Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[F:22])=[CH:11][C:10]=1[Cl:23])(=[O:3])[CH3:2].[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]([NH:29][C:30](=[O:32])[CH3:31])([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:40][C:37]3[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)=[CH:17][C:16]=2[F:22])=[CH:11][C:10]=1[Cl:23])(=[O:3])[CH3:2]
Reactant: Cc1ccc(S)cc1
Reactant: CC(=O)NC(CCc1ccc(-c2ccc(Br)cc2F)cc1Cl)(COC(C)=O)COC(C)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)NC(CCc1ccc(-c2ccc(Sc3ccc(C)cc3)cc2F)cc1Cl)(COC(C)=O)COC(C)=O
Yield: 84 %

Procedure:
A solution of N-[1,1-bis(acetoxymethyl)-3-(4′-bromo-3-chloro-2′-fluorobiphenyl-4-yl)propyl]acetamide (264 mg) of Reference Example 23, 4-methylbenzenethiol (62 mg), diisopropylethylamine (129 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (12.9 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (14.9 mg) in 1,4-dioxane (2 mL) was heated under reflux for 9 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.24 g) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:25](=[O:26])[N:16]2[C:17]([C:22]([OH:24])=[O:23])=[C:18]([CH3:21])[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[N:9]=[N:10][S:11][CH:12]=1)[C:5]([NH:13][CH:14]1[C:25](=[O:26])[N:16]2[C:17]([C:22]([OH:24])=[O:23])=[C:18]([CH3:21])[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csnn1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)c1csnn1
Yield: 65.3 %

Procedure:
2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer)(3.74 g) and 7-amino-3-methyl-3-cephem-4-carboxylic acid (4.3 g) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-methyl-3-cephem-4-carboxylic acid (syn isomer)(5.0 g), mp 111° to 116° C. (dec.).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[NH:12][CH:11]=[CH:10]2.[OH-].[Na+].O.CN([CH:23]=[O:24])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[NH:12][CH:11]=[C:10]2[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1cc2[nH]ccc2cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A round-bottom flask was charged with DMF (54 mL). Phosphorus oxychloride (6.21 mL, 66.8 mmol) was added dropwise over 5 minutes, and the reaction mixture was stirred at room temperature for an additional 5 minutes. A solution of 5-bromo-6-chloro-1H-indole (7700 mg, 33.41 mmol) in DMF (7 mL) was added dropwise to the reaction mixture, which caused a precipitate to form. The reaction mixture was then heated to 95° C. for 25 minutes. The reaction mixture was treated with 1N aqueous sodium hydroxide (170 mL) and water (170 mL). The reaction mixture was stirred at 95° C. for 11 minutes. The reaction mixture was cooled to 0° C., and the solids were collected by filtration. The solids were washed with water (50 mL) and diethyl ether (50 mL) and dried in vacuo for 16 hours at 65° C. to afford the title compound (7.77 g, 90%) as a tan solid. MS (AP+) 257.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.40 (s, 1H), 8.38 (s, 1H), 7.80 (s, 1H).
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:8][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1.[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=O.C([BH3-])#N.[Na+].[C-]#N>CO>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:16][N:5]2[CH2:6][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)C1CNC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of tert-butyl azetidine-3-carboxylate acetic acid salt (92.0 g, 0.423 mol) in methanol (1.0 L) at room temperature was added 4-formylbenzonitrile (50.8 g, 0.381 mol). The reaction mixture was cooled to 0° C., and sodium cyanoborohydride (28.8 g, 0.458 mol) was added portion-wise (caution: potential cyanide generation). The reaction mixture was allowed to warm to room temperature and stirring continued overnight. After the reaction mixture was concentrated under reduced pressure the residue was diluted with 10% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was collected, washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by silica gel chromatography using 20% ethyl acetate in petroleum ether afforded tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (89%) (After chromatography, Int.1-D contained a small amount of 4-hydroxymethylbenzonitrile but was taken forward to the next step without further purification). LC/MS M+1=273.18. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.22-3.31 (m, 3H), 3.48-3.56 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.28 Hz, 2H), and 7.60 (d, J=8.28 Hz, 2H).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][C:9](=[O:24])[C:10](=[CH:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH:2]=1>CN(C)C=O>[CH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:8][C:9](=[O:24])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][N:16]2[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:3][CH:2]=1
Reactant: COC(=O)C(=CNc1ccc(O)cc1)C(=O)C=CC1CC=CCC1
Solvent: CN(C)C=O
Product: COC(=O)C1=CN(c2ccc(O)cc2)C(C2CC=CCC2)CC1=O
Yield: 70 %

Procedure:
In 20 ml of N,N-dimethylformamide was dissolved 2.0 g of methyl 5-(cyclohexen-4-yl)-2-(4-hydroxyphenylaminomethylene)-3-oxo-4-pentenoate, and they were reacted at 140° C. for 4 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and to the residue was added 50 ml of dioxane, after which the precipitated crystals were collected by filtration and washed with 30 ml of diethyl ether to obtain 1.4 g of methyl 6-(cyclohexen-4-yl)-1-(4-hydroxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinate having a melting point of 155°-157° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C@H:22]([C@@H:27]4[O:31]C(C)(C)O[C:28]4=[O:34])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[C@H:16]([CH3:35])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:36][OH:37]>CC(O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C@H:27]([OH:31])[C:28]([NH:36][OH:37])=[O:34])=[O:21])[C@H:16]([CH3:35])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cc2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cc2)C[C@H]1C)[C@H](O)C(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a suspension of (5S)-5-((1S)-1-{[(2R)-4-(4′-fluorobiphenyl-4-yl)-2-methylpiperazin-1-yl]carbonyl}-3-methylbutyl)-2,2-dimethyl-1,3-dioxolan-4-one (230 mg, 0.48 mmol, 1.0 eq) in a mixture of iPrOH (4 mL) and THF (4 mL) was added a 50% aq. solution hydroxylamine (0.08 mL, 1.43 mmol, 3.0 eq). The reaction mixture was stirred at rt for 8 h. Evaporation of the solvent gave a white solid. This product was washed with iPr2O (2×), filtered and dried under vacuum to give the title compound as a white powder (89%). M−(ESI): 456.3; M+(ESI): 458.4. HPLC (Condition A), Rt: 3.9 min (HPLC purity: 97.5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)([C:14]([O:16]CC2C=CC=CC=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
To a solution of 4-(4-methoxycarbonyl-benzyl)-piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (10.65 mmol; 4.98 g) in tetrahydrofuran (20 mL) and ethanol (40 mL) was added 10% palladium on carbon (3 g), and the resulting mixture was hydrogenated under 50 psi of hydrogen pressure for 5 hours at room temperature. The catalyst was removed via filtration, and the filtrate was evaporated to yield 4-(4-methoxycarbonyl-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. 1H-NMR (CDCl3): 7.95 (2H, d), 7.19 (2H, d), 3.90 (3H, s), 2.92 (4H, m), 2.05 (2H, s), 1.40-1.70 (4H, m), 1.45 (9H, s).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([C:10]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=2[Cl:17])=O)=[CH:5][CH:4]=1)[CH3:2].C(#N)C.C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Br:16][C:14]1[CH:13]=[CH:12][C:11]([Cl:17])=[C:10]([CH2:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:15]=1
Reactant: CCc1ccc(C(=O)c2cc(Br)ccc2Cl)s1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCc1ccc(Cc2cc(Br)ccc2Cl)s1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.2 %

Procedure:
5-Bromo-2-chlorobenzoic acid (5.00 g) was suspended in dichloromethane (10 ml), and thereto were added oxalyl chloride (2.2 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzoyl chloride. This compound and 2-ethylthiophene (2.38 g) were dissolved in dichloromethane (20 ml), and thereto was added aluminum chloride (3.11 g) at 0° C. The mixture was stirred at the same temperature for one hour. The reaction mixture was poured into a cold 10% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1) to give 5-bromo-2-chlorophenyl 5-ethyl-2-thienyl ketone (5.29 g) as an oil. APCI-Mass m/Z 329/331 (M+H). (2) A solution of the above 5-bromo-2-chlorophenyl 5-ethyl-2-thienyl ketone (5.29 g) in dichloromethane (50 ml)-acetonitrile (50 ml) was cooled under ice-cooling, and thereto were added dropwise triethylsilane (7.69 ml) and boron trifluoride•diethyl ether complex (6.1 ml). Subsequently, the mixture was stirred at room temperature for 3.5 hours, and was cooled again under ice-cooling. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform, washed with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 5-bromo-2-chloro-1-(5-ethyl-2-thienylmethyl)benzene (4.52 g) as a colorless liquid.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:5][C:6](=[O:21])[CH:7]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH3:10].CO.[OH-].[Li+].Cl>CCCCCC.C(OCC)(=O)C.O1CCCC1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][S:11][CH:7]([CH2:8][CH2:9][CH3:10])[C:6]([NH:5][C@H:4]([C:3]([OH:30])=[O:2])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: CCCC(SCc1ccc(OC)cc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(SCc1ccc(OC)cc1)C(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reaction time: 18 h

Procedure:
Combine 2-(4-methoxybenzylthio)-pentanoyl-(L)-homophenylalanine methyl ester (3.50 g, 8.15 mmol) and methanol (30 mL)and tetrahydrofuran (30 (mL). Cool in an ice bath. Add an aqueous 2M lithium hydroxide solution (8.2 mL, 16.4 mmol). After 18 hours, adjust the pH to about 6 using an aqueous 10% hydrochloric acid solution and evaporate in vacuo to give a residue. Partition the residue between dichloromethane and water, adjust the pH of the aqueous layer to about 1 using an aqueous 10% hydrochloric acid solution. Separate the layers, extract the aqueous layer repeatedly with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 95% 1/1 hexane/ethyl acetate/5% acetic acid to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]2)=[O:7])=[C:4]([F:18])[CH:3]=1.N1(CCN)CCC[CH2:20]1>>[NH2:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:14][CH2:20][CH2:13][CH2:12]2)=[O:7])=[C:4]([F:18])[CH:3]=1
Reactant: CN1CC[C@@H](NC(=O)c2cc(F)c(N)cc2F)C1
Reactant: NCCN1CCCC1
Product: Nc1cc(F)c(C(=O)NCCN2CCCC2)cc1F

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 229, on a 5.77 mmol scale utilising 2-pyrrolidin-1-ylethanamine (Aldrich; 725 mg, 6.35 mmol), as a beige solid (648 mg, 42%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16](C(=O)C(F)(F)F)[CH2:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[K+]>CCO>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH2:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Nc3nccs3)cc2C1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CNCC2
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
2-(2,2,2-Trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid thiazol-2-ylamide (5.0 g, 0.013 mol), was suspended in EtOH (50 mL). After slowly adding KOH (3.0 g, 0.05 mol) over 5 minutes, the solution started to clear. After an additional 10 minutes of stirring, the formed precipitate was filtered, washed several times with EtOH, and dried under high vacuum to give the amine (3.0 g, 0.012 mmol, 95% yield). LC/MS (10-99% CH3CN), M/Z: M+1 obs=296.2; tR=0.66 min.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([Cl:15])[CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](OB(O)O)=[CH:19][CH:18]=1>>[Cl:15][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)COc1ccc(Br)cc1Cl
Reactant: OB(O)Oc1ccc(F)cc1
Product: CCOC(=O)COc1ccc(-c2ccc(F)cc2)cc1Cl

Procedure:
Prepared analogously to Example 130a from ethyl (4-bromo-2-chloro-phenoxy)-acetate (Z26) and 4-fluoro-phenylboric acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]=[C:20]=[O:21]>C(Cl)Cl>[CH3:18][NH:19][C:20](=[O:21])[NH:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]1
Reactant: CN=C=O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)C1
Solvent: ClCCl
Product: CNC(=O)NCCN1CCC(CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethylamine (1 g) was dissolved in methylene chloride (10 ml) and a solution of methyl isocyanate (0.24 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure to give 1-(2-(3-methylureido)ethyl)-3-tert-butoxycarbonylaminomethylpyrrolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:21]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:28]([NH:30][NH2:31])=O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:17]([CH:18]([CH3:20])[CH3:19])[CH:28]=[N:30][N:31]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:21]=1
Reactant: NNC=O
Reactant: CC(C)NC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)n1cnnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of in 8-bromo-N-isopropyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (180 mg, 0.49 mmol) in 5 mL toluene was added phosphorus pentachloride (0.184 g, 0.88 mmol) under nitrogen and the reaction mixture was heated at 80° C. for 2 h. The mixture was cooled and carefully concentrated. The crude residue was dissolved in mL THF and treated sequentially with formyl hydrazine (118 mg, 2.0 mmol) and potassium carbonate (0.340 g, 2.46 mmol). The mixture was stirred overnight at room temperature, diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The crude residue was dissolved in toluene (10 mL) and treated with p-toluenesulfonic acid (15 mg, 0.087 mmol). The whole was sealed and heated at 90° C. for 15 min. The reaction mixture was cooled to room temperature, concentrated, diluted with ethyl acetate and washed with water, sodium bicarbonate and brine. The organics were dried over sodium sulfate and concentrated to give 224 as the crude product which could be used without purification in subsequent operations. A small amount was purified by reverse-phase HPLC for analytical purposes. 1H NMR (dmso-d6, 400 MHz) δ 11.9 8.84 (s, 1H), 7.65 (d, 1H), 7.45 (s, 1H), 7.32-7.27 (m, 2H), 4.75 (m, 1H), 4.34 (t, 2H), 3.25 (t, 2H), 1.48 (d, 6H). MS (ESI) 392.1
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.B(OC)(OC)[O:25]C.C(O)(=O)C.OO>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([OH:25])[CH:18]=1
Reactant: COB(OC)OC
Reactant: Fc1ccc(Br)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Oc1cc(Br)ccc1F
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 85.3 %

Procedure:
To a solution of 2,2,6,6-tetramethyl piperidine (5.6 mL, 33.2 mmol) in THF at −20° C. was added n-BuLi (1.6 M in hexanes, 18.8 mL, 30 mmol). The mixture was stirred at −20° C. for 10 min before it was cooled to −78° C. 1-Bromo-4-flurobenzene (2.95 mL, 27 mmol) was added over 10 min and the mixture was stirred at −78° C. for 2.0 h before trimethyl borate (6.0 mL, 54 mmol) was added. The mixture was stirred at −78° C. for 30 min and then at rt for 2.0 h. After it was cooled back to 0° C., glacial acetic acid (4.86 mL, 81 mmol) was added and stirred for 30 min, followed by addition of 30% H2O2 (4.86 mL, 81 mmol). The mixture was stirred at rt for 24 h, quenched by addition of MnO2 (40 mg). After stirring at rt for 30 min, the cloudy solution was filtered through a pad of wet Celite® and extracted with EtOAc. The EtOAc layer was washed with aquous NaHSO3, brine and dried over Na2SO4. The crude residue was purified by flash column chromatography (EtOAc:hexanes=1:5) to give 4.4 g (85%) of 23A as a liquid. 1H NMR (400 MHz, CDCl3) δ ppm 5.39 (s, 1H) 6.90-6.98 (m, 2H) 7.14 (dd, J=8.13, 1.98 Hz, 1H).
Reaction SMILES: C1(=O)[N:5]([CH:6]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:7][P:8]([NH:13][CH:14]2[CH2:19][S:18][C@H:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:15]2=[O:32])([O:10][CH2:11][CH3:12])=[O:9])[C:4](=[O:40])[C:3]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:2]12.O.NN>O1CCOCC1>[C:4]([NH:5][CH:6]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:7][P:8]([NH:13][CH:14]1[CH2:19][S:18][C@H:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:16]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:15]1=[O:32])([O:10][CH2:11][CH3:12])=[O:9])(=[O:40])[C:3]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:2]=1
Reactant: CCOC(=O)CN1C(=O)C(NP(=O)(CC(Cc2ccccc2)N2C(=O)c3ccccc3C2=O)OCC)CS[C@@H]1c1ccccc1
Agent: NN
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CN1C(=O)C(NP(=O)(CC(Cc2ccccc2)NC(=O)c2ccccc2)OCC)CS[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (R)-dihydro-5-[[[2-phthalimido-3-phenylpropyl]ethoxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester in dioxane is treated with hydrazine hydrate and stirred for 24 hours at room temperature. The mixture is then partitioned between ethyl acetate-water and the ethyl acetate phase was washed with water and saturated sodium chloride, dried (Na2SO4), and evaporated. The residue is taken up in dry toluene and refluxed for one hour. The mixture is filtered, treated with triethylamine and benzoyl chloride and stirred at room temperature for 30 minutes. The mixture is diluted with ethyl acetate, washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, and saturated sodium chloride, dried (Na2SO4), and evaporated. The residue is chromatographed on silica gel to give (R)-dihydro-5-[[[2-(benzoylamino)-3-phenylpropyl]ethoxyphosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][C:11]3[CH2:12][C:13]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)=[N:18][N:17](COCC[Si](C)(C)C)[C:14]=4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][C:4]=1[OH:36].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][C:11]3[CH2:12][C:13]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)=[N:18][NH:17][C:14]=4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][C:4]=1[OH:36]
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(O)c(OC)c4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4ccc(O)c(OC)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 84.4 %

Procedure:
2-Methoxy-4-[6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenol (0.47 g, 0.9 mmol) was dissolved in MeOH and treated with concentrated HCl (0.3 mL, 9.03 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 2-Methoxy-4-[6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenol (0.35 g, 0.76 mmol) as brown solid in 85% yield.