Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.Cl.[NH2:24][CH:25]1[C:37](=[O:38])[N:27]2[C:28]([C:34]([OH:36])=[O:35])=[C:29]([O:32][CH3:33])[CH2:30][S:31][C@H:26]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>O.C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:10]([NH:24][CH:25]2[C:37](=[O:38])[N:27]3[C:28]([C:34]([OH:36])=[O:35])=[C:29]([O:32][CH3:33])[CH2:30][S:31][C@H:26]23)=[O:12])[N:8]=1)=[O:2]
Reactant: COC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: C#CCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(OC)CS[C@H]12)c1csc(NC=O)n1
Yield: 43.1 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 1.27 g.), N,N-dimethylformamide (402 mg.), phosphoryl chloride (843 mg.) and ethyl acetate (11.2 ml.) were treated in a conventional manner to prepare an activated acid solution. On the other hand, a mixture of 7-amino-3-methoxy-3-cephem-4-carboxylic acid hydrochloride (1.33 g.), trimethylsilylacetamide (4 g.), bis(trimethylsilyl)acetamide (2 ml.) and ethyl acetate (20 ml.) was stirred at 40° to 45° C. for an hour. To the solution was added the activated acid solution obtained above all at once at -15° C., and then stirred at -5° to -10° C. for 1.5 hours. Water (30 ml.) was added to the resultant solution, filtered and the organic layer was separated. The insoluble substance filtered out was dissolved in a saturated aqueous solution of sodium bicarbonate, and the solution was added to the organic layer. The solution was adjusted to pH 7.5 and the aqueous solution was separated, and then extracted with ethyl acetate at pH 2.0. The extract was washed with water, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-methoxy-3-cephem-4-carboxylic acid (syn isomer, 1.0 g.), yellow powder.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([O:24][CH2:25][C:26]([N:28]2[CH2:32][CH2:31][CH2:30][C@@H:29]2[C:33]([O:35]C(C)(C)C)=[O:34])=[O:27])=[C:18]([F:40])[C:17]=1[F:41])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[C:17]([F:41])=[C:18]([F:40])[C:19]([O:24][CH2:25][C:26]([N:28]2[CH2:32][CH2:31][CH2:30][C@@H:29]2[C:33]([OH:35])=[O:34])=[O:27])=[C:20]([F:23])[C:21]=1[F:22])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1c(F)c(F)c(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1c(F)c(F)c(OCC(=O)N2CCC[C@@H]2C(=O)O)c(F)c1F
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 80 mg (0.13 mmol) (R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2,3,5,6-tetrafluoro-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 64 mg (96%) of the title compound as a white powder.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH2:13]([O:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH3:14].NC1C=CC=CC=1>>[CH2:13]([O:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:24][CH:25]=1)[CH3:14]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCOC(=O)CCCc1ccc(N)cc1
Solvent: Nc1ccccc1
Product: CCOC(=O)CCCc1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
By using 2-bromomethyl-benzoic acid methyl ester and 4-(4-amino-phenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester (Compound 19) as a white powdery substance.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:29](O)(=O)[C:30]([CH3:33])([CH3:32])[CH3:31].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[C:30]([C:33]1[O:24][C:23]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C@H:15]3[CH2:16][CH2:17][C@H:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])[CH2:13][CH2:14]3)=[CH:28][CH:27]=2)=[N:25][N:26]=1)([CH3:32])([CH3:31])[CH3:29]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NN)cc3)CC2)CC1
Reactant: CC(C)(C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(-c4nnc(C(C)(C)C)o4)cc3)CC2)CC1

Procedure:
A mixture of 60 mg (0.15 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid hydrazide, 0.02 ml (0.2 mmol) of pivalic acid and 2 ml of phosphorus oxychloride was refluxed for 2 hr. To the mixture, 1N NaOH solution was added. The mixture was extracted with AcOEt, washed with saturated NaHCO3 solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 19:1. The combined product fractions were evaporated to dryness to yield 25 mg (36%) of the title compound. MS (m/e): 455.4 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][N:27]=1)#[CH:25]>C(Cl)Cl>[N:17]1([CH2:16][CH:12]2[CH2:13][CH2:14][CH2:15][N:10]([C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:1]4[CH:25]=[C:24]([C:26]5[C:34]6[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=6)[NH:28][N:27]=5)[N:3]=[N:2]4)=[CH:23][CH:22]=3)=[O:9])[CH2:11]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C#Cc1n[nH]c2ccccc12
Reactant: [N-]=[N+]=Nc1ccc(C(=O)N2CCCC(CN3CCCC3)C2)cc1
Solvent: ClCCl
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1)N1CCCC(CN2CCCC2)C1

Procedure:
The title compound was prepared following procedure described for intermediate 10, but starting from 1-(4-azidobenzoyl)-3-(pyrrolidin-1-ylmethyl)piperidine (420 mg; 1.34 mmol; 1.0 eq.) and 3-ethynyl-1H-indazole (190 mg; 1.34 mmol; 1.0 eq.). After purification by preparative HPLC, it was obtained as the formic acid salt. The salt was solubilized in DCM and washed with a saturated solution of NaHCO3 then brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting oil was suspended in EtOH, and concentrated to dryness to afford the title compound as a yellow powder. 1H NMR (300 Mz, DMSO-d6) δ: 13.37 (s, 1H), 9.37 (s, 1H), 8.36 (d, J=8.1 Hz, 1H), 8.15 (d, J=8.7 Hz, 2H), 7.61 (m, 3H), 7.43 (m, 1H), 7.26 (m, 1H), 4.48 (m, 0.4H), 4.25 (m, 0.6H), 3.70 (m, 0.6H), 3.52 (m, 0.4H), 3.04 (m, 0.4H), 2.91 (m, 0.6H), 2.74 (m, 0.4H), 2.20-2.43 (m, 4H), 2.02 (m, 0.6H), 1.69 (m, 6H), 1.48 (m, 4H), 1.20 (m, 1H). HPLC (Condition A): Rt 2.69 min (purity 99.9%). MS (ESI+): 456.4, MS (ESI−): 454.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][OH:25])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCC(CCO)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
A solution of 0.174 g of methyl 8-(p-chlorophenylsulfonamido)-4-(2-hydroxyethyl)octanoate in 2 mL methylene chloride is cooled to 0° C. and 0.1 mL of triethylamine is added followed by 0.042 mL of methanesulfonyl chloride. After 1 hour, the reaction is washed with saturated sodium bicaronate and the organic layer is dried, filtered and evaporated to yield methyl 8-(p-chlorophenylsulfonamido)-4-(2-methanesulfonyloxyethyl)-octanoate as an oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([OH:26])[CH:11]([P:13](C(OCC)(OCC)C)(=[O:17])[O:14]CC)[F:12])=O)(C)(C)C.Cl>CO>[NH2:8][CH2:9][CH:10]([OH:26])[CH:11]([PH:13](=[O:14])[OH:17])[F:12]
Reactant: CCOC(C)(OCC)P(=O)(OCC)C(F)C(O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: NCC(O)C(F)[PH](=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 5.7 %

Procedure:
Ethyl (3-(N-(tert-butoxycarbonyl)amino)-1-fluoro-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate (180 mg, 4.5 mmol) was dissolved in methanol (2 mL), treated with 3 N Hydrochloric acid (20 mL, 60.0 mmol, sparged with argon immediately prior to use). The mixture was stirred at room temperature for 6 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, the crude product was re-dissolved in methanol (5 mL); the residual water removed by co-evaporation under reduced pressure with methanol. The crude product (70 mg) was purified by column chromatography (1×10 cm column) eluting with methylene chloride, methanol, concentrated ammonium hydroxide (6:3:1). The fractions containing product were concentrated under reduced pressure, co-evaporated with acetonitrile (2×10 ml) then with methanol (1×10 mL) and dried overnight under high vacuum (0.1 mm Hg). This procedure afforded (3-amino-1-fluoro-2-hydroxypropyl)phosphinic acid as a white solid (40 mg, 56%). 1H NMR (300 MHz, D2O) δ 7.93 (s, 0.5H), 6.11 (s, 0.5 H), 4.60-4.20 (m, 2H), 3.42-3.08 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[C:4]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:3]=12.[CH2:16]([C:18]1[CH:23]=[C:22]([CH:24]=O)[CH:21]=[C:20]([CH3:26])[C:19]=1[CH:27]=[CH:28][C:29]([OH:31])=[O:30])[CH3:17].Cl>[OH-].[Na+]>[CH2:16]([C:18]1[CH:23]=[C:22]([CH:24]=[CH:8][C:7](=[O:9])[C:5]2[S:6][C:2]([CH3:1])=[C:3]3[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:4]=23)[CH:21]=[C:20]([CH3:26])[C:19]=1[CH:27]=[CH:28][C:29]([OH:31])=[O:30])[CH3:17]
Reactant: CC(=O)c1sc(C)c2c1CCC(C)(C)C2
Reactant: CCc1cc(C=O)cc(C)c1C=CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(C=CC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1C=CC(=O)O
Yield: 61.1 %

Procedure:
A solution of 1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (355 mg, 1.55 mmol) and 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid (373 mg, 1.70 mmol, Aldehyde 5) in methanolic NaOH (8 mL, 10 g NaOH in 100 mL methanol) is stirred at rt for 3 h before it is carefully acidified to pH 1 by adding 2 N aq. HCl. The mixture is extracted twice with DCM, the organic extracts are washed with water and brine, dried over MgSO4, filtered and evaporated. The crude product is crystallised from acetonitrile (120 mL) to give 3-{2-ethyl-6-methyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propenyl]-phenyl}-acrylic acid (400 mg) as yellow crystals; LC-MS: tR=1.17 min, [M+1]=423.34; 1H NMR (CDCl3): δ 7.97 (d, J=16.4 Hz, 1H), 7.68 (d, J=15.2 Hz, 1H), 7.33 (s, 2H), 7.28 (d, J=15.8 Hz, 1H), 6.13 (d, J=15.8 Hz, 1H), 3.16 (t, J=7.0 Hz, 2H), 2.77 (q, J=7.6 Hz, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.32 (s, 2H), 1.57 (t, J=6.4 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H), 1.00 (s, 6H).
Reaction SMILES: O1CCCC1.[CH2:6]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH:19]2[CH2:21][CH:20]2[C:22](O)=[O:23])=O)[CH2:13][CH2:12]1)[CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH2:6]([N:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH:19]2[CH2:21][CH:20]2[CH2:22][OH:23])[CH2:15][CH2:16]1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCN1CCN(C(=O)C2CC2C(=O)O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCN1CCN(CC2CC2CO)CC1

Procedure:
To 100 mL of tetrahydrofuran is added 24.0 g (0.1 mol) of 2-[(4-pentylpiperazin-1-yl)carbonyl]cyclopropanecarboxylic acid and 13.6 g (0.4 mol) of lithium aluminum hydride. Reflux the reaction and monitor by thin-layer chromatography. Upon completion add 14 mL of H2O, 14 mL of 15% aqueous NaOH, and 42 mL of H2O. Remove the precipitate by suction filtration through celite and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[N:22][N:23](CC3C=CC(OC)=CC=3)[CH:24]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:5].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[N:23][NH:22][CH:21]=2)=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:5]
Reactant: COc1ccc(Cn2cc(-c3ccc(Cl)c(C(=O)NCCc4ccccc4Cl)c3)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(NCCc1ccccc1Cl)c1cc(-c2cn[nH]c2)ccc1Cl
Temperature: 110 °C
Reaction time: 16 h
Yield: 112.4 %

Procedure:
To as solution of 2-chloro-N-[2-(2-chloro-phenyl)-ethyl]-5-[1-(4-methoxy-benzyl)-1H-pyrazol-4-yl]-benzamide (20 mg, 0.042 mmol) in dichloromethane (0.2 mL) was added trifluoroacetic acid (24 mg, 0.21 mmol) and anisole (45 mg, 0.42 mmol). The mixture was stirred at 110° C., for 16 h. A second portion of trifluoroacetic acid (0.2 mL) and anisole (45 μL) was added and the mixture was stirred at 110° C. for a further 6 h. The mixture was concentrated in vacuo to dryness and triturated with hexane to afford the title compound as an orange solid (17 mg). LCMS (m/z) 358.5 M+1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19].C=O.[C:25](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:9][C:10]2[S:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH3:25])[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21]
Reactant: O=C(Nc1ccc(NCc2ccc(Cl)s2)cc1Cl)C(F)(F)F
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(Cc1ccc(Cl)s1)c1ccc(NC(=O)C(F)(F)F)c(Cl)c1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of N-{2-Chloro-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-2,2,2-trifluoroacetamide (3.28 g, 8.88 mmol), 37% aqueous formaldehyde (5 mL), and acetic acid (3 mL), sodium cyanoborohydride (NaBH3CN) (1.1 g) in methanol (10 mL) was added dropwise with stirring during 30 minutes. The reaction mixture was allowed to stand at room temperature for 2 hours and poured into water. After the oil solidified, it was filtered, washed with water and dried in vacuo to give 3.26 g of pale yellow-brown solid. Yield 95%. 1H NMR (DMSO-d6): 2.97 (s, 3H, NMe), 4.72 (s, 2H), 6.82 (m, 1H), 6.91 (m, 2H), 6.97 (d, 1H), 7.21 (d, 1H), 10.92 (br. s, 1H, NHCO). LC/MS (m/z) 382.0 (M+); RT=3.66, (UV, ELSD) 85%, 98%.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[OH:34])[N:17]=2)[CH2:12]1.Cl[C:36]([O:38][C@H:39]1[CH2:43][CH2:42][O:41][CH2:40]1)=[O:37]>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][C@@H:11]([NH:10][C:36](=[O:37])[O:38][C@H:39]3[CH2:43][CH2:42][O:41][CH2:40]3)[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[N:19]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Reactant: O=C(Cl)O[C@H]1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)O[C@H]4CCOC4)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
At room temperature, N-ethyl-N-isopropylpropan-2-amine (155 mL, 0.88 mmol) was added to a solution of 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (150 mg, 0.40 mmol) in THF. The mixture was cooled in an ice bath, and (S)-tetrahydrofuran-3-yl chloroformate (63 mg, 0.42 mmol) was added slowly over a period of 10 minutes. After warming to room temperature, the reaction was quenched with water and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc in CH2Cl2/hexanes (1:1) gave (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (160 mg, 84%). LC/MS: m/z 453.3 (M+H)+ at 2.12 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSOd6) δ 8.18 (d, J=8.6 Hz, 1H), 7.70 (d, J=6.3 Hz, 1H), 7.58 (s, 1H), 7.29-7.38 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.67-6.72 (m, 1H), 5.14 (s, 1H), 4.23-4.24 (m, 1H), 3.99-4.13 (m, 3H), 3.64-3.85 (m, 5H), 2.50 (s, 3H), 2.07-2.22 (m, 2H), 2.00-2.03 (m, 1H), 1.85-1.90 (m, 1H).
Reaction SMILES: N[CH:2]1[C:18](=[O:19])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[CH:6][CH:7]([CH3:9])[S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:23].Cl>C(N(CC)CC)C>[O:23]=[C:2]1[C:18](=[O:19])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[CH:6][CH:7]([CH3:9])[S:8][C@H:3]12
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=O)[C@H]2S1

Procedure:
2,2,2-Trichloroethyl 7-amino-2-methyl-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give 2,2,2-trichloroethyl 7-oxo-2-methyl-3-cephem-4-carboxylate. Mp. 98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH:10][N+:11]([O-])=O)[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=C[N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CCN)c1
Yield: 73.3 %

Procedure:
Using analogous reaction conditions and workup as described in Example 1, step 2, 1-methoxy-3-(2-nitro-vinyl)-benzene (I-11a: 10.5 g, 58.659 mmol) in dry THF (110 mL) was reacted with LAH (6.68 g, 175.97 mmol) to afford 6.5 g of the product (73% yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][CH2:12]O.Cl>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H]1CC[C@H](N)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of (trans)-4-aminocyclohexanecarboxylic acid (5 g, 34.9 mmol) in EtOH (100 mL, 1713 mmol) was treated with HCl (9.09 mL, 105 mmol) and the mixture was stirred at 60° C. overnight. The reaction mixture turned to clear solution. It was concentrated under reduced pressure and the residue was triturated with Et2O in CH3CN (50%) and the resulting white solid was collected. There was some product left in the filtrate so it was concentrated and triturated with Et2O in CH3CN (50%), the white solid was collected by filtration and combined with the white solid that was collected previously to provide 13A.HCl (5.25 g, 25.3 mmol, 72.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 4.06 (q, 2H, J=7.1 Hz); 3.01-3.15 (m, 1H); 1.34-2.31 (m, 9H); 1.18 (t, 3H, J=7.1 Hz).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH:10]([O:12][CH3:13])[CH3:11])[C:3]=1[O:14][CH3:15].[C:16]1([C:22]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:23]2[CH:27]=[C:26]([CH:28]=[O:29])[N:25]=[CH:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:15][O:14][C:3]1[C:4]([CH:10]([O:12][CH3:13])[CH3:11])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:28]([C:26]1[N:25]=[CH:24][N:23]([C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:27]=1)[OH:29]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COc1ccc(C(C)OC)c(OC)c1Br
Product: COc1ccc(C(C)OC)c(OC)c1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 49.7 %

Procedure:
Starting from 1-bromo-2,6-dimethoxy-3-(1-methoxyethyl)benzene and 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The reaction product is purified by chromatography on silica (eluent: 98:2 v/v dichloromethanemethanol). Yield: 49.7% of theory; M.P.: 96°-99° C. (recrystallized from acetonitrile).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCCl>[F:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([C:17](=[O:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(F)cccc2c1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(F)c2ccc(F)cc12
Temperature: 0 °C
Yield: 80 %

Procedure:
1,6-Difluoronaphthalene (0.164 g, 1.0 mmol) was dissolved in 1,2-dichloroethane (5 mL) and cooled to 0° C. Aluminum trichloride (0.264 g, 2.0 mmol) was added as a solid to the solution. Acetic anhydride (0.1 mL, 1.0 mmol) was added slowly over 20 minutes to the solution while maintaining a temperature of 0° C. The reaction was poured onto ice-cold 10% aqueous hydrochloric acid and extracted with methylene chloride (2×10 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by column chromatography to give 1-(4,7-difluoronaphth-1-yl)-ethanone as an oil (0.165 g, 80%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([C:13]([C:15]2[CH:16]=[CH:17][C:18]([NH:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[C:19]([CH:24]=2)[C:20]([O:22]C)=O)=[O:14])[N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12.Cl>CO.O>[Br:3][C:4]1[N:5]=[C:6]([C:13]([C:15]2[CH:24]=[C:19]3[C:18](=[CH:17][CH:16]=2)[NH:25][C:26](=[O:38])[N:27]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:20]3=[O:22])=[O:14])[N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12
Reactant: COC(=O)c1cc(C(=O)c2nc(Br)c3ccccn23)ccc1NC(=O)NCCOc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(c1ccc2[nH]c(=O)n(CCOc3ccc(F)cc3)c(=O)c2c1)c1nc(Br)c2ccccn12
Yield: 92.8 %

Procedure:
60.1 ml (60.1 mmol) of a 1N aqueous solution of sodium hydroxide are added to 6.67 g (12 mmol) of methyl 5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-({[2-(4-fluorophenoxy)ethyl]carbamoyl}amino)benzoate dissolved in 600 ml of methanol. After refluxing for 2 hours, the reaction medium is acidified with 120 ml of a 1N aqueous solution of hydrochloric acid and then diluted with 2000 ml of water. The precipitate obtained is filtered off, and dried under reduced pressure at 40° C. overnight. 5.83 g of a yellow solid are obtained.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH:8]1(C=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl>N1C=CC=CC=1.N1CCCCC1>[CH:8]1([CH:1]=[CH:2][C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(O)CC(=O)O
Reactant: O=CC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=CC1CCCCC1
Yield: 107.4 %

Procedure:
3.34 g (32.1 mmol) of malonic acid are dissolved in pyridine (10 ml), after the weakly exothermic reaction has subsided 3.0 g (26.7 mmol) of cyclohexanecarbaldehyde and 0.23 g (2.7 mmol) of piperidine are added, and the reaction mixture is heated to reflux for 4 h. The cooled reaction solution is added to a mixture of ice and concentrated hydrochloric acid, the aqueous phase is extracted three times with diethyl ether, the combined organic phases are dried over sodium sulfate, filtered, and the solvent is removed in vacuo. 4.42 g of product are obtained, which is reacted further without purification.