Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C@@H:13]([OH:26])[CH2:14][C@:15]4([CH3:25])[C@@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2.[C:27]([O:31][C:32]([NH:34][C@H:35]([C:39]([OH:41])=[O:40])[CH:36]([CH3:38])[CH3:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[OH:26][C@H:13]1[CH2:14][C@@:15]2([CH3:25])[C@@H:16]([CH2:17][CH2:18][C@:19]2([OH:24])[C:20](=[O:21])[CH:22]([O:41][C:39](=[O:40])[C@@H:35]([NH:34][C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:33])[CH:36]([CH3:37])[CH3:38])[OH:23])[C@H:11]2[C@H:12]1[C@:2]1([CH3:1])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC(O)C(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
A solution of 3.63 g (10 mmol) of hydrocortisone in 150 ml of dichloromethane is mixed with 2.34 g (10.8 mmol) of N-(tert -butoxycarbonyl)-valine, 500 mg (4.1 mmol) of 4-dimethylaminopyridine and 3.1 g (15 mmol) of dicyclohexylcarbodiimide. The solution is stirred for 3 hours at room temperature, the precipitate that is produced is suctioned off and washed with dichloromethane. The filtrate is concentrated by evaporation in a vacuum. The chromatography on silica gel (hexane→hexane/ethyl acetate 1:1) provides 2.87 g (51%) of (2S)-2-((1,1-dimethylethoxycarbonyl)-amino)-3-methylbutyric acid [11β,17,21-trihydroxy-3,20-dioxo-pregn-4-en-21-yl] ester. Crystallization from dichloromethane/diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[C:26]([NH:28][CH2:29][C:30]([O-:32])=[O:31])=[O:27])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C(=O)NCC(=O)[O-])c[nH]c34)no2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C(=O)NCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a solution of ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]carbonyl}glycinate (D96) (50 mg) in THF (5 mL) was added aqueous NaOH (2 M, 2 mL). The reaction was stirred at room temperature overnight. The mixture was acidified with aqueous HCl (2 M) to pH 4-5, partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]carbonyl}glycine (E72) (28 mg). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 3.93 (2H, d), 4.90 (1H, m), 7.34 (1H, t), 7.47 (1H, d), 8.00 (1H, dd), 8.23 (2H, m), 8.42 (2H, m), 8.54 (1H, t), 11.55 (1H, s), 12.54 (1H, br s). MS (ES): C22H19ClN4O6 requires 454; found 455.2 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].[N+]([C:16]1[N:20]=[CH:19][N:18]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]=1)([O-])=O.[H-].[Na+]>C1COCC1>[C:34]1([C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:18]2[CH:19]=[N:20][C:16]([O:1][CH2:2][CH2:3][O:4][C:5]3[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=3)[C:8]#[N:9])=[N:17]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=[N+]([O-])c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N#Cc1cccc(OCCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
A solution of 3-[(2-hydroxyethyl)oxy]benzonitrile obtained in Reference Example 30 (19.2 g, 118 mmol) in THF (100 mL) was added dropwise to a suspension of 3-nitro-1-(triphenylmethyl)-1H-1,2,4-triazole obtained in Reference Example 33 (40.0 g, 112 mmol) and 60% sodium hydride (oil dispersion, 6.06 g, 151.52 mmol) in THF (300 mL), and the mixture was stirred at room temperature for 12 hr. The mixture was cooled to 0° C., and extracted with water and ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexane) to give the title compound as a white powder (25.0 g, 46%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][CH2:15][C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[C:27]([CH2:29][CH3:30])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:18][C@@H:17]1[O:31]C(=O)C)=[O:13])(=[O:3])[CH3:2].N>CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][CH2:15][C@H:16]1[O:20][C@@H:19]([N:21]2[CH:28]=[C:27]([CH2:29][CH3:30])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:18][C@@H:17]1[OH:31])=[O:13])(=[O:3])[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](OC(C)=O)[C@@H](CNC(=O)Cc3ccccc3NC(C)=O)O2)c(=O)[nH]c1=O
Agent: N
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3ccccc3NC(C)=O)O2)c(=O)[nH]c1=O
Reaction time: 17 h

Procedure:
A solution of 0.2 g of 5'-[2-(2-acetamidophenyl)acetamido]-3'-O-acetyl-2',5'-dideoxy-5-ethyluridine in 20 ml of methanol was treated with 20 ml of methanol saturated with ammonia. The mixture was left to stand at room temperature for 17 hours. A white solid separated and was collected by filtration, washed twice with 5 ml of ethanol each time and twice with 5 ml of diethyl ether each time and subsequently dried to give 5'-[2-(2-acetamidophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine of melting point 266°-267° C.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[CH:37]=[CH:36][N:35]2[CH:38]=[N:39][N:40]=[C:34]2[CH:33]=1.C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:32]3[CH:37]=[CH:36][N:35]4[CH:38]=[N:39][N:40]=[C:34]4[CH:33]=3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:7])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1ccn2cnnc2c1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ccn3cnnc3c2)c(F)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a 20 mL vial were added N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide (45 mg, 0.10 mmol), 7-bromo-[1,2,4]triazolo[4,3-a]pyridine (21 mg, 0.10 mmol) K2CO3 (29 mg, 0.21 mmol), Pd(dppf)Cl2.CH2Cl2 (4 mg, 0.005 mmol), and a stir bar. The vial was sealed with a teflon lined cap and the vial sparged with N2. The vial was then charged with freshly sparged DMSO (2 mL) and stirred for 16 hours at 80° Celsius. The reaction mixture was then cooled to rt, filtered, and purified by HPLC to give the title compound (30 mg, 53%). MS (ESI): mass calcd. for C22H21FN4O2S, 424.14; m/z found, 425.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.40 (s, 1H), 8.79 (s, 1H), 8.20-8.11 (m, 2H), 7.77 (m, 1H), 7.70-7.57 (m, 3H), 7.47-7.38 (m, 3H), 1.10 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([O:15][CH3:16])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19]([CH:23]([CH3:25])C)[CH:20]([CH3:22])C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCC1>C(Cl)Cl>[CH3:16][O:15][C@H:13]([CH3:14])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[N:19]1[CH2:20][CH2:22][CH2:25][CH2:23]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCNC1
Solvent: ClCCl
Product: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
(2S,3R)-2-(Tert-butoxycarbonylamino)-3-methoxybutanoic acid (643 mg, 2.76 mmol), which is commercially available, and DIPEA (1.440 mL, 8.27 mmol) was mixed in DCM (10 mL). The mixture was cooled to 0° C. TBTU (974 mg, 3.03 mmol) was added and the mixture stirred at rt for 10 min. Pyrrolidine (0.274 mL, 3.31 mmol) was added and the resultant mixture was stirred at rt for 16 h. The mixture was diluted with DCM (10 mL). The organic phase was washed with NaHCO3 (8% in aq. solution) and brine, filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (gradient; DCM/iso-propanol, 99:1 to 95:5, KP-SIL 340 g column). The solvent was removed under reduced pressure to give the title compound (0.704 g, 95%). 1H NMR (400 MHz, CD3OD) δ 1.15, 1.44, 1.82-2.05, 3.33, 3.35-3.52, 3.54-3.65, 3.66-3.79, 4.36. Total no of protons: 25. LCMS (M+H)+: 287.
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[OH:5][CH:6]([CH3:16])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]([OH:15])[CH3:14]>C(O)C.CO.CCOCC>[OH:4][CH:2]([CH3:3])[CH2:1][N:8]([CH2:7][CH:6]([OH:5])[CH3:16])[CH2:9][CH2:10][NH:11][CH2:12][CH:13]([OH:15])[CH3:14]
Reactant: CC1CO1
Reactant: CC(O)CNCCNCC(C)O
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: CC(O)CNCCN(CC(C)O)CC(C)O
Yield: 55 %

Procedure:
(V-a): Propylene oxide (181.6 g, 0.3 mol) in 25 mL of absolute ethanol was added dropwise for 4.5 hours to a solution of N,N'-bis(2-hydroxypropyl)ethylenediamine (IV-a) (55 g, 0.3 mol) in 50 mL each of absolute ethanol, methanol and distilled water at 80° C. The reaction mixture was cooled and concentrated to give a milky white viscous suspension. The suspension was dissolved in ether and dried over anhydrous sodium sulfate. Unreacted (IV-a) precipitated and was removed by filtration. Ether was removed from the clear filtrate to produce a viscous liquid. Fractional distillation of the oil produced N,N,N'-tris(2-hydroxypropyl)ethylenediamine [bp. 140° C. at 0.15 mm; yield 55 percent; IR(neet): 3350(broad OH); NMR(CDCl3): δ 3.8(broad m, 3H); 2.5(broad m, 10H); 1.1(d, 9H)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1C=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)C[N:28]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O.ClC1([N+]([O-])=O)C=CC=NC1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[C:16]([N+:21]([O-:23])=[O:22])=[CH:17][CH:18]=[CH:19][N:28]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: O=[N+]([O-])C1(Cl)C=CC=NC1
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ncccc1[N+](=O)[O-])C(=O)O

Procedure:
(2S)2-tert-Butoxycarbonylamino-3-(3-nitropyridin-2-ylamino)propionic acid was prepared by a similar method as (2S)2-tert-butoxycarbonylamino-3-(2-nitrophenyl-amino)propionic acid in Step A of the synthesis of 600a, except that 3-chloro-3-nitro pyridine was used instead of 2-fluoronitrobenzene, to give 4.05 g (64%) of a yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][O:13][C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H](O)CCOCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O[C@@H](CCOCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
In toluene (100 ml) were dissolved (S)-4-benzyloxy-1,2-butanediol (25.8 g, 0.132 mol), triethylamine (20.2 ml, 0.145 mol) and 4-N,N-dimethylaminopyridine (DMAP) (0.80 g, 6.58 mmol). After cooling in ice bath, trityl chloride (36.69 g, 0.1316 mol) was added to the solution and the mixture was stirred at room temperature for 10 hours. The mixture was condensed in vacuo, diluted with ethyl acetate, washed with water and then saturated brine, dried on sodium sulfate, filtered and condensed in vacuo to give (S)-4-benzyloxy-1-trityloxy-2-butanol quantitatively (55.89, yield 100%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1>[C].[Pd].C(O)(=O)C>[F:1][C:2]1[CH:31]=[CH:30][C:5]([NH:6][C:7]2[CH:19]=[C:18]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccccc1/C=C/c1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccccc1CCc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To the obtained tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(2-methoxyphenyl)vinyl)benzoate were added acetic acid 4.0 mL and 10% palladium-carbon 26 mg sequentially, and it was stirred under hydrogen atmosphere at room temperature for 7 hours. Subsequently, 10% palladium-carbon 39 mg was added to it, it was stirred under hydrogen atmosphere at the same temperature for 3 hours, subsequently it was stirred at 40° C. for 2 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, 10% palladium-carbon 64 mg was added to it, and it was stirred under hydrogen atmosphere at 40° C. for 3 hours and 30 minutes. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and the solvent was removed under reduced pressure. To the obtained residue were added water, ethyl acetate and saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure to give tert-butyl 2-(4-fluoroanilino)-4-(2-(2-methoxyphenyl)ethyl)benzoate 0.11 g of a pale red oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:27]#[N:28])=[CH:12][N:13]=[C:14]([NH:15][C@@H:16]4[CH2:25][CH2:24][C:19]5(OCC[O:20]5)[CH2:18][C@H:17]4[CH3:26])[C:5]=3[C:4]=2[CH:3]=1.Cl>CC(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([C:27]#[N:28])=[CH:12][N:13]=[C:14]([NH:15][C@@H:16]4[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][C@H:17]4[CH3:26])[C:5]=3[C:4]=2[CH:3]=1
Reactant: C[C@@H]1CC2(CC[C@H]1Nc1ncc(C#N)c3[nH]c4ccc(F)cc4c13)OCCO2
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CC(=O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3ccc(F)cc3c12
Temperature: 50 °C

Procedure:
To a stirred solution of 8-fluoro-1-{[(7R,8R)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl]amino}-5H-pyrido[4,3-b]indole-4-carbonitrile (8.5 g, 22.3 mmol) in acetone (100 mL) was added HCl (1 M, 100 mL, 100 mmol). The mixture was heated to 50° C. for 1 h, diluted with EtOAc, and washed with 1 N NaOH. The organic layer was dried (sodium sulfate), and concentrated to afford the title compound. LRMS (APCI) calc'd for (C19H17FN4O) [M+H]+, 337.1. found 337.0.
Reaction SMILES: [CH2:1]([O:3]/[N:4]=[C:5](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][CH:40]=1)\[C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([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:13]([CH2:16][Cl:17])[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].ClC1C=CC=C(C(OO)=[O:69])C=1>C1C=CC=CC=1>[CH2:1]([O:3]/[N:4]=[C:5](/[C:36]1[N:37]=[C:38]([NH:41][C:42]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[S:39][CH:40]=1)\[C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])=[C:13]([CH2:16][Cl:17])[CH2:14][S:15](=[O:69])[C@H:10]12)=[O:7])[CH3:2]
Reactant: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: c1ccccc1
Product: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92.9 %

Procedure:
4.0 g (4.7 mmol) of benzhydryl 7-[(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate was dissolved in 40 ml of benzene, and 1.0 g (5.8 mmol) of m-chloroperbenzoic acid was added under cooling with ice. The mixture was stirred at room temperature for 40 minutes. The reaction solution was poured into ice water, and extracted with ethyl acetate. The extract solution was washed with a 5% acid sodium bisulfite aqueous solution and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue was solidified by an addition of n-hexane, collected by filtration and dried to obtain 3.8 g (yield: 93%) of a powder of the above identified compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[H-].[Na+].[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1>CN(C)C=O>[CH:23]1[CH:22]=[CH:21][N:13]2[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[CH:34]=[N:33][CH:32]=[N:31]4)=[CH:3][C:4]=3[C:24]([F:27])([F:26])[F:25])=[O:9])[CH2:11][C:12]=12
Reactant: c1nc[nH]n1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cncn2)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Yield: 31.8 %

Procedure:
In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.20 g), 1,2,4-triazole (0.20 g), and dimethylformamide (25 ml), the title compound (0.36 g) was obtained as a colorless amorphous solid, MS, m/z: 424.2 (M+H)+, 847.3 (2M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][C:17]([O:19]CC)=[O:18])=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)CC1CCCCN1Cc1cccnc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ncccc1CN1CCCCC1CC(=O)O
Yield: 114.6 %

Procedure:
2.8 g of ethyl 2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]acetate, 20 ml of a 2N aqueous sodium hydroxide and 20 ml of methanol were stirred at 70° C. for 1.5 hours. 8 ml of a 5N aqueous hydrochloric acid was added thereto, and the solvent was evaporated. Ethanol was added to the residue and sodium chloride was filtered off. Ethanol was evaporated, to give 2.9 g of a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[NH:10][CH:9]=[C:8]([C:11]([OH:13])=O)[C:7](=[O:14])[N:6]2[CH:15]=1)[CH3:2].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.N1C=CC=CC=1.[NH2:40][C:41]1[C:42]([C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:43][C:44]([C:48]([CH3:51])([CH3:50])[CH3:49])=[C:45]([OH:47])[CH:46]=1>CC1CCCO1>[C:52]([C:42]1[CH:43]=[C:44]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:45]([OH:47])=[CH:46][C:41]=1[NH:40][C:11]([C:8]1[C:7](=[O:14])[N:6]2[CH:15]=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]2[NH:10][CH:9]=1)=[O:13])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)cc1N
Reactant: CCc1cc2[nH]cc(C(=O)O)c(=O)n2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: CCc1cc2[nH]cc(C(=O)Nc3cc(O)c(C(C)(C)C)cc3C(C)(C)C)c(=O)n2c1
Temperature: 45 °C

Procedure:
To a solution of 7-ethyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-3-carboxylic acid (32.3 mg, 0.1566 mmol) in 2-methyltetrahydrofuran (400 μL) was added 1-Propanephosphonic acid cyclic anhydride (249.1 mg, 233.0 μL, 0.3915 mmol) followed by the addition of pyridine (24.77 mg, 25.33 μL, 0.3132 mmol). The reaction was sealed and heated at 45° C. for 30 minutes upon which 5-amino-2,4-di-tert-butylphenol (41.59 mg, 0.1879 mmol) was added and the reaction was heated at 45° C. for 16 h. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC (40-100% acetonitrile with 0.035% TFA in water with 0.05% TFA) to give N-(2,4-di-tert-butyl-5-hydroxyphenyl)-7-ethyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-3-carboxamide. LC/MS (10-99% CH3CN/0.05% TFA in H2O/0.05% TFA gradient over 3 min): M+H m/z 410.5, retention time 2.24 minutes. 1H NMR (400.0 MHz, DMSO) δ 13.07 (d, J=6.6 Hz, 1H), 10.72 (s, 1H), 9.20 (s, 1H), 8.55 (d, J=6.8 Hz, 1H), 7.32 (s, 1H), 7.16 (s, 1H), 7.11 (s, 1H), 6.11 (d, J=1.7 Hz, 1H), 2.59 (q, J=7.5 Hz, 2H), 1.36 (s, 18H) and 1.22 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([C:19]#[N:20])=[CH:8][CH:7]=2.CS(C)=[O:28]>O>[NH2:1][CH2:2][C:3]1[N:4]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([C:19]([NH2:20])=[O:28])=[CH:8][CH:7]=2
Reactant: CS(C)=O
Reactant: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(C#N)ccc2c1=O
Solvent: O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(C(N)=O)ccc2c1=O
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carbonitrile (20.0 g), 2N aqueous sodium-hydroxide solution (6 ml), dimethyl sulfoxide (100 ml) and water (40 ml) was stirred at an inner temperature of 85° C. for 30 min. The reaction mixture was cooled to 40° C., cooled to not higher than 5° C. and stirred for 1 h. The precipitated crystals were collected by filtration and washed twice with water (40 ml) to give the title compound (21.7 g) as pale yellow crystals.