Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:36][O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:44][C:45]([NH2:47])=[S:46].C([O-])(=O)C.[Na+]>O1CCCC1.O>[CH3:42][O:41][C:39]([CH2:38][O:37][N:36]=[C:4]([C:3]1[N:44]=[C:45]([NH2:47])[S:46][CH:2]=1)[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6])=[O:40]
Reactant: NC(N)=S
Reactant: COC(=O)CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of benzhydryl 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (1.65 g) in a mixture of tetrahydrofuran (10 ml) and water (10 ml) were added thiourea (0.39 g) and sodium acetate (1.05 g). The mixture was stirred at ambient temperature for 2 hours and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with diisopropyl ether and collected by filtration to give benzhydryl 7-[2-methoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (1.45 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:42])([CH3:41])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:40]>>[CH3:42][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:41])[CH2:29][CH2:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][C:32]1=[O:40]
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC(C)(N)CCn1c(=O)[nH]c2ccccc21
Product: CC(C)(CCn1c(=O)[nH]c2ccccc21)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
The target compound is prepared according to General Method 2 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 219 mg (1 mmol) 1-(3-amino-3-methyl-butyl)-1,3-dihydro-benzimidazol-2-one. Yield: 187 mg (44%); mass spectroscopy: [M+H]+=427.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH3:12])[C:8]2=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].Cl[C:16]1[N:21]=[C:20]([NH:22][CH3:23])[C:19]([C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl>[CH3:14][O:13][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:16]1[N:21]=[C:20]([NH:22][CH3:23])[C:19]([C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=1)[C:8](=[O:11])[N:7]([CH3:12])[CH2:6]2
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc2c(cc1N)C(=O)N(C)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc3c(cc2OC)CN(C)C3=O)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 13 %

Procedure:
A mixture of impure 6-amino-5-methoxy-2-methylisoindolin-1-one (<0.57 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (66 mg, 0.31 mmol) and pTSA (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 4 h. DCM (10 mL) and saturated aqueous NaHCO3 (10 mL) were added and the organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via reversed phase preparative HPLC gave 5-methoxy-2-methyl-6-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)isoindolin-1-one (15 mg, 13%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=368 at 2.89 min. 1H NMR (400 MHz, CDCl3): δ 9.04 (s, 1H), 8.17 (s, 1H), 7.80 (s, 1H), 6.93 (s, 1H), 5.26 (br s, 1H), 4.31 (s, 2H), 3.97 (s, 3H), 3.20 (d, J 4.7, 3H), 3.18 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1([OH:13])[CH2:12][CH2:11]1.[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:14]([O:13][C:10]1([CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:11][CH2:12]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1
Reactant: OC1(CCOC2CCCCO2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OC1(CCOC2CCCCO2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a mixture of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)cyclopropanol (730 mg, 4.05 mmol) and benzoic acid (590 mg, 4.86 mmol) in 30 mL of CH2Cl2 was added DMAP (98.8 mg, 0.81 mmol, Shanghai Haiqu chemical Ltd.) and EDCI (1.16 g, 6.08 mmol, Shanghai Haiqu chemical Ltd.) at rt. The reaction mixture was stirred at rt overnight, then concentrated and purified by a silica gel column chromatography (20:1 (v/v) petroleum ether/EtOAc)) to afford the title compound as colorless oil (690 mg, 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([N:12](S(C1C(C)=CC(OC)=C(C)C=1C)(=O)=O)[CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CSCC>ClC(Cl)C.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:30])[CH:4]([NH:12][CH2:13][C:14]#[CH:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCN(C(Cc1ccccc1)C(=O)OC)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Agent: CCSC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: C#CCNC(Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-[(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester (150 mg, 0.349 mmol) in anhydrous dichloroethane (1.5 mL), trifluoroacetic acid (3.5 mL) and ethyl methyl sulfide (0.16 mL, 1.75 mmol) were added. The reaction mixture was stirred at room temperature under a N2 atmosphere for 12 h. Excess of solvents were removed under reduced pressure and the residue was extracted between saturated NaHCO3 solution and ethyl acetate. The organic layer was separated, dried (Na2SO4), concentrated. The crude product was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 3-Phenyl-2-prop-2-ynylamino-propionic acid methyl ester as a thick syrup, 70 mg (92%). 1H NMR (CDCl3, 400 MHz): δ7.32-7.19 (m, 5H), 3.78 (t, 1H), 3.68 (s, 3H), 3.40 (ABq, 2H), 3.03 (dd, 1H), 2.98 (dd, 1H), 1.99 (t, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[Cl:8][C:9]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:24]([O-:26])=[O:25])=[C:16]([CH:23]=1)[C:17]([O:19][CH2:20][CH2:21][OH:22])=[O:18].C(N(CC)CC)C>CCOCC>[Cl:8][C:9]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:24]([O-:26])=[O:25])=[C:16]([CH:23]=1)[C:17]([O:19][CH2:20][CH2:21][O:22][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])=[O:18]
Reactant: O=C(OCCO)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)OCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 23.4 %

Procedure:
Dimethylsulfamoyl chloride (7.2 g, 0.05 mole) was added dropwise to a solution of 2-hydroxyethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate (10 g, 0.025 mole), triethylamine (10 ml) and ethyl ether (200 ml). The mixture was heated to and held at reflux for 5 hrs., cooled, added 200 ml of ether and washed three times with water. The ethereal solution was dried over MgSO4, concentrated to 13.9 g of yellow gum. The gummy material was run through a silica gel with 30% acetone-70% cyclohexane as eluent to afford 3.0 g of pure 2-(N,N-dimethylsulfamoyloxy)ethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate as colorless gum; nmr (CDCl3) 2.96 (S, 6H), 3.84 (m, 2H), 4.52 (m, 2H), 6.88-8.24 (m, 6H).
Reaction SMILES: [Na].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:29])[CH:11]2[NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[C:8]=1[C:30]([OH:32])=[O:31])(=[O:4])[CH3:3].[C:33]([O:39][CH2:40]Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[C:33]([O:39][CH2:40][O:31][C:30]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22]1)[C:10]2=[O:29])=[O:32])(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CSC12)n1cccc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC(C)=O)CSC12)n1cccc1
Reaction time: 0.5 h

Procedure:
The sodium salt of 3-[(acetyloxy)methyl]-7-[[2-carboethoxy-2-(1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (3 grams) was added to about 40 ml of dry dimethylformamide (DMF) and stirred for about 30 minutes. Then 4.0 ml of chloromethyl pivalate in 5 ml of DMF was added. The mixture was stirred for about 4 hours at room temperature. This mixture is diluted with ethyl acetate and thoroughly washed with water. The ethyl acetate portion is dried over sodium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.O.C1(C)C=CC(S(O)(=O)=[O:20])=CC=1>CC(CC)=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:20])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A solution of 5.0 g. of acetonine in 33.8 g. of methylethyl ketone was added with 6.2 g. of p-toluenesulfonic acid monohydrate under stirring. The mixture was stirred at room temperature for 8 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 8 to obtain triacetonamine in a yield of 91.7%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:27])[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl.CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:24]3[CH2:25][CH2:26][CH:21]([N:20]([CH3:27])[CH3:19])[CH2:22][CH2:23]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN(C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CO
Solvent: ClCCCl
Product: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidine-6-carbaldehyde (5.0 g, 17.7 mmol) and dimethylpiperidin-4-ylamine (2.7 g, 21.2 mmol) in DCE (100 mL) was stirred at room temperature for 4 hours then triacetoxyborohydride (5.6 g, 26.5 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (2×70 g). The cartridge was washed with MeOH/DCM (1/1: v/v) and the desired product was eluted with (2M NH3 in MeOH)/DCM (1/1: v/v). The solvents were removed and the residue was precipitated from IMS to give [1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]dimethylamine as a white solid (4.45 g, 64%). LCMS (Method B): RT 0.37 min and 1.85 min; [M+H]+ 396
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4]([CH3:11])=[N:3]1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:8]([C:5]4[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=4[CH3:7])=[O:10])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A dry flask was charged with 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid (0.122 g, 0.791 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (8 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.793 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.169 g, 0.440 mmol, 56%).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=3[F:26])=[CH:12][CH:11]=2)C=CC=CC=1.[CH2:28]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:29]1[CH:37]=[CH:36][C:35]2[O:34][CH2:33][O:32][C:31]=2[CH:30]=1.O>CN(C=O)C>[F:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[O:16][C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:8]([N:41]2[CH2:42][CH2:43][N:38]([CH2:28][C:29]3[CH:37]=[CH:36][C:35]4[O:34][CH2:33][O:32][C:31]=4[CH:30]=3)[CH2:39][CH2:40]2)=[O:27])=[CH:15][CH:14]=1
Reactant: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1)Oc1ccccc1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(2-fluoro-4-nitrophenoxy)phenyl]carbamate phenyl ester (0.700 g, 1.90 mmol) in DMF (15 mL) was added 1-piperonylpiperazine (0.460 g, 2.09 mmol), and the resulting solution was stirred for 2 hours at room temperature. water was added to the resulting reaction solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, and evaporated, to thereby yield 0.939 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=2)[C:23]([N:25]([CH2:27][CH2:28][OH:29])[CH3:26])=[O:24])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:33])[CH:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=2)[C:23]([N:25]([CH2:27][CH2:28][OH:29])[CH3:26])=[O:24])[CH2:9]/[C:10](=[N:35]\[OH:36])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:33])[CH:3]=1
Reactant: CN(CCO)C(=O)c1cccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(CCO)C(=O)c1cccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1

Procedure:
In analogy to example 151, step 3, 3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-(2-hydroxyethyl)-N-methylbenzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid containing 7% of the corresponding Z isomer, MS (ESI+): m/z=486.4 [M+H]+.
Reaction SMILES: [Si](Cl)(Cl)(C)C.[CH3:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([CH:23]([CH3:25])[CH3:24])[CH-:18]3)[CH:10]=[C:11]([CH3:13])[CH:12]=1.[Li+]>C1COCC1>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([CH:23]([CH3:25])[CH3:24])[CH2:18]3)[CH:8]=[C:7]([CH3:6])[CH:12]=1
Reactant: Cc1cc(C)cc(-c2cccc3[cH-]c(C(C)C)cc23)c1
Agent: C[Si](C)(Cl)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2cccc3c2C=C(C(C)C)C3)c1
Yield: 72.8 %

Procedure:
SiMe2Cl2 (0.69 g, 5.4 mmol) was dissolved in 80 mL of THF. While stirring, lithium 4-(3′,5′-dimethylphenyl)-2-isopropylindenide (2.9 g, 11 mmol) was added as a dry powder and the contents allowed to stir overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in pentane and filtered to removed LiCl salts. The pentane was removed in vacuo to yield a flaky white solid (2.1 g, 67%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([CH2:15][CH2:16][NH2:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:17][CH2:16][CH2:15][C:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(Br)cc1
Reactant: NCCC1=CCCCC1
Product: Cc1ccc(NCCC2=CCCCC2)cc1
Yield: 92 %

Procedure:
Using the general procedure, 4-bromotoluene (172 mg, 1.0 mmol) was coupled with 2-(1-cyclohexenyl)ethylamine (209 μL, 1.5 mmol) at 100° C. for 20 h. Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (20:1) as eluent afforded the desired product as a colorless oil (198 mg, 92% yield). Rf=0.6 (hexane/ethyl acetate=10:1).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:6]1([CH3:20])[N:10]2[C:11](=[O:18])[C:12]3[C:17]([C:9]2=[N:8][C:7]1=[O:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:5])[CH3:4].Cl>C(O)C.O1CCCC1>[CH:3]([C:6]1([CH3:20])[N:10]2[C:11](=[O:18])[C:12]3[C:17]([CH:9]2[NH:8][C:7]1=[O:19])=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:5])[CH3:4]
Reactant: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C1(C)C(=O)NC2c3ccccc3C(=O)N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a stirred suspension of 10.4 g (0.274 mole) sodium borohydride in 164 ml absolute ethanol under nitrogen was added dropwise at 5° C a solution of 133.9 g (0.548 mole) of 2,5-dihydro-3-isopropyl-3-methyl-3H-imidazo[2,1-a]isoindole-2,5-dione in 155 ml tetrahydrofuran. After the addition, the mixture is stirred a further 3 hours at room temperature and then poured over 1070 g ice with stirring. The mixture is acidified with concentrated HCl and after stirring for 1.5 hours, the precipitate removed by filtration, washed with water and air-dried to give 118.7 g of 1,9b-dihydro-3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H),5-dione, melting point 178°-200° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:9])=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Yield: 85 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide (130 mg, 0.38 mmol) in ethyl acetate (50 mL) and methanol (5 mL) was treated with a catalytic amount of 10% palladium on activated carbon (50 mg). The resulting mixture was shaken at 25° C. under 60 psi of hydrogen gas in a Parr apparatus for 24 h. At this time, the catalyst was removed by filtration through a plug of celite. The filtrate was concentrated in vacuo to afford 2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (99.9 mg, 84.3%) as a tan oil: EI-HRMS m/e calcd for C19H23N3O (M+) 309.1834, found 309.1849.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].Cl.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.Cl.N>CO.O>[NH2:6][C:5]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:21]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COc1ccc(NN)cc1
Reactant: COC(OC)C(C#N)=NO
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: COc1ccc(-n2ncc(N=O)c2N)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged, 2.97 g (20 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 96.9% by weight synthesized in the same manner as in Example 1, 3.74 g (21 mmol) of 4-methoxyphenylhydrazine hydrochloride with a purity of 98% by weight, 1.4 ml of water, 10 ml of methanol and 1.3 ml (15 mmol) of conc. hydrochloric acid, and the mixture was reacted at 50 to 52° C. for one hour. After completion of the reaction, 25 ml of water and 5 ml of methanol were added to the mixture to cool the same up to 10° C., and 2.3 ml (37.9 mmol) of 28% by weight aqueous ammonia was gradually added dropwise to the mixture and the resulting mixture was stirred for 30 minutes while maintaining the liquid temperature to 5° C. or lower. Precipitated crystals were collected by filtration, and then, the crystals were washed with 10 ml of cold water and dried under reduced pressure to obtain 3.07 g of 5-amino-1-(4-methoxyphenyl)-4-nitrosopyrazole (Isolation yield: 55.3%) as a yellowish solid with a purity of 78.6% by weight (absolute calibration curve method by high performance liquid chromatography).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].CN(C(ON1N=NC2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl.CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:37]3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: NC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Nc1nc(-n2cc(C(=O)NC3CCCC3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The trisilyl derivative acid 20 (0.14 g, 0.2 mmol) was then dissolved in 5 mL dichloromethane. To the solution was added HBTU (0.19 g, 0.4 mmol), HOBt (.076 g, 4 mmol), N-methylmorpholine (0.04 g, 0.4 mmol) and cat. DMAP. The mixture was allowed to stir at RT for 24 h. The mixture was then washed with 10% citric acid, saturated NaHCO3, brine and dried over MgSO4. The solvent was removed and the residue was treated with 5 mL 0.5N NH4F/MeOH. The solution was heated at reflux for 24 h. The solvent was evaporated and the residue was purified by preparative TLC to afford compound 21, MS 445.26 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[N:4]=[CH:3]1.[H][H]>C(O)(=O)C.[Pd].[Zn]>[NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][CH2:3]1
Reactant: NC1C=Nc2ccccc2NC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: [Zn]
Solvent: CC(=O)O
Product: NC1CNc2ccccc2NC1=O

Procedure:
Reduction of intermediate 21 using, for example, zinc dust in glacial acetic acid then provides 3-amino-1,3-dihydro-1,5-benzodiazepin-2-one 22. This reaction is typically conducted at ambient temperature for about 0.5 to about 6 hours. Alternatively, intermediate 21 can be reduced with hydrogen using a catalyst, such as palladium on carbon, to afford 3-amino-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one 23. Typically, this reaction is conducted at ambient temperature for about 12 to about 48 hours. If desired, compounds 22 and 23 can then be coupled with an amino acid derivative using the procedures described herein.