Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].C(O)C.[CH3:15][CH:16]([S-:18])[CH3:17].[Na+]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([S:18][CH:16]([CH3:17])[CH3:15])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)[S-]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: [Na+]
Solvent: CCO
Product: CC(C)Sc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,3-Difluoro-2-nitro-benzene (5.00 g, 31.4 mmol) was stirred in Ethanol (25 mL, 430 mmol) and treated with sodium 2-propanethiolate (3.08 g, 31.4 mmol) in several portions over 5 min. The reaction mixture was stirred at rt for 30 mins, was concentrated under reduced pressure, diluted with water, and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(N3CCOCC3)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1cc(OC[C@@H]2CCCN2)ccc1Cc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a 20 mL vial which contained a solution of (S)-2-[4-(4-morpholin-4-yl-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol) in dioxane (1 mL) was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. the resulting solid was filtered out and dried under vacuo to yield the title product (70 mg, 80%); LCMS; 90%, ESI+ Calcd: 352.5, found m/z: 353.7 (M+1); 1H NMR (400 MHz, DMSO-d6); δ 1.66-1.76 (m, 1H), 1.84-2.02 (m, 2H), 2.04-2.14 (m, 1H), 3.05-3.24 (m, 4H), 3.73-4.12 (m, 10H), 4.19 (dd, J1=10.8 Hz, J2=3.6 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.20 (m, 6H):
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][N:11]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=3[C:21]([F:24])([F:23])[F:22])[C:7]=2[CH:6]=[CH:5][N:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:56][C:57]1[CH:68]=[CH:67][C:60]2[NH:61][C:62]([C@@H:64]([NH2:66])[CH3:65])=[N:63][C:59]=2[CH:58]=1.ClCl>CS(C)=O.ClCCl.CO>[Cl:56][C:57]1[CH:68]=[CH:67][C:60]2[NH:61][C:62]([C@@H:64]([NH:66][C:16](=[O:18])[C:15]3[CH:19]=[CH:20][C:12]([N:11]4[C:7]5[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=5[N:9]=[CH:10]4)=[C:13]([C:21]([F:22])([F:24])[F:23])[CH:14]=3)[CH3:65])=[N:63][C:59]=2[CH:58]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: COc1nccc2c1ncn2-c1ccc(C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1nccc2c1ncn2-c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1C(F)(F)F
Yield: 46 %

Procedure:
Prepared analogously to Example 1g from 4-(4-methoxyimidazo[4,5-c]pyridin-1-yl)-3-trifluoromethylbenzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylsulfoxide. Yield: 46%; Rf value: 0.39 (silica gel: dichloromethane/methanol=10:1); C24H18ClF3N6O2 (514.893); mass spectrum: (M+H)+=515/517 (chlorine isotope).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[CH2:10][C:11]([CH3:14])([OH:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12]
Reactant: CC(C)(O)CCl
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)COc1ccccc1Br
Temperature: 90 °C
Yield: 0.6 %

Procedure:
To a solution of 2-bromophenol (3.0 g, 1.745 mmol, Aldrich) and 1-chloro-2-methylpropan-2-ol (2.8 g, 6.397 mmol, Spectrochem) in DMF (15 mL) was added sodium carbonate (1.23 g, 11.63 mmol). The reaction mixture was heated at 90° C. for 12 h. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material that was purified by combiflash silica gel column chromatography (column size: 12 g; elution: 0-5% ethyl acetate in hexane) to yield 1-(2-bromophenoxy)-2-methylpropan-2-ol (2.7 mg, 64.2%) as a transparent liquid. m/z (ESI) 243.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.[Cl:54][CH2:55][CH2:56][C:57](Cl)=[O:58]>O1CCCC1>[Cl:54][CH2:55][CH2:56][C:57]([N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:4]=2)[N:14]2[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:13]12)=[O:58]
Reactant: O=C(Cl)CCCl
Reactant: N#Cc1ncn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: C1CCOC1
Product: N#Cc1ncn2c1N(C(=O)CCCl)CC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a stirred mixture of 4.5 g of 1,2-dihydro-4-[3-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrimidine-8-carbonitrile (prepared as described in Example 2) and 3.6 g of [1,8-bis(dimethylamino)naphthalene-N,N,N',N'-tetramethyl-1,8-naphthalenediamine] in 120 ml of dry tetrahydrofuran at room temperature, under nitrogen was added over a period of 12-15 minutes a solution of 3.9 g of 3-chloropropionyl chloride in 30 ml of dry tetrahydrofuran. The mixture was stirred at room temperature under nitrogen for one hour then under reflux for 4 hours. The solution was filtered hot and the filtrate was evaporated to dryness in vacuo. The residue was triturated with anhydrous ether and gave 5.95 g of the product of the example as an off-white solid. The product was recrystallized from ethyl acetate, mp 165° 166° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[F:22])[CH3:13].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:12][CH3:13])=[C:16]([F:22])[C:17]=2[F:21])=[O:8])[CH:10]=1
Reactant: CCOc1cccc(F)c1F
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)c(F)c1F
Reaction time: 16 h
Yield: 69.8 %

Procedure:
5-bromo-2-chloro-benzoyl chloride 2a (7.74 g, 30.5 mmol) was dissolved in 200 mL dichloromethane, followed by addition of 1-ethoxy-2,3-difluoro-benzene 3b (4.82 g, 30.5 mmol) and aluminum trichloride (4.07 g, 30.5 mmol). The reaction mixture was stirred for 16 hours. Thereafter, the mixture was partitioned after 100 mL 2 M hydrochloric acid were added. The organic extract was washed with saturated sodium chloride solution (100 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (5-bromo-2-chloro-phenyl)-(4-ethoxy-2,3-difluoro-phenyl)methanone 3c (8.0 g, yellow grease), yield: 70.2%. MS m/z (ESI): 376.9 [M+1].
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[C:12]1([C:18]2([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:27]([O:34][C:35](ON1C(=O)CCC1=O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:27]([O:34][C:35]([N:21]1[CH2:20][CH2:19][C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of commercially available 4-phenyl-4-carboxypiperidine toluenesulfonate (7.55 g, 20 mmol), N-(benzyloxycarbonyloxy)succinimide (5.0 g, 20 mmol) and TEA (5 mL, 36 mmol) in CHCl3 (100 mL) is stirred at r.t. for 48 h. The mixture is diluted with CH2Cl2 (100 mL) and extracted with 1 M aq. NaOH (3×50 mL). The aq. phase is extracted with Et2O (2×50 mL), acidified (pH 2) with 6N aq. HCl and extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 extracts are dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[C:19](=[O:24])[NH:20][CH:21]=[CH:22][N:23]=2)[CH2:13][CH2:12]1)=O.Cl.[NH2:26][OH:27].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C(O)C.ClCCl.O>[OH:27][N:26]=[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[C:19](=[O:24])[NH:20][CH:21]=[CH:22][N:23]=2)[CH2:13][CH2:12]1)[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C(Cc1ccccc1F)C1CCN(Cc2ncc[nH]c2=O)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=c1[nH]ccnc1CN1CCC(C(Cc2ccccc2F)=NO)CC1
Yield: 69.5 %

Procedure:
After suspending 150 mg of 3-[4-[2-(2-fluorophenyl)acetyl]piperidino]methyl-1H-pyrazin-2-one in 3 ml of ethanol, 47 mg of hydroxylamine hydrochloride and 193 mg of sodium carbonate were added while stirring and the mixture was heated to reflux for 1 hour. Water and saturated aqueous ammonium chloride solution were added to the reaction solution for adjustment to pH 7, and extraction was performed with dichloromethane. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added and the insoluble portion was filtered out to obtain the title compound (109 mg, 70% yield).
Reaction SMILES: [F:1][C:2]([F:15])([CH:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=CN=1)[C:3]([NH:5][NH2:6])=[O:4].FC(F)(C(O)C1[S:25]C=CC=1)C(OCC)=O.NN>>[F:1][C:2]([F:15])([CH:7]([OH:14])[C:8]1[S:25][CH:11]=[CH:12][CH:13]=1)[C:3]([NH:5][NH2:6])=[O:4]
Reactant: NNC(=O)C(F)(F)C(O)c1ccccn1
Reactant: CCOC(=O)C(F)(F)C(O)c1cccs1
Agent: NN
Product: NNC(=O)C(F)(F)C(O)c1cccs1

Procedure:
α,α-difluoro-β-hydroxy-2-thiophenepropanoic acid, hydrazide (26) was prepared in the same manner as α,α-difluoro-β-hydroxy-3-(2-pyridinyl)-propanoic acid, hydrazide (10), as described above in Example 10, on a 1.4 mmol scale from ethyl α,α-difluoro-β-hydroxy-2-thiophenepropanoate and hydrazine to yield 0.23 g (74%) of product. Analysis calculated for C7H8N2O2F2S (M.W. 222.21): C, 37.84; H, 3.63; N, 12.61. Found: C, 37.72; H, 3.51; N, 12.42.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:54]([OH:55])[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:56]([CH3:58])[CH3:57])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH2:44]([O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:56]([CH3:57])[CH3:58])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:54]([OH:55])[CH:41]1[O:40]3)[O:36]2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 56.5 %

Procedure:
44.3 mg of compound (49) was dissolved in 5 ml of ethyl acetate and allowed to react in the presence of a catalytic amount of 10% palladium-carbon under stirring under a hydrogen atmosphere at room temperature for 70 minutes. The reaction solution was filtered, and the filtrate was concentrated in vacuo to give the crude reaction product. The crude reaction product was charged onto a silica gel column (Kieselgel 60, Merck, 1.5φ×15 cm) and eluted with 150 ml of n-hexane-ethyl acetate (2:1), 200 ml of n-hexane-ethyl acetate (1:3) and finally chloroform-methanol (10:1) to give 19.8 mg of compound (50) as a colorless oily substance.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[CH2:4][CH2:5][CH:6]([N+:11]([O-])=O)[CH:7]([OH:10])[CH2:8][F:9]>CO.[Ni]>[CH3:1][NH:2][C:3](=[O:14])[CH2:4][CH2:5][CH:6]([NH2:11])[CH:7]([OH:10])[CH2:8][F:9]
Reactant: CNC(=O)CCC(C(O)CF)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CNC(=O)CCC(N)C(O)CF
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of 6-fluoro-5-hydroxy-4-nitro-hexanoic acid methylamide (0.325 g, 1.56 mmol) in MeOH (12 mL) was added Raney Ni (about 0.12 g), and the mixture was shaken under H2 (40-45 psi) at room temperature for 18 h. The black mixture was filtered through celite, and the celite was washed with additional MeOH (100 mL). The yellow solution was concentrated to give yellow oil (0.250 g, 90%), which was used without further purification. 1H NMR (CDCl3): 5.68 (br s, NH, 1H), 4.64-4.38 (m, 2H), 3.64-3.49 (m, 1H), 2.90-2.85 (m, 1H), 2.81 (d, J=5.10 Hz, 3H), 2.40-2.29 (m, 2H), 1.97-1.88 (m, 2H); Mass Spectra: ESI: calculated: 178.11. found: MH+ 179.18.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:12]([CH3:24])[C:13]([C:22]#[N:23])=[C:14]2[C:18]=1[O:17][C:16]([CH2:19][O:20][CH3:21])=[N:15]2.O.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:12]([CH3:24])[C:13]([C:22]#[N:23])=[C:14]3[C:18]=2[O:17][C:16]([CH2:19][O:20][CH3:21])=[N:15]3)[CH2:4]1
Reactant: COCc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCc1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 90 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (76 μl, 0.60 mmol) was added to a dimethyl sulfoxide (4 ml) solution of 7-fluoro-2-(methoxymethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-59) (58 mg, 0.20 mmol), followed by stirring at 90° C. for 1 hour. After cooling to room temperature, the above brown oily substance and saturated sodium bicarbonate water were added, followed by extraction three times with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with chloroform:methanol (50:1) was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed twice with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration tinder reduced pressure, the entitled compound (39 mg, 17%) was obtained as a brown oily substance.
Reaction SMILES: C(Cl)CCl.Cl.[N:6]1[C:11]2[NH:12][CH2:13][CH2:14][O:15][CH2:16][C:10]=2[CH:9]=[C:8]([CH:17]=[CH:18][C:19]([OH:21])=O)[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:32][NH:33][CH2:34][C:35]1[N:36]([CH3:44])[C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH3:32][N:33]([CH2:34][C:35]1[N:36]([CH3:44])[C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:19](=[O:21])[CH:18]=[CH:17][C:8]1[CH:7]=[N:6][C:11]2[NH:12][CH2:13][CH2:14][O:15][CH2:16][C:10]=2[CH:9]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=C(O)C=Cc1cnc2c(c1)COCCN2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2ccccc2n1C)C(=O)C=Cc1cnc2c(c1)COCCN2
Temperature: 35 °C
Reaction time: 8 h

Procedure:
EDC (0.10 g, 0.52 mmol) was added to a solution of 3-(5,7,8,9-Tetrahydro-6-oxa-1,9-diaza-benzocyclohepten-3-yl)-acrylic acid hydrochloride (0.11 g, 0.43 mmol), HOBt (64 mg, 0.47 mmol), Methyl-(1-methyl-1H-indol-2-ylmethyl)-amine (128 mg, 0.47 mmol) and (i-Pr)2EtN (0.36 mL, 2.15 mmol) in DMF (6 mL). The mixture was allowed to stir overnight at 35° C. The mixture was cooled to 0° C. and diluted with H2O (15 mL) with rapid stirring. The resulting gummy precipitate was filtered, washed with H2O (30 mL) then with Et2O (20 mL). The solid was dissolved in dichloromethane (100 mL), washed with H2O (50 mL), brine (50 mL), dried over MgSO2, and treated with charcoal. The mixture was filtered and the filtrate was passed through a plug of silica gel. The silica gel was washed with ethyl acetate (50 mL) then with 5% methanol: dichloromethane (50 mL). The combined organic fractions were concentrated to give an oil. The resulting oil was triturated with ether:hexanes (20 mL) until the oil was converted to a beige solid. Yield: 40 mg (25%) as a mixture of amide rotamers; 1H NMR (400 MHz, DMSO-d6) δ 8.24 (br s, 1H), 7.92 and 7.85 (2×s, 1H), 7.50-7.39 (m, 3H), 7.18-6.92 (m, 3H), 6.78 (br s, 1H), 6.41 and 6.20 (2×s, 1H), 5.07 and 4.83 (2×s, 2H), 4.52 and 4.45 (2×s, 2H), 3.71-3.61 (m, 5H), 3.50-3.40 (m, 2H), 3.10 and 2.95 (2×s, 3H); ESI MS m/z 377 [C22H24N4O2+H]+
Reaction SMILES: FC(F)(F)C([O-])=O.C([NH:27][C:28]1[S:29][CH:30]=[C:31](/[C:33](=[N:71]/[O:72][C@H:73]([C:75]([O:77]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:76])[CH3:74])/[C:34]([NH:36][CH:37]2[C:69](=[O:70])[N:39]3[C:40]([C:57]([O:59]CC4C=CC(OC)=CC=4)=[O:58])=[C:41]([CH2:44][S:45][C:46]4[N+:47]([CH3:56])=[C:48]5[CH:53]=[CH:52][N:51]([CH3:54])[CH:50]=[C:49]5[N:55]=4)[CH2:42][S:43][C@H:38]23)=[O:35])[N:32]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Na]>>[NH2:27][C:28]1[S:29][CH:30]=[C:31](/[C:33](=[N:71]/[O:72][C@H:73]([C:75]([OH:77])=[O:76])[CH3:74])/[C:34]([NH:36][CH:37]2[C:69](=[O:70])[N:39]3[C:40]([C:57]([O-:59])=[O:58])=[C:41]([CH2:44][S:45][C:46]4[N+:47]([CH3:56])=[C:48]5[CH:53]=[CH:52][N:51]([CH3:54])[CH:50]=[C:49]5[N:55]=4)[CH2:42][S:43][C@H:38]23)=[O:35])[N:32]=1
Reactant: COc1ccc(COC(=O)C2=C(CSc3nc4cn(C)ccc-4[n+]3C)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [Na]
Product: C[C@H](O/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nc4cn(C)ccc-4[n+]3C)CS[C@H]12)c1csc(N)n1)C(=O)O
Yield: 52.5 %

Procedure:
Using 334 mg of p-methoxybenzyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-{(S)-1-diphenylmethoxycarbonylethoxyimino}acetamido]-3-(1,5-dimethylimidazolo[4,5-c]pyridinium-2-yl)thiomethyl-3-cephem-4-carboxylate trifluoroacetate as a starting material, the reaction and purification were carried out in the same manner as in Example 1(b) to obtain 87 mg of the title compound in the form of a sodium salt in a yield of 51%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH2:13][CH2:12][CH2:11][C:10](=[O:17])[C:9]2=1.[CH3:18]I>C1COCC1.[Cl-].[Na+].O>[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[N:15]([CH3:18])[C:14]1[CH2:13][CH2:12][CH2:11][C:10](=[O:17])[C:9]2=1
Reactant: CI
Reactant: O=C1CCCc2[nH]c3c(F)cccc3c21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c2c(c3cccc(F)c31)C(=O)CCC2
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (80% dispersion in oil; 1.15 g) in dry THF (50 ml) under nitrogen was added 8-fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (6.5 g) in dry THF (50 ml), and the mixture was stirred for 1 h. Methyl iodide (4.1 ml) was added, and the mixture was stirred for 3 h. The mixture was then poured into brine (300 ml) and extracted with ether (2×300 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (5.77 g), m.p. 126°-128°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:2]=12.O>COCCO.[Pd]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH:2]12
Reactant: CC(C)(C)OC(=O)N1Cc2cccnc2C1
Agent: [Pd]
Solvent: O
Solvent: COCCO
Product: CC(C)(C)OC(=O)N1CC2CCCNC2C1
Temperature: 70 °C
Reaction time: 6 h
Yield: 61.6 %

Procedure:
To a solution of tert-butyl 5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate (1.50 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The suspension was heated to 70° C. and stirred for 6 h under H2. The resulted mixture was cooled to rt, poured into 100 mL of water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as pale yellow oil (0.95 g, 65.00%). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 227.2 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]1([CH3:28])[N:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:18]2[C:17](=[O:24])[N:16]1[CH:25]([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C)C=O>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:22]1[CH2:21][CH2:20][N:19]2[C:15]([CH3:14])([CH3:28])[N:16]([CH:25]([CH3:26])[CH3:27])[C:17](=[O:24])[CH:18]2[CH2:23]1
Reactant: CC(C)N1C(=O)C2CNCCN2C1(C)C
Reactant: Cc1cccc(C)c1NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)CN1CCN2C(C1)C(=O)N(C(C)C)C2(C)C
Temperature: 75 °C
Yield: 72.7 %

Procedure:
A mixture of 8.2 parts of 2-chloro-N-(2,6-dimethylphenyl)acetamide, 7.2 parts of hexahydro-3,3-dimethyl-2-(1-methylethyl)imidazo[1,5-a]pyrazin-1(5H)-one, 7 parts of N,N-diethylethanamine and 54 parts of N,N-dimethylformamide was stirred and heated for 3 hours at 75° C. After cooling to 0° C., the precipitate was filtered off and the filtrate was evaporated. The residue was dissolved in 300 parts of trichloromethane. This solution was washed with 50 parts of water, dried, filtered and evaporated. The residue was triturated in 2,2'-oxybispropane. After cooling to 0° C., the product was filtered off and dried, yielding 9.2 parts (72.7%) of N-(2,6-dimethylphenyl)hexahydro-3,3-dimethyl-2-(1-methylethyl)-1-oxoimidazo[1,5-a]pyrazine-7(8H)-acetamide; mp. 155° C. (intermediate 101).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[N:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][C:35]([SH:37])=[N:34][N:33]=2)=[CH:28][CH:27]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:37][C:35]3[O:36][C:32]([C:29]4[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=4)=[N:33][N:34]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Sc1nnc(-c2ccncc2)o1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(-c4ccncc4)o3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 5-(4-pyridyl)-1,3,4-oxadiazole-2-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate.