Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](OC1C=CC=CC=1)=[O:3].[NH2:11][C:12]1[CH:20]=[CH:19][C:15]2[N:16]=[CH:17][NH:18][C:14]=2[CH:13]=1.[NH2:21][CH2:22][C:23](=O)[C:24]([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([CH:23]1[N:11]([C:12]2[CH:20]=[CH:19][C:15]3[NH:16][CH:17]=[N:18][C:14]=3[CH:13]=2)[C:2](=[O:3])[NH:21][CH2:22]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)C(=O)CN
Reactant: Nc1ccc2nc[nH]c2c1
Solvent: ClCCl
Product: CC(C)(C)C1CNC(=O)N1c1ccc2[nH]cnc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Phenyl chloroformate (0.98 mL, 7.8 mmol) was dissolved in CH2Cl2, cooled down to 0° C. and 5-aminobenzimidazole (0.865 g, 6.5 mmol) was added slowly. The mixture was kept at 0° C. for 30 min and then the mixture was allowed to adapt ambient temperature. The mixture was stirred at ambient temperature for 2 h. The resulting solid was withdrawn by suction, dried and taken up in a small amount of DMF. To the solution, 1-amino-3,3-dimethylbutan-2-one (0.986, 6.5 mmol) and TEA (2.73 mL, 19.5 mmol) were added. The mixture was kept at 40° C. for 2 h. The solvent was removed and purified by means of preparative HPLC. The remains were re-dissolved in MeOH and a small amount of HCl was added (1-2%). The solution was subjected to hydrogenation (PdC, 10% on charcoal, 4 bar, 60° C.) for 4 h. The catalyst was removed by filtration through a pad of CELITE® and the residue was washed with water. The organic layer was dried, filtrated and the solvent was removed to result in the final product. Yield: 0.087 g (6.3%); MS m/z 259.4 (M+H)+; 1H NMR (DMSO, 400 MHz): δ 0.72 (s, 9H); 3.23-3.27 (m, H); 3.46-3.50 (m, H); 4.37-4.41 (m, H); 6.84 (bs, H); 7.56 (dd, H, 3J=9.1 Hz, 4J=1.7 Hz); 7.70 (d, H, J=9.1 Hz); 7.81 (d, H, 4J=1.7 Hz); 9.27 (s, H), HPLC (λ=214 nm, [B]: rt 6.83 min (99%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2F)([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.O>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(F)c(CC2(O)CCN(Cc3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)CC1(CCN(Cc3ccccc3)CC1)O2
Temperature: 110 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a suspension of NaH (55% in mineral oil, 200 mg, 5 mmol) in toluene (10 mL) was slowly added a solution of crude 1-benzyl-4-(2-fluoro-5-methylbenzyl)piperidin-4-ol in toluene (15 mL). After addition was completed, the reaction mixture was heated to 110° C. and stirred for 5 min. DMF (9 mL) was added and stirring was continued at reflux temperature for 10 h. The reaction mixture was cooled to room temperature, poured into water (50 ml), and extracted with ethyl acetate (2×25 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (ethyl acetate/n-heptane) to give the subtitle compound (240 mg, 41%).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([F:18])[C:16]=3[CH:17]=[C:9]2[C:8]2[N:19]=[C:20](Cl)[CH:21]=[CH:22][C:7]=2[O:6]1)=[N+:2]=[N-:3].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][C:33]3[CH:43]=[C:42]([N:44]([CH3:49])[S:45]([CH3:48])(=[O:47])=[O:46])[C:41](B4OC(C)(C)C(C)(C)O4)=[CH:40][C:34]=3[C:35]=2[C:36]([NH:38][CH3:39])=[O:37])=[CH:27][CH:26]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CCOC(C)=O>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:1]([CH2:4][CH:5]1[N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([F:18])[C:16]=3[CH:17]=[C:9]2[C:8]2[N:19]=[C:20]([C:41]3[C:42]([N:44]([CH3:49])[S:45]([CH3:48])(=[O:47])=[O:46])=[CH:43][C:33]4[O:32][C:31]([C:28]5[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=5)=[C:35]([C:36]([NH:38][CH3:39])=[O:37])[C:34]=4[CH:40]=3)[CH:21]=[CH:22][C:7]=2[O:6]1)=[N+:2]=[N-:3]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: [N-]=[N+]=NCC1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CN=[N+]=[N-])O4)cc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of 6-(azidomethyl)-2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (1.4 g, 4.25 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (1.8 g, 3.73 mmol) and K3PO4.3H2O (3.4 g, 12.75 mmol) in Dioxane/water (10 mL/1 mL), Pd2(dba)3 (195 mg, 0.21 mmol) and X-Phos (200 mg, 0.42 mmol) were added. The reaction mixture was stirred at 90° C. for 2 hours under N2 protection. Then cooled to room temperature and added EtOAc, then filtered through a Celite pad. The combined organic phase was washed with water and brine, dried over Na2SO4. The solvent was concentrated in vacuo giving 5-(6-(azidomethyl)-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide. The crude product was used in the next step without purification. 1H-NMR (CDCl3, 400 MHz) δ 2.73 (s, 3H), 2.97˜3.03 (d, J=4.8 Hz, 3H), 3.04˜3.15 (d, J=10.8 Hz, 1H), 3.20˜3.32 (m, 1H), 3.40 (s, 3H), 5.93˜6.02 (m, 1H), 6.33˜6.40 (m, 1H), 6.81˜6.89 (m, 1H), 7.14˜7.26 (m, 5H), 7.45˜7.53 (m, 2H), 7.67 (s, 1H), 7.93˜8.01 (m, 2H), 8.03 (s, 1H). MS (M+H)+: 670.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH:5]1[N:8]([CH2:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:20])[CH2:6]1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>>[OH:1][CH2:2][CH2:3][S:4]([CH:5]1[N:8]([CH2:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7](=[O:20])[CH2:6]1)=[O:29]
Reactant: O=C(CCc1ccccc1)CN1C(=O)CC1SCCO
Reactant: O=C(OO)c1cccc(Cl)c1
Product: O=C(CCc1ccccc1)CN1C(=O)CC1S(=O)CCO
Yield: 20 %

Procedure:
Treatment of 4-(2-hydroxyethylthio)-N-(4-phenyl-2-oxobutyl)azetidin-2-one with mCPBA as described for Example 17 gave the title compound by crystallisation: white crystals, m.p. 104-5° C., 20% yield
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]5[C:29](O)=[O:30])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CC[N:34]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]5[C:29]([NH2:34])=[O:30])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCCCC3C(=O)O)cc1OCC2
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCCCC3C(N)=O)cc1OCC2
Reaction time: 18 h
Yield: 7 %

Procedure:
A mixture of 1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-2-carboxylic acid (1.15 g, 2.73 mmol), EDCI (0.58 g, 3.0 mmol), HOBt (0.41 g, 3.0 mmol) and DIPEA (2.34 mL, 13.65 mmol) in DMF was stirred at RT (2 mL) for 5 min before ammonium chloride (0.44 g, 8.18 mmol) was added and the reaction mixture stirred for 18 h. The reaction mixture was concentrated in vacuo and the resultant residue triturated with water before being subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 459 as a white solid (0.08 g, 6%). LCMS: RT=3.48 min, [M+H]+=422. 1H NMR 400 MHz (DMSO-d6) δ: 8.18 (1 H, d, J=9.06 Hz), 7.89 (1 H, d, J=0.63 Hz), 7.80 (1 H, s), 7.31 (1 H, br, s), 7.01 (1 H, br, s), 6.72 (1 H, dd, J=9.16, 2.60 Hz), 6.40 (1 H, d, J=2.54 Hz), 5.92-5.91 (1 H, m), 4.44-4.43 (4 H, m), 4.39 (1 H, m), 3.60 (1 H, d, J=12.44 Hz), 3.39-3.32 (1 H, m), 2.06 (1 H, d, J=13.57 Hz), 1.75 (2 H, m), 1.58 (3 H, m), 1.48 (6 H, dd, J=6.60, 2.59 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:31])[N:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=2[Cl:26])=[O:20])[C:3]=1[N+:32]([O-])=O.O.[NH4+].[Cl-]>CCO.[Fe]>[NH2:32][C:3]1[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:31])[N:23]=[C:24]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:25]=2[Cl:26])=[O:20])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])=[CH:7][C:2]=1[Cl:1]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1N
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (109 mg, 0.211 mmol, prepared as described in the previous step) in EtOH (5 mL) and water (2.5 mL) was treated with NH4Cl (113 mg, 2.11 mmol) and iron powder (58.9 mg, 1.06 mmol). The mixture was heated to 60° C. for 5 h, then the EtOH was evaporated in vacuo. The remaining aqueous mixture was diluted with water (30 mL) and extracted twice with EtOAc (25 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 35 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-amino-4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a colorless glassy solid. Mass Spectrum (LCMS, ESI pos.): Calculated for C21H20N5OCl2F3: 486.1 (M+H). Measured: 486.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:11]=[C:10]([OH:12])[CH:9]=1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Yield: 32.2 %

Procedure:
A mixture of 50.0 g (0.297 mol) of methyl 3,5-dihydroxybenzoate, 99.2 g (0.297 mol) of 1-bromooctadecane and 41 g (0.297 mol) of potassium carbonate in 100 ml of acetone and 50 ml of DMF was stirred at reflux under argon for 24 hours. The solvents were removed at reduced pressure and the residue was heated with methylene chloride and filtered hot. The filtrate was concentrated at reduced pressure to a solid which was recrystallized from methylene chloride-methanol to give the 3,5-dialkylated product. The filtrate was concentrated to dryness and the residue was recrystallized from methylene chloride-methanol to give more of the dialkylated product. The filtrate was concentrated to dryness and recrystallized from ether-hexane to give 40.2 g (32% yield, mp 95°-97°) of 3-hydroxy-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=2[CH3:1])=[O:6])[CH2:26][CH2:27]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3C)CC2)c(C)c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
2-Methyl-4-nitrobenzoic acid (500 mg), 1-(2,4-dimethylphenyl)piperazine (523 mg) and 1-hydroxybenzotriazole 1 hydrate (373 mg) were dissolved in N,N-dimethylformamide (13 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (531 mg) was added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg). Then, to a mixed solution of ethanol (11 mL) and water (3 mL) were added ammonium chloride (660 mg) and iron (480 mg), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (833 mg).
Reaction SMILES: CO[N:3]([C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[C:11]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:10]=1)[CH2:4][C:5](NC)=[O:6].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[CH2:38][Mg]Cl.O.C(OCC)(=O)C>C1COCC1>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH2:38][C:5](=[O:6])[CH2:4][NH:3][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)=[C:11]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)[N:10]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: CNC(=O)CN(OC)c1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c(=O)n1C
Reactant: COc1cccc(C[Mg]Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(CC(=O)CNc2nc(-c3ccncc3)c(-c3ccc4ccccc4c3)c(=O)n2C)c1
Reaction time: 3 h

Procedure:
To a solution of 2-(N′-methoxy-N′-methylaminocarbonylmethylamino)-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (400 mg, 0.93 mmol) in THF (10 mL) at 0° C. was slowly added 3-methoxybenzylmagnesium chloride (Rieke Metal, 0.25 M in THF, 20 mL). After 3 h, water (100 mL) and ethyl acetate (200 mL) were added. The layers were separated. The organic layer was washed with brine (3×80 mL), dried, and evaporated to give crude product. Column chromatograph purification (silica gel, 1-2% MeOH/CH2Cl2) gave the product as a solid. M+1=491.2.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:4][O:3]1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:20]=[C:21]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[C:28]([C:35](O)=[O:36])[CH:29]=[CH:30][CH:31]=3)[N:26]=2)[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:35]([C:28]2[CH:29]=[CH:30][CH:31]=[C:32]3[C:27]=2[N:26]=[C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:39])([F:17])[F:38])[CH:20]=2)[CH:34]=[CH:33]3)=[O:36])=[CH:14][CH:15]=1
Reactant: O=C(O)c1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CC1(C)OCC(COc2ccc(N)cc2)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(OCC(O)CO)cc1)c1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.2 %

Procedure:
To a mixture of 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)aniline (167 mg, 0.750 mmol), 2-(3-(trifluoromethyl)phenyl)quinoline-8-carboxylic acid (159 mg, 0.500 mmol), HATU (285 mg, 0.75 mmol) in NMP (5 mL) was added DIPEA (173 μL, 1.0 mmol). The reaction was stirred for 72 hours at room temperature, water (5 mL) was added and the resulting precipitates were collected by filtration and recrystallized from ethanol. The yellow solid was treated with a mixture of 1:3 6N HCl/Dioxane (8 mL) overnight. The mixture was concentrated to dryness, triturated with water, collected by filtration, washed with water and dried to obtain N-(4-(2,3-dihydroxypropoxy)phenyl)-2-(3-(trifluoromethyl)phenyl)quinoline-8-carboxamide (191 mg, 79% yield). MS (ESI) calcd for C26H21F3N2O4 (m/z): 482.15. found: 483 [M+1].
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[N:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCOCC1>[ClH:1].[ClH:1].[CH3:21][N:17]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([C:3](=[O:4])[CH2:2][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:6]=2[C:19]([CH3:20])=[N:18]1
Reactant: Cc1nn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: Cc1nn(C)c2c1N(C(=O)CN1CCN(C)CC1)c1ccccc1NC2=O
Product: Cl
Reaction time: 0.33 h

Procedure:
15.0 g of 4-chloroacetyl-1,3-dimethyl-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, 21 g of N-methylpiperazine and 70 ml of dioxane are stirred at 80° C. for 1 hour (complete reaction being already indicated by a thin layer chromatogram after 20 minutes), and the thus-obtained solution is concentrated to dryness in vacuo. 150 ml of isopropanol and 40 ml of water are added to the residue, 25 ml of concentrated hydrochloric acid are then added dropwise and the resulting mixture is cooled in an icebath to obtain 1,3-dimethyl-4-[(4-methylpiperazin-1-yl)acetyl]-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one dihydrochloride mixed with N-methylpiperazine hydrochloride. The hydrochlorides are dissolved in water and chloroform, the pH is adjusted to 8.2 with 2 N sodium hydroxide solution, the aqueous phase is exhaustively extracted by shaking it with chloroform and the organic solution is dried and concentrated to dryness in vacuo. This yields 17.6 g of 1,3-dimethyl-4-[(4-methylpiperazin-1-yl)acetyl]-1,4,9,10-tetrahydropyrazolo[4,3-b][1,5]benzodiazepin-10-one, mp 186° to 188° C. (from toluene); dihydrochloride, mp 222° to 224° C. (dec.); hemi fumarate, mp 257° to 258° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[C:24](=[O:48])[NH:25][C:26](=[O:47])[C:27]=2[C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=3)[CH:29]=2)=[N:15]1)(=O)=O.O>CC(N(C)C)=O>[CH:38]1[C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:45]=[CH:46][C:37]=1[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]([C:27]2[C:26](=[O:47])[NH:25][C:24](=[O:48])[C:23]=2[C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([CH2:13][CH2:12][CH2:11][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:15]=2)=[CH:29]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)OCCCn1nc(C2=C(c3cn(-c4ccc5ccccc5c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C1NC(=O)C(c2nn(CCCN3CCCC3)c3ccccc23)=C1c1cn(-c2ccc3ccccc3c2)c2ccccc12
Temperature: 65 °C
Yield: 18 %

Procedure:
Pyrrolidine (1 mL) was added to the 3-[1-[3-[(methylsulfonyl)oxy]propyl]-1H-indazol-3-yl]-4-[1-(2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione (0.5 g, 0.975 mmol) in DMA (10 mL). The mixture was heated to 65° C. for 3 h, then cooled to rt. Water (5 mL) was added, followed by extraction with EtOAc (3×50 mL). The organic layers were combined, washed with H2O and brine, then dried (Na2SO4) and evaporated in vacuo to a dark brown oil. The oil was purified by flash column chromatography (97:3:0.3; DCM:MeOH:NH4OH) to afford Compound 85 (0.1 g, 18%) as an orange flaky solid. Compound 85 was dissolved in excess dilute HCl, then frozen and lyophilized to give the hydrochloride salt. 1H NMR (CD3OD) δ 8.22 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.89 (m, 3H), 7.49 (m, 7H), 7.00 (m, 2H), 6.64 (t, J=7.5 Hz, 1H), 6.39 (d, J=8.1 Hz, 1H), 4.47 (t, J=6.2 Hz, 2H), 3.44 (m, 2H), 3.07 (t, J=7.4 Hz, 2H), 2.82 (m, 2H), 2.16 (m, 2H), 1.93 (m, 4H). ES-MS m/z 566 (MH+).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:23][C@H:24]([C:29]([OH:31])=O)[CH2:25][CH2:26][CH2:27][CH3:28])([O:18]C(C)(C)C)=O.[CH2:32]([NH:39][CH2:40]C(OCC)=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([N:39]1[CH2:40][C:16](=[O:18])[NH:23][C@@H:24]([CH2:25][CH2:26][CH2:27][CH3:28])[C:29]1=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared according to the procedure described by John S. Kiely and Stephen R. Priebe in Organic Preparations and Procedures Int., 22 (6), 761-768 (1990). Thus dicyclohexylcarbodiimide (9.33 g, 45.2 mmol) in methylene chloride (0.5M) was added to methylene chloride (250 mL). This solution was cooled to 0° C. under nitrogen and Boc-L-norleucine (10.5 g, 45.2 mmol) was added. The resulting slurry was stirred for 5 min, and then ethyl N-benzylglycinate (8.72 g, 45.2 mmol) was added. The reaction was stirred for 2 h at 0° C., then at 20° C. overnight. The precipitate was removed by filtration, and hydrogen chloride gas bubbled through the methylene chloride solution for 2-4 h, until the reaction was shown to be complete by tic. The solvent was removed in vacuo, and the residue partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate solution (42 mL). The organic phase was washed with saturated sodium chloride, dryed over magnesium sulfate, filtered and evaporated. The crude diketopiperazine was triturated with hexane to give the title compound as a white powder. 1HNMR (300 MHz, CDCl3) δ 7.24-7.40 (5H, m), 6.22 (1H, br s), 4.07 (1H, dt, J=3, 6 Hz), 3.87 (1H, d, J=17 Hz), 3.80 (1H, d, J=17 Hz), 1.88 (2H, m), 1.35 (4H, m), 0.91 (3H, t, J=7 Hz).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([O-:17])=[O:16])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>CO.C1COCC1.O>[CH:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:19])=[O:20])[C:15]([OH:17])=[O:16])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@@](CCn1cc(C2CCCCC2)cn1)(C(=O)[O-])S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@](CCn1cc(C2CCCCC2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of (2R)-4-(4-cyclohexyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoate (87 mg, 0.24 mmol, 1 eq) in MeOH/THF (2 mL:2 mL) was added LiOH (21.5 mg, 0.512 mmol, 2.1 eq) in H2O (1 mL). The mixture was allowed to stir at RT overnight. The mixture was washed with Et2O and the aqueous layer acidified with 1M HCl. The solid precipitate was filtered off to give (2R)-4-(4-cyclohexyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (70 mg, 87%) which was used without further purification. LC-MS M+H+329.1.