Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([OH:38])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].Cl>O.CN(C)C=O>[C:15]([O:14][C:13]([N:12]([CH2:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)[CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]2[C:37]3[C:32](=[C:33]([O:38][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][C:29]2=[O:39])[CH2:22][CH2:21]1)=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(O)cccc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3 mL of an N,N-dimethylformamide solution containing 166 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-hydroxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 65 mg of potassium carbonate and 43 μL of ethyl bromoacetate were added, and stirred at room temperature for 2 hours. After water was added to the reaction mixture and acidified with hydrochloric acid, the mixture was extracted with a mixture of ethyl acetate:toluene=5:1. The extracts were washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1], to give 196 mg of ethyl (1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yloxy)acetate as a pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH3:44])=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:28][CH2:29]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH3:44])=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:33])[F:34])[N:3]=1
Reactant: CCCc1ccc([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)c(-c2cccc(S(C)(=O)=O)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1ccc([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OCC)C4)nc(N)n2)C(F)(F)F)c(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate in CH2Cl2 (4 mL) was added TFA (2.0 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/MeOH) provided (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]1.[ClH:27]>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1.[ClH:27]
Reactant: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-tert-Butyl 3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate (27 mg, 0.074 mmol) was mixed with 4M HCl in 1,4-dioxane (3 mL) and stirred for 30 min at rt. LC-MS showed complete removal of the Boc protecting group. The mixture was concentrated to afford (R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine as its HCl salt. This material was used without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:26]([O-])=O)=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C([O-])=O.[NH4+].C1(C)C=CC=CC=1>[Fe].O>[NH2:26][C:3]1[C:2]([Cl:1])=[CH:24][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH2:12]2)=[C:5]([CH3:25])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(N)c(Cl)cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 88.9 %

Procedure:
A flask was charged with tert-butyl 4-(3-(5-chloro-2-methyl-4-nitrophenoxy)propyl)-piperazine-1-carboxylate (1.2 g, 2.9 mmol), ammonium formate (0.84 g, 13 mmol), and iron powder (0.74 g, 13 mmol). Toluene (20 mL) and water (20 mL) were added to the flask and the mixture was heated to reflux for 6 hours, after which time, the mixture was filtered through a plug of Celite. The supernatant was extracted with ethyl acetate and water. The organic solvent was removed on a rotary evaporator under reduced pressure to yield tert-butyl 4-(3-(4-amino-5-chloro-2-methylphenoxy)propyl)piperazine-1-carboxylate as a brown oil (0.99 g, 89% yield). 1H-NMR (400 MHz, DMSO-d6): δ 6.77 (s, 1H), 6.61 (s, 1H), 4.76 (s, 2H), 3.86 (t, 6.1 Hz, 2H), 3.30 (s, br, 4H), 2.50 (m, 2H), 2.31 (m, 2H), 2.03 (s, 3H), 1.82 (m, 2H), 1.39 (s, 9H). MS (EI): 384 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([NH:14]C(=O)C)[C:3]=1[C:4]([OH:6])=[O:5].Cl>[OH-].[Na+]>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([NH2:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c([N+](=O)[O-])ccc(N)c1C(=O)O
Temperature: 95 °C
Reaction time: 1 h

Procedure:
450 ml of 2N NaOH are initially taken and 75.6 g (0.317 mol) of 2-methyl-3-nitro-6-acetamidobenzoic acid are added. The reaction mixture is then warmed to 95° C. and is stirred at this temperature for one hour. After cooling to 10° C., it is acidified by addition of 425 ml of 2N HCl, and the precipitate which deposits is filtered off with suction, washed with water and dried under reduced pressure at 50° C. Yield: 50.7 g (0.258 mol)=82% of theory, m.p.: 183°-184° C.
Reaction SMILES: C(O)(=O)C.[C:5]1([CH3:20])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[C:14]([CH3:19])=[N:15][NH:16][C:17]=1[NH2:18].[C:21]([CH:24]([C:30](OCC)=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=O)[CH3:22]>C1(C)C(C)=CC=CC=1>[C:5]1([CH3:20])[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]1[C:14]([CH3:19])=[N:15][N:16]2[C:30](=[O:31])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH3:22])[NH:18][C:17]=12
Reactant: CCOC(=O)C(C(C)=O)C(=O)OCC
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Yield: 36.6 %

Procedure:
Acetic acid (5 mL) was added to a solution of 4-mesityl-3-methyl-1H-5-pyrazoleamine (5 g, 23.22 mmol) and diethyl 2-acetylmalonate (4.7 g, 23.22 mmol) in xylene (40 mL), followed by heating under reflux for seven hours. The reaction mixture was evaporated as it was, and water was added thereto. After extracting with ethyl acetate, the organic layer was washed with an aqueous saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane), to give the title compound (3 g).
Reaction SMILES: [NH2:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=O.C(O[C:18](=[NH:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)C>>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]1=[N:27][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[N:1][N:2]1[CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1)CCN(N)C2=O
Reactant: CCOC(=N)c1cccc(OC)c1
Product: COc1cccc(-c2nc3n(n2)CCc2cc(OC)ccc2-3)c1

Procedure:
The compound is prepared according to the procedure of Example 1 from 2-amino-6-methoxy-3,4-dihydro-1(2H)-isoquinolinone (prepared according to the procedure described in Belgian Pat. No. 780,885; m.p. 101°-3° C.) and m-methoxybenzimidic acid ethyl ester; m.p. 132°-3° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([CH3:19])=[CH:13][C:10]=1[CH:11]=O>CCO.Cl>[CH3:18][O:17][C:15]1[C:14]([CH3:19])=[CH:13][C:10]([CH:11]=[C:3]2[C:4](=[O:7])[C:5](=[CH:11][C:10]3[CH:13]=[C:14]([CH3:19])[C:15]([O:17][CH3:18])=[CH:16][C:9]=3[CH3:8])[CH2:6][O:1][CH2:2]2)=[C:9]([CH3:8])[CH:16]=1
Reactant: COc1cc(C)c(C=O)cc1C
Reactant: O=C1CCOCC1
Agent: Cl
Solvent: CCO
Product: COc1cc(C)c(C=C2COCC(=Cc3cc(C)c(OC)cc3C)C2=O)cc1C
Reaction time: 24 h
Yield: 38.9 %

Procedure:
A solution of 7.0 g (0.07 mole) of tetrahydro-4H-pyran-4-one and 25.2 g (0.15 mole) of 2,5-dimethyl-p-anisaldehyde in 75 ml of EtOH and 10 ml of concentrated HCl is stirred and heated at reflux for 3 hours. The resulting mixture is kept at room temperature for 24 hours, yielding 10.7 g (39%) of yellow solid, m.p. 182°-184°.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][OH:16].[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:27]=[CH:26][C:25]=1[C:36]1[N:41]=[CH:40][C:39](O)=[CH:38][N:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:27]=[CH:26][C:25]=1[C:36]1[N:37]=[CH:38][C:39]([O:16][CH2:15][C@H:14]([F:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:40][N:41]=1
Reactant: CCCCCC[C@@H](F)CO
Reactant: CCCCCc1ccc(-c2ncc(O)cn2)c(F)c1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC[C@@H](F)COc1cnc(-c2ccc(CCCCC)c(F)c2F)nc1
Yield: 55.3 %

Procedure:
--DEAD (470 mg, 2.70 mmol) in THF (3 ml) was added dropwise via syringe to a stirring solution of (R)-(+)-2-fluorooctanol (396 mg, 2.70 mmol), the hydroxypyrimidine 33 (750 mg, 2.70 mmol) and triphenylphosphine (707 mg, 2.70 mmol) in THF (10 ml) under nitrogen at ambient temperature for 15 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (3 to 5% ethyl acetate-light petroleum) to give the 2-fluorooctyloxypyrimidine 34 (610 mg, 55%) (from MeOH), m.p. 74.7° C.; [α]D25 -3.6° (c 2.7 in CHCl3); νmax /cm-1 (KBr) 2950, 2920, 1575, 1545, 1460, 1440, 1280, 1210, 1130, 1080 and 995; δ 0.90 (6H, overlapping t, Me), 1.26-1.93 (16H, m), 2.70 (2H, t, ArCH2), 4.22 (2H, dd, 3JHF 22 and Jvic 4, OCH2), 4.87 (1H, d of sext, 2JHF 49 and J4, CHF), 7.02 (1H ddd, J7.5, 7 and 2, 5'-H), 7.6 (1H, ddd, J7.5, 7 and 2, 6'-H) and 8.55 (2H, s, 4- and 6-H); m/z 408 (M+), 365, 351, 291, 278, 250 and 221.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]1([S:20][CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:21][S:20][C:14]1[CH:19]=[CH:18][C:17]([C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:13])=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: CSc1ccccc1
Product: CSc1ccc(C(=O)c2cccc3ccccc23)cc1
Temperature: 80 °C

Procedure:
A mixture of 1-naphthoic acid (10 g, 58.08 mmol), thioanisol (8.19 ml, 69.7 mmol) and polyphosphoric acid (100 g) was heated for 12 hours on water bath at 80° C. Reaction mixture was poured onto ice water and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to give oil, which was crystallized from methanol to give the desired compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@@H:17]1[CH:19]=[CH2:20])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH2:24]([O:23][C:21]([C@:16]1([NH:15][C:14]([C@@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]2)=[O:26])[CH2:18][C@@H:17]1[CH:19]=[CH2:20])=[O:22])[CH3:25]
Reactant: C=C[C@H]1C[C@@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C[C@H]1C[C@@]1(NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)OCC

Procedure:
Compound 90 was kept in 30% trifluoroacetic acid in dichloromethane and 1% MeOH for 2 hrs before it was concentrated to dryness. The residue was re-dissolved In dichloromethane and during stirring 1N NaOH was added to pH 10-11. The organic layer was separated and concentrated which gave 1.6 g of the title product. HPLC purity ca. 90% M+H+269.1.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)([CH3:19])[C:14](OCC)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CO.[NH3:34]>>[NH2:34][C:14](=[O:15])[C:13]([NH:12][C:10]([C:7]1[CH:6]=[C:5]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:11])([C:20]1[N:24]=[C:23]([CH3:25])[O:22][N:21]=1)[CH3:19]
Reactant: N
Reactant: CCOC(=O)C(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1noc(C)n1
Solvent: CO
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(N)=O)no1
Yield: 69 %

Procedure:
A solution of ethyl 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoate (example 147b, 0.05 g, 113 μmol) in ammonia 7N in MeOH (1.00 ml, 7.01 mmol) was stirred at room temperature overnight. Volatiles were removed in vacuo and the crude material was purified by preparative HPLC without any work-up protocol to yield the title compound (32 mg, 69%). MS (ESI, m/z): 414.5 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]#[N:18])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([C:17]([NH:20][NH2:21])=[NH:18])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Cc1cc(C#N)sc1C(=O)NCc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1cc(C(=N)NN)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A mixture of N-benzyl-5-cyano-3-methylthiophene-2-carboxamide (0.80 g, 3.12 mmol) and hydrazine monohydrate (8.00 mL, 164.9 mmol) in ethanol was stirred at reflux for 18 h. The reaction mixture was allowed to cool to ambient temperature, and concentrated in vacuo. The residue was triturated with ethyl acetate to afford N-benzyl-5-(hydrazinyl(imino)methyl)-3-methylthiophene-2-carboxamide as a light yellow solid (0.65 g, 72%): MS (ES+) m/z 289.2 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:23])[C:10]3[C:15]([O:16][C:17]=2[C:18]=1[O:19][CH2:20][CH:21]=[CH2:22])=[CH:14][CH:13]=[CH:12][CH:11]=3)C=C.[C:24]1(OC2C=CC=CC=2)[CH:29]=CC=C[CH:25]=1>>[CH2:29]([C:18]12[C:5](=[O:4])[CH:6]3[CH:7]=[C:8]4[C:17]1([CH:21]([CH2:22]3)[CH2:20][O:19]2)[O:16][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:9]4=[O:23])[CH:24]=[CH2:25]
Reactant: C=CCOc1ccc2c(=O)c3ccccc3oc2c1OCC=C
Reactant: c1ccc(Oc2ccccc2)cc1
Product: C=CCC12OCC3CC(C=C4C(=O)c5ccccc5OC431)C2=O
Temperature: 25 °C
Yield: 12 %

Procedure:
A stirred solution of 3,4-bis-allyloxy-xanthen-9-one (236.4 mg, 0.767 mmol) and diphenyl ether (3.0 mL) was refluxed in an oil bath at 190° C. for 11 h. The solution was cooled to room temperature and product was purified twice by flash column chromatography (dichloromethane) to yield 28.0 mg (12%) of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz): δ 7.95 (dd, J1=7.69 Hz, J2=1.65, 1H), 7.56 (ddd, J1=8.17 Hz, J2=7.07, J3=1.58, 1H), 7.34 (d, J=7.14Hz, 1H), 7.08 (m, 1H), 5.22 (m, 1H), 4.69 (m, 1H), 4.53 (m, 1H), 3.91 (d, J=7.97 Hz, 1H), 3.53 (ddd, J1=6.11 Hz, J2=3.43, J3=2.06, 1H), 2.82 (dd, J1=13.33 Hz, J2=5.35, 1H), 2.63 (m, 1H), 2.51 (dd, J1=13.60 Hz, J2=9.48, 1H), 1.90 (m, 1H), 1.78 (ddd, J1=12.22 Hz, J2=10.38, J3=2.39, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:10]([CH2:11][NH:12]2)[CH2:9]1)=[O:7].Br[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1>>[CH2:28]([O:27][C:25](=[O:26])[C:24]1[CH:30]=[CH:31][C:21]([N:12]2[CH2:11][CH:10]3[CH:13]2[CH2:14][N:8]([C:6](=[O:7])[NH:5][CH2:4][C:3]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=2[Cl:1])[CH2:9]3)=[CH:22][CH:23]=1)[CH3:29]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)N1CC2CNC2C1
Reactant: CCOC(=O)c1ccc(Br)cc1
Product: CCOC(=O)c1ccc(N2CC3CN(C(=O)NCc4ccc(Cl)cc4Cl)CC32)cc1

Procedure:
In analogy to the experimental procedure of example 20) rac-3-(2,4-Dichloro-benzylcarbamoyl)-3,6-diaza-bicyclo[3.2.0]heptane using ethyl 4-bromobenzoate instead of 2-bromopyrimidine was converted into the title compound which was obtained as a white solid and directly used without further purification.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[N:29]=[C:30]([CH3:33])[S:31][CH:32]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:34]>CO>[ClH:34].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[N:29]=[C:30]([CH3:33])[S:31][CH:32]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: Cc1nc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(NC=O)n2)cs1
Agent: Cl
Solvent: CO
Product: Cc1nc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(N)n2)cs1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 96.7 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-methylthiazol-4-ylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 240 mg.) and conc. hydrochloric acid (71 mg.) in methanol (2.5 ml.) was stirred at room temperature for 6.5 hours. After removing the solvent from the resultant solution in vacuo, the residue was triturated with diisopropyl ether. The precipitates were collected by filtration and washed with diisopropyl ether to give colorless crystals of 7-[2-(2-aminothiazol-4-yl)-2-(2-methylthiazol-4-ylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 236 mg.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH:11]([CH3:13])[N:10]([CH3:14])[C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>ClCCl>[Si:31]([O:1][C:2]1[CH:3]=[C:4]([C:8]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH:11]([CH3:13])[N:10]([CH3:14])[C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CC1CC(c2ccccc2)(c2cccc(O)c2)C(=O)N1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC1CC(c2ccccc2)(c2cccc(O[Si](C)(C)C(C)(C)C)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Product of Step 6 (4.9 g) was dissolved in dichloromethane (200 mL). To this, imidazole (5 g) and tertiarybutyldimethylsilyl chloride (5 g) was added. The reaction mixture was stirred at 25° C. for 16 hrs. Then, the reaction mixture was extracted with water (200 mL) and the organic layer was dried on anhydrous magnesium sulfate. The organic layer was filtered and concentrated under vacuum. The crude product was loaded on a SNAP cartridge containing 340 g silica gel and eluted with a gradient of ethyl acetate and hexane using the BIOTAGE® AB ISOLERA™ flash chromatography system. Fractions containing product were pooled and evaporated to obtain product of Step 7 as a viscous, colorless oil. Yield of purified product: 2.75 g. 1H NMR (CDCl3): 0.1 δ (6H, —Si—(CH3)2), 0.9 δ (9H, (—CH3)3 of tertiary butyl), 1.3 δ (3H, —CH—CH3 of isopropyl), 2.8 δ (3H, —N—(CH3)), 2.25, 3.1, 3.5 δ (1H, 1H, 1H —CH2-CH—CH3 of isopropyl), 6.8-7.5 δ (9H, phenyl rings). Mass spectrometry: m/z=396 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][N+:15]([O-])=[C:14]([CH3:19])[C:13]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:24][CH2:19][C:14]1[C:13]([CH3:20])=[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][N:15]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OCCOCc2ccccc2)cc[n+]([O-])c1C
Product: CC(=O)OCc1nccc(OCCOCc2ccccc2)c1C
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture comprising 6.5 g of 4-(2-benzyloxyethoxy-2,3-dimethylpyridine N-oxide and 56 ml of acetic anhydride was stirred at 80 to 90° C. for one hour and distilled to remove the acetic anhydride. The obtained residue was made weakly basic with an aqueous solution of sodium carbonate and extracted with methyl ethyl ketone. The extract was dried over magnesium sulfate and distilled to remove the methyl ethyl ketone. Thus, 7.0 g of 2-acetoxymethyl-4-(2-benzyloxyethoxy)-3-methylpyridine was obtained. This intermediate was dissolved in 90 ml of ethanol, followed by the addition of 1.43 g of sodium hydroxide. The obtained mixture was stirred at 40° C. for one hour, followed by the addition of water. The mixture was extracted with methyl ethyl ketone. The obtained extract was dried over magnesium sulfate to obtain 5.4 g of 4-(2-benzyloxyethoxy)-2-hydroxymethyl-3-methylpyridine.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)=[N:5][N:4]=1)#[N:2].Cl.[NH2:27][OH:28].C(N(CC)CC)C>CO>[OH:23][B:14]1[C:13]2[CH:24]=[C:9]([O:8][C:6]3[S:7][C:3]([C:1](=[NH:2])[NH:27][OH:28])=[N:4][N:5]=3)[CH:10]=[C:11]([CH3:25])[C:12]=2[CH:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:15]1
Reactant: NO
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C#N)s3)cc(C)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C(=N)NO)s3)cc(C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 2-(6-(5-cyano-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.63 g, 4.54 mmol, 1 eq.) and hydroxylamine hydrochloride (0.79 g, 11.35 mmol, 2.5 eq.) in methanol was added triethylamine (2.22 ml, 15.88 mmol, 3.5 eq.). After stirring at room temperature for one hour, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc and then washed with water. The organic layers were collected, dried with Na2SO4 and evaporated to give the crude product (1.73 g, yield 97.2%). The crude was used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:8][C:5]1[C:4]([O:9][CH3:10])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1nc(Cl)cnc1N
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example I (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g) and 2,3-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.05 g.