Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.[ClH:14].[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>CC(=O)CC.CC(C)=O.C(O)(C)C>[ClH:14].[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:4]([CH2:3][CH2:2][N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:19][CH2:20]2)[CH2:5][CH2:6]1
Reactant: BrCCC1CCOc2ccccc21
Reactant: O=C(NC1CCNCC1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)O
Solvent: CCC(C)=O
Solvent: CC(C)=O
Product: O=C(NC1CCN(CCC2CCOc3ccccc32)CC1)c1ccc(F)cc1
Yield: 63.3 %

Procedure:
The procedure is as in Example 4, but starting with 4-(2-bromoethyl)-3,4-dihydro-2H-benzopyran (1.9 g), N-(4-piperidyl)-4-fluorobenzamide hydrochloride (2 g), dry potassium carbonate (2.15 g) and potassium iodide (0.95 g) in 2-butanone (60 cc). The yellow oil obtained is purified by chromatography on a column 4 cm in diameter containing a silica gel (110 g), eluting with a toluene/diethylamine/ethanol mixture (60:20:20 by volume) (300 cc) and collecting 30-cc fractions. The fractions between 330 and 900 cc are concentrated to dryness. The yellow crystals obtained are dissolved in acetone (25 cc) and treated with a 3.4N solution (3 cc) of hydrochloric acid in isopropanol. The precipitate formed is filtered off on sintered glass and then recrystallized in an ethanol/acetone mixture (20:60 by volume) (80 cc). After the addition of ethyl ether (10 cc), N-{1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-piperidyl}-4-fluorobenzamide hydrochloride (2.05 g) is obtained in the form of a crystalline white solid, m.p. 240° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[O:15]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16]1.C(=O)(O)[O-].[Na+]>O.C(COC)OC.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>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:17]2[CH:18]=[CH:19][O:15][CH:16]=2)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2]
Reactant: OB(O)c1ccoc1
Reactant: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)Nc1ccc(-c2ccoc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 63 %

Procedure:
A mixture of 1d from Example 18 (8.5 g, 32.8 mmol), 3-furanylboronic acid (3.67 g, 32.8 mmol), sodium bicarbonate (13.8 g, 0.16 mol) and tetrakis(triphenylphosphine)palladium(0) (0.5 g) in a mixture of water (40 ml) and dimethoxyethane (80 ml) is heated to 80° C. under a stream of nitrogen over night. After cooling the mixture is poured into water and extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated under reduced pressure.(*). The residue is dissolved in 40 ml dimethoxyethane. Aqueous sodium hydroxide (78 ml, 1 M) is added and the mixture is stirred at ambient temperature over night. The mixture is poured into water and rendered acidic with diluted hydrochloric acid. The precipitate is filtered off, washed with water and dried to yield 1e (5.09 g, 76%). Mp 152-154° C.
Reaction SMILES: Br[C:2]1[C:3]2[CH:4]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][CH:5]3[N:6](C(OC(C)(C)C)=O)[C:7]=2[CH:8]=[CH:9][CH:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[S:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[CH:40]=[C:39]1B(O)O.N#N>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.CN(C=O)C>[S:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[CH:40]=[C:39]1[C:2]1[C:3]2[C@@H:4]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][C@@H:5]3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3c(Br)cccc3N(C(=O)OC(C)(C)C)C2CC1
Reactant: OB(O)c1cc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: c1cc2c(c(-c3cc4ccccc4s3)c1)[C@@H]1CCNCC[C@@H]1N2
Temperature: 80 °C
Yield: 58.3 %

Procedure:
A 30-mL shaker vial was charged with di(tert-butyl) 10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate (0.10 g, 0.214 mmol), potassium phosphate (0.068 g, 0.32 mmol), benzothiophene-2-boronic acid (0.114 g, 0.642 mmol), and DMF (2 mL). The vial was purged with N2, and tetrakis(triphenylphosphine)palladium (0.025 g, 0.02 mmol) was added and the mixture was agitated at 250 RPM with heating at 80° C. overnight. The mixture was filtered through Celite, washing with MeOH (3-5 mL), and sulfonic acid resin (DOWEX®50W-X2, washed and dried, 4.8 meq/g dry weight) was added (1 g). The vial was then purged with N2, capped and agitated at 250 RPM with heating at 65° C. for 72 h. The mixture was filtered through a sintered funnel and the resin was washed 1:1 methylene chloride/methanol and then consecutively washed with MeOH and THF to ensure that all excess reagent was removed from the resin (the methanol and THF washes are alternated to swell and then shrink the resin to help expel reagents from inside the resin). The resin was then washed with 4M ammonium hydroxide in methanol (4×2 ml) and THF (2×2 ml) into an accurately weight round-bottomed flask. The filtrate was concentrated to give 0.040 g (68%) of an amber oil: MS (EI) m/z 321 (MH+); HPLC rt=3.68 min (100%).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:14][CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCC2CCC3(CC2)OCCO3)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 8.86 g) in tetrahydrofuran (170 mL) was added a solution of EXAMPLE 341B (30.52 g) in tetrahydrofuran (100 mL). This mixture was stirred for 30 minutes and benzyl bromide (24 mL) was added. After stirring for 72 hours, the reaction was quenched with saturated ammonium chloride solution (400 mL) and diluted with ether (500 mL). The layers were separated and the aqueous layer was extracted with ether (2×150 mL). The combined organics were dried over sodium sulfate, filtered and concentrated. The crude product was purified on silica gel eluting with a 0, 10, 15, 75% ethyl acetate in hexanes step gradient to provide the title compound.
Reaction SMILES: CO[C:3](=[N:12][N+:13]([O-:15])=[O:14])[NH:4][CH2:5][C:6]1[S:10][C:9]([Cl:11])=[N:8][CH:7]=1.[CH3:16][NH2:17].Cl>O>[Cl:11][C:9]1[S:10][C:6]([CH2:5][NH:4][C:3]([NH:17][CH3:16])=[N:12][N+:13]([O-:15])=[O:14])=[CH:7][N:8]=1
Reactant: CN
Reactant: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Agent: Cl
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a suspension of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea (87% purity, 47.2 g, 0.164 mol) in water (410 ml) was added 40% aqueous solution of methylamine (25.5 g, 0.328 mol, 2.0 equivalents) dropwise at 23° C. After 2 hours of stirring at room temperature, the mixture was allowed to stand under ice-cooling and then, 36% hydrochloric acid (14.3 mol, 0.168 mol) was added dropwise at 13-20° C. The resulting crystals were collected by filtration to provide 39.1 g (95.6% yield) of 1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]2[CH2:9][N:10](C(=O)C)[CH2:11][CH2:12][C:13]=2[N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:13]=2[N:14]=1
Reactant: CC(=O)N1CCc2nc(-c3cccs3)sc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1csc(-c2nc3c(s2)CNCC3)c1

Procedure:
1 mmol of 1-(2-Thiophen-2-yl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-ethanone was refluxed for 30 min. in 15 ml of 2 M aqueous hydrochloric acid. The reaction mixture was cooled and made alkaline by addition of sodium carbonate. Extraction with ethyl acetate yields the title compound as a brownish solid. MS (m/e): 223.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[N:10]=[C:9](Cl)[C:8]([Cl:12])=[C:7]([O:13][CH3:14])[N:6]=1.O.C(OCC)(=O)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[N:6]=[C:7]([O:13][CH3:14])[C:8]([Cl:12])=[C:9]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:10]=1
Reactant: COC(=O)Cc1nc(Cl)c(Cl)c(OC)n1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1nc(OC)c(Cl)c(N2CCOCC2)n1

Procedure:
A solution of 4.08 g of (4,5-dichloro-6-methoxypyrimidin-2-yl)acetic acid methyl ester in 35 ml of morpholine is stirred at ambient temperature for one and a half hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with 50 ml of water and 200 ml of ethyl acetate. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure so as to give 4.61 g of (5-chloro-4-methoxy-6-morpholin-4-ylpyrimidin-2-yl)acetic acid methyl ester in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: C(=O)(OCC(F)(F)F)OCC(F)(F)F.FC(F)(F)C[NH:18][C:19](=[O:38])[O:20][CH2:21][CH:22]1[CH:27]=[CH:26][CH2:25][CH:24]([CH2:28][O:29][C:30](=[O:37])[NH:31]CC(F)(F)F)[CH2:23]1>>[C:30](=[O:37])([O:29][CH2:28][CH:24]1[CH:25]=[CH:26][CH2:27][CH:22]([CH2:21][O:20][C:19](=[O:38])[NH2:18])[CH2:23]1)[NH2:31]
Reactant: O=C(NCC(F)(F)F)OCC1C=CCC(COC(=O)NCC(F)(F)F)C1
Agent: O=C(OCC(F)(F)F)OCC(F)(F)F
Product: NC(=O)OCC1C=CCC(COC(N)=O)C1
Yield: 93.2 %

Procedure:
The reaction was carried out in the same manner as Example 7 except for using 37.1 g (0.1642 mol) of bis(2,2,2-trifluoroethyl) carbonate (to be referred to as “BTrFC” hereinafter) synthesized in the above Synthesis Example 2 in place of BTFC, and it was confirmed that tetrahydro-m-xylylene bis(2,2,2-trifluoroethyl carbamate) (to be referred to as H-XDC-2 hereinafter) was generated as the main product (H-XDA base yield 93.2%). Structural assignment of the product H-XDC-2 was carried out by 19F-NMR and GC-Mass analyses as well as 1H-NMR. Analytical Results of mass fragments of H-XDC-2, 1H-NMR and 19F-NMR were shown in the following.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([OH:19])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C>[CH2:20]([O:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A combination of (2) (14 g, 0.050 mol), benzyl chloride (6.3 mL, 0.055 mol) and potassium carbonate (20.7 g, 0.15 mol) was heated to 100° C. for 3 h. After cooling to room temperature, water (200 mL) and ethyl acetate (400 mL) were added; the organic layer was separated and washed with water (5×200 mL), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to produce the crude product as a yellow oil. This was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([OH:7])=[O:6].[Si:10]([O:17][C@H:18]1[CH2:27][C@H:26](O)[C@H:25]2[C:20]([CH:21]=[CH:22][C@H:23]([CH3:46])[C@@H:24]2[CH2:29][CH2:30][C@H:31]2[O:36][C:35](=[O:37])[CH2:34][C@H:33]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:32]2)=[CH:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][C@H:18]1[CH2:27][C@H:26]([O:6][C:5](=[O:7])[C:4]([CH2:3][O:2][CH3:1])([CH3:9])[CH3:8])[C@H:25]2[C:20]([CH:21]=[CH:22][C@H:23]([CH3:46])[C@@H:24]2[CH2:29][CH2:30][C@H:31]2[O:36][C:35](=[O:37])[CH2:34][C@H:33]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[CH2:32]2)=[CH:19]1)([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: COCC(C)(C)C(=O)O
Product: COCC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 35 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 960 mg of 2-methoxymethyl-2-methylpropionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 423 mg of the title compound as a colorless foam.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18]>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: Cc1ccccc1
Product: CC(C)(C)NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of t-butyl isocyanate (400 mg, 4.04 mmol) in toluene, the 2-amino-5-nitrophenol (622 mg, 4.04 mmol) was added. The reaction mixture was stirred at 80° C. for 24 hours, then cooled to room temperature. The product was purified by precipitation from toluene and filtering (864 mg, 85%). m.p: 99.0-101.1° C.; EI-MS m/z 254 (M+H)+.
Reaction SMILES: N[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl.COC>[N:10]1([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:6]2[CH:5]=[CH:4][N+:3]([O-:26])=[CH:2][C:7]=2[CH:8]=[CH:9]1
Reactant: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: COC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)n1ccc2c[n+]([O-])ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A stirred suspension of benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (1 g, 3.9 mmol, Step a)) in a mixture of dichloromethane and dimethyl ether (10:1 mL) was treated portion wise with 3-chloroperoxybenzoic acid (0.85 g, 4.9 mmol) followed by stirring at room temperature for 4 hours. The reaction was neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to yield benzyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate 5-oxide (1 g, 99%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([C:26]([C:28]1[CH:38]=[C:37]([O:39][CH3:40])[C:31]2[O:32][C:33]([CH3:36])([CH3:35])[O:34][C:30]=2[CH:29]=1)=[O:27])[CH2:15][C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=O)(C)(C)C.ClCCl.[C:44]1(=O)[CH2:47]C[CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>FC(F)(F)C(O)=O.ClCCl.C(=O)(O)[O-].[Na+]>[CH:6]1([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][N:14]([CH2:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[C:26]([C:28]2[CH:38]=[C:37]([O:39][CH3:40])[C:31]3[O:32][C:33]([CH3:35])([CH3:36])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH2:47][CH2:44][CH2:45]1
Reactant: COc1cc(C(=O)N(Cc2cnc3ccccc3n2)C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc2c1OC(C)(C)O2
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N(Cc2cnc3ccccc3n2)C[C@@H]2CCCN2C2CCC2)cc2c1OC(C)(C)O2

Procedure:
73 mg of (S)-2-{[(7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl)-quinoxalin-2-ylmethyl-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester were dissolved in 3 mL 10% trifluoroacetic acid/dichloromethane and neutralized with aqueous sodium bicarbonate after 2 hours. The crude material was submitted to reductive amination reaction in dichloromethane using 53 mg (0.67 mmol) of cyclobutanone and 0.14 g (0.67 mmol) sodium triacetoxyborohydride. After overnight the reaction was quenched with aqueous sodium bicarbonate and purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 40 min. The residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate and evaporated in vacuum to yield 42 mg pale yellow solid as the free base. LC-MSD, m/z for C29H34N4O4 [M+H]+: 503.6. 1H NMR (400 MHz, CDCl31HCl): δ 1.7 (s, 6 H), 1.7-3.0 (m, 11 H), 3.6-4.2 (m, 8 H), 5.3-5.4 (m, 1 H), 5.8-5.9 (m, 1 H), 6.6 (s, 1 H), 6.8 (s, 1 H), 8.0 (bs, 2 H), 8.3 (bs, 1 H), 8.5-8.6 (m, 1 H), 9.1 (bs, 1 H), 12.0 (bs, 1 H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.C([Li])CCC.[O:15]1[C:19]2([CH2:23][CH2:22][CH:21]([C:24]3[C:29]([F:30])=[CH:28][C:27](C(N4C=CN=C4)=O)=[C:26]([F:38])[CH:25]=3)[CH2:20]2)[O:18][CH2:17][CH2:16]1.Cl>CCCCCC.O1CCCC1.N1C=CC=CC=1C1C=CC=CN=1.O>[F:38][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][C:19]3([O:15][CH2:16][CH2:17][O:18]3)[CH2:20]2)[C:29]([F:30])=[CH:28][C:27]=1[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(c1cc(F)c(C2CCC3(C2)OCCO3)cc1F)n1ccnc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)c1cc(F)c(C2CCC3(C2)OCCO3)cc1F
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
A solution of 16.4 g (0.2 mol) of monoethyl malonate, 0.1 g of 2,2'-bipyridyl and 175 ml of dry tetrahydrofuran was cooled to -35° under a dry nitrogen atmosphere and treated dropwise with 80 ml (0.2 mol) of a 2.5 M solution of n-butyl lithium in hexane. After the addition was complete, the reaction mixture was allowed to warm to -5° where it was treated dropwise with 80 ml (0.2 mol) of 2.5 M n-butyl lithium in hexane, titrating the final addition to a pale pink color which persisted for 5 minutes. The mixture was cooled to -78° and treated with a solution of 16.7 g (50 mmol) of 1-[[4-(1,4-dioxaspiro[4.4]non-7-yl)-2,5-difluorophenyl]carbonyl]-1H-imidazole in 100 ml of dry tetrahydrofuran. The suspension was stirred at -78° for 45 minutes, then allowed to warm to -35° and poured into a mixture of ice, water, and concentrated hydrochloric acid (17.0 ml-0.2 mole). The organic layer was separated, washed with water, 5% sodium bicarbonate, dilute hydrochloric acid, and water. After drying over magnesium sulfate, the solvent was removed in vacuo to give 13.8 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(Cl)c2)c(OC)c1

Procedure:
Prepared according to Preparation 207 using (2,4-dimethoxybenzyl)-[1,2,4]thiadiazol-5-yl-amine (Preparation 14) and 3-chloro-4-fluorobenzenesulfonyl chloride.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH2:28][NH:38][CH:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CNC3CCN(C)CC3)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and 1-methylpiperidin-4-amine.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[O:13])=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3]1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[O:13])=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3]1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(c2ccccc2)=CC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)C=C(c2ccccc2)c2cc(NC(=O)c3ccc(C(=O)O)cc3)ccc21
Yield: 78.2 %

Procedure:
Methyl 4-[[(1,1-dimethyl-3-phenyl-1H-inden-5-yl)amino]carbonyl]benzoate (325 mg, 0.82 mmol), 4.1 mL of 2N NaOH in 10 mL of tetrahydrofuran and 10 mL of methanol were stirred for 2 hours. The mixture was concentrated and acidified with 1N HCl (20 mL), extracted with ethyl acetate (35 mL×2). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was triturated in ether-hexane to give 246 mg (78% yield) of the title compound as white solids; NMR (DMSO-d6) δ1.35 (s, 6H), 6.58 (s, 1H), 7.38-7.70 (m, 7H), 7.73 (d, J=7.9 Hz, 1H), 7.90 (s, 1H), 8.04 (s, 4H), 10.38 (bs, 1H), 13.25 (bs, 1H); MS m/e 384 (MH+).
Reaction SMILES: CC1CS[C@@H]2C(NC(=O)C(C3N=C(N[C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)SC=3)=NOC(C)(OC)C)C(=O)N2C=1C(OC(C)(C)C)=O.FC(F)(F)C(O)=[O:57]>C(O)=O>[C:34]1([C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[OH:57])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(C)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2 g of the product of Step B were added with stirring at room temperature to 20 ml of trifluoroacetic acid held under nitrogen and after stirring for 10 minutes at room temperature, the mixture was concentrated under vacuum to a volume of 8 ml. The mixture was cooled in an ice water bath and 60 ml of isopropyl ether were slowly added thereto. The mixture was stirred for 10 minutes at room temperature and was vacuum filtered and the filter was rinsed with isopropyl ether. The filtrate was evaporated to dryness under reduced pressure to obtain 1.5 g of raw product. The latter was placed under an argon atmosphere and 7.5 ml of 50% aqueous formic acid were added thereto. The mixture was stirred at 40° C. for 15 minutes and was then vacuum filtered. The recovered product was rinsed twice with 1 ml of 50% aqueous formic acid and 3 times with 1 ml of distilled water to obtain 319 mg of triphenyl carbinol. The filtrate was distilled to dryness and ethanol was added. The mixture was triturated with 15 ml of ether and was vacuum filtered. The recovered product was rinsed with ether and dried to obtain 0.973 g of the syn isomer of 3-methyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3 -eme-4-carboxylic acid with an Rf=0.3 (acetone containing 10% water).