Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:27])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:10][CH:11]=1.[C:28](O)(=O)C(C)O.C(O)(=O)CO>ClCCl>[CH:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][CH:7]=1.[CH2:1]([S:2]([O-:5])(=[O:4])=[O:3])[CH3:28]
Reactant: CS(=O)(=O)O
Reactant: CC(O)C(=O)O
Agent: O=C(O)CO
Agent: OC(CCN1CCCCC1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCS(=O)(=O)[O-]

Procedure:
In 3.0 ml of 30% gelatin (dissolved by warming) is dissolved 50 mg of pridinol methanesulfonate and the solution is added to 10 ml of a 30% dichloromethane solution of lactic acid-glycolic acid copolymer (78.1/21.9, average mol. wt. 10,000). The mixture is then worked up in the same manner as Example 1 to give pridinol ethanesulfonate microcapsules for injection.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:22]1[C:30]2[C:25](=[C:26]([CH2:31][S:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)NC=1)[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=O)=O.C[N:35]([CH:37]=O)C>>[CH3:33][S:32][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[NH:2][CH:1]=[C:22]2[CH:11]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH2:10][CH2:9][C:37]#[N:35]
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc4ccccc4c3)c[nH]c12
Reactant: [C-]#N
Reactant: CN(C)C=O
Agent: [K+]
Product: CSCc1cccc2c(C(CCC#N)c3ccc4ccccc4c3)c[nH]c12
Temperature: 80 °C
Reaction time: 4 h

Procedure:
97.5 mg (1.50 mmol) of potassium cyanide were added to 329 mg (0.75 mmol) of the compound from Example 64A in 15 ml of DMF. The mixture was stirred at 80° C. for 4 h and then concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 181 mg (65% of theory) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:41])[C:10]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[O:12].[OH:42][C:43]1[CH:48]=[CH:47][C:46](/[CH:49]=[CH:50]/[C:51]([O:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])=[CH:56][CH:55]=2)=[O:52])=[CH:45][CH:44]=1.[C:66](=[O:69])([O-])[O-:67].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(=O)CC>[CH2:61]([O:60][C:57]1[CH:56]=[CH:55][C:54]([O:53][C:51](=[O:52])/[CH:50]=[CH:49]/[C:46]2[CH:45]=[CH:44][C:43]([O:42][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9](=[O:41])[C:10]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:42][C:43]3[CH:44]=[CH:45][C:46](/[CH:49]=[CH:50]/[C:66]([O:67][C:54]4[CH:55]=[CH:56][C:57]([O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])=[CH:58][CH:59]=4)=[O:69])=[CH:47][CH:48]=3)=[O:12])=[CH:48][CH:47]=2)=[CH:59][CH:58]=1)[CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: O=C(OCCCCCCCl)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCCCCCCl
Reactant: O=C([O-])[O-]
Reactant: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(O)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCOc1ccc(OC(=O)/C=C/c2ccc(OCCCCCCOC(=O)C(Cc3ccc([N+](=O)[O-])cc3)(Cc3ccc([N+](=O)[O-])cc3)C(=O)OCCCCCCOc3ccc(/C=C/C(=O)Oc4ccc(OCCCCC)cc4)cc3)cc2)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
2.80 g (4.6 mmol) bis[6-chlorohexyl]2,2 bis(4-nitrobenzyl)malonate, 3.0 g (9.2 mmol) 4-pentoxyphenyl (2E)-3-{4-hydroxyphenyl}acrylate and 0.17 g (0.46 mmol) tetrabutylammonium iodide were dissolved in 30 ml 2-butanone. 2.53 g (18.3 mmol) potassium carbonate were added. The resulting suspension was heated at refluxing temperature and allowed to react for 48 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation to yield 3.6 g bis[6-{4-[(1E)-3-(4-pentyloxyphenoxy)-3-oxoprop-1-enyl]phenoxy}hexyl]2,2 bis(4-nitrobenzyl)malonate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[C:13]([CH:18]4[O:22][CH2:21][CH2:20][O:19]4)[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:23])=[CH:5][CH:4]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>ClCCl.O>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][C:9](=[O:23])[N:8]2[CH2:7][C:6]1[CH:24]=[CH:25][C:3]([CH2:2][N:27]([CH3:26])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][CH:5]=1
Reactant: CNc1ccccc1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1Cc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CN(Cc1ccc(CN2C(=O)CCc3c(C4OCCO4)cccc32)cc1)c1ccccc1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
1-(4-Chloromethylbenzyl)-5-(1,3-dioxolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (100 mg, 0.28 mmol), N-methylaniline (0.045 ml, 0.42 mmol) and potassium carbonate (57.9 mg, 0.42 mmol) were added to acetonitrile (1 ml), followed by heating under reflux for 4 hours. After cooling to room temperature, water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dry product was concentrated under reduced pressure, and the residue was purified by preparative silica gel thin layer chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 80 mg (yield: 67%) of 5-(1,3-dioxolan-2-yl)-1-(4-[(N-methyl-N-phenylamino)methyl]benzyl)-3,4-dihydro-1H-quinolin-2-one as a light yellow amorphous solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>O.C(N(CC)CC)C>[NH3:1].[C:9]([N:4]1[CH2:5][CH2:6][NH:1][CH:2]([CH2:7][OH:8])[CH2:3]1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCNC(CO)C1
Product: N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-piperazinemethanol (197 mg) and triethylamine (0.35 ml, 0.26 g) in water (4 ml) was treated with a mixture of acetic anhydride (0.16 ml) and water (1.5 ml) and was stirred at room temperature for 2 h. The solution was basified with sodium carbonate solution (2N, 1 ml), saturated with sodium chloride (1 g) and washed with dichloromethane (10 ml). The aqueous phase was evaporated in vacuo to give a solid which was purified by flash column chromatography eluting with dichloromethane:methanol:ammonia, (75:10:1.5) to give the title compound as an oil (188 mg).
Reaction SMILES: CN(C)/[C:3](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[CH:4]\[CH:5]=[C:6]([C:9]#[N:10])C#N.[NH3:28].O.[CH3:30]O>>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:3]2[N:10]=[CH:9][CH:6]=[CH:5][C:4]=2[C:30]#[N:28])=[CH:24][CH:23]=1
Reactant: N
Reactant: COc1ccc(COc2ccccc2/C(=C/C=C(C#N)C#N)N(C)C)cc1
Reactant: CO
Solvent: O
Product: COc1ccc(COc2ccccc2-c2ncccc2C#N)cc1
Temperature: 120 °C
Yield: 4.3 %

Procedure:
To a cold (−78° C.) solution of 2-((2Z)-3-(dimethylamino)-3-{2-[(4methoxy-benzyl)oxy]phenyl}-2-propenylidene)malononitrile ( 1.26 g, 3.51 mmol) in MeOH was added liquid NH3, and the mixture was heated at 120° C. in a sealed tube overnight. After cooled to room temperature, the reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The separated organic phase was washed with brine, and dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (hexane:ethyl acetate, 70:30) to give 2-amino-6-({2-[(4-methoxybenzyl)oxy]phenyl}nicotinonitrile (0.050 g, yield; 4.3%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:2]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][C:13]([O:15][CH2:21][CH3:22])=[O:14])[CH:2]=1
Reactant: O=C(O)CCc1cnc2ccccc2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1cnc2ccccc2c1

Procedure:
A solution 3-(3-quinolinyl)propanoic acid (4.4 g) and concentrated sulphuric acid (2 ml) in absolute ethanol (50 ml) was refluxed for 5 h. then, evaporated to dryness. Aqueous sodium bicarbonate (8%, 50 ml) was added, the mixture extracted with ether (2×100 ml) and the ethereal extracts dried (Na2SO4). Evaporation of the ether and distillation of the residual oil (150°/0.06 mm) gave the title compound (4.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[CH:16][C:12]=2[C:13](O)=[O:14])[CH3:9])=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:34]1(OC(N(C)C)=[N+](C)C)[C:38]2C=CC=CC=2N=N1.C(N(CC)CC)C.CN.O1CCCC1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[CH:16][C:12]=2[C:13]([NH:34][CH3:38])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@H](Nc1nc(Nc2cnccn2)ccc1C(=O)O)c1ccc(F)cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Nc2cnccn2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
80 mg of (S)-2-[1-(4-Fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)nicotinic acid was dissolved in 1 ml of tetrahydrofuran, 86 mg of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate salt (HBTU) and 59 mg of triethylamine were added thereto. The mixture was stirred at room temperature for 30 minutes, and then 119 μl of 2M methylamine/tetrahydrofuran solution was added thereto, and the mixture was stirred for 5 hours. The reaction solution was purified by silica gel column chromatography to obtain 45 mg of the objective compound as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][C:36]1[CH:41]=[CH:40][C:39](CO)=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][C:39]2[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CO)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccc(C)cc4)cc3)c2cc1OC
Yield: 88.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (151 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (4-methylphenyl)methanol (62 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (133 mg, yield 81%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:13]([O:15]C)=[O:14])[CH:12]=1)[N:9](C(OC(C)(C)C)=O)[CH:8]=[C:7]2[CH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1.BrC1C=C2C(=C(C(OCC)=O)C=1)N(C(OC(C)(C)C)=O)C=C2C1CCS(=O)(=O)CC1>CO.O>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:13]([OH:15])=[O:14])[CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:24]1[CH2:25][CH2:26][S:27](=[O:30])(=[O:31])[CH2:28][CH2:29]1
Reactant: COC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)cn(C(=O)OC(C)(C)C)c12
Agent: CCOC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)cn(C(=O)OC(C)(C)C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 85 °C

Procedure:
A solution of 6 M NaOH (12 mL, 72.0 mmol) was added to a suspension of 1-(1,1-dimethylethyl) 7-methyl 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-1,7-dicarboxylate (0.93 g, 1.912 mmol) and 1-(1,1-dimethylethyl) 7-ethyl 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-1,7-dicarboxylate (3.08 g, 6.16 mmol) in MeOH (50 mL) and water (25 mL) in a 250 mL round bottomed flask fitted with a reflux condenser. The reaction was heated at 85° C. (bath temp) for 1.5 h. The MeOH was removed by rotovap, and a solution of 6 M HCl was added until the mixture had attained a pH of ˜1 by pH paper. The yellow solid was filtered off, and the filtrate was extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure, and the residue was combined with the precipitate from the filtration and dried under house vacuum at 45° C. overnight. Recovered 2.98 g (86%) of the title compound.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:6]1)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[NH:5]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:6]1
Reactant: CCCCOC(=O)/C=C/c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOC(=O)/C=C/c1cc[nH]c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a solution of (E)-butyl 3-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]acrylate (10.0 g, 28.7 mmol) in 200 mL of THF was added tetra-n-butylammonium fluoride trihydrate (7.5 g, 23.8 mmol, 0.83 equiv.) at room temperature under N2. The solution was stirred for 30 min at room temperature, diluted with EtOAc (500 mL), and washed with water (2×100 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column, which was eluted with EtOAc/petroleum ether 1:5 to afford (E)-butyl 3-(1H-pyrrol-3-yl)acrylate (4.0 g, 72%) as a light yellow solid. LC-MS (ESI) m/z 194 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:15][CH2:16][CH:17]1[CH2:24][CH:23]([C:25]2[S:26][CH:27]=[C:28]([Cl:30])[N:29]=2)[C:22]2[N:18]1[C:19]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1)=[C:20]1[C:34](=[O:35])[N:33]([CH3:36])[C:32](=[O:37])[N:31]([CH3:38])[C:21]1=2)(C(C)(C)C)(C)C>CO.O>[Cl:30][C:28]1[N:29]=[C:25]([CH:23]2[C:22]3[N:18]([C:19]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=4)=[C:20]4[C:34](=[O:35])[N:33]([CH3:36])[C:32](=[O:37])[N:31]([CH3:38])[C:21]4=3)[CH:17]([CH2:16][OH:15])[CH2:24]2)[S:26][CH:27]=1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)CC3CO[Si](C)(C)C(C)(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)CC3CO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Trifluoroacetic acid (2 mL, 26.0 mmol) was added to a solution of 7-(((tert-butyldimethylsilyl)oxy)methyl)-9-(4-chlorothiazol-2-yl)-5-(3-fluorophenyl)-1,3-dimethyl-8,9-dihydro-1H-pyrimido[4,5-a]pyrrolizine-2,4(3H,7H)-dione (570 mg, 0.991 mmol) in methanol (20 mL) and water (3 mL). The mixture stirred at room temperature 20 mins. Further portions of water (1 mL) and trifluoroacetic acid (1 mL) were added and the mixture stirred for a further 3 hours. The reaction was quenched with saturated NaHCO3(aq) and extracted with chloroform (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane afforded the title compounds as a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21]O)[C:9]2=[O:23])[CH:7]=1.P(Cl)(Cl)[Cl:28]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][Cl:28])[C:9]2=[O:23])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CO)c2cc(C(F)(F)F)ccc21
Reactant: ClP(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of (S)-3-(5-chloro-2-methoxyphenyl)-1-(hydroxymethyl)-3-fluoro-6-(trifluoromethyl)indolin-2-one ((S)-VI) (64.5 g, 0.166 mol) in CH2Cl2 (700 mL) was added PCl3 (2.0 M in CH2Cl2, 255.0 mL, 0.510 mol) dropwise at 0° C. under N2 over a period of 50 min. The resultant mixture was warmed to rt. and the stirring continued overnight (16 h). The mixture was quenched with ice at 0° C. and the resultant mixture was stirred vigorously for 30 min. The organic layer was separated and the aqueous layer was washed with CH2Cl2. The combined organic layer was washed with brine and dried over Na2SO4. Chromatography (silica gel, EtOAc/Hexanes) provided the title compound as a white dry foam (42.0 g, 62% yield). LC/MS m/e: (no molecular ion), 97% purity. 1H NMR (CDCl3): δ 3.55 (s, 3H), 5.39 (d, J=10.5 Hz, 1H), 5.95 (d, J=11.0 Hz, 1H), 6.76 (dd, J=1.5, 9.0 Hz, 1H), 7.28 (m, 2H), 7.35 (dd, J=1.5, 9.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.78 (dd, J=1.0, 2.5 Hz, 1H).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Yield: 81.9 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 2.4 g.), conc.hydrochloric acid (1.84 g.), methanol (36 ml.) and tetrahydrofuran (30 ml.) was stirred at 30° C. for 2 hours. The resultant solution was concentrated in vacuo. Water (60 ml.) was added to the residue and the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.86 g.).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@H:10]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[O:4].CC(C)([O-])C.[Na+].O>O1CCCC1.C(O)(C)(C)C>[C:23]([O:22][C:20]([N:7]1[CH2:8][CH2:9][C@@H:10]([NH:11][C@@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O)c1ccccc1
Reaction time: 16 h
Yield: 48.8 %

Procedure:
In a dry flask (3R,4R)-4-[(R)-1-Phenyl-ethylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (4.50 g, 12.4 mmol) was dissolved in tetrahydrofuran (170 mL) and t-butanol (11 mL), and sodium t-butoxide (04.85 g, 50.5 mmol) was added. The reaction mixture was stirred for 16 hours. Water was added and the mixture was extracted with ethyl acetate five times. There was minimal residue after concentration in vacuo of the combined organic extracts. The aqueous extract was acidified to pH 3 with 1N hydrochloric acid, saturated with sodium chloride and then extracted five times with ethyl acetate. The combined organic layers were dried with magnesium sulfate, filtered and concentrated in vacuo to give an orange glass (2.11 g, 49%). MS (ESI), m+/z: (M+H)+=349.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=[N+:8]=[N-:9].[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22](=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CS(C)=O>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:7]1[C:22]([CH:18]2[CH2:19][CH2:20][CH2:21][O:17]2)=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:9]=[N:8]1
Reactant: CCOC(=O)CC(=O)C1CCCO1
Reactant: [N-]=[N+]=Nc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1nnn(-c2ccccc2F)c1C1CCCO1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (2.419 g; 17.50 mmol; 2 eq.) was dissolved in DMSO (18 ml) and put under nitrogen atmosphere. 1-Azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (1.2 g; 8.75 mmol; 1 eq.) was dissolved in 10 mL of DMSO and ethyl 3-(tetrahydrofuran-2-yl)-3-oxopropanoate (Pharmacore, 1.793 mg; 9.63 mmol; 1.10 eq.) was added. This solution was added dropwise to the potassium carbonate solution at room temperature. The mixture was stirred at 70° C. for 3 hours. Water (30 mL) was added to the mixture and it was extracted with EtOAc (2×40 mL). Organics were washed with brine, dried over MgSO4 and concentrated under vacuum affording the title compound as a brown oil. It was used in the next step without further purification. HPLC (Method A) Rt 4.14 min (Purity: 86.6%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[Cl:14][C:15]1[C:20](Cl)=[N:19][CH:18]=[CH:17][N:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])[C:20]1[C:15]([Cl:14])=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: CNc1ccccc1[N+](=O)[O-]
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccccc1[N+](=O)[O-])c1nccnc1Cl
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of 1.52 g of N-methyl-2-nitroaniline in N,N-dimethylformamide (50 ml) was added in a nitrogen atmosphere 0.44 g of sodium hydride. After stirring for 30 minutes, 1.75 g of 2,3-dichloropyrazine was added thereto and the resulting mixture was stirred at room temperature for additional 6 hours. Then the reaction mixture was distributed into ethyl acetate and a saturated aqueous solution of sodium dihydrogenphosphate and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.586 g of the title compound as an oily substance.