Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=2)=[N:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([N:38]=[C:39]=[S:40])[CH:31]=1>O1CCCC1.[Cl-].[NH4+].ClCCl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH:38][C:39]([CH:15]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[N:8]=[C:9]23)=[S:40])[CH:31]=1
Reactant: COc1ccc(Cl)cc1N=C=S
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1NC(=S)C1CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
To a solution of 0.400 g (1.65 mmol) of 2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one (step 1 of example 6) in 16 mL of dry tetrahydrofuran at −50° C., was added 1.82 mL (1.82 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The resulting mixture was stirred at −50° C. for 10 min. 0.494 g (2.48 mmol) of 4-chloro-2-isothiocyanato-1-methoxy-benzene dissolved in 2 mL of tetrahydrofuran was added at −50° C. the resulting mixture was stirred for 2 hours. The mixture was dissolved in a saturated solution of ammonium chloride and dichloromethane. The organic phases were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (dichloromethane/methanol/ammoniac in proportions of 99/1/0.1 to 98/2/0.2) to afford 0.224 g (31%) of a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([O:13][C:14]([O:16]C3C=CC=CC=3)=O)[C:11]3[S:23][CH2:24][CH2:25][S:26][C:10]=3[C:9]2=[O:27])=[N:6][CH:7]=1.[CH:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([CH3:30])[CH3:29]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([O:13][C:14]([N:34]3[CH2:35][CH2:36][N:31]([CH:28]([CH3:30])[CH3:29])[CH2:32][CH2:33]3)=[O:16])[C:11]3[S:23][CH2:24][CH2:25][S:26][C:10]=3[C:9]2=[O:27])=[N:6][CH:7]=1
Reactant: O=C(Oc1ccccc1)OC1C2=C(SCCS2)C(=O)N1c1ccc(Cl)cn1
Reactant: CC(C)N1CCNCC1
Solvent: CC#N
Product: CC(C)N1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc(Cl)cn2)CC1
Temperature: 2 °C
Yield: 63.8 %

Procedure:
6-(5-Chloropyrid-2-yl)-7-oxo-5-phenoxycarbonyloxy-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (10.0 g.) and 1-isopropylpiperazine (6.1 g.) in anhydrous acetonitrile (100 cc.) is stirred for 20 hours at a temperature of about 25° C. The reaction mixture is filtered and then evaporated under reduced pressure (20 mm. Hg). The residue is dissolved in methylene chloride (250 cc.). The organic solution is washed twice with N sodium hydroxide solution (total 160 cc.) and once with distilled water (80 cc.) and then evaporated. The residue is dissolved in an ice-cold 0.5N aqueous solution of methanesulphonic acid (200 cc.). The aqueous acid solution is washed twice with diethyl ether (total 100 cc.) and then rendered alkaline by adding 10N sodium hydroxide solution. The oil which separates out is extracted twice with methylene chloride (total 240 cc.). The organic solution is washed three times with distilled water (total 240 cc.) dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.2 g.) and evaporated. The crystals obtained (10.3 g.; m.p. 130°-135° C.) are dissolved in boiling acetonitrile (26 cc.). After filtering the boiling solution and then cooling it for 2 hours at 2° C, the crystals which have appeared are filtered off, washed twice with ice-cold acetonitrile (total 15 cc.) and dried under reduced pressure (20 mm. Hg). 6-(5-Chloropyrid-2-yl)-5-(4-isopropylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (6.9 g.), melting at 156° C, is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH:6]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])[CH2:5]2.Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7]3[NH:19][C:17](=[O:18])[C:13]4[N:12]([CH:16]=[CH:15][N:14]=4)[C:6]=3[CH2:5][C:4]=2[CH:3]=1
Reactant: NC(=O)c1nccn1C1Cc2cc(Cl)ccc2C1=O
Agent: Cl
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)Cc1cc(Cl)ccc1-2
Yield: 142.8 %

Procedure:
The procedure is carried out as in Example 1 but starting with 0.84 g of 1-(5-chloro-1-oxo-2-indanyl)imidazole-2-carboxamide, a total of 55 ml of methanol and 4 ml of a 12N aqueous hydrochloric acid solution. 0.64 g of 8-chloro-5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride is thus obtained which decomposes without melting above 300° C. [NMR spectrum: (200 MHz; DMSO-d6 ; δ in ppm): 4.07 [s, 2H: --CH2-- in position 10 (observed in DMSO-d6 plus a few drops of CD3COOD-d4)]; 7.55 (dd, J=8 and 2 Hz 1H: --H7); 7.76 (d, J=2 Hz, 1H: --H9); 7.95 (d, J=8 Hz, 1H: --H6); 7.95 and 8.25 (2d, J=1.5 Hz, 1H each: --H of imidazole); 13.00 (unresolved complex, 1H: --CONH--)].
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:16][CH:15]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=1[Cl:37].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[Cl:37][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:28]=1[N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13](=[O:26])[NH:12][C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:7][CH:8]=3)=[CH:15][N:16]=2)[CH2:21][CH2:22]1)[C:32]([OH:34])=[O:33]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCNCC4)nc3)cc21
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)cc5Cl)CC4)nc3)cc21

Procedure:
3-Chloro-4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(1-ethyl-1H-indol-6-yl)-6-piperazin-1-yl-nicotinamide and 4-bromo-3-chloro-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C27H26ClN5O3 (m/e) 503, obsd 504 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.C[O:14][C:15]([C:17]1[C:26]2[C:25]3[N:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH2:23][NH:22][CH2:21][C:20]=2[NH:19][CH:18]=1)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([C:17]2[C:26]3[C:25]4[N:27]=[CH:28][CH:29]=[CH:30][C:24]=4[CH2:23][NH:22][CH2:21][C:20]=3[NH:19][CH:18]=2)=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1c[nH]c2c1-c1ncccc1CNC2
Reactant: Nc1cccc(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(Nc1cccc(F)c1)c1c[nH]c2c1-c1ncccc1CNC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.38 mL (4 mmol) of 3-fluoroaniline in 2 mL of methylene chloride under a nitrogen atmosphere is added dropwise 1.5 mL (3 mmol) of trimethyl aluminum (2M solution of toluene). This mixture is stirred at room temperature for 30 minutes. To this mixture is added a solution of 0.12 g (0.5 mmol) of 3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene-1-carboxylic acid methyl ester dissolved in 8 mL of methylene chloride. The reaction mixture is heated to 40° C. for 24 hours; cooled to room temperature and quenched with 0.5 mL of saturated NaCl. After stirring for 30 minutes an additional 5 mL of methylene chloride and 2 grams of anhydrous sodium sulfate is added. The reaction mixture is filtered. The filtrate is evaporated and chromatographed on 10 grams of silica gel using 10/1/0.5 chloroform/methanol/ammonium hydroxide as the eluant. Appropriate fractions are combined and evaporated to 23 mg of 3,4,5,6-tetra hydro-3,5,10-triaza-benzo(e)azulene-1-carboxylic acid (3-fluoro-phenyl)-amide. 1H NMR (CD3OD) δ 8.70 (m, 1H), 7.90 (m, 1H), 7.80 (m, 1H), 7.60 (s, 1H), 7.30 (m, 3H), 6.90 (m, 1H), 3.87 (s, 2H), 3.70 (s, 2H). Mass spectrum: m/e=323.2 (p+1). TLC (10/1/0.1 chloroform/methanol/ammonium hydroxide) Rf=0.3.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[C:29]5[O:34][CH2:35][O:36][C:28]=45)=[N:21][CH:22]=[N:23]3)=[C:18]([O:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C=O>C(O)=O>[Cl:33][C:32]1[C:27]([NH:26][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]4)=[CH:17][C:18]=3[O:37][CH:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[N:23]=[CH:22][N:21]=2)=[C:28]2[O:36][CH2:35][O:34][C:29]2=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(OC3CCOCC3)c3c(Nc4c(Cl)ccc5c4OCO5)ncnc3c2)CC1
Agent: C=O
Solvent: O=CO
Product: CN1CCC(COc2cc(OC3CCOCC3)c3c(Nc4c(Cl)ccc5c4OCO5)ncnc3c2)CC1
Temperature: 100 °C
Yield: 46.5 %

Procedure:
A mixture of 7-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline (0.25 g), a concentrated aqueous formaldehyde solution (37%, 0.5 ml) and formic acid (5 ml) was stirred and heated to 100° C. for 2 hours. The mixture was cooled to ambient temperature and evaporated. The residue was purified by column chromatography on silica using a 24:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was partitioned between methylene chloride and an aqueous ammonium hydroxide solution. The organic layer was dried over magnesium sulphate and evaporated. There was thus obtained the title compound (0.1 g); NMR Spectrum: (CDCl3) 1.4-1.6 (m, 2H), 1.75-1.9 (m, 3H), 1.9-2.1 (m, 4H), 2.2-2.3 (m, 2H), 2.29 (s, 3H), 2.9 (d, 2H), 3.6-3.7 (m, 2H), 3.95 (d, 2H), 4.04.1 (m, 2H), 4.75 (m, 1H), 6.05 (s, 2H), 6.5 (d, 1H), 6.72 (d, 1H), 6.81 (d, 1H), 6.97 (d, 1H), 8.5 (s, 1H), 9.26 (s, 1H); Mass Spectrum: M+H+ 527 and 529.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=2)=O)=[CH:9][CH:8]=1)[CH3:4].Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[OH:35]/[N:34]=[C:15](/[C:17]1[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=1)\[CH2:14][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]([NH:5][C@H:3]([CH3:4])[CH2:2][OH:1])=[O:32])=[CH:12][CH:11]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](C)CO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](C)CO)cc1

Procedure:
In analogy to example 151, step 3, N—((R)-1-hydroxypropan-2-yl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid, MS (ESI+): m/z=448.2 [M+H]+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]2[CH3:31])=[O:24])[CH:20]=[C:19]([Cl:32])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:32][C:19]1[CH:20]=[C:21]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]2[CH3:31])=[O:24])[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1
Reactant: CC1CCCCN1C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCCN1C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 5 h

Procedure:
A solution of {2-[3-chloro-5-(2-methyl-piperidine-1-carbonyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.065 g) in a mixture of dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 5 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.061 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[F:8][C:9]([F:19])([F:18])[CH2:10][CH2:11][S:12]([CH2:15][C:16]#[N:17])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:19][C:9]([F:8])([F:18])[CH2:10][CH2:11][S:12]([CH:15]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[CH:2])[C:16]#[N:17])(=[O:13])=[O:14]
Reactant: C#CCCCCCl
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCCC(C#N)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 29.4 %

Procedure:
To a solution of 1.0 g of 6-chloro-1-hexyne and 1.7 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 20 ml of dimethyl sulfoxide, 1.2 g of potassium carbonate was added at room temperature. The mixture was stirred at 60° C. for 4 hours and then at 90° C. for 2 hours, and then allowed to stand near room temperature. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.70 g of 2-(3,3,3-trifluoropropylsulfonyl)-7-octynenitrile (hereinafter referred to as the present compound (23)).
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][CH3:26])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]4([CH2:22][O:23][C:17]=3[C:16]([CH3:24])=[CH:15][CH:14]=2)[CH2:21][CH2:20]4)=[N:10][CH:11]=1)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:25]([C@H:2]1[NH:1][C:28](=[O:30])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]5([CH2:22][O:23][C:17]=4[C:16]([CH3:24])=[CH:15][CH:14]=3)[CH2:21][CH2:20]5)=[N:10][CH:11]=2)[C:3]1=[O:4])[CH3:26]
Reactant: CC[C@@H](N)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2cnc(Oc3ccc(C)c4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
To a solution of (2R)-2-amino-N-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]butanamide (Intermediate 21, 24 mg, 0.068 mmol) in dry DCM (3 ml) TEA (0.028 ml, 0.2 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (15 mg, 0.05 mmol) in dry DCM (1.5 ml) was slowly added and the reaction mixture was stirred for 15 minutes at the same temperature. The reaction was quenched with water (10 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affording the title compound (11 mg) as a white solid.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:18]>CCOCC>[OH:9][C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:11][C:10]([NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18]
Reactant: NNc1ccccc1
Reactant: O=C1Cc2ccccc2O1
Solvent: CCOCC
Product: O=C(Cc1ccccc1O)NNc1ccccc1
Reaction time: 3 h

Procedure:
Phenyl hydrazine (0.73 ml) was added to a solution of 2-Coumaranone (1 g) in ether (25 ml) and the mixture stirred for 3 hours. The product was collected by filtration, washed with ether and dried.
Reaction SMILES: [NH2:1][OH:2].Cl.NO.C(=O)([O-])[O-].[Na+].[Na+].S([C:22]1[CH:27]2[CH2:28][CH:24]([CH:25]=[CH:26]2)[N:23]=1)(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[CH:24]12[CH2:28][CH:27]([CH:26]=[CH:25]1)[C:22](=[N:1][OH:2])[NH:23]2
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)C2=NC3C=CC2C3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: ON=C1NC2C=CC1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
To a solution of hydroxylamine (from 2.1 g (0.03 m) of hydroxylamine hydrochloride, 4.3 g (0.015 m) of sodium carbonate, 10 ml of water and 200 ml of tetrahydrofuran) at 0° C. was added 5.16 g (0.021 m) of 3-tosyl-2-azabicyclo[2.2.1]hepta-2,5-diene (prepared by the procedure of J. Organic Chemistry, 39, 564 (1974)) in 50 ml of tetrahydrofuran. After being stirred overnight, during which time the temperature was allowed to warm to 25° C., the organic layer was separated, dried, and stripped of solvent. Purification of the residue by chromatography (silica gel: 1:1::dichloromethane:ethyl acetate) gave 0.8 g of material whose spectra were consistent with the title structure.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9].[NH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:27]([O:26][C:24]([N:16]([CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@@H](C)Oc1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C)Oc1cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
300 mg of methyl (2R)-2-[3-(hydroxymethyl)phenoxy]propionate, 465 mg of di-tert-butyl iminodicarboxylate, and 543 mg of triphenylphosphine were dissolved in 3.00 mL of toluene, and 445 mg of diisopropyl azodicarboxylate was added thereto under ice-cooling, followed by stirring at room temperature overnight. The reaction liquid was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 0:100) to obtain 584 mg of methyl (2R)-2-(3-{[bis(tert-butoxycarbonyl)amino]methyl}phenoxy)propionate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH:13]([C:17]1[N:18]=[C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[S:20][CH:21]=1)[C:14]([OH:16])=O.[CH3:27][N:28]1[C:32]([S:33][CH2:34][C:35]2[CH2:36][S:37][C@@H:38]3[CH:45]([NH2:46])[C:44](=[O:47])[N:39]3[C:40]=2[C:41]([OH:43])=[O:42])=[N:31][N:30]=[N:29]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C)C=O>[CH3:27][N:28]1[C:32]([S:33][CH2:34][C:35]2[CH2:36][S:37][C@@H:38]3[CH:45]([NH:46][C:14](=[O:16])[CH:13]([O:12][CH:7]4[CH2:8][CH2:9][CH2:10][CH2:11][O:6]4)[C:17]4[N:18]=[C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[S:20][CH:21]=4)[C:44](=[O:47])[N:39]3[C:40]=2[C:41]([OH:43])=[O:42])=[N:31][N:30]=[N:29]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CS(=O)(=O)Nc1nc(C(OC2CCCCO2)C(=O)O)cs1
Agent: CS(=O)(=O)N=c1[nH]c(C(OC2CCCCO2)C(=O)O)cs1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC3CCCCO3)c3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Temperature: -20 °C

Procedure:
To dimethylformamide (0.12 g.) was dropwise added phosphorus oxychloride (0.29 g.) under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40° C. and then cooled to -20° C. To the mixture was added all at once a solution of 2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetic acid, which can be represented as 2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetic acid, (0.52 g.) in ethyl acetate (7 ml.) at -20° C. with stirring, and then the mixture was stirred for 30 minutes at -20° to -10° C. Thus obtained mixture was added all at once to the solution prepared in the similar manner as in Example 1 from 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-amino-3-cephem-4-carboxylic acid (0.51 g.), bis(trimethylsilyl)acetamide (1.5 ml.) and ethyl acetate (10 ml.), at -40° C. The mixture was stirred for 30 minutes at the same temperature and further stirred for 1.5 hours at -20° to -10° C. After the reaction, the reaction mixture was poured into 5% sodium bicarbonate aqueous solution (20 ml.). The mixture was washed with ethyl acetate, and the aqueous layer was separated therefrom. Thus obtained aqueous layer was post-treated in a similar manner as that of example 5 to give 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylamino-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-(2-tetrahydropyranyl)oxy-2-(2-mesylimino-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid, (0.41 g.)
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:14][N:13](C(=O)C(F)(F)F)[C@H:12]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][NH:9][C@H:10]1[CH2:14][NH:13][C@H:12]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)[C@@H]1C[C@@H](NOCc2ccccc2)CN1C(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)[C@@H]1C[C@@H](NOCc2ccccc2)CN1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of allyl (4R)-4-[(benzyloxy)amino]-1-(trifluoroacetyl)-L-prolinate (1.19 g, 3.20 mmol) in methanol (9.5 mL) was added slowly to a solution of sodium borohydride (312 mg, 8.25 mmol) in methanol (9.5 mL) at −10° C. The reaction mixture was allowed to warm to 0° C. slowly then stirred at 0° C. for 3 hours. Additional sodium borohydride (0.29 g, 7.67 mmol) was added at 0° C. and the reaction mixture was stirred at 0° C. for three hours then silica gel (to pre-absorb the crude product for chromatography) was added and the solvent removed under vacuum. The residue was chromatographed on silica gel eluted with 15:9:1 dichloromethane:ethyl acetate:methanol to afford the title compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[C:24](=[O:26])[CH3:25])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:6]([O:27][CH3:28])[CH:7]=3)[N:12]=[CH:11][CH:10]=2)=[C:17]([C:24](=[O:26])[CH3:25])[CH:18]=1
Reactant: COc1ccc(Oc2ccnc3cc(OCCCl)c(OC)cc23)c(C(C)=O)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccnc3cc(OCCN4CCOCC4)c(OC)cc23)c(C(C)=O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
1-(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methoxyphenyl)-1-ethanone (compound 119) (89 mg), morpholine (57 mg), and potassium carbonate (152 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (24 mg, yield 24%).