Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5]C)=O.[Na].[C:11]1([N:17]2[C:21]([NH2:22])=[C:20]([CH:23]=O)[N:19]=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.O>[C:11]1([N:17]2[C:21]3[NH:22][C:3](=[O:5])[C:2]([C:1]([O:8][CH3:9])=[O:7])=[CH:23][C:20]=3[N:19]=[N:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1c(C=O)nnn1-c1ccccc1
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2nnn(-c3ccccc3)c2[nH]c1=O
Reaction time: 18 h
Yield: 49.1 %

Procedure:
Dimethyl malonate (0.31 ml, 2.7 mmol) was added at room temperature to a stirred solution of sodium (0.065 g, 2.7 mmol) dissolved in dry methanol (8 ml) under nitrogen. A solution of 1-phenyl-4-formyl-5-amino-1,2,3-triazole (Bull. Soc. Chim. Belg., 1988, 97, 85-86) (0.50 g, 2.66 mmol) in dry methanol (4 ml) was added and the mixture was stirred for 18 h. The white suspension was diluted with water (50 ml) and the solids were collected and dissolved in dichloromethane-methanol (2:1, 100 ml). The solution was washed with aqueous citric acid (1 M, 50 ml), dried (Na2SO4), filtered and concentrated to give 3-phenyl-5-oxo-6-methoxycarbonyl-4H-1,2,3-triazolo[4,5-b]pyridine (0.353 g, 49%) as a white powder. δH (360 MHz; DMSO) 3.89 (3H, s), 7.56 (1H, t, J=7.5), 7.68 (2H, dd, J=7.5 and 7.5), 8.09 (2H, d, J=7.5), 8.92 (1H, s) and 12.67 (1H, br s); m/z (ES+) 271 (M+H+).
Reaction SMILES: [C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([O:18]CC)=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+]>O>[C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([OH:18])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (2.8 g.) and ethanol (10 ml.) was mixed with a solution of sodium hydroxide (0.54 g.) in water (20 ml.), and the mixture was stirred for 1 hour at room temperature. After the reaction, a small amount of ethanol was distilled off. The remaining reaction mixture was washed with diethyl ether and then the aqueous layer was separated therefrom. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid and then the ethyl acetate layer was separated therefrom. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then treated with activated charcoal. The solvent was distilled off from the ethyl acetate layer to give yellow brown powder of 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid (1.75 g.).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c[nH]c23)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A154) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([N:31]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1)(OC(C)(C)C)=O.[ClH:40].C(N=C=N)C.C(O)(C(F)(F)F)=O.Cl>CC#N.CO.C(Cl)(Cl)Cl>[ClH:40].[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:37]([CH:34]4[CH2:35][CH2:36][NH:31][CH2:32][CH2:33]4)=[O:38])[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Agent: CCN=C=N
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(1-naphthylsulfonyl)-1H-indazol-5-amine (300 mg, 0.928 mmol), 1-Boc-piperidine-4-carboxylic acid (276 mg, 1.21 mmol), 1-[3-(dimethylamino)propyl)]-3-ethylcarbodimide hydrochloride (231 mg, 1.21 mmol) in CH3CN was stirred at room temperature overnight and concentrated to dryness to provide a residue. The residue was treated with TFA at room temperature for 2 hours and concentrated to dryness in vacuo. The resultant residue was purified by reverse phase HPLC to give a solid. The solid was dispersed in methanol and chloroform, treated with aqueous HCl solution, concentrated and dried in vacuo to provide the title compound as a milky light orange solid, characterized by HNMR and mass spectral analyses, MS (ES+) m/e 435 (MH+).
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(O[CH2:9][C@H:10]1[CH2:22][CH2:21][N:13]2[C:14]3[C:19]([CH:20]=[C:12]2[CH2:11]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[C:12]1[CH2:11][C@@H:10]([CH2:9][C:1]#[N:2])[CH2:22][CH2:21][N:13]12
Reactant: CS(=O)(=O)OC[C@H]1CCn2c(cc3ccccc32)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CC[C@H]1CCn2c(cc3ccccc32)C1
Temperature: 70 °C
Yield: 52.7 %

Procedure:
18.0 g (367 mmol) of sodium cyanide were added to a solution of 65.0 g (233 mmol) of (6,7,8,9-tetrahydropyrido[1,2-a]indol-8(S)-yl)methyl methanesulfonate in 500 ml of dimethylformamide and the mixture was heated at 70° C. for 24 hours. The mixture was partitioned between 1000 ml of water and 600 ml of ethyl acetate. The aqueous phase was extracted twice with 700 ml of ethyl acetate each time and the combined extracts were washed in twice with 500 ml of water each time, dried over magnesium sulfate and evaporated. The brown solid obtained was dissolved in ethyl acetate and the solution was filtered through a pad of silica gel. The solvent was removed in a vacuum and the residue was crystallized from methanol to give 25.8 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-acetonitrile as a light brown solid of melting point 100°-101° C.; [α]D20 -40.6° (c=0.84%, CH2Cl2).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[C:23]#[C:24][CH2:25][F:26])C>>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]3=[N:16][C:22](=[O:21])[CH:23]=[C:24]([CH2:25][F:26])[N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C#CCF
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Product: CC(C)(C)c1ccc(OC[C@@H]2Cn3c(CF)cc(=O)nc3O2)cc1

Procedure:
The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-yl-amine and 4-fluoro-but-2-ynoic acid ethyl ester (prepared in accordance with the procedures as described in Poulter, J Org Chem 1981, 46, 1532) according to the procedures employed for the preparation of the compound in Example 98.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][C:7]3=[CH:6][C:5]=2[CH:4]=1.OP(O)(O)=O.[CH3:20][N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.[OH-].[NH4+]>CC(O)=O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][C:7]3=[C:6]([C:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH:23]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)cc1n2CCC1
Reactant: CN1CCC(=O)CC1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(C1=CCN(C)CC1)c1n2CCC1
Temperature: 60 °C
Yield: 98.9 %

Procedure:
To a solution of 7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole (718 mg, 3.83 mmol) (Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippen, L. A.; Repke, D. B.; Souchet, M. Synthesis 10,871-878(1991); Ishikura, M.; Terashima, M. Tetrahedron Lett. 33, 6849-6852(1992)) in glacial AcOH (20 mL) at 60° C. was added H3PO4 (5.0 mL, 10 mmol, 2.0 N) and 1-methyl-4-piperidone (1.2 mL, 11.5 mmol). The reaction was heated for 1 h at 60° C., cooled to room temperature and poured into a mixture of ammonium hydroxide in ice water. This reaction mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure yielded 1.07 g (99%) of the title compound as a brown oil: MS (ES+): m/e 283.0 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:8])[C@H:4]([CH2:6][OH:7])[NH2:5].C(N(C(C)C)CC)(C)C.[N:18]1[NH:19][N:20]=[N:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:47]=[CH:46][C:32]2[N:33]([CH:36]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:37](O)=[O:38])[CH:34]=[N:35][C:31]=2[CH:30]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>>[O:38]=[C:37]([NH:5][C@H:4]([C:3]([OH:2])=[O:8])[CH2:6][OH:7])[CH:36]([N:33]1[C:32]2[CH:46]=[CH:47][C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]3[N:18]=[N:19][NH:20][N:21]=3)=[CH:30][C:31]=2[N:35]=[CH:34]1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Reactant: COC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(C(=O)N[C@@H](CO)C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Yield: 10.6 %

Procedure:
Serine methyl ester (1.0 mmoles, 0.119 g ), diisopropylethylamine (1.0 mmoles, 0.206 g), 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid (1.0 mmoles, 0.405 g), hydroxybenzotriazole (1.0 mmole, 0.135 g), and dicyclohexylcarbodiimide (1.0 mmoles, 0.206 g) were reacted as in Example 37. The resulting ester 0.19 moles, 0.097 g) was hydrolyzed as in Example 37 to yield 0.052 g of N-[1-oxo-2-[5-[2-(2H-tetrazol-5-yl]phenyl]-1H-benzimidazol-1-yl]octyl]-L-serine (MS).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.C([O-])(=O)C.[Na+].[Br-:15].[K+].BrBr>CO>[Br:15][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]2=[N:1][CH:2]=1
Reactant: c1cnc2nccn2c1
Reactant: [Br-]
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: Brc1cnc2ncccn12
Yield: 87 %

Procedure:
Imidazo[1,2-α]pyrimidine (0.20 g, 1.68 mmol) and sodium acetate 207 mg, 2.52 mmol) were dissolved in methanol (2 ml) which had been saturated with potassium bromide and this mixture was cooled to −10° C. before dropwise addition of bromine (269 mg, 1.68 mmol) over 5 min. On complete addition the mixture was quenched by addition of 1M sodium sulfite solution (2 ml) and the solvent removed in vacuo. The residue was treated with water (15 ml) and saturated sodium hydrogencarbonate solution (15 ml) and extracted with ethyl acetate (2×50 ml). The organics were combined then washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to give an off-white solid. This solid was purified by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-2%) to give 3-bromoimidazo[1,2-α]pyrimidine (0.29 g, 87%) as a white solid: δH (400 MHz, CDCl3) 7.02 (1H, dd, J 7 and 4), 7.83 (1H, s), 8.43 (1H, dd, J 7 and 2), 8.59 (1H, dd, J 7 and 2).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[CH3:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:29][CH2:28]5)=[N:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (120 mg. 0.187 mmol) was alkylated using (S)-2-methyloxirane (33 mg, 0.562 mmol), DIPEA (145 mg, 1.124 mmol) and ethanol (5 mL) to get 100 mg (crude) of the titled compound. MS: m/z=662.3 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](CC[Si](C)(C)C)(=[O:13])=[O:12])=[CH:7][C:6]=1[C:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:28]=2)[CH2:23]1)=[O:21])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Na+:68].[Cl-]>C1COCC1>[Na+:68].[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH:28]=2)[CH2:23]1)=[O:21])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(=O)[O-])cc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1
Yield: 55 %

Procedure:
1.40 g (2.64 mmol) of [2-isopropoxy-5-(2-trimethylsilanyl-ethanesulfonyl)-phenyl]-[5-(tetrahydro-pyran-4-yl)-1,3-dihydro-isoindol-2-yl]-methanone was dissolved in 14 ml of THF and treated with 4.0 ml (4.0 mmol) of a 1 M solution of TBAF in THF at 60° C. during 3.5 hours. The reaction mixture was poured on an aqueous solution of citric acid/NaCl, then extracted with MTBE/THF 1:1. The organic solvent was evaporated, the residue was dissolved in MeOH/water (3:1) and treated with 600 mg of NaHCO3. After evaporation, the residue was purified chromatographically on a reverse phase column (RP-18, water/methanol) to provide 0.66 g (55%) of the title compound as a white foam. MS (m/e): 430.2 [M+H]+.
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][CH:7]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]2[C:16](=[O:37])[CH:17]([NH:18][C:19](=[O:36])[C:20](=[N:33][O:34][CH3:35])[C:21]3[N:22]=[C:23]([NH:26]C(=O)C(F)(F)F)[S:24][CH:25]=3)[C@H:9]2[S:8]1.C(=O)(O)[O-].[Na+].Cl>O>[CH3:6][CH:7]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]2[C:16](=[O:37])[CH:17]([NH:18][C:19](=[O:36])[C:20](=[N:33][O:34][CH3:35])[C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)[C@H:9]2[S:8]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC(=O)C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(=NC(=O)C(F)(F)F)[nH]1
Agent: Cl
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1

Procedure:
To a solution of sodium acetate (11.6 g.) in water (43 ml) was added 2-methyl-7-[2-methoxyimino-2-(2-trifluoroacetylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-trifluoroacetylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (2.1 g.) with stirring, and the mixture was adjusted to pH 6 with 5% aqueous sodium bicarbonate solution. The mixture was stirred overnight at room temperature. After the reaction, the reaction mixture was adjusted to pH 2.8 to 3 with 10% hydrochloric acid and then cooled. The precipitates were collected by filtration and then dried to give 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (1.1 g.), dp>241° C. The same object compound (0.25 g.) was further obtained from the filtrate by a conventional manner.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.ClC1C=C(O)C=CC=1C=O.C(O)(=O)[CH2:28][C:29]([OH:31])=[O:30].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:28][C:29]([OH:31])=[O:30]
Reactant: O=Cc1ccc(OC2CCCCO2)cc1Cl
Reactant: O=C(O)CC(=O)O
Agent: O=Cc1ccc(O)cc1Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccc(OC2CCCCO2)cc1Cl
Yield: 55 %

Procedure:
Using 4.8 g of 2-chloro-4-(2-tetrahydropyranyloxy)benzaldehyde derived from 2-chloro-4-hydroxybenzaldehyde by the introduction of tetrahydropyranyl group thereinto, 4.2 g of malonic acid, 80 ml of pyridine, and 0.5 ml of piperidine, a reaction similar to that performed in Example 99 was carried out. As a result, 3.1 g of 2-chloro-4-(2-tetrahydropyranyloxy)cinnamic acid was obtained as crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][C@@:2]12[C:12]3[C:13]([S:19]([C:22]4[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][C:25]([CH:31]([CH3:33])[CH3:32])=[CH:24][C:23]=4[CH:34]([CH3:36])[CH3:35])(=[O:21])=[O:20])=[CH:14][CH:15]=[C:16]4[NH:17][CH:18]=[C:10]([C:11]=34)[CH2:9][C@H:3]1[NH:4][C:5](=O)[CH2:6][O:7]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][C@@:2]12[C:12]3[C:13]([S:19]([C:22]4[C:23]([CH:34]([CH3:36])[CH3:35])=[CH:24][C:25]([CH:31]([CH3:33])[CH3:32])=[CH:26][C:27]=4[CH:28]([CH3:30])[CH3:29])(=[O:21])=[O:20])=[CH:14][CH:15]=[C:16]4[NH:17][CH:18]=[C:10]([C:11]=34)[CH2:9][C@H:3]1[NH:4][CH2:5][CH2:6][O:7]2
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3[nH]cc4c3c2[C@@]2(C)OCC(=O)N[C@@H]2C4)c(C(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)c2ccc3[nH]cc4c3c2[C@@]2(C)OCCN[C@@H]2C4)c(C(C)C)c1
Temperature: 0 °C
Yield: 49.8 %

Procedure:
To a solution of trans-4,6,6a,7,9,10a-hexahydro-10a-methyl-1-(2,4,6-triisopropylphenylsulfonyl)-indolo[3,4-gh][1.4]benzoxazin-8-one (220 mg, 0.43 mmol) in THF (10 ml) was added, while stirring under ice-cooling, LAH (3 equivalents). The mixture was heated for 3 hours under reflux. After completion of the reaction, ethanol was added to the reaction mixture to inactivate the excess amount of LAH. The reaction mixture was added to an ice-cooled saturated aqueous solution of Na2SO4, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous saline solution, followed by drying (anhydrous Na2SO4). The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with n-hexane-ethyl acetate (1:5), to afford 106 mg (50%) of the title compound as a syrupy product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:42]=[CH:41][C:24]([C:25]([N:27]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH2:31][N:30]3[CH:38]=[CH:39][CH:40]=[C:29]3[CH2:28]2)=[O:26])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:40]1[CH:39]=[CH:38][N:30]2[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:15]([C:10]4[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=5)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:16])=[CH:42][CH:41]=3)=[O:26])[CH2:28][C:29]=12
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1.14 g of [4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.0 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.52 g of N,N-diisopropylethylamine in 25 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate two times to give 1.70 g of the desired product as an amphorous compound.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]4[C:29]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:23]=5[N:22]([CH3:37])[C:21]=4[N:38]=3)[C:13](=[O:39])[CH:12]=2)=[N:7][CH:8]=1>CO.CCOCC>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]4[C:29]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24][C:23]=5[N:22]([CH3:37])[C:21]=4[N:38]=3)[C:13](=[O:39])[CH:12]=2)=[N:7][CH:8]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc31)CCNCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
1.25 M HCl in MeOH (6.0 mL) was added to tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.12 g, 0.22 mmol) and the resulting solution was stirred under N2 at ambient temperature for 20 h. The resulting suspension was diluted with Et2O (30 mL), and the resulting solids were collected by filtration to provide the title compound (92 mg, 92%) as an off-white solid: mp 238-240° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.43 (s, 2H), 8.62 (d, J=2.0 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.84-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.30 (d, J=8.5 Hz, 1H), 6.19 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 3.73 (s, 3H), 3.40-3.37 (m, 2H), 3.34-3.30 (m, 4H), 3.18-3.14 (m, 2H); ESI MS m/z 420 [M+H]−; HPLC (Method A) 98.8% (AUC), tR=13.5 min.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=O)=[CH:4][CH:3]=1.CC([NH2:18])(C)CO.C1(C)C(C)=CC=CC=1.[NH2-].[Li+]>>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[O:8][CH2:9][CH2:10][N:18]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1C
Product: Nc1ccc(C2=NCCO2)cc1

Procedure:
Ethyl p-aminobenzoate, 20.65 g (0.125 mol), 2-methyl-2-aminopropanol, 22.3 g (0.25 mol) 150 ml of xylene, and 0.25 g of lithium amide were combined and heated at the reflux temperature for 50 hr. The alcohol and water liberated was collected in a Dean-Stark trap, providing indication when the reaction was complete. The xylene solvent was removed and the viscous liquid was added to water to precipitate the product. After drying, a 15.5 g (65%) yield of the 4,4-dimethyl derivative of 4-aminophenyl oxazoline was obtained. The product was recrystallized from ethyl acetate, giving white, crystalline material with mp 172° C. FT-IR, with peaks centered at 3445 (NH), 1635 (—C═N—), and 1602 (phenyl) cm−1 confirmed the desired amino functionalized oxazoline. Following the Example 6 procedure, TDO was used to covert the aforesaid compound to the desired acetoacetamide. The structure of this new composition is as follows: