Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([OH:71])[C@@H:3]1[NH:27][C:25](=[O:26])[C@H:24]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[NH:23][C:21](=[O:22])[C@@H:20]([CH2:33][C:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[NH:36][CH:35]=2)[NH:19][C:17](=[O:18])[C@H:16]([CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:15][C:13](=[O:14])[C@@H:12]([NH:50][C:51]([C@H:53]([NH2:61])[CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[O:52])[CH2:11][S:10][S:9][CH2:8][C@@H:7]([C:62]([NH:64][C@@H:65]([C@H:68]([OH:70])[CH3:69])[CH2:66][OH:67])=[O:63])[NH:6][C:4]1=[O:5].C(Cl)Cl.C[OH:76]>>[CH3:1][C@@H:2]([OH:71])[C@@H:3]1[NH:27][C:25](=[O:26])[C@H:24]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[NH:23][C:21](=[O:22])[C@@H:20]([CH2:33][C:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[NH:36][CH:35]=2)[NH:19][C:17](=[O:18])[C@H:16]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[NH:15][C:13](=[O:14])[C@@H:12]([NH:50][C:51]([C@H:53]([NH2:61])[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:52])[CH2:11][S:10][S:9][CH2:8][C@@H:7]([C:62]([NH:64][C@@H:65]([C@H:68]([OH:70])[CH3:69])[CH2:66][OH:67])=[O:63])[NH:6][C:4]1=[O:5].[CH3:1][C@@H:2]([OH:71])[C@@H:3]1[NH:27][C:25](=[O:26])[C@H:24]([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[NH:23][C:21](=[O:22])[C@@H:20]([CH2:33][C:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[NH:36][CH:35]=2)[NH:19][C:17](=[O:18])[C@H:16]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[NH:15][C:13](=[O:14])[C@@H:12]([NH:50][C:51]([C@H:53]([NH2:61])[CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:52])[CH2:11][S:10][S:9][CH2:8][C@@H:7]([C:62]([NH:64][C@@H:65]([C@H:68]([OH:70])[CH3:69])[CH2:66][OH:67])=[O:63])[NH:6][C:4]1=[O:5].[CH3:69][C:68]([OH:70])=[O:76]
Reactant: CO
Agent: C[C@@H](O)[C@@H]1NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)[C@H](N)Cc2ccccc2)CSSC[C@@H](C(=O)N[C@H](CO)[C@@H](C)O)NC1=O
Solvent: ClCCl
Product: CC(=O)O

Procedure:
Various Octreotide microspheres were prepared from a clear dispersed phase containing the polymer, octreotide, methylene chloride (DCM) and methanol. Octreotide acetate was obtained from Polypeptide Laboratories or Peninsula Lab. Polymer concentration was varied for the batches to obtain appropriate particle size and also to obtain efficient drug load. Methanol (MeOH) to DCM ratio was increased while making higher drug load batches to get a clear dispersed phase. The continuous phase was a 0.35% PVA solution in all preparations. In a typical preparation, CP was taken in a beaker and stirred using a Silverson homogenizer (standard emulsor screen). To the stirring CP, the dispersed phase was added just below the Silverson head using a laboratory syringe with a bent needle. After 30 sec to 1 minute homogenization, the entire suspension was transferred into a 3 liter Applikon bioreactor for solvent removal. The solvent removal from the microsphere was achieved by initial CP replacement with water followed by heating the suspension at 40° C. along with air sweep. After the solvent removal the microspheres were collected on a filter membrane, washed and dried under vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18](I)([CH3:20])[CH3:19]>CN(C)C=O>[CH:18]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)([CH3:20])[CH3:19]
Reactant: CC(C)I
Reactant: Cc1ccc2c(c1)NCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)N(C(C)C)CCC2
Temperature: 60 °C
Reaction time: 24 h
Yield: 82.5 %

Procedure:
To a cooled solution of 7-methyl quinoline (5.00 g, 35 mmol) and nickel (II) chloride hexahydrate (1.40 g, 6 mmol) in methanol (130 mL) was added sodium borohydride (5.50 g, 140 mmol) portionwise. The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. Hydrochloric acid (2N, 200 mL) was added to the black residue and the mixture stirred at room temperature until disappearance of the black precipitate. The acidic solution was neutralized with concentrated ammonium hydroxide and extracted with ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, filtered and evaporated to give 5.28 g of 7-methyl-1,2,3,4-tetrahydro-quinoline (100%), used without further purification. A mixture of 7-methyl-1,2,3,4-tetrahydro-quinoline (1.20 g, 8.2 mmol), potassium carbonate (2.3 g, 16.4 mmol) and isopropyl iodide (3.3 mL, 32.8 mmol) in N,N-dimethylformamide (10 mL) was heated at 60° C. with stirring for 24 hours. The solution was cooled to room temperature and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 1.28 g (82%) of 1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline. To a solution of 1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline (1.04 g, 5.5 mmol) in dichloromethane was added tetrabutylammonium tribromide (2.65 g, 5.5 mmol) and the solution stirred at room temperature for 5 hours. The solution was washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed and silica gel (ethyl acetate/hexane, 1:9) to give 1.00 g of 6-bromo-1-isopropyl-7-methyl-1,2,3,4-tetrahydro-quinoline (67%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:12])[CH2:10][CH3:11])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:16])(=O)=O>C(O)(=O)C>[Cl:16][CH:10]([CH3:11])[C:9](=[O:12])/[C:3](=[N:2]/[OH:1])/[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(=N\O)C(=O)CC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)/C(=N\O)C(=O)C(C)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-(Z)-hydroxyimino-3-oxopentanoate (10 g) in 10 ml of acetic acid was cooled to 0° C. and treated dropwise with sulfuryl chloride (5.3 ml). The mixture was stirred for 3 hours at room temperature and quenched by ice-water. The mixture was extracted with ethyl acetate, and the extracts were washed with brine and dried with magnesium sulfate. The solvent was removed under reduced pressure to afford ethyl 4-chloro-2-(Z)-hydroxyimino-3-oxopentanoate (11.97 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:9]1[NH:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]1=O)[CH3:8]>C1COCC1>[CH2:7]([CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][NH:15]1)[CH3:8]
Reactant: CCC1NCCCNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1CNCCCN1
Temperature: 55 °C
Yield: 100 %

Procedure:
Lithium aluminium hydride (475 mg, 12.49 mmol) was added portionwise to a stirred solution of 3-ethylperhydro-1,4-diazepin-2-one (740 mg, 5.20 mmol) in THF (10 mL). After the resultant effervescence had subsided, the reaction mixture was heated at 50-60° C. for 3 h. The reaction mixture was cooled and quenched by the slow addition of water and 10% NaOH (aq.). The reaction mixture was diluted with diethyl ether (20 mL) and filtered through celite. The filter cake was washed thoroughly with THF (50 mL), diethyl ether (50 mL), THF (50 mL) and diethyl ether (50 mL). Evaporation under reduced pressure afforded 2-ethylperhydro-1,4-diazepine (INTERMEDIATE X.1) (615 mg, 5.20 mmol), 92%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:28])[CH2:13][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)(O)[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:28])[CH:13]=[C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]([F:18])([F:16])[F:17])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)nc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
After adding 5.34 g of toluene to 1.78 g (4.12 mmol) of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 0.98 g (8.25 mmol) of thionyl chloride and 0.65 g (8.25 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction solution was cooled to room temperature, and separated by adding 20 ml of ethyl acetate and 10 ml of water. After washing the ethyl acetate phase with an aqueous solution of 0.33 g of sodium hydroxide dissolved into 10 ml of water, the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 1.69 g of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (yield 99.4%).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C@H:4]([CH3:14])[C@H:5]([NH:9][C:10]([O:12][CH3:13])=[O:11])[C:6]([OH:8])=O.[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[NH:22][C:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([B:36]4[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]4)[CH:32]=3)[CH:27]=2)=[CH:24][N:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:15][CH:2]([F:1])[O:3][C@H:4]([CH3:14])[C@H:5]([NH:9][C:10](=[O:11])[O:12][CH3:13])[C:6](=[O:8])[N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[NH:22][C:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([B:36]4[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]4)[CH:32]=3)[CH:27]=2)=[CH:24][N:25]=1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC(F)F
Reactant: CC1(C)OB(c2ccc3cc(-c4cnc([C@@H]5CCCN5)[nH]4)ccc3c2)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)[C@@H](C)OC(F)F
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of (2S,3R)-3-(difluoromethoxy)-2-(methoxycarbonylamino)butanoic acid (205 mg, 0.9 mmol) and (S)-2-(pyrrolidin-2-yl)-5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazole (315 mg, 0.8 mmol) in dimethylformamide (8 mL) was added HATU (325 mg, 0.85 mmol) and diisopropylethylamine (0.565 mL, 3.2 mmol). The reaction was stirred for 1 hour and then diluted with ethyl acetate. The organic layer was washed twice with saturated NaHCO3 solution and brine, dried (MgSO4) and concentrated. The resulting residue was purified by flash chromatography to yield methyl (2S,3R)-3-(difluoromethoxy)-1-oxo-1-((S)-2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (230 mg, 47%). LCMS-ESI+: calculated for C30H37BF2N4O6: 598.45; observed [M+1]+: 599.31.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[CH3:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:13]2[N:12]=1>N1C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[C:18]([S:20]([NH:4][C:3]3[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=3[F:9])(=[O:22])=[O:21])[N:19]=[C:13]2[N:12]=1
Reactant: Cc1ccn2nc(S(=O)(=O)Cl)nc2n1
Reactant: Nc1c(F)cccc1F
Solvent: c1ccncc1
Product: Cc1ccn2nc(S(=O)(=O)Nc3c(F)cccc3F)nc2n1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 72.5 %

Procedure:
The starting 2,6-difluoroaniline (18.1 g, 0.140 mol) was dissolved in 45 ml of pyridine and 36.1 g (0.155 mol) of 5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride was added. After an exothermic reaction subsided the reaction mixture was stirred at room temperature for 15.5 hours. The pyridine was removed by evaporation at reduced pressure, and the residue was treated with 600 ml of 0.5N naOH. After stirring to dissolve all soluble material the mixture was filtered through celite and the filtrate was acifified with 3N HCl. The precipitate which separated upon acidification was collected by filtration and dried to yield 33.0 g (73%) of the desired product as a pale red solid, mp 245°-247° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.Cl.[NH2:12][OH:13].CCN(CC)CC>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[NH:12][OH:13])=[C:4]([F:10])[CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(Br)cc1F
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 144.8 %

Procedure:
To a solution of 4-Bromo-2-fluorobenzonitrile 11 (800 g, 4 mol, 1 eq), hydroxylamine hydrochloride (695 g, 10 mol, 2.5 eq) in MeOH (2 L, 2.5 vol) was added Et3N (485 g, 4.8 mol, 1.2 eq), then the mixture was stirred at 60° C. for 40 min and checked by HPLC (no nitrile remaining) Reaction was then quenched by H2O (30 L), and lots of off-white solid was separated out, and then filtered, the filter cake was washed with water (10 L×2) and 1350 g wet 4-bromo-2-fluoro-N-hydroxybenzimidamide 24 was obtained with 96% purity
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[CH:4]=[C:3]1[C:12]([OH:14])=[O:13].C(OC(=O)C(C(=O)C)CC1C=CC(C)=CC=1)C.S(=O)(=O)(O)O>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[CH2:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: Cc1ccc2c(c1)C(C)C(C(=O)O)=C2
Agent: CCOC(=O)C(Cc1ccc(C)cc1)C(C)=O
Agent: O=S(=O)(O)O
Product: CC1=C(C(=O)O)Cc2ccc(C)cc21
Yield: 59 %

Procedure:
The 1,6-dimethyl-indene-2-carboxylic acid can be prepared by the treatment of α-acetyl-4-methylbenzenepropanoic acid ethyl ester with sulfuric acid (Shadbolt, R. S., J. Chem. Soc. (C), (1970) 920). Recrystallization from ethanol, m.p. 174°-182° C. Yield 59%.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:16][CH:17]([CH3:19])[CH3:18])=[C:7]([C:10]([CH3:15])=[C:11]([C:13]#[CH:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:14]#[C:13][C:11]2[CH:12]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([O:16][CH:17]([CH3:19])[CH3:18])=[C:7]([CH:8]=[O:9])[C:10]=2[CH3:15])=[CH:28][CH:29]=1
Reactant: C#Cc1cc(C(C)(C)C)c(OC(C)C)c(C=O)c1C
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(C=O)c2C)cc1

Procedure:
Following General Procedure B and using 3-tert-butyl-5-ethynyl-2-isopropoxy-6-methyl-benzaldehyde (Intermediate 143, 0.35 g, 1.35 mmol), 4-iodo phenyl acetic acid methyl ester (0.374 g, 1.35 mmol), triethyl amine (8 mL), copper(I)iodide (0.02 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.072 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 3-5% ethyl acetate in hexane as the eluent, the title compound was obtained as a white solid (0.37 g, 75%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[O:13])=[C:7]([CH2:10][Cl:11])[CH2:8][S:9][C@H:4]12.[C:26](OCC)(=[O:28])C.[OH-].[Na+]>O>[Cl:11][CH2:10][C:7]1[CH2:8][S:9][C@@H:4]2[CH:3]([NH:2][CH:26]=[O:28])[C:24](=[O:25])[N:5]2[C:6]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13]
Reactant: CCOC(C)=O
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N)C(=O)N23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC=O)C(=O)N23)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
To 15 g (37 mM) of p-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate hydrochloride, 500 ml of ethyl acetate and 100 ml of water were added. Under cooling with ice, the mixture was adjusted to pH 7.5 with a 1N sodium hydroxide aqueous solution and dissolved. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and then concentrated under reduced pressure. The oily residue was dissolved in 150 ml of methylene chloride. To this solution, a mixed anhydride solution prepared from 4.8 ml (127 mM) of 99% formic acid and 12 ml (127 mM) of acetic anhydride, was dropwise added under cooling with ice, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure. To the residue, 300 ml of ethyl acetate, 300 ml of tetrahydrofuran and 100 ml of water were added, and the mixture was adjusted to pH 7.5 with a 1N sodium hydroxide aqueous solution. The organic layer was separated, and washed with a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 14.5 g (yield: 99%) of p-methoxybenzyl 3-chloromethyl-7-formamido-3-cephem-4-carboxylate.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.COCCOCCN(CCOCCOC)CCOCCOC.F[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[NH:42][S:43]([CH3:46])(=[O:45])=[O:44].Cl>ClC1C=CC=CC=1>[CH:3]1([O:9][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=2[NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Reactant: OC1CCCCC1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: Cl
Agent: [H-]
Solvent: Clc1ccccc1
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1OC1CCCCC1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To 2000 ml of a chlorobenzene solution containing 52.8 g of 60% sodium hydride were successively added 128.0 g of cyclohexanol and 8 ml of tris[2-(2-methoxyethoxy)ethyl]amine at room temperature, and then after stirring for 30 minutes, 100.0 g of N-(2-fluoro-5-nitrophenyl)methanesulfonamide was added under ice cooling, followed by stirring for 19 hours. The reaction solution, after addition of 1500 ml of 3N hydrochloric acid, was extracted with dichloromethane, and the organic layer was successively washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethanol to give 98.5 g of N-(2-cyclohexyloxy-5-nitrophenyl)methanesulfonamide as yellow plates.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[CH2:14]1[O:17][CH:15]1[CH3:16].C(C1C=CC=CC=1O)(C)(C)C.C1OC1CC>>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:13][CH2:14][CH:15]([OH:17])[CH3:16])([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: CC1CO1
Agent: CC(C)(C)c1ccccc1O
Agent: CCC1CO1
Product: CC(O)COc1c(C(C)C)cccc1C(C)C
Yield: 89.9 %

Procedure:
The synthesis was carried out in the same manner as described in Example 3a, except that 50.0 g (0.28 mol) of 2,6-diisopropylphenol and 22.0 g (0.31 mol) of propyleneoxide were used instead of 350 g (2.33 mol) of 2-tert-butylphenol and 176 g (2.45 mol) of 1,2-butyleneoxide. 59.5 g of 1-(2,6-diisopropylphenyloxy)-2-propanol (bp. 138° C./5 mm Hg) were obtained in a 90% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=S)[NH:11][C:12]1[C:13]([NH:24][CH3:25])=[CH:14][C:15]([F:23])=[C:16]([CH:22]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].CC(C)N=C=NC(C)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:24]([CH3:25])[C:13]2[CH:14]=[C:15]([F:23])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][C:12]=2[N:11]=1
Reactant: CCOC(=O)c1cc(NC(=S)Nc2c(Cl)cccc2Cl)c(NC)cc1F
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Product: CCOC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)n(C)c2cc1F

Procedure:
Prepared analogously to example 127e from ethyl 5-(3-(2,6-dichlorophenyl)-thioureido)-2-fluoro-4-(methylamino)-benzoate and DIC in acetonitrile.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[OH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1O
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccccc2O)cc1
Yield: 94.8 %

Procedure:
The general procedure described in Example 3 was used with 4-chlorobenzoic acid (157 mg, 1.00 mmol), 2-hydroxyphenylboronic acid (166 mg, 1.20 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (2.0 mL), 12 h, 100° C. The product was isolated as a white solid (203 mg, 95%). Mp=186° C. 1H NMR (400 MHz, d4-MeOH) δ: 8.04 (d, 2H, J=8.4 Hz), 7.65 (d, 2H, J=8.4 Hz), 7.25 (dd, 1H, J=7.6 Hz, 1.6 Hz), 7.16 (td, 1H, J=7.6 Hz, 1.6 Hz), 6.89 (m, 2H). 13C NMR (125 MHz, d4-MeOH) δ: 170.2, 155.6, 145.4, 131.7, 130.5 (2), 130.48, 130.4, 129.8, 128.7, 121.2, 117.2. IR (neat, cm−1): 3391, 2529, 1683, 1274, 1008, 753.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:24].C(N(CC)CC)C.Cl.[CH2:33]([O:35][CH:36]1[O:41][CH2:40][CH2:39][NH:38][CH2:37]1)[CH3:34]>O1CCCC1>[CH2:33]([O:35][CH:36]1[CH2:37][N:38]([C:2]2[N:10]=[C:9]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=3)[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH3:24])[CH2:39][CH2:40][O:41]1)[CH3:34]
Reactant: CCOC1CNCCO1
Reactant: COc1ccc(CSc2nc(Cl)c3ncn(C)c3n2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC1CN(c2nc(SCc3ccc(OC)c([N+](=O)[O-])c3)nc3c2ncn3C)CCO1
Yield: 69.1 %

Procedure:
6-chloro-2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-9H-purine (850 mg, 2.32 mmol) was dissolved in tetrahydrofuran (100 ml), triethylamine (1.57 g, 15.51 mmol) and 2-ethoxymorpholine hydrochloride (520 mg, 3.10 mmol) were added and heated to reflux for 7 hours. After distilling away the solvent under reduced pressure, water was added to the residue and extracted twice with ethyl acetate, then the organic layers were washed with a saturated saline solution and dried with MgSO4. After distilling away the solvent under reduced pressure, purification was performed by silica gel column chromatography (ethyl acetate:hexane=1:3) to obtain 738 mg (69% yield) of 6-(2-ethoxymorpholino)-2-(4-methoxy-3-nitrobenzylsulfanyl)-9-methyl-9H-purine.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCCn2c1cc1cc(F)cc(-c3ccncc3)c12

Procedure:
The title compound, white solid (24 mg, 33%), MS (ISP) m/z=296.3 [(M+H)+], mp 309° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available pyridine-4-ylboronic acid (39.9 mg, 0.325 mmol).