Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:41])[NH:19][CH2:20][C:21]([N:23]2[CH:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:33][CH2:32][CH:24]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1>CO.[OH-].[K+]>[C:28]([O:27][C:25]([CH:24]1[CH2:32][CH2:33][CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[N:23]1[C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:41])[NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:9]([OH:10])=[O:8])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccn2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCC(c2ccccn2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 36.9 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 9, but starting from 0.55 g of tert-butyl (2RS,5SR)-1-{2-[3-(3-benzyloxycarbonylphenyl)-ureido]acetyl}-5-(2-pyridyl)prolinate in solution in 20 cm3 of methanol and 10 cm3 of 0.1N aqueous potassium hydroxide solution. After treatment, 0.17 g of (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-(2-pyridyl)-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 174° C., is obtained.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[ClH:6].Cl.Cl.[CH:9]([C@H:22]1[N:27]2[CH2:28][CH2:29][NH:30][CH2:31][C@H:26]2[CH2:25][N:24]([CH2:32][C:33]2[CH:38]=[C:37]([N:39]3[C:43]([C:44]([F:47])([F:46])[F:45])=[N:42][N:41]=[N:40]3)[CH:36]=[CH:35][C:34]=2[O:48][CH3:49])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>ClCCl>[ClH:5].[ClH:6].[CH:9]([C@H:22]1[N:27]2[CH2:28][CH2:29][N:30]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:31][C@H:26]2[CH2:25][N:24]([CH2:32][C:33]2[CH:38]=[C:37]([N:39]3[C:43]([C:44]([F:47])([F:46])[F:45])=[N:42][N:41]=[N:40]3)[CH:36]=[CH:35][C:34]=2[O:48][CH3:49])[CH2:23]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@@H]2CNCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1CN1C[C@@H]2CN(S(C)(=O)=O)CCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.7 %

Procedure:
Methanesulfonyl chloride (22.1 mg) was added to a mixture of (4R,9aS)-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine trihydrochloride (100 mg) and N,N-diisopropylethylamine (116 μl) in dichloromethane under ice-cooling. After being stirred at the same temperature for 2 hours the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulphate, and evaporated under reduced pressure. The resulting oil was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol. The fractions containing the objective compound was collected and evaporated under reduced pressure and the resulting residue was treated with 4N hydrogen chloride in ethyl acetate to give (4R,9aR)-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]-8-(methylsulfonyl)octahydro-2H-pyrazino[1,2-a]pyrazine dihydrochloride (52.8 mg) as colourless powder.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]2[C:16]([C:17]=1[O:18][C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7].Cl.C([O-])(O)=O.[Na+]>>[C:19]([O:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:9][C:8]=1[C:6]([NH:5][CH2:4][C:3]([OH:28])=[O:2])=[O:7])(=[O:21])[CH3:20]
Reactant: COC(=O)CNC(=O)c1nc(-c2ccccc2)c2ccccc2c1OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Oc1c(C(=O)NCC(=O)O)nc(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.1 %

Procedure:
A mixture of [(4-Acetoxy-1-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid methyl ester (3.8 mg, 0.01 mmol) and aqueous 6N HCl (1 ml) was stirred at ambient temperature for 16 h before the pH of the solution was adjusted to ca. 8 by addition of concentrated aqueous NaHCO3 solution. The solution was washed with EtOAc (2×10 ml) before it was acidified by addition of aqueous 2N HCl. Subsequently, the mixture was extracted with EtOAc (2×10 ml). The combined organic phases were dried over MgSO4 and evaporated in vacuo to give the title compound as a yellow oil (1.9 mg); MS-(+)-ion: M+1=364.9.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:38]=[CH:37][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:27])[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH:65]2[CH2:67][O:66]2)=[CH:59][CH:58]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:29]([NH:28][C:26]([N:23]1[CH2:22][CH2:21][CH:20]([C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:37]=[CH:38][C:7]([CH2:6][CH2:5][NH:4][CH2:67][C@H:65]([OH:66])[CH2:64][O:63][C:60]4[CH:61]=[CH:62][C:57]([OH:56])=[CH:58][CH:59]=4)=[CH:8][CH:9]=3)[CH2:13][CH2:14]2)=[O:19])[CH2:25][CH2:24]1)=[O:27])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCNC(=O)N1CCC(C(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)CC1
Yield: 26.9 %

Procedure:
4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}carbonyl)-N-octyl-1-piperidinecarboxamide formate(0.41 g, 0.771 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.27 g, 0.668 mmol) according to Procedure G to give the title compound (0.16 g, 0.180 mmol).
Reaction SMILES: [F: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:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].[CH3:18][O:19][C:20]1[CH:41]=[CH:40][C:23]([C:24](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1.C(OCC)(=O)C.O>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([O:9][CH2:8][C@H:5]2[O:4][C@@H:3]([N:10]3[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]3=[O:12])[C@H:2]([F:1])[C@@H:6]2[OH:7])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23]2[CH:40]=[CH:41][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 126.7 %

Procedure:
An operation of dissolving 2′-Deoxy-2′-fluorouridine (3.00 g, 12.2 mmol) in dry pyridine, followed by concentration under reduced pressure was repeated 3 times to perform dehydrative azeotropic distillation. Thereafter, under an argon atmosphere, the reaction mixture was dissolved in dry pyridine (120 ml), 4,4′-dimethoxytrityl chloride (4.55 g, 13.4 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The completion of the reaction was confirmed, and ethyl acetate (150 ml) and water (60 ml) were added to the reaction mixture to allow layer separation. The organic layer was washed 3 times with 5% aqueous sodium hydrogen carbonate solution (20 ml), washed with water (20 ml) and saturated brine (20 ml), and the obtained organic layer was dried over sodium sulfate. The solvent in the filtrate was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50-0/100 (v/v), containing 1% triethylamine). The object fractions were collected and concentrated to give the title compound (8.48 g, quant).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=[N:9][OH:10])[NH2:8])([O-:3])=[O:2].[CH3:14][C:15]([CH3:24])([CH3:23])[C:16](=[O:22])[CH2:17][C:18](OC)=O>C1(C)C=CC=CC=1>[CH3:14][C:15]([CH3:24])([CH3:23])[C:16](=[O:22])[CH2:17][C:18]1[O:10][N:9]=[C:7]([C:6]2[CH:11]=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:8]=1
Reactant: NC(=NO)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(=O)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Cc1nc(-c2cccc([N+](=O)[O-])c2)no1
Yield: 89.6 %

Procedure:
In a 250 ml flask, place 16 g (0.088 m) of 3-nitrobenzamidoxime (9a), 21.3 g (0.135 m) of methyl 4,4-dimethyl-3-oxovalerate (10a; R1=t-butyl), and 120 ml of toluene. Heat and stir the reaction mixture under reflux with a Dean-Stark trap for 23 hrs. Distill off toluene under a reduced pressure at 50-60° C. to thick oil. Add 60 ml of heptane to the oil with stirring, cool and stir at 0-5° C. for 30 min. Collect solid, wash with heptane, and dry in air to give 22.9 g (90%) of 5-(3,3-dimethyl-2-oxobutyl)-3-(3-nitrophenyl)-1,2,4-oxadiazole [Formula II: R1=t-butyl and R2=3-nitrophenyl].
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10]OS(C)(=O)=O.CC(C)([O-])C.[K+]>CCOCC>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10]
Reactant: CS(=O)(=O)OCCc1ccccc1CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1ccccc1CCl
Temperature: -35 °C
Yield: 82 %

Procedure:
Dissolve methanesulfonic acid 2-(2-chloromethyl-phenyl)-ethyl ester (8.8 g, 35.4 mmol) in ether (80 mL) and cool to -35° C. Add potassium t-butoxide (10 g, 89 mmol) and stir for 30 minutes. Add water (50 mL) and ether (150 mL), extract, dry (Na2SO4) and purify by silica gel chromatography (2:3 methylene chloride/pentane) to give 1-chloromethyl-2-vinyl-benzene as a colorless oil (4.43 g, 82%).
Reaction SMILES: [O:1]([C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)C.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]([C:8]1[O:12][C:11]([C:13]([NH:28][C:24]2[CH:23]=[C:22]([CH:21]=[CH:20][C:19]([OH:29])=[O:18])[CH:27]=[CH:26][CH:25]=2)=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(Oc2ccccc2)o1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C=Cc1cccc(NC(=O)c2ccc(Oc3ccccc3)o2)c1

Procedure:
5-phenoxy-2-furoic acid (3) (213 mg, 1.05 mmol) was coupled to aniline (2) (200 mg, 1.05 mmol) using Method B, except that DIPEA (270 mg, 2.09 mmol) and DMF (2 mL) were used to give the title compound. Yield: 178 mg, 96%; LC/MS tr 1.65 min; HPLC Purity: 95%; MS (ES+) m/z 378 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH2:12])[CH:5]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH:12][S:15]([CH3:14])(=[O:17])=[O:16])[CH:5]=1
Reactant: COC(=O)c1cccc(CCN)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(CCNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a solution of 3-(2-amino-ethyl)-benzoic acid methyl ester (500 mg) in CH2Cl2 (35 mL) at 0° C. was added methanesulfonyl chloride (292 mg, 2.55 mmol) and triethylamine (1.6 mL, 11.5 mmol). The reaction was stirred at room temperature for 18 h and was washed consecutively with 5.5% HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to yield the title compound (522 mg) as a white solid. MS 275 (M+18).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:30])[NH:17][C:18]2[S:26][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:38]([NH:45][CH2:46][CH2:47][CH2:48]Br)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>CN(C=O)C>[C:27]([C:19]1[C:20]2[CH2:25][CH2:24][N:23]([CH2:48][CH2:47][CH2:46][NH:45][C:38](=[O:39])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:22][C:21]=2[S:26][C:18]=1[NH:17][C:16](=[O:30])[NH:15][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=1)(=[O:28])[NH2:29]
Reactant: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCN1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 59.1 %

Procedure:
A solution of 2-[3-(4-Chlorophenyl)ureido]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamide trifluoroacetate (0.48 mmol) in anhydrous DMF was treated with triethyl amine (200 μL, 1.43 mmol) and N-Boc-bromopropylamine (114 mg, 0.48 mmol) and the reaction mixture was allowed to stir at room temperature for 14 h. Analytical HPLC showed close to 50% progression. Another 100 μL of triethyl amine and 70 mg of N-Boc-bromopropylamine were added and the reaction mixture was stirred at room temperature. Upon completion (48 h), DMF was removed under vacuo and the resultant crude mixture was diluted with DCM and washed with water (×2). The organic layer was dried (anhydrous Na2SO4) and concentrated to afford an oil which was purified by flash chromatography Isolera system (SiO2 gel as stationary phase, 40 g HP column, dry loading) using DCM-DCM/MeOH (0%-15% MeOH in DCM) to afford the title compound as a light brown solid (144 mg, 60% yield). 1H NMR (300 MHz, dmso-d6) δ 10.95 (s, 1H), 10.18 (s, 1H), 7.55-7.43 (m, 2H), 7.37-7.27 (m, 2H), 6.82 (s, 1H), 3.53-3.43 (m, 2H), 3.03-2.90 (m, 2H), 2.85-2.57 (m, 4H), 2.50-2.40 (m, 2H), 1.69-1.53 (m, 2H), 1.37 (s, 9H). LRMS [M+H]508.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([CH:20]=C)[CH:3]=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:31].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[O:31])[C:5]2[CH:6]=[CH:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: O=Cc1cc(F)cc2c1ccn2S(=O)(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 104.4 %

Procedure:
OsO4 (26 mg, 0.1 mmol) was added to a stirred mixture of 6-fluoro-1-(phenylsulfonyl)-4-vinyl-1H-indole (309 mg, 1.03 mmol; Intermediate 37) and 2,6-lutidine (239 μL, 2.05 mmol) in dioxane (18 mL). The mixture turned from colorless to black in 1 minute. Sodium periodate (0.877 g, 4.1 mmol) in water (6 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 15 min, extracted with water (30 mL) and DCM (2×30 mL). The organic layers were combined, dried, filtered and concentrated to give the title compound (326 mg, 105%) as a black solid. MS (ESI+) for C15H10FNO3S m/z 304 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][O:18][C:19](=[O:32])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[N:14]=[CH:13]1)[N:8]=[C:7]([C:33]([O:35]CC)=[O:34])[C:6]([O:38]CC)=[N:5]2.Br.C(O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH2:17][O:18][C:19](=[O:32])[NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[N:14]=[CH:13]1)[N:8]=[C:7]([C:33]([OH:35])=[O:34])[C:6](=[O:38])[NH:5]2
Reactant: CCOC(=O)c1ccc(NC(=O)OCc2cn(-c3cc4nc(C(=O)OCC)c(OCC)nc4cc3Cl)cn2)cc1
Agent: Br
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NC(=O)OCc2cn(-c3cc4nc(C(=O)O)c(=O)[nH]c4cc3Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.5 %

Procedure:
To a solution of ethyl 6-chloro-3-ethoxy-7-(4-(((4-ethoxycarbonylphenyl)carbamoyloxy)methyl)imidazole-1-yl)quinoxaline-2-carboxylate (64.0 mg, 113 μmol) in acetic acid (3 ml) was added 47% hydrobromic acid (0.3 ml), and the mixture was stirred for 3 hours at room temperature. After allowed to stand overnight, the mixture was stirred for 1 hour at 40° C. After cooling, ethanol was added to the residue obtained by concentrating the reaction mixture under reduced pressure. The precipitated crystals were collected by filtration and air-dried, thereby obtaining 18.8 mg of title compound as brown powder. The residue obtained by concentrating the filtrate under reduced pressure was washed with water and air-dried, thereby obtaining additional 37.4 mg. Total yield 56.2 mg. Yield 97%.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].Cl[C:11]1[C:16]2[CH:17]=[N:18][C:19]3[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=3[C:15]=2[N:14]2[N:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:13]2[N:12]=1>C1C=CC=CC=1>[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][O:8][C:11]1[C:16]2[CH:17]=[N:18][C:19]3[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][C:20]=3[C:15]=2[N:14]2[N:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:13]2[N:12]=1
Reactant: CCOC(=O)c1cnn2c1nc(Cl)c1cnc3c(cnn3CC)c12
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1cnn2c1nc(OCCCN(C)C)c1cnc3c(cnn3CC)c12
Reaction time: 10 h

Procedure:
To a suspension of 3.6 g of sodium hydride in 100 ml of dry benzene 15.3 g of 3-(dimethylamino)propanol are added dropwise at reflux temperature with stirring. Heating is continued for 10 hours. After this time, 34.4 g of 5-chloro-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester are added and the solution is refluxed for 5 additional hours. The solution is evaporated to dryness and the residue is treated with water, filtered off and recrystallized from ethyl acetate. 12 g of 5-[3-(dimethylamino)propoxy]-8-ethyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine-3-carboxylic acid, ethyl ester are obtained (29.3%); m.p. 106°-107°.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[H-].[Na+].Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[CH:26]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=1)[CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:49][O:48][C:46]([C:43]1[CH:42]=[CH:41][C:40]([CH2:39][CH:26](/[CH:25]=[CH:24]/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:4]2[CH2:5][CH2:6][O:7][CH:2]([CH3:1])[C:3]2=[O:8])[CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)=[CH:45][CH:44]=1)=[O:47]
Reactant: CC1OCCNC1=O
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCCl)Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCN2CCOC(C)C2=O)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 66 mg (0.57 mmol) of 2-methylmorpholin-3-one [CAS Reg. No. 100636-23-5] is initially charged in 4.5 ml of dry DMF, and 23.6 mg (0.196 mmol) of sodium hydride (60% in paraffin oil) are added. The mixture is stirred at room temperature for 45 min. The reaction solution is then cooled to 0° C. and a solution of 90 mg (0.163 mmol) of methyl 4-{(4E)-5-{2-[(5-chloropentyl)oxy]phenyl}-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate; Example 32A) in 1.5 ml of dry DMF is added. The mixture is stirred at room temperature for 1.5 h. The reaction solution is then carefully poured into 15 ml of ice-cold 10% strength ammonium chloride solution. The mixture is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated. This gives 103 mg (0.57 mmol, 100% of theory) of a colorless oil which is reacted without further purification.
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[ClH:12]>ClC1C=CC=CC=1>[Cl:12][C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1
Reactant: Cl
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Yield: 70.7 %

Procedure:
65.8 g of 2,4-Dinitroimidazole wetted with chlorobenzene (wetted with 31 mass % of chlorobenzene) was added to 660 mL of 35 mass % of hydrochloric acid and the temperature of the reaction liquid was elevated to 100° C. and reacted for 5 hours. After the reaction ended, the solution was cooled for crystallization. After the crystals were filtered, the crystals were heated and dissolved in 930 mL of water at 90° C. and 33.0 g of 2-chloro-4-nitroimidazole (yield 70.7%) (HPLC purity 97.6%) was obtained by cooling, filtration and drying. This was identified to be 2-chloro-4-nitroimidazole by
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=O>>[CH3:43][N:42]([CH3:44])[CH2:40][CH2:39][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C)C(=O)CCl
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN(C)C)cc2)c1
Yield: 72.9 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-dimethylacetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.9 mg) was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(O)(=O)[CH2:30][C:31]([OH:33])=[O:32].N1CCCCC1>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[CH:30][C:31]([OH:33])=[O:32]
Reactant: O=Cc1ccccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
2-[3-(Quinolin-2-ylmethoxy)-benzyloxy]-benzaldehyde (110 mg, 0.3 mmol, example 56) is dissolved in pyridine (1 mL). Malonic acid (63 mg, 0.6 mmol) and piperidine (10 μL, 0.1 mmol) are added and the contents are heated to 85° C. for 2 hrs, then at 110° C. for another 2 hrs. The reaction is cooled and placed under a nitrogen stream at 40° C. to remove the pyridine. A small amount of toluene is added and the contents are again placed under a nitrogen stream at 40° C. (repeat). The crude material is purified on silica gel by flash chromatography (silica, 2.5% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.33 (d, 1H), 8.21–8.16 (m, 2H), 7.81–7.70 (m, 3H), 7.56–7.50 (m, 2H), 7.37–7.25 (m, 3H), 7.03–6.93 (m, 4H), 6.50 (d, 1H), 5.48 (s, 2H), 5.14 (s, 2H); MS (ion spray) 412 (M+H)+.