Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19](=[O:31])[N:20]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:21]=[CH:22][CH:23]=2)=[O:17])=[CH:11][C:10]=1[F:32].C(OC([N:40]1[CH2:44][CH2:43][CH:42]([CH:45]=O)[CH2:41]1)=O)(C)(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:65]>ClCCCl.O1CCOCC1.CO.CCOC(C)=O>[ClH:65].[F:32][C:10]1[CH:11]=[C:12]([NH:15][C:16]([C:18]2[C:19](=[O:31])[N:20]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)=[O:17])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][CH2:45][CH:42]1[CH2:43][CH2:44][NH:40][CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Reactant: Nc1cnccc1Oc1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccncc2NCC2CCNC2)c(F)c1)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
To N-(4-(3-aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Example 120, 30 mg, 0.07 mmol) in DCE (1 mL) was added 3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (CB Research and Development Inc., 28 mg, 0.14 mmol), acetic acid (5 uL, 0.084 mmol), then sodium triacetoxyborohydride (23 mg, 0.104 mmol). After stirring at rt for 6 h, a second portion (23 mg) of sodium triacetoxyborohydride was added. After stirring at rt for 2 h, the reaction mixture was charged with 4N HCl in dioxane (5 mL) and stirred an additional 1 h at rt. The reaction was diluted with 10% MeOH/EtOAc (10 mL) and washed with saturated sodium bicarbonate solution (10 mL). The aqueous phase was back-extracted with 10 mL of 10% MeOH/EtOAc and the combined organic layers were dried over anhydrous Na2SO4 and then concentrated in vacuo. The resulting crude product was purified by prep HPLC. The appropriate fractions were concentrated to remove methanol and then made basic with saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with 10% MeOH/EtOAc (3×20 mL) and the pooled organic extracts were dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was lyophilized from acetonitrile (1 mL)/water (3 mL)/1N aq HCl (0.2 mL) to give the HCl salt of the title compound (25 mg, 60%) as a white solid. 1H NMR (DMSO-d6) δ 12.17 (s, 1H), 8.59 (dd, 1H, J=7.6, 2 Hz), 8.30 (s, 1H), 8.16 (dd, 1H, J=6.4, 2 Hz), 8.10 (dd, 1H, J=12.8, 2 Hz), 8.00 (d, 1H, J=6.4 Hz), 7.64-7.58 (m, 3H), 7.52 (t, 1H, J=9.2 Hz), 7.46-7.42 (m, 2H), 7.00 (d, 1H, J=6 Hz), 6.75 (t, 1H, J=7.2 Hz), 3.72-3.64 (m, 3H), 3.37-3.26 (m, 1H), 3.17-3.10 (m, 1H), 2.97-2.92 (m, 1H), 2.74-2.66 (m, 1H), 2.10-2.03 (m, 1H), 1.75-1.68 (m, 1H); MS (ESI+) m/z 518.29 (M+H)+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O1CCOCC1.CCOC(C)=O.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>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:6]1[O:7][CH:8]=[CH:9][N:10]=1
Reactant: Brc1ccccn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1ccc(-c2ncco2)nc1
Yield: 67 %

Procedure:
2-(Tributylstannyl)oxazole (1.00 g, 2.79 mmol), (Ph3P)4Pd (0.1 equiv), and 2-bromopyridine (2 equiv) were dissolved in anhydrous 1,4-dioxane (15 mL) and the mixture was warmed at reflux for 24 h under Ar. The mixture was diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude product that was purified by flash chromatography (SiO2, 10-60% EtOAc-hexanes) to yield the title compound (275 mg, 67%) as a light yellow oil: 1H NMR (CDCl3, 500 MHz) δ 8.63 (m, 1H), 8.04 (d, 1H, J=7.5 Hz), 7.73-7.70 (m, 2H), 7.26-7.22 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 161.0, 150.2, 146.4, 140.1, 137.3, 129.1, 125.0, 122.3.
Reaction SMILES: O1CCCC1.B.[Cl:7][C:8]1[CH:9]=[C:10]([C:18](O)=[O:19])[C:11](=[CH:15][C:16]=1[Cl:17])[C:12](O)=[O:13]>O1CCCC1>[Cl:7][C:8]1[C:16]([Cl:17])=[CH:15][C:11]([CH2:12][OH:13])=[C:10]([CH2:18][OH:19])[CH:9]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(Cl)cc1CO
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 100.9 %

Procedure:
To a stirred solution of borane tetrahydrofuran complex (45 mL of 1.5 M solution in tetrahydrofuran/diethyl ether) cooled to 0° C. under nitrogen was added a solution of 4,5-dichlorophthalic acid (5.013 g; 21.1 mmol) in tetrahydrofuran (35 mL) dropwise over a 20 minute period. At the end of the addition, the mixture was allowed to stir for 2.5 h at 0° C. The mixture was quenched by slow addition of methanol until gas evolution ceased. The mixture was allowed to stir at room temperature for 30 minutes and the solvent removed in vacuo. The residue was taken up into ethyl acetate, washed with saturated sodium bicarbonate solution followed by brine solution. The organic extract was dried (sodium sulfate), filtered and concentrated in vacuo to give 4.41 g (100%) of 4,5-dichloro-1,2-di-hydroxymethyl benzene as a white solid: ES-LRMS calcd for C8H7C12O2 (M+−1) 205, found 205.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)[OH:6].[Br:13]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][C:8]([CH2:11][Br:13])=[CH:9][CH:10]=1)[OH:6]
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1O
Reaction time: 0.5 h

Procedure:
A refluxing solution of 4-methylsalicylic acid methyl ester (5.1 g, 31.3 mmol) in carbon tetrachloride (50 mL) was treated dropwise with a solution of bromine (1.6 mL, 31.3 mmol) in carbon tetrachloride (5 mL) while under illumination by a 200 W incandescent light bulb. The reaction mixture was stirred for an additional 30 min at reflux and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with aqueous sodium thiosulfate (5%, 50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over Na2SO4, concentrated, and the product 4-bromomethylsalicylic acid methyl ester was isolated by recrystallization from heptane (1.6 g, 21%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[C:21]([O:25][C:26](=[O:47])[NH:27][CH:28](S(C1C=CC=CC=1)(=O)=O)[C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=1[Br:37])([CH3:24])([CH3:23])[CH3:22]>CC1CCCO1>[C:21]([O:25][C:26](=[O:47])[NH:27][CH:28]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][C:30]=1[Br:37])[C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH2:15][C:10]=1[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Reactant: CC(C)(C)OC(=O)NC(c1ccc(C#N)cc1Br)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)NC(C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)c1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-(3-Trifluoromethyl-phenylamino)-cyclohex-2-enone (INTERMEDIATE 3, 10.7 g, 42 mmol) is suspended in 2-methyl-tetrahydrofurane (150 mL) and sodium hydride (60% in mineral oil) (1.76 g, 43.9 mmol) is added in portions. The mixture is stirred at room temperature for 20 min and [benzenesulfonyl-(2-bromo-4-cyano-phenyl)-methyl]-carbamic acid tert-butyl ester (INTERMEDIATE 19, 16.5 g, 36.6 mmol) is added. The mixture is stirred for 1 h at room temperature. The organic phase is washed with water, dried over MgSO4 and concentrated. The product is precipitated from cyclohexane. Yield: 20.6 g. ESI mass spectrum: [M+H]+=564 (bromine isotope pattern); Retention time HPLC: 0.81 min (X012_S02).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=O.S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH3:15][C:2]1([CH3:1])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4](=[O:6])[CH2:3]1
Reactant: CC(C)(CCc1ccccc1)CC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)CCc2ccccc2C(=O)C1
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
82 g of 3,3-dimethyl-5-phenylvaleric acid are treated with 57 ml of thionyl chloride and heated to reflux for half an hour. Thereafter, the excess reagent is evaporated, finally under a high vacuum for 1.5 hours. The acid chloride prepared, dissolved in 300 ml of methylene chloride, is added within 3.5 hours under an argon atmosphere to 79 g of aluminum trichloride in 650 ml of methylene chloride. Thereafter, the reaction mixture is stirred for an additional 10 minutes and poured on to ice. The organic phase is washed with water dried and evaporated. After chromatography on silica gel with petroleum ether (low-boiling)/ethyl acetate (98:2), there are obtained 62 g of 6,7,8,9-tetrahydro-7,7-dimethyl-5H-benzocycloheptene-5-one.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6]=1[C:15]([C:17]1[S:21][N:20]=[N:19][C:18]=1[CH3:22])=[O:16].Cl>C(O)(=O)C>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:15]([C:17]1[S:21][N:20]=[N:19][C:18]=1[CH3:22])=[O:16])=[C:5]2[CH2:4][C:3]([OH:23])=[O:2]
Reactant: COC(=O)Cc1c(C(=O)c2snnc2C)[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nnsc1C(=O)c1[nH]c2ccc(Cl)cc2c1CC(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of methyl[5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate (Example 228, 190 mg, 0.54 mmol), 2N aqueous HCl (4 ml), and acetic acid (20 ml) was heated at reflux temperature for 2 h. After cooling to room temperature, the mixture was concentrated. The crystalline residue was diluted with THF (100 ml) and dried (MgSO4) and concentrated. The residual solids were washed with ethyl acetate gave 145 mg (79%) of the title compound as yellow solids.
Reaction SMILES: [SH:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:16][S:17]S(C)(=O)=O>O.C(O)C>[CH3:8][C:2]([S:1][S:17][CH3:16])([CH3:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CSS(C)(=O)=O
Reactant: CC(C)(S)CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSSC(C)(C)CCC(=O)O
Reaction time: 3 h
Yield: 69.5 %

Procedure:
A solution of mercaptopentanoic acid 7 (6.0 mL, 40 mmol) was dissolved in 50 mL of deionized water in a 250 mL flask. The solution was magnetically stirred as sodium carbonate (6.4 g, 60 mmol) was added to the acid at a rate that would not cause excessive frothing. The flask was equipped with a 100 mL addition funnel, which was charged with a solution of methyl methanethiolsulfonate (7.5 g, 60 mmol) dissolved in 30 mL of glass-distilled 100% ethanol. The flask was cooled in an ice/water bath and the system was maintained under an argon atmosphere. The methyl methanethiolsulfonate solution was added drop-wise to the flask as rapidly as possible but without causing excessive frothing. The cooling bath was removed and the reaction mixture was allowed to stir for an additional 3 hours. Solvent was removed by rotary evaporation under vacuum, until approximately 20 mL remained. After which 10 mL of saturated sodium bicarbonate and 30 mL of deionized water were added. The mixture was washed three times with 25 mL portions of ethyl acetate in a separatory funnel. The aqueous layer was adjusted to approximately pH 2 with 5 M HCl and was extracted twice with 120 mL portions of ethyl acetate. The organic layers were combined and washed with 20 mL of a solution composed of saturated NaCl and 1M HCl at a ratio of 4:1. The organic layer was then dried over 14 g of anhydrous sodium sulfate and solvent was removed by rotary evaporation under vacuum to give 5.4 g of product 8 (70% yield). The material can be taken to the next step without further purification. 1H NMR (CDCl3): δ1.54 (6H, s), 2.15-2.21 (2H, m), 2.64 (3H, s), 2.69-2.72 (2H, m). MS (M+Na+) calc.: 217.0, found: 217.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].O([C:17]1[C:18]2[C:23]([N:24]=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)C1C=CC=CC=1.CCOCC>C1(O)C=CC=CC=1>[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:17]1[C:18]2[C:23]([N:24]=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:9])=[O:8]
Reactant: c1ccc(Oc2c3ccccc3nc3ccccc23)cc1
Reactant: NCCCCCC(=O)O
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: O=C(O)CCCCCNc1c2ccccc2nc2ccccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
6-Aminohexanoic acid (1.47 g, 11.2 mmol) was added to a solution of 9-phenoxyacridine (2.7 g, 10 mmol) in phenol (15 g). The suspension was stirred at 120° C. for 2 h. The solution was cooled to room temperature and poured into ether whereby the product precipitated as a yellow-green solid. It was triturated with hot ethanol, filtered then washed with ethanol, giving crude 9-(5-carboxypentyl) aminoacridine.Yield 2.4 g (78%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=O)[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[K+].C(OC1N=C(NC=O)SC=1Cl)(=O)C=O.[K].Cl.[NH2:35][O:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>O1CCCC1.N1C=CC=CC=1>[C:41]([O:40][C:38]([CH2:37][O:36][N:35]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][C:6]=1[Cl:16])[C:10]([OH:12])=[O:11])=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Reactant: CC(C)(C)OC(=O)CON
Agent: Cl
Agent: O=CNc1nc(OC(=O)C=O)c(Cl)s1
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nc(NC=O)sc1Cl
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
Ethyl (2-formamido-5-chlorothiazol-4-yl)glyoxylate (14.5 g) was added to a solution of 1N aqueous potassium hydroxide (110 ml) at ambient temperature, and the mixture was stirred for 10 minutes to prepare the solution of potassium (2-formamido-5-chlorothiazol-4-yl) glyoxylate. After this solution was adjusted to pH 2 with 10% hydrochloric acid under ice-cooling, thereto were added pyridine (20 ml) and a solution of tert-butyl 2-aminooxyacetate (10.3 g) in tetrahydrofuran (50 ml), followed by stirring at ambient temperature for 5 hours. After the reaction mixture was washed with ethyl acetate, the remaining aqueous solution was adjusted to pH 1.5 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave 2-tert-butoxycarbonylmethoxyimino-2-(2-formamido-5-chlorothiazol-4yl)acetic acid (syn isomer) (8.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N:8]=1)[OH:6].ClC1C=CC=C(C(OO)=[O:28])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH:5]([C:7]1[C:12]([O:13][CH2:14][O:15][CH3:16])=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:28])[OH:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCOc1cccnc1C(O)c1cccc(Br)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc[n+]([O-])c1C(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A mixture of 2-(3-bromo-α-hydroxybenzyl)-3-methoxymethoxy pyridine (4.65 g), 70% m-chloro-perbenzoic acid (7.10 g) and tetrahydrofuran (200 mL) was stirred overnight at room temperature, to which was poured an aqueous solution of sodium sulfite. The mixture was stirred for 30 minutes, and then subjected to extraction with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromo-α-hydroxybenzyl)-3-methoxymethoxypyridine 1-oxide (4.58 g). Spectrum data of the product are shown below:
Reaction SMILES: [CH3:1][C@:2]1([NH:7]C(=O)OC(C)(C)C)[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[C:22]([C:24]1[C:29]2[N:30]=[C:31]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[O:32][C:28]=2[C:27](F)=[C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:25]=1[CH3:45])#[N:23]>CS(C)=O>[NH2:7][C@@:2]1([CH3:1])[CH2:6][CH2:5][N:4]([C:27]2[C:28]3[O:32][C:31]([C:33]([N:35]([CH3:36])[CH3:37])=[O:34])=[N:30][C:29]=3[C:24]([C:22]#[N:23])=[C:25]([CH3:45])[C:26]=2[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:3]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@](C)(N)C2)c2oc(C(=O)N(C)C)nc2c1C#N
Temperature: 150 °C
Yield: 41.6 %

Procedure:
A dimethyl sulfoxide (1 ml) solution of tert-butyl [(3S)-3-methylpyrrolidin-3-yl]carbamate (I-345) (300 mg, 1.50 mmol) and triethylamine (244 μl, 1.75 mmol) was added to a dimethyl sulfoxide (6 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (404 mg, 1.25 mmol) stirred in an oil bath at 150° C., followed by stirring in an oil bath at 150° C. for 30 minutes. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with aqueous 10% citric acid solution, water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1→1:2, v/v). The obtained yellow foamy substance was dissolved in dichloromethane (5 ml), and with cooling with ice, trifluoroacetic acid (10 ml) was added, followed by stirring at room temperature for 5 hours. The reaction liquid was concentrated under reduced pressure, then an aqueous saturated sodium hydrogencarbonate solution and water were added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v), and the obtained eluate was purified in slurry with isopropyl ether to obtain the entitled compound (210 mg, 41%) as a pale yellow solid.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])[C:25](=[N:32][OH:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19])(=[O:9])[CH3:8].[C:36](Cl)(=[O:38])[CH3:37].O>C(OCC)(=O)C>[C:36]([O:33][N:32]=[C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:24]([NH:23][C@@H:22]1[C:21](=[O:35])[N:16]2[C:17]([C:18]([OH:20])=[O:19])=[C:12]([CH2:11][O:10][C:7](=[O:9])[CH3:8])[CH2:13][S:14][C@H:15]12)=[O:34])(=[O:38])[CH3:37]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC(C)=O)c3ccccc3)[C@H]2SC1

Procedure:
To a solution of pyridine (1.5 ml.) in ethyl acetate (20 ml.) was added 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylic acid (syn-isomer) (0.5 g.) and the stirred mixture was treated dropwise with a solution of acetyl chloride (1.0 ml.) in ethyl acetate (5 ml.) and stirring continued for ten minutes. The mixture was poured into water, the ethyl acetate phase separated and washed with 2 N-hydrochloric acid, water, and extracted with saturated aqueous sodium bicarbonate. The combined aqueous extracts were acidified and extracted with ethyl acetate and the extracts were dried and concentrated to ca. 5 ml. The concentrate was added dropwise with stirring to petroleum (250 ml.). The precipitated solid was collected and dried, giving the title acid (0.32 g; 58%), [α]D +83° (c C.8, DMSO), λmax. (pH 6 buffer) 258 nm (ε 20,800), νmax. (Nujol) 3270 (NH), 1780 (β-lactam), 1680 and 1546 cm.-1 (CONH), τ (DMSO-d6) values include -0.10 (doublet J 8 Hz; NH), 2.2 to 2.6 (multiplet; aromatic protons), 7.78 (singlet; --N.O.COCH3), 7.94 (singlet; OCOCH3).
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].O.[CH:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O.[OH-].[K+]>C(O)C>[O:4]=[C:3]1[CH2:5][CH2:7][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:10]2)[CH:2]=[CH:1]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2

Procedure:
Methyl vinyl ketone (1.64 ml), ethanol (5 ml) and water (5 ml) were added to benzyl 4-formylpiperidine-1-carboxylate (5 g). The mixture was then added to a boiling solution of potassium hydroxide (0.22 g) in ethanol (10 ml), and the resulting reaction mixture was refluxed for 1 h (TLC monitoring). When the reaction was complete, the mixture was added to water (25 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (Na2SO4) and concentrated under vacuum. The crude product so obtained was purified by column chromatography (silical gel, 25% ethyl acetate/hexane). Yield: 2.8 g (46%)
Reaction SMILES: N1C(=O)CC(=O)NC1=O.F[C:11]1[C:28]([F:29])=[C:27]2[C:14]([CH2:15][C:16]3([C@H:25]4[C@H:33]([CH3:34])[O:32][C@H:31]([CH3:35])[CH2:30][N:26]42)[C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18][C:17]3=[O:24])=[CH:13][C:12]=1[C:36](=[N:43][OH:44])[C:37]1[CH:42]=[N:41][CH:40]=[CH:39][N:38]=1>>[F:29][C:28]1[C:11]2[O:44][N:43]=[C:36]([C:37]3[CH:42]=[N:41][CH:40]=[CH:39][N:38]=3)[C:12]=2[CH:13]=[C:14]2[C:27]=1[N:26]1[CH2:30][C@@H:31]([CH3:35])[O:32][C@@H:33]([CH3:34])[C@@H:25]1[C:16]1([C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18][C:17]1=[O:24])[CH2:15]2
Reactant: C[C@@H]1CN2c3c(cc(C(=NO)c4cnccn4)c(F)c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: O=C1CC(=O)NC(=O)N1
Product: C[C@@H]1CN2c3c(cc4c(-c5cnccn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Barbituric acid and (2R,4S,4aS)-rel-9,10-difluoro-8-[(hydroxyimino)(pyrazin-2-yl)methyl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Intermediate 583) were reacted using a method similar to the one described for the synthesis of Example 8.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)[CH:8]=[N:7]1)C.[OH-].[Li+].Cl>CO.O>[N:27]1[C:28]2[C:23](=[CH:22][C:21]([CH2:20][N:17]3[C:15]4=[N:16][C:11]([C:9]5[CH:8]=[N:7][N:6]([CH2:5][C:4]([OH:31])=[O:3])[CH:10]=5)=[CH:12][CH:13]=[C:14]4[N:19]=[N:18]3)=[CH:30][CH:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)Cn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.5 %

Procedure:
To a solution of Example 154 (0.085 g, 0.218 mmol) in methanol (1.4 ml), lithium hydroxide (0.026 g, 1.09 mmol) in water (0.36 ml) was added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under to afford the title compound as a yellow solid (0.034 g, 38%). M.P.: >270° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.87 (d, J=2.7 Hz, 1H), 8.47 (d, J=8.7 Hz, 1H), 8.39 (m, 2H), 8.08 (s, 1H), 8.00 (s. 1H), 7.99 (d, J=7.1 Hz, 1H), 7.82 (t, J=8.9 Hz, 2H), 7.52 (q, J=4.1 Hz, 1H), 6.10 (s, 2H), 4.48 (s, 2H), MS (m/z): 385.87 (M+).