 10.3 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.0 g, 51.5 mmol) in toluene (200 mL), and the reaction mixture was heated to 90° C. for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (100 mL), and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 10% to 50% ethyl acetate in petroleum ether) provided the product as a white solid. Yield: 13.4 g, 48.2 mmol, 94%. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.83 (s, 1H), 5.41 (dd, J=9.5, 2.5 Hz, 1H), 4.01-4.08 (m, 1H), 3.65-3.74 (m, 1H), 1.98-2.18 (m, 3H), 1.6-1.76 (m, 3H), 1.32 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[N+:10]([O-])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C-:18]#[N:19].[Na+]>P([O-])(O)(O)=O.[K+].CO.O.C(Cl)Cl>[C:11]1([N:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[C:18]#[N:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [C-]#N
Reactant: [O-][N+](=Cc1cccc(Cl)c1Cl)c1ccccc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: N#CC(=Nc1ccccc1)c1cccc(Cl)c1Cl
Temperature: 0 °C

Procedure:
635 mMol of N-(2,3-dichlorophenylmethylene)anilin-N-oxide (IX) are dissolved in a 5.61 mixture (1:1) of an aqueous 0.5 molar solution of potassium dihydrogenphosphate and methanol adjusted to pH5. To this are added 65 g (1.3 Mol) of sodium cyanide in 200 ml water at approximately 50° C. During the reaction the pH balance is held constant between 8.0 and 8.5. After the reaction is complete (DC control), the reaction mixture is neutralized and cooled to 0° C. The separated yellow-brown crystals are then dissolved in methylene dichloride. The organic phase is washed in water, dried and evaporated under vacuum. The residue is recrystallized from a small amount of methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH:15]([F:17])[F:16])=[CH:12][CH:11]=[C:10]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][NH2:26])=[N:23][CH:24]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>ClCCl>[C:38]1([O:37][C:35](=[O:36])[NH:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][C:10]3[CH:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[C:13]([O:14][CH:15]([F:16])[F:17])=[CH:12][CH:11]=3)=[CH:24][N:23]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCc1ccc(Cc2ccc(OC(F)F)c(-c3cccc(Cl)c3)c2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Cc2ccc(OC(F)F)c(-c3cccc(Cl)c3)c2)cn1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
In an 8 mL vial equipped with a stir bar was placed C-[5-(3′-chloro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methylamine (P-596, 115 mg, 0.307 mmol), dichloromethane (1.5 mL) and triethylamine (85.6 uL, 0.614 mmol). The solution was cooled to 0° C. and then phenyl chloroformate (57.8 uL, 0.461 mmol) was added and the mixture was stirred at 0° C. for 15 minutes. The reaction was quenched with water (3 mL) and then the organic portion was removed. The aqueous portion was extracted with dichloromethane (2 mL), the organic portions were combined, washed with brine (3 mL), dried (MgSO4), concentrated and purified by silica gel column chromatography utilizing 70% ethyl acetate/hexanes as the eluent to produce 78 mg of I-149 as a yellow viscous oil in 51% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][OH:35]>C(#N)C>[CH3:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]3[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]3[N:3]=[C:2]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34][OH:35])[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1cccc(-c2cc(Cl)nc3c(I)c(C)nn23)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2cc(N3CCC[C@H]3CO)nc3c(I)c(C)nn23)c1
Yield: 53.1 %

Procedure:
5-Chloro-7-(3-methylphenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine (580 mg), DIPEA (0.4 mL) and (S)-2-pyrrolidinemethanol (400 mg) are stirred at 90° C. in an acetonitrile (60 mL) solvent for 6 hours. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (360 mg). 1H NMR (CDCl3, 300 MHz): δ 7.67 (m, 2H), 7.40 (m, 2H), 7.27 (s, 1H), 6.10 (s, 1H), 4.48 (br, 1H), 3.88-3.55 (m, 4H), 2.44 (s, 3H), 2.38 (s, 3H), 2.08-1.97 (m, 3H), 1.76 (m, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14](Br)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:24]=[N:23][C:22](I)=[CH:21][N:20]=1>O1CCCC1.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>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:22]2[CH:21]=[N:20][C:19]([Br:18])=[CH:24][N:23]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: Brc1cnc(I)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2cnc(Br)cn2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 9 %

Procedure:
Part B. An oven-dried sealed tube was charged with 2-bromo-4-methyl-thiazole-5-carboxylic acid benzylamide (400 mg, 1.28 mmol, 1.0 equiv). The sealed tube was purged with nitrogen and Rieke zinc (4 mL, 10 g of zinc in 100 mL of tetrahydrofuran) was added. The reaction was heated in the microwave oven for 15 min at 100° C. Stirring was stopped and the remaining zinc was allowed to settle. The supernatant containing the zinc reagent was transferred via syringe to a solution of 2-bromo-5-iodo-pyrazine (292 mg, 1.0 mmol, 0.8 equiv), Pd(PPh3)4 (59 mg, 0.05 mmol, 4 mol %) in tetrahydrofuran (3 mL). The reaction mixture was purged with nitrogen for 10 min, then stirred at 160° C. for 20 hr. After cooling, the solvent was removed in vacuo and the crude product was purified by preparative HPLC (acetonitrile/water, 0.1% trifluoroacetic acid) to afford 2-(5-bromo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (35 mg, 7%). 1H NMR (400 MHz, CD2Cl2) δ 9.12 (s, 1H), 8.63 (s, 1H), 7.28-7.36 (m, 5H), 6.22 (bs, 1H), 4.59 (d, J=8.0 Hz, 2H), 2.72 (s, 3H); HRMS (M+H)+=389.01.
Reaction SMILES: [CH3:1][C:2]1[NH:3][O:4][C:5](=[O:7])[CH:6]=1.N1C=CC=CC=1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15].O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:25][CH:24]=2)[O:4][C:5](=[O:7])[CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(=O)o[nH]1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(=O)on1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
4 gm of 3-methyl-3-isoxazolin-5-one was added to 20 ml of toluene along with 3.5 gm of pyridine. 8.2 gm of 4-nitrobenzoyl chloride in 80 ml of toluene was added dropwise. The solution was stirred at room temperature for 4 hours. Afterwards, the system was poured into 200 ml water. The resulting solution was filtered and the organic phase then separated and dried over sodium sulfate. The toluene was removed by stripping to give 6.9 gm of a mixture of 3-methyl-2-(4'-nitrobenzoyl)-3-isoxazolin-5-one and 3-methyl-5-hydroxyisoxazolyl4'-nitrobenzoate. The crude product was recrystallized in ethanol to give 4.6 gm of the mixture. The product 3-methyl-2-(4-nitrobenzoyl)-3-isoxazolin-5-one was separated by column chromatography using 200 gm of E.M. silica gel 60 in an 80×90 mm column and a 2% solution of acetone in methylene chloride as the elutant. Listed as compound number 1, Table I.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]2)[CH:3]=1.[BH4-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[S:19](=[O:28])(=[O:27])[CH2:18][CH2:17]2)[CH:3]=1
Reactant: COC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN(c2cc(Cl)c3cc(CO)ccc3n2)Cc2ccccc21
Yield: 75 %

Procedure:
To a solution of methyl 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4 (5H)-yl)quinoline-6-carboxylate (2.0 g, 4.8 mmol) in tetrahydrofuran (50 mL) was added sodium borohydride (729 mg, 19.2 mmol). After being refluxed for 60 hours, the reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (50 mL×2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 1.4 g of the crude product.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C@H:12]([C:23]([O:25][CH3:26])=[O:24])[CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:10])=[C:7]([Cl:29])[CH:6]=1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]1[CH:28]=[CH:27][C:8]([C:9]([NH:11][C@H:12]([C:23]([O:25][CH3:26])=[O:24])[CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:10])=[C:7]([Cl:29])[CH:6]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(CN=[N+]=[N-])cc1Cl
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(CN)cc1Cl
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of N-[4-(azidomethyl)-2-chlorobenzoyl]-3-(benzoylamino)-L-alanine, methyl ester (4.34 g, 10.4 mmol) and 10% palladium on carbon (0.20 g, 0.2 mmol) in ethanol (200 mL) was hydrogenated at atmospheric pressure for 1 h. The mixture was filtered through Celite and the filter cake was washed with ethanol (100 mL). The combined filtrates were evaporated to give N-[4-(aminomethyl)-2-chlorobenzoyl]-3-benzoylamino-L-alanine, methyl ester (3.65 g, 90%) as a colorless foam.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:8]=1)[CH3:5])(O)=[O:2].C(N1C=CN=C1)([N:21]1C=CN=C1)=O.[OH-].[NH4+]>CN(C)C=O>[NH2:21][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:8]=1)[CH3:5])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1ncn(-c2cccc(F)c2)n1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(Oc1ncn(-c2cccc(F)c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Two g of the product of Example 58 was dissolved in 10 ml of dimethylformamide and 1.9 g of carbonyldiimidazole was added. The mixture was stirred at room temperature for 20 minutes, and 0.6 g of 35% ammonium hydroxide was added. The mixture was then stirred for 20 hours at room temperature and was poured over ice-water. The product was collected by filtration and dried to obtain 1.4 g of the desired product, m.p. 156°-158°.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[S:10](N)(=O)=O)(=[O:3])[CH3:2].[Cl:14]Cl>>[C:1]([C:4]1[CH:8]=[C:7]([Cl:9])[S:6][C:5]=1[S:10][Cl:14])(=[O:3])[CH3:2]
Reactant: ClCl
Reactant: CC(=O)c1cc(Cl)sc1S(N)(=O)=O
Product: CC(=O)c1cc(Cl)sc1SCl

Procedure:
The process comprises displacing the C(2)-chloro of 3-acetyl-2,5-dichlorothiophene (1) with benzyl mercaptide to form the thioether of structure (2), which is then converted to 3-acetyl-5-chloro-2-thiophenesulfonamide (3) by reaction with chlorine to form 3-acetyl-5-chloro-2-thiophenesulfenyl chloride, followed by reaction with ammonia to form 3-acetyl-5-chloro-2-thiophenesulfenamide, and finally oxidation. Bromination provides 3-bromoacetyl-5-chloro-2-thiophenesulfonamide (4), which is converted to (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (5) by reduction with (+)-β-chlorodiisopinocampheylborane followed by treatment with aqueous base. Alkylation at N(2) provides the (S)-3,4-dihydro-6-chloro-4-hydroxy-2-substituted-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide of structure (6). Formation of the C(6) anion is accomplished by halogen-metal exchange, and the anion is reacted with sulfur dioxide to form a lithium sulfinate, which upon reaction with hydroxylamine-O-sulfonic acid provides the (S)-3,4-dihydro-4-hydroxy-2-substituted-2H-thieno[3,2-e] -1,2-thiazine-6-sulfonamide-1,1-dioxide of structure (7). Protection of the C(6)-sulfonamide functionality, followed by activation of the C(4)-hydroxyl and displacement with an appropriate amine provides the (R)-3,4-dihydro-4-alkylamino-2-substituted-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide of structure I.