Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](Cl)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2].[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: COc1cc(CCN)ccc1O
Reactant: CCOc1ccc(-c2ccnc(Cl)n2)cc1
Product: CCOc1ccc(-c2ccnc(NCCc3ccc(O)c(OC)c3)n2)cc1

Procedure:
Intermediate 47 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 366. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.0 (d, 1H), 7.1-7.0 (m, 4H) 6.8 (s, 1H), δ 6.7-6.6 (m, 3H), δ 4.0 (q, 2H), δ 3.7 (s, 3H), 3.5 (t, 2H), δ 2.7 (t, 2H), 1.3 (t, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH2:9][OH:10])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](CO)c1ccc(Br)cc1
Yield: 116.5 %

Procedure:
A solution of [(R)-1-(4-bromo-phenyl)-2-hydroxy-ethyl]-carbamic acid t-butyl ester (946 mg, 3 mmol) in MeOH (15 ml) was treated with HCl in dioxane (4 M, 15 ml) for 1.5 h. The mixture was concentrated to give the titled compound (755 mg, 100%) as a white solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C.O>[Si:14]([O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1
Reaction time: 20 h
Yield: 48.2 %

Procedure:
To a solution of resorcinol (5.5 g, 50 mmol) in anhydrous DMF (15 mL) was added imidazole (7.14 g, 210 mol %) and tert-butyldimethylsilyl chloride (7.53 g, 105 mol %). The reaction mixture was stirred for 20 h. The reaction mixture was diluted with water (a white precipitate formed) and then it was extracted with ether (3×300 mL). The combined extract was dried (Na2SO4), filtered and concentrated to yield 5.4 g (48.3%) of the title compound; 1H-NMR (CDCl3) δ7.07 (t, 1 H, J=8.0), 6.42 (pseudot, 2 H, J=7.6), 6.36 (s, 1 H), 5.06 (bs, 1 H), 0.98 (s, 9 H), 0.20 (s, 6 H); 13C--NMR (CDCl3) δ157.90, 156.51, 129.89, 112.66, 108.42, 107.53, 25.61, 18.14, 14.49.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:18][C:19]1[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=[O:32])[CH:28]=[CH:27][C:20]=1[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22].Cl.O>CN(C)C=O>[Cl:18][C:19]1[CH:30]=[C:29]([C:31]([NH:33][N:34]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:10][CH:11]=2)[CH3:17])=[O:32])[CH:28]=[CH:27][C:20]=1[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NCCO)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCO)c(Cl)c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (40 mg, 0.14 mmol) and 2-chloro-4-hydrazinocarbonyl-N-(2-hydroxyethyl)benzamide (43 mg, 0.17 mmol) prepared in Reference Synthetic Example 8 in dimethylformamide (0.7 mL), concentrated hydrochloric acid (12 μL, 0.14 mmol) was added at room temperature, and the resulting mixture was stirred at room temperature for 1 day and stirred with 2-chloro-4-hydrazinocarbonyl-N-(2-hydroxyethyl)benzamide (18 mg, 0.07 mmol) for 1 day. After addition of water, the resulting crystals were recovered by filtration and dried. Chloroform was added, and the resulting crystals were recovered by filtration to give the desired product (yield 83%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([N:24]([CH2:34][C:35]([O:37]CC)=[O:36])[S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([N:24]([CH2:34][C:35]([OH:37])=[O:36])[S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:26])=[O:27])=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[O:13])=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CN(c1ccc2c(c1)CCCN2C(=O)CCc1ccc(C(=N)N)cc1)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)c1ccc(CCC(=O)N2CCCc3cc(N(CC(=O)O)S(=O)(=O)c4ccccc4)ccc32)cc1

Procedure:
370 mg of 1-[3-(4-amidino-phenyl)propionyl]-6-(N-ethoxycarbonylmethyl-phenylsulphonamido)-1,2,3,4-tetrahydro-quinoline are dissolved in 5 ml of ethanol and stirred overnight with 1.6 ml of 1N sodium hydroxide solution. Then the mixture is neutralised with hydrochloric acid, concentrated by evaporation and the residue is chromatographed with methanol over a silica gel column.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8]C(=O)OC(C)(C)C)[N:5]2[N:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:4]2[N:3]=1.O1CCOCC1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[NH2:8][C:6]1[N:5]2[N:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:4]2[N:3]=[C:2]([NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[C:28]([Cl:27])[CH:29]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc2c(C=O)cnn12
Reactant: Nc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(Nc2cccc(Cl)c2)nc2c(C=O)cnn12
Temperature: 95 °C
Yield: 38 %

Procedure:
Tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-ylcarbamate (1.1 g, 3.8 mmol) was added to 1,4-dioxane (15 mL) along with 3-chloroaniline (2.4 mL, 22.6 mmol) and p-toluenes ulfonic acid monohydrate (73 mg, 0.4 mmol). The reaction was heated at 95° C. for 12 hours then cooled to room temperature, diluted with water and filtered. Analysis of the recovered solid by LCMS showed product mass (M+1=288), as well as, product with chloro aniline imine mass (M+1=397). To completely convert this mixture to the desired product, the solid was dissolved in 6 mL of MeOH/conc. HCl solution (1:1) and heated at 60° C. for 1.5 hours. The reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water then the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, 7-amino-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde, was collected as orange-red solid in 38% yield. LCMS (M+1=288)
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])([O-:7])=[O:6]>C(OCC)(=O)C>[CH2:1]([NH:4][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: C=CCN
Solvent: CCOC(C)=O
Product: C=CCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
Step 1′ A 3-L, three-necked, round-bottomed flask equipped with a mechanical stirrer, a nitrogen inlet adapter, and a 500-mL pressure-equalizing addition finnel fitted with a glass stopper was purged with nitrogen. The flask was charged with allylamine (K) 33.9 g (0.593 mol), 50 mL of ethyl acetate, triethylaamine 60.0 g (0.593 mol), and then cooled with an ice-water bath. The addition funnel was charged with 3-nitro-benzoyl chloride (J) 100.0 g (0.539 mol) and 230 mL ethyl acetate, and this solution was then added dropwise to the reaction mixture over 1 h while the reaction mixture was maintained at 0° C. The reaction mixture was stirred at 0° C. for 3 h and then filtered. The filtrate was transferred to a separatory finnel and washed with 150 mL of a 10% (by volume) HCl aqueous solution, 100 mL of saturated sodium chloride solution, dried over magnesium sulfate, and the solvent volume was reduced to one-third the original volume under reduced pressure. The clear solution was cooled to 0° C. overnight. The resulting yellow solid was collected by filtration and dried in a vacuum oven at 50° C. for 6 h to afford 89.4 g (80% yield) of N-allyl-3-nitrobenzamide (L) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N=C2CCCCC2=O)=[CH:5][CH:4]=1.[OH2:18].S(=O)(=O)(O)O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:9][C:4]1[C:5](=[O:18])[CH2:6][CH2:7][CH2:8][C:3]2=1
Reactant: COc1ccc(NN=C2CCCCC2=O)cc1
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CCCC3=O

Procedure:
232 g. (1 mole) of cyclohexanedione-mono-p-methoxyphenylhydrazone, 1200 ml. of water, 350 g. of sulfuric acid (65 Be) and 100 ml. of ethanol are allowed to boil under reflux for three hours. After cooling down, the mixture is filtered with suction and rendered free from acid by washing with water. The resultant 6-methoxy-1,2,3,4-tetrahydrocarbazol-1-one melts at 222° C. and gives a yield of 193 g. (=90% of the theoretical).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3([C:18]([O:20]C)=[O:19])[CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[N:5][N:4]=[N:3]1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]3([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)=[N:5][N:4]=[N:3]1
Reactant: COC(=O)C1(Cc2ccc(-c3nnnn3C)cc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnnc1-c1ccc(CC2(C(=O)O)CCC2)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of methyl 1-[[4-(1-methyltetrazol-5-yl)phenyl]methyl]cyclobutane carboxylate (0.33 g, 1.15 mmol) in a mixture of THF (7 mL) and methanol (7 mL) was added 1 N sodium hydroxide (7 mL). The mixture was heated to 55° C. and stirred for 4 h at which point TLC analysis indicated the absence of starting material. After cooling to room temperature, the solvent was removed under vacuum and the residue was diluted with water and extracted with ethyl acetate to remove any neutral impurities. Then, the aqueous layer was neutralized with 1 N hydrochloric acid and the product was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with saturated brine and dried over sodium sulfate. After filtration, the solution was concentrated under vacuum and the residue was dried under high vacuum to afford 1-[[4-(1-methyl-5-tetrazolyl)phenyl]methyl]cyclobutane carboxylic acid (180 mg, 57%) as a light yellow syrup.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:25]>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])=[CH:9][CH:10]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2ccccc2F)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccccc2F)cc1
Yield: 30 %

Procedure:
Prepared in analogy to example 3 from N-[4-(2-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=30%. Colorless solid. MS: m/e=303.2 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[C:8]([CH:9]=1)[O:10][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCCN2CCCC2)c1
Temperature: 70 °C

Procedure:
A flask was charged with 5-nitro-2-pentafluoroethylphenol (3.67 g, 14.2 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (9.71 g, 57.1 mmol), DMF (20 mL) and combined with K2CO3 (5.9 g, 42.1 mmol) and heated to 70° C. for 24 h. The reaction was cooled to RT, taken up in to EtOAc and washed with 2N NaOH, and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The aqueous layer was acidified, extracted with EtOAc and dried with MgSO4, filtered, concentrated in vacuo and combined with the other portion. The title compound was purified by column chromatography using 0-10% MeOH in CH2Cl2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[N:28]=[C:29]=[S:30]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:2]=1[NH:1][C:29](=[S:30])[NH:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[Cl:19]
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCCO
Reactant: COc1ccc(N=C=S)c(Cl)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ccc(OC)cc2Cl)c1NCCCCO
Yield: 45.3 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(4-hydroxybutyl)amino]benzoate (2.00 g, 7.33 mmol) and 2-chloro-1-isothiocyanato-4-methoxybenzene (2.94 g, 14.7 mmol) in tetrahydrofuran (20 mL) was stirred for 36 h at 70° C. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel eluting with a 50% ethyl acetate/n-hexane mixture to give the title compound as a pale yellow oil (1.57 g, 3.32 mmol, 45%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(S(F)(F)[F:21])CC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([C:8]2([F:21])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OC1(c2nccnc2F)CCOCC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1nccnc1C1(F)CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-(3-fluoropyrazin-2-yl)tetrahydro-2H-pyran-4-ol (0.4 g, 2.018 mmol) in CH2Cl2 (6.73 mL) was cooled to 0° C. DAST (0.533 mL, 4.04 mmol) was added to the reaction mixture dropwise and the resulting mixture was allowed to stir at 0° C. for 2 hr. A solution of saturated sodium carbonate was added dropwise to the reaction mixture at 0° C. to quench the reaction. The heterogeneous mixture was stirred vigorously for 1 hr to ensure complete quenching. Mixture was transferred to a separatory funnel and the layers were separated after addition of more DCM and saturated bicarbonate solution. The organic layer was dried over magnesium sulfate and rotovapped to remove the volatile solvent.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:18]=[C:17]2[C@@H:7]([CH2:8][C:9]3[C:19]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH:10]=3)[N:5]([CH3:6])[CH2:4]1.CN(C)C=O>[Pd].N1C=CC=CC=1>[OH:1][CH2:2][C@@H:3]1[CH:18]=[C:17]2[C@@H:7]([CH2:8][CH:9]3[C:19]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH2:10]3)[N:5]([CH3:6])[CH2:4]1
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN1C[C@H](CO)C=C2c3cccc4c3C(CN4)C[C@H]21

Procedure:
catalytically hydrogenating under a pressure of 1 to 5 bar, a reaction mixture comprising lysergol and least one aprotic solvent containing a tertiary nitrogen a solvent mixture of N,N-dimethylformamide and pyridine and a 5 to 10% palladium catalyst applied on activated carbon, at a temperature between 40° C. and the boiling point of the reaction mixture, to form dihydrolysergol; and
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.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.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[CH2:45]([N:49]1[N:53]=[C:52]([CH3:54])[S:51]/[C:50]/1=[CH:55]\[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])=[O:6])[CH2:46][CH2:47][CH3:48]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: Cc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-methylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.84-0.93 (m, 3 H) 1.27-1.37 (m, 2 H) 1.67-1.75 (m, 2 H) 2.36, (s, 3 H) 2.47 (s, 3 H) 4.11-4.17 (m, 2 H) 6.19-6.25 (m, 1 H) 7.17-7.26 (m, 2 H) 7.26-7.33 (m, 1 H) 7.43-7.51 (m, 1 H); MS (ESI) m/z 289 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33]([N:35]([CH2:39][C:40]2[CH:41]=[C:42]([CH:51]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:53]=2)[O:43][CH2:44][C@@H:45]2[CH2:47][C@H:46]2[C:48]([OH:50])=[O:49])[CH:36]2[CH2:38][CH2:37]2)=[O:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:66][C:67]([N:69]([CH3:71])[CH3:70])=[O:68]>CN(C=O)C.CCOCC>[CH:36]1([N:35]([CH2:39][C:40]2[CH:53]=[C:52]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[CH:51]=[C:42]([O:43][CH2:44][C@@H:45]3[CH2:47][C@H:46]3[C:48]([O:50][CH2:66][C:67]([N:69]([CH3:71])[CH3:70])=[O:68])=[O:49])[CH:41]=2)[C:33]([C@@H:10]2[C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]4[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[Cl:32])=[CH:16][CH:15]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]2)=[O:34])[CH2:37][CH2:38]1
Reactant: CN(C)C(=O)CCl
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@@H]2C[C@H]2C(=O)OCC(=O)N(C)C)c1
Temperature: 80 °C

Procedure:
To a solution of (1R,2R)-2-{[3-{[[((3R,4S)-1-(tert-butoxycarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidin-3-yl)carbonyl](cyclopropyl)-amino]methyl}-5-(3-methoxypropyl)phenoxy]methyl}cyclopropanecarboxylic acid (1 eq.) from the previous step in DMF (0.1 M) was added cesium carbonate (2 eq.) and 2-chloro-N,N-dimethylacetamide (1.8 eq.). The reaction was heated to 80° C. for 2 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified was flash column chromatography (SiO2, 90% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [NH2:1][NH2:2].O.[CH2:4]([O:6][C:7](=[O:19])[C:8](=O)[CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>CO>[CH3:4][O:6][C:7]([C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:2][N:1]=1)=[O:19]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(-c2ccccc2)[nH]n1
Yield: 77.3 %

Procedure:
NH2—NH2—H2O (1.0 g, 20 mmol) was added to a solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (1.94 g, 8.81 mmol) in methanol (17 mL). The resulting reaction mixture was heated to reflux for two and half hours. The methanol was evaporated and the resulting solid was heated with 2.5% ethyl acetate in hexane to afford 5-phenyl-1H-pyrazole-3-carboxylic acid methyl ester as a solid in 77.3% yield. LC-MS purity: 93.345%.
Reaction SMILES: [OH:1][C:2]1[C:15]([CH2:16][C:17]([NH:19][CH2:20][CH2:21][Cl:22])=[O:18])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=12.[N+](=[CH2:29])=[N-]>C(O)C>[CH3:29][O:1][C:2]1[C:15]([CH2:16][C:17]([NH:19][CH2:20][CH2:21][Cl:22])=[O:18])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=12
Reactant: O=C(Cc1c(O)c2ccccc2c2nc3ccccc3nc12)NCCCl
Reactant: C=[N+]=[N-]
Solvent: CCO
Product: COc1c(CC(=O)NCCCl)c2nc3ccccc3nc2c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a suspension of 100 of 5-hydroxy-N-β-chloroethylbenzo[a]phenazine-6-carboxyamide in 10 ml of ethanol was added an excess amount of diazomethane ethereal solution, followed by stirring at room temperature overnight. The solvent was concentrated under reduced pressure, and the resulting solid was recrystallized from acetic acid to give 103 mg (99% yield) of 5-methoxy-N-β-chloroethylbenzo[a]-phenazine-6-carboxyamide as yellow needles, m.p. 211°-213° C., Anal. Calcd. (%) for C20H16N3O2Cl; C, 65.89; H, 4.29; N, 11.28; Found: C, 65.67; H, 4.41; N, 11.49
Reaction SMILES: C([O:4][C@H:5]1[C@H:14]([O:15]C(=O)C)[C@@H:13]([CH2:19][O:20]C(=O)C)[O:12][CH:7]([O:8][CH2:9][CH2:10][Cl:11])[C@@H:6]1[F:24])(=O)C.O(C)[Na]>CO>[F:24][C@@H:6]1[C@@H:5]([OH:4])[C@H:14]([OH:15])[C@@H:13]([CH2:19][OH:20])[O:12][CH:7]1[O:8][CH2:9][CH2:10][Cl:11]
Reactant: CC(=O)OC[C@H]1OC(OCCCl)[C@H](F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CO[Na]
Solvent: CO
Product: OC[C@H]1OC(OCCCl)[C@H](F)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloroethyl 3,4,6-tri-O-acetyl-2-deoxy-2-fluoro-D-glucopyranoside (0.85 g, 2.293 mmol) in CH3OH (10 mL) was added NaOCH3 (0.46 mL, 0.230 mmol, 0.5 M in CH3OH). The resulting mixture was stirred at rt for 2 hr. Dowex 50wx2-200 (H) ion exchange resin (pre-washed with CH3OH 3×10 mL) was added to the reaction mixture. After stirring for 15 min, the resin was filtered off and the filtrate was concentrated down to give the title compound. This anomeric mixture was used directly in the next step without further purification. TLC: silica gel, hexane/EtOAc: 1/1, Rf=0.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1-c1cccc(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: Cc1ccc[n+]([O-])c1-c1cccc(F)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 81.3 %

Procedure:
To a solution (100 mL) of 2-(3-fluorophenyl)-3-methylpyridine (4.83 g, 25.8 mmol) in ethyl acetate was added 3-chloroperbenzoic acid (7.1 g, 28.4 mmol), and the mixture was stirred at 50° C. for 5 hr. The disappearance of 3-chloroperbenzoic acid was confirmed using potassium iodide starch paper (manufactured by ADVANTEC MFS, INC), and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (4.26 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH3:17][O:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:20]=1/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)cc3OC)nc2n(CCC)c1=O

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.04 g (14.60 mmol) of 2,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.26 g (yield of Compound 24 as white crystals.