Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C1CCN2C(=NCCC2)CC1.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOCC>[N:52]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:14][N:13]=[C:12]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=3)[N:16]=2)=[CH:18][CH:19]=1)=[N+:53]=[N-:54]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(CO)cc3)n2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CN=[N+]=[N-])cc3)n2)cc1Cl
Yield: 61.5 %

Procedure:
To a solution of (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)methanol (0.100 g, 0.290 mmol) in THF (1.5 ml) was added DBU (0.048 ml, 0.319 mmol) followed by diphenyl phosphorazidate (0.069 ml, 0.319 mmol). After about 15 h the reaction mixture was poured into ether and saturated NaHCO3. The organic layer was separated, washed with brine, dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide 5-(4-(azidomethyl)phenyl)-3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole (0.066 g, 60%) as a colorless solid. LCMS (Table 1, Method c) Rt=3.22 min, m/z 370 (M+H)+
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:12]([C:24]#[N:25])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:26][NH:27]N.[CH2:29]([N:31](CC)CC)C>CCO>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:13]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:12]([C:24]3[N:31]=[CH:29][N:27]([CH3:26])[N:25]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CNN
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)N2C(C#N)CCC2c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2C(c3ccc(F)cc3)CCC2c2ncn(C)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.7 %

Procedure:
To a freshly prepared solution of hydrochloric acid in EtOH (10 ml) was added at 0° C. (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carbonitrile (0.50 g, 1.45 mmol), the reaction mixture was stirred at room temperature for 1.5 h and evaporated. The light brown solid (0.65 g) was dissolved in EtOH (10 ml), methyl-hydrazine (86.9 mg, 1.89 mmol) and triethylamine (0.51 ml, 3.63 mmol) were added and the mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated, subsequently dissolved in formic acid (10 ml), stirred at room temperature for 0.5 h and heated under reflux conditions for 1.5 h. Evaporation, aqueous work-up, column chromatography on silica gel (ethyl acetate) and crystallization from ethyl acetate/hexane yielded the title compound (0.37 g, yield 64%) as a white solid, m.p. 160° C. and MS: m/e=400 (M+).
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH:13]([C:18]([O:20]C)=[O:19])[C:14]3=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>ClCCl.CO>[CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:18]([OH:20])=[O:19])=[CH:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1CCc2ccc(C3CCCCC3)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C1=Cc2cc(C3CCCCC3)ccc2CC1
Reaction time: 1 h
Yield: 20.4 %

Procedure:
Methyl 7-cyclohexyl-1-tetralone-2-carboxylate (8.6 g) was dissolved in dichloromethane (40 ml)-methanol (50 ml). To this solution, sodium borohydride (1.13 g) was added in small portions at room temperature. The reaction mixture was poured into water (80 ml) and extracted with dichloromethane. The dichloromethane layer was successively washed with water and brine, and dried (MgSO4), after which the solvent was distilled off. The residual oil was dissolved in methanol (40 ml), followed by dropwise addition of 2N NaOH (45 ml) at room temperature and stirring for 1 hour. The reaction mixture was washed with ether; the aqueous layer was acidified with concentrated hydrochloric acid and extracted with dichloromethane. The dichloromethane layer was successively washed with water and brine, and dried (MgSO4), after which the solvent was evaporated off. To the residual oil, dioxane (25 ml) and concentrated hydrochloric acid (4.2 ml) were added, followed by stirring at 90° C. for 40 minutes, after which the mixture was concentrated under reduced pressure. After water was added, the residue was extracted with ethyl acetate. The ethyl acetate layer was successively washed with water and brine, and dried (MgSO4), after which the solvent was evaporated off, to yield 7-cyclohexyl-3,4-dihydronaphthalene-2-carboxylic acid (1.57 g, 20%), which was then recrystallized from ethanol to yield colorless prisms having a melting point of 179°-180° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:25].C(O)(C)C>C(OCC)(=O)C>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=1
Reactant: Cc1cc(N)ccc1Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncnc3ccn(CCNC(=O)OC(C)(C)C)c23)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of tert-butyl [2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (297 mg), 3-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (401 mg) and isopropyl alcohol (2.97 mL) was stirred at 80° C. for 16 hrs. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→0/100) to give the title compound (528 mg) as a white powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8](CC3C=CC=CC=3)[CH2:9][C@@H:4]2[CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][NH:8][CH2:9][C@@H:4]2[CH2:3]1
Reactant: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O[C@@H]1C[C@H]2CNCCN2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 9.75 g (42.0 mmol) of (7R,8aS)-7-hydroxy-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Diafi, L.; et al. J. Het. Chem., 1990, 27, 2181) and 29.4 mL of 5M ammonium formate in 140 mL of methanol was treated with an aqueous slurry of 4.9 g of 10% palladium on carbon and the mixture was stirred at ambient temperature for 18 h. The mixture was filtered through Celite and evaporated to give (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine as a clear oil.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=3[CH:30]=[O:31])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C1C[O:41]CC1.Cl([O-])=O.[Na+].S(=O)(=O)(O)N>O>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=3[C:30]([OH:41])=[O:31])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C=O)c1
Reactant: C1CCOC1
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3.10 g (6.28 mmol) of ethyl 4-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-3-formylbenzoate are introduced into 50 ml of THF. At about 0° C. (internal temperature), solutions of 2.13 g (18.8 nmol) of sodium chlorite in 2.5 ml of water and 1.83 g (18.8 mmol) of sulphamic acid in 9 ml of water are simultaneously added dropwise. The mixture is then stirred at 0° C. for 15 minutes. The reaction mixture is added to 120 ml of water and extracted with ethyl acetate (four times 60 ml). The combined organic phases are washed with saturated sodium chloride solution (twice 50 ml). A finely dispersed precipitate is evident in the organic phase. 300 ml of dichloromethane are added, and the solution is dried over sodium sulphate and concentrated. The resulting product (2.96 g) is reacted without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].S(=O)(=O)(O)[OH:27]>>[Cl:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[N:21]=[CH:22][C:23]([C:24]([NH2:25])=[O:27])=[C:6]12)=[O:4]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Product: NC(=O)c1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]-pyrimidine-3-carbonitrile and 20 ml of concentrated sulfuric acid was stirred at room temperature for 2 hours, then poured into ice water, stirred, and filtered. The product was washed with water and dried giving 2 g of the desired intermediate, mp 174°-176°.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]=1.O1C2C=CC=CC=2N=C1.[N+:26]([O-])([OH:28])=[O:27]>>[F:6][C:7]1[C:8]([N+:26]([O-:28])=[O:27])=[CH:9][C:10]2[O:14][C:13]([CH3:15])=[N:12][C:11]=2[CH:16]=1
Reactant: Cc1nc2cc(F)ccc2o1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: c1ccc2ocnc2c1
Product: Cc1nc2cc(F)c([N+](=O)[O-])cc2o1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Concentrated sulfuric acid (60 mL) was stirred mechanically and cooled in an ice/water bath. To this was gradually added 5-fluoro-2-methylbenzoxazole (9), (20 g, 0.132 Moles), at such a rate that the temperature stayed at 15–20° C., over a 15–20 minute period. A solution of concentrated sulfuric acid (11 mL), and concentrated nitric acid (10 mL), was prepared and added drop by drop to the benzoxazole solution at such a rate that the temperature was maintained at approximately 10° C. When this acid solution had been added the cooling bath was removed and the mixture allowed to stir at room temperature for 1 hour. At the end of this period the solution was carefully poured onto ice with good stirring. Sufficient water was then added to get good mixing. The solid was filtered off, washed well with water and air-dried. Yield 16.0 g.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([CH:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][CH:3]2[CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CNS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.9 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (144 mg) in THF (1.5 mL) were added triethylamine (0.08 mL) and methanesulfonyl chloride (66 mg), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (186 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12]O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.C1C=CC(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.[Cl-].[Na+].O>[N:39]([CH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=2)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc2cc(CO)cnc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1ccc2cc(CN=[N+]=[N-])cnc2c1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
To a solution of (7-methylquinolin-3-yl)methanol 41.5 mg, 0.232 mmol) and DBU (0.063 ml, 0.418 mmol) in DMF (0.8 ml) was added DPPA (0.085 ml, 0.395 mmol). The reaction mixture was stirred for 1.5 h at 23° C. Reaction mixture was poured in brine and extracted twice with ethyl acetate. Organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound. HPLC (Method G) Rt=1.174 min, MS (Method V) [M+H]+=199.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[C:15]([NH:22][C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:5][CH:4]=1.[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C.O>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]3[N:14]=[C:15]([NH:22][C:23]4[CH:30]=[CH:29][CH:28]=[C:25]([C:26]5[N:31]=[N:32][NH:33][N:27]=5)[CH:24]=4)[C:16]4[C:21]([C:12]3=[N:11][N:10]=2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(C#N)c4)nn23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2nnc3c4ccccc4c(Nc4cccc(-c5nn[nH]n5)c4)nn23)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 53.7 %

Procedure:
To a suspension of 3-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzonitrile (compound T1) (5.0 g, 12.7 mmol) in N-methylpyrrolidinone (80 mL) are added sodium azide (2.90 g, 44.6 mmol) and triethyl amine hydrochloride (6.14 g, 44.6 mmol). The mixture is stirred at 100° C. for 2 days. Upon cooling, water (400 mL) is added to the reaction mixture and the resulting precipitate is filtered. The solid is washed successively with MeOH, AcOEt, a saturated solution of NH4Cl and water. The residue is dried azeotropically with toluene to yield 2.97 g (54%) of the title compound as light brown solid.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([N:23]1[C:27](=[O:28])[CH:26]=[CH:25][C:24]1=[O:29])(=[O:22])[NH2:21]>>[C:27]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:28])/[CH:26]=[CH:25]\[C:24](=[O:29])[NH:23][C:20](=[O:22])[NH2:21]
Reactant: NC(=O)N1C(=O)C=CC1=O
Reactant: CCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCCOC(=O)/C=C\C(=O)NC(N)=O
Yield: 97 %

Procedure:
The addition of octadecanol to N-carbamylmaleimide under the conditions of Example G afforded a 97% yield of octadecyl maleurate. M.P.: 109°-11° C. (dec.); 1H NMR (CDCl3): δ10.5 (brs, 1H), 8.2 (br s, 1H), 6.3 (m, 2H), 5.4 (br s, 1H), 4.2 (t, 2H), 1.6 (m, 2H), 1.2 (m, 30H), 0.9 (t, 3H); HPLC (80% CH3CN/H2O, C18): Rt=12.8 minutes.
Reaction SMILES: [CH3:1][O:2][P:3]([CH:7]([F:17])[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)([O:5][CH3:6])=[O:4].C(OC(=O)[NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][C:26]=1[NH2:36])(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:6][O:5][P:3]([CH:7]([C:8]1[CH:9]=[CH:10][C:11]([C:12](=[O:14])[NH:36][C:26]2[CH:27]=[C:28]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[CH:29]=[CH:30][C:25]=2[NH2:24])=[CH:15][CH:16]=1)[F:17])(=[O:4])[O:2][CH3:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: COP(=O)(OC)C(F)c1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COP(=O)(OC)C(F)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[(Dimethoxy-phosphoryl)-fluoro-methyl]-benzoic acid (52 mg, 0.198 mmol), (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (69 mg, 0.238 mmol), EDC (57 mg, 0.298 mmol), HOBT (36 mg, 0.238 mmol), and DIPEA (77 mg, 0.595 mmol) were combined and diluted with DMF (0.79 mL). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was purified directly by HPLC (20-85% MeCN in water w/0.025% TFA). Pure fractions were combined and concentrated in vacuo. The residue was diluted with 10:1 DCM:TFA and stirred at ambient temperature. After 2 hours the deprotection was complete and the mixture was concentrated in vacuo to give the title compound: 1H NMR (DMSO-d6, 600 MHz) δ 9.87 (br-s, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.56 (d, J=7.8 Hz, 2H), 7.48 (s, 1H), 7.37 (d, J=5.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.24-7.27 (m, 1H), 7.04 (dd, J=3.6 Hz, J=5.0 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.33 (dd, J=8.4 Hz, J=43.8 Hz, 1H), 3.64-3.71 (m, 6H). MS: cal'd 435 (MH+), exp 435 (MH+)
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4C(C(O)=O)=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32](Cl)(=[O:36])[C:33](Cl)=O.C(N(CC)C(C)C)(C)C.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>ClCCl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:33]([C:32]([N:51]5[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]5)=[O:36])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:30][CH:31]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.4 %

Procedure:
To a stirred suspension of 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 22 (3.14 g) in dichloromethane (25 mL) was added oxalyl chloride (3.0 g). The reaction mixture was stirred for five hours at room temperature and then evaporated to dryness. The crude acid chloride thus obtained was dissolved in dichloromethane (50 mL) and added to a mixture of N,N-diisopropylethyl amine (1.0 g) and N-methyl piperazine (1.52 g) in dichloromethane (50 mL). The mixture was stirred at room temperature overnight, then washed with water and saturated aqueous sodium bicarbonate. The solution was dried over anhydrous sodium sulfate and then filtered through a short column of Magnesol®. Removal of the solvent followed by the addition of diethyl ether provided the title compound (2.50 g) as a pale yellow solid, m.p. 134–136° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[C:22]3[CH2:23][CH2:24][CH2:25][N:21]3[CH3:20])[C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(N2C(=O)Cc3ccccc32)cc1F
Reactant: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)C(=C3CCCN3C)c3ccccc32)cc1F

Procedure:
By the procedure of Example B5, except to use ethyl acetate as eluant, 1-(3-fluoro-4-methoxyphenyl)-2(1H,3H)-indolone (2.0 g, 7.8 mmoles) and 1-methyl-2-pyrrolidone (1.5 ml, 15.6 mmole) were converted to title product, 0.32 g, m.p.68°-71°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C@@H:6]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:36](Br)[CH:37]=[CH2:38]>O1CCCC1>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:38][CH:37]=[CH2:36])[CH2:5][C@@H:6]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H](C[C@@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a stirred, cold (−78° C.) solution of (2R)-2-benzyloxycarbonylamino-pentanedioic acid 1-tert-butyl ester 5-methyl ester (5.6 g, 15.9 mmol), prepared as described in J. Org. Chem., 55, 1711-1721 (1990) and J. Med. Chem., 39, 73-85 (1996), in 30 mL of tetrahydrofuran was added lithium bis(trimethylsilyl)amide (40 mL, 1 M in tetrahydrofuran, 39.8 mmol). The resulting mixture was stirred for 1 hour at −45° C. and then recooled to −78° C. Allyl bromide (5.2 mL, 63.7 mmol) was then added. After 2 hours the reaction was quenched by the addition of 1 M aqueous hydrogen chloride at −78° C. The mixture was then extracted with diethyl ether. The combined ethereal extracts were washed with brine and the mixture was dried over sodium sulfate. After filtration and concentration of the filtrate, the crude product was purified by silica gel chromatography (elution with 1:5 ethyl acetate/hexanes) to provide (2R,4R)-4-allyl-2-benzyloxycarbonylamino-pentanedioic acid 1-tert-butyl ester 5-methyl ester.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[N:7]=[CH:6][C:5]=1[CH2:15][C:16]([O-:18])=[O:17]>C1COCC1>[CH3:3][C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[N:7]=[CH:6][C:5]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: Cc1cc(-n2cnnn2)ncc1CC(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-n2cnnn2)ncc1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium hydroxide (1 N, 4.75 ml) was added to a stirred mixture of [4-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]acetate (1.00 g, 4.29 mmol) in THF (10 ml) and the mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH ˜3-4 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to provide title compound which was used directly: LC-MS (IE, m/z): 206 [M+1]+.