Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[N:6][CH:7]=[C:8]([CH:10]=O)[CH:9]=1.[C:25]([O:28][CH2:29][CH3:30])([CH3:27])=[O:26].O>C1COCC1>[Cl:3][C:4]1[C:5]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[N:6][CH:7]=[C:8](/[CH:10]=[CH:27]/[C:25]([O:28][CH2:29][CH3:30])=[O:26])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(C=O)cc2Cl)C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 15 °C

Procedure:
A solution of diethylphosphonoacetcacid ethyl ester (980 mg), in THF (5 ml) was added dropwise to admixture of 60% sodium hydride in oil (187 mg) in THF (30 mL) with stirring at 10-20° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (0.95 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (6:4). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (0.98 g)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:17][C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:17][C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:14][CH2:13][CH2:12][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:2]([F:15])([F:1])[F:16])[CH:4]=3)[NH:8][CH:7]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: NCCc1c[nH]c2ccc(C(F)(F)F)cc12
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(C(F)(F)F)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 13.7 %

Procedure:
4-(3-Fluorobenzyl)-N-(2-(5-(trifluoromethyl)-1H-indol-3-yl)ethyl)benzamide was prepared according to Method A starting from 2-(5-(trifluoromethyl)-1H-indol-3-yl)ethanamine (0.080 g; 0.347 mmol), 4-(3-fluorobenzyl)benzoic acid (0.080 g, 0.347 mmol), HATU (0.132 g; 0.347 mmol) and N,N-diisopropylethylamine (0.149 mL; 0.869 mmol) in DMF (3 mL). The crude material was purified by preparative HPLC (method 2) to afford 0.021 g (14%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4](S(N=S(C)(C)=O)(=O)=O)=[CH:3][CH:2]=1.[H-].[Na+].C=C1CC[C:22](=[O:25])[CH2:21]C1>CS(C)=O.[Na+].[Cl-]>[CH2:15]=[C:1]1[CH2:6][CH2:5][C:4]2([O:25][CH2:22][CH2:21]2)[CH2:3][CH2:2]1
Reactant: C=C1CCC(=O)CC1
Reactant: Cc1ccc(S(=O)(=O)N=S(C)(C)=O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=C1CCC2(CCO2)CC1
Yield: 100.2 %

Procedure:
N-(para-Toluenesulfonyl)dimethylsulfoximine (1.49 g, 6.01 mmol) and anhydrous DMSO (5 mL) were added to NaH 60% oil dispersion (0.22 g, 5.46 mmol) kept under stirring under anhydrous inert gas atmosphere in a flamed 3 necks flask. The mixture became greenish, and then changed to yellow. After stirring at 35° C. for 10 h, a solution of 4-methylidenecylohexanone (0.2 g, 1.82 mmol) in 5 mL of DMSO was added and the reaction mixture was stirred at 50° C. for 20 h. Afterwards, the reaction mixture was diluted with a saturated solution of NaCl and extracted with Et2O (3 times). After drying on Na2SO4 and evaporation to dryness, the residue from evaporation was purified by means of automated flash chromatography (Isolera®TM-Biotage; isocratic Petroleum Ether-EtOAc 9:1) to give 0.252 g of the title compound as a colorless oil. Yield: 27.8%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O>C(#N)C.CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:25][C:26]([F:29])([F:28])[F:27]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)c(OCC(F)(F)F)c1
Temperature: 150 °C
Yield: 35.4 %

Procedure:
To a stirred solution of methyl 4-bromo-3-hydroxybenzoate (2.5 g) in acetonitrile (0.5 mL) and DMF (10 mL) in a microwave tube was added potassium carbonate (2.93 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.79 g). The mixture was heated to 150° C. in a microwave oven for 30 minutes. The solvent was removed in vacuum, ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Recrystallization of the residue from ethanol gave 1.2 g of the title compound. The mother liquor was concentrated in vacuum and purified by aminophase-silica-gel chromatography followed by recrystallized from methanol and water to give further 0.64 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O1CCOCC1>[N:23]1([CH2:2][CH2:3][CH2:4][C:5]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][C:9]3[CH:19]=[CH:20][CH:21]=[N:22][C:8]2=3)=[O:6])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCCl)c2ccccc21
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CCCN2CCCC2)c2ccccc21

Procedure:
5.5 gm of 11-(4-chlorobutyryl)-5,11-dihydro-6H-pyrido [2,3-b][1,4]-benzodiazepin-6-one, 1.4 gm of pyrrolidine and 2.1 gm of sodium carbonate were refluxed in a mixture of 80 ml of absolute ethanol and 20 ml of absolute dioxane for 10 hours. Then the hot mixture was suction-filtered, the filtrate was evaporated in vacuo to dryness, and the residue was purified on a silica gel column. The eluate was evaporated in vacuo to dryness, and the residue was recrystallized from acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:35]([O:37][CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([O:37][CH2:38][CH2:39][NH:40][C:29]([C:14]1[C:15](=[O:28])[N:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2=[O:27])[C:17]2[C:12]([C:13]=1[OH:34])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:18]=2)=[O:30])[CH3:36]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Reactant: CCOCCN
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(ethyloxy)ethanamine using methods similar to Example 563 to provide a white solid: 1H NMR (CDCl3) δ 10.36 (1H, b), 8.53 (1H, s), 8.16 (1H, s), 7.37 (2H, dd, J=6, 8 Hz), 7.11 (2H, t, J=9 Hz), 4.37 (2H, t, J=6 Hz), 4.13 (2H, s), 3.42-3.50 (8H, m), 3.24 (2H, t, J=6 Hz), 1.99 (2H, t, J=6 Hz), 1.48-1.62 (4H, m), 1.10 (3H, t, J=7 Hz); ES+ MS: 511 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:25]1([CH:24]=[CH:23][C:22]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=3[CH:14]=2)=[O:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1nc2cc(OC(=O)C=Cc3ccccc3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole), 4-dimethylaminopyridine (100 mg., catalyst) and triethylamine (1.4 ml., 0.01 mole) in dimethylformamide (20 ml.) is added cinnamoyl chloride (1.7 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 2 hours and then poured into ice water and excess hydrochloric acid to give 2-sulfamoyl-5-benzothiazolyl 3-phenyl-2-propenoate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[C:16]3[O:25][CH2:26][O:27][C:15]=13)=[CH:10][C:9]([O:28][CH3:29])=[C:8]([O:30][CH3:31])[CH:7]=2)#[N:2].[CH3:32][O:33][CH2:34][CH2:35][NH2:36]>>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:36][CH2:35][CH2:34][O:33][CH3:32])=[O:23])=[C:16]3[O:25][CH2:26][O:27][C:15]=13)=[CH:10][C:9]([O:28][CH3:29])=[C:8]([O:30][CH3:31])[CH:7]=2)#[N:2]
Reactant: COCCN
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(/C=C/C(=O)O)c4c3OCO4)c2cc1OC
Product: COCCNC(=O)/C=C/c1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c2c1OCO2
Yield: 64 %

Procedure:
Using an analogous procedure to that described in Example 16, (2E)-3-[4-(3-cyano-6,7-dimethoxyquinolin-4-ylamino)-2,3-methylenedioxyphenyl]acrylic acid was reacted with 2-methoxyethylamine to give the title compound in 64% yield; NMR Spectrum: (DMSOd6) 3.22–3.43 (m, 7H), 3.95 (s, 3H), 3.96 (s, 3H), 6.1 (s, 2H), 6.74 (d, 1H), 6.87 (d, 1H), 7.07 (d, 1H), 7.32 (s, 2H), 7.73 (s, 1H), 8.22 (t, 1H), 8.48 (s, 1H), 9.62 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](O)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][OH:33])[CH:27]=2)=[CH:22][CH:21]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:33][CH2:32][C:28]3[CH:27]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=4)[N:30]([CH3:31])[N:29]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cn1nc(CO)cc1-c1ccc(Cl)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cn1nc(COc2ccc3c(ccn3CC(=O)OC(C)(C)C)c2)cc1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 1 d]) was reacted with [5-(4-chloro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {5-[5-(4-chloro-phenyl)-1-methyl-1H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as colorless solid.
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[C:14]([NH2:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC(Cl)C>C(Cl)Cl>[C:15]1([C:14]2[O:21][C:2]3[CH2:3][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=3[N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Reactant: NC(=O)c1ccccc1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CCc2nc(-c3ccccc3)oc2C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
16.0 g (64.23 mmol) ethyl 3-bromo-4-oxo-cyclohexanecarboxylate are combined with 7.8 g (64.39 mmol) benzamide and 50 ml of dichloroethane in a pressure vessel and stirred overnight at 120° C. The reaction mixture is diluted with DCM and washed 2× with 5% potassium carbonate solution as well as 1× with sat. saline solution. The org. phase is dried on magnesium sulphate and the solv. is eliminated completely in vacuo, the residue is purified through silica gel (eluant cyclohexane/EA).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C@@H:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:11][CH:12]([CH2:15][CH3:16])[CH2:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CC[C@H](C)CO
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1
Yield: 88.1 %

Procedure:
0.29 mole (40.0 g) of 4-hydroxybenzoic acid and 0.35 mole (30.9 g) of (S)-(-)-2-methylbutanol were refluxed for 20 hours in 150 ml of toluene in the presence of 1 ml of conc. sulfuric acid. The reaction solution was concentrated, and then purified by column chromatography to obtain 53.2 g of 4-hydroxybenzoic acid 2-methylbutyl ester [[α]D23 =+4.95* (CHCL3)]. (yield: 88%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH2:8][CH2:7]2.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH:27]=[N:28][CH:29]=2)[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[C:9](=[O:13])[CH:8]=[CH:7]2
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c21
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCc1cncc(-c2cc(F)c3c(ccc(=O)n3C)c2)c1
Temperature: 120 °C
Yield: 10.1 %

Procedure:
A mixture of 8-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (example 208 [E], 20 mg, 0.066 mmol), ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11, 27.4 mg, 0.098 mmol), bis(triphenylphosphine)-palladium(II) chloride (4.6 mg, 0.0066 mmol), and aq. sodium carbonate solution (2 N, 0.07 mL) in DMF (1 mL) was heated in a microwave at 120° C. for 30 minutes. After dilution of the reaction mixture with EtOAc, the organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was then purified by prep-HPLC to afford the title compound (2.5 mg, 10%) as a white solid. MS: 376.3 (M+H+)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13](=[O:20])[NH:14][NH:15][C:16]=2[CH:17]([CH3:19])[CH3:18])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CC([O:24][CH2:25][C@H:26]1[O:31][C@H:30](Br)[C@H:29]([O:33]C(C)=O)[C@@H:28]([O:37]C(C)=O)[C@@H:27]1[O:41]C(C)=O)=O.[OH-].[Na+]>ClCCl>[C@@H:30]1([O:20][C:13]2[C:12]([CH2:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=3)=[C:16]([CH:17]([CH3:19])[CH3:18])[NH:15][N:14]=2)[O:31][C@H:26]([CH2:25][OH:24])[C@@H:27]([OH:41])[C@H:28]([OH:37])[C@H:29]1[OH:33]
Reactant: CC(C)Cc1ccc(Cc2c(C(C)C)[nH][nH]c2=O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)Cc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a suspension of 4-[(4-isobutylphenyl)methyl]-5-isopropyl-1,2-dihydro-3H-pyrazole-3-one (0.082 g), acetobromo-α-D-glucose (0.62 g) and benzyl(n-tributyl)ammonium bromide (0.054 g) in dichloromethane (3 mL) was added a sodium hydroxide aqueous solution (5 mol/L, 0.9 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent:tetrahydrofuran). The obtained semi purified 5-isopropyl-4-[(4-isobutylphenyl)methyl]-3-(2,3,4,6-tetraacetyl-β-D-glucopyranosyloxy)-1H-pyrazole was dissolved in methanol (5 mL), and sodium methoxide (28% methanol solution, 0.29 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours. The solvent of the reaction mixture was removed under reduced pressure, and water was added to the residue. The mixture was purified by solid phase extraction (washing solvent:water, eluent:methanol). Further purification by column chromatography on silica gel (eluent:dichloromethane/methanol=20/1-7/1) gave the title compound (0.080 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1.[OH-].[Na+:24]>C(O)C>[Na+:24].[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([O-:20])=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)c1ccc2[nH]c(-c3ccnc(NC)n3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1nccc(-c2cc3cc(C(=O)[O-])ccc3[nH]2)n1
Yield: 100 %

Procedure:
25 g of ethyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate were admixed with 200 ml of ethanol and 24.5 g of 33% sodium hydroxide solution, and heated to from 65° C. to 70° C. for 4 h. After cooling, the mixture was filtered with suction and the precipitate was washed with 15 ml of ethanol/water (9:1). 24.5 g (87.6% of theory) of 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid sodium salt were obtained (98.1 HPLC area %). LCMS: [M+H]⊕ 269.10
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][C:8]=1Cl>C(O)C>[CH3:4][O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][C:8]=1[NH:3][CH2:1][CH3:2]
Reactant: COC(=O)c1ccc(C)nc1Cl
Reactant: CCN
Solvent: CCO
Product: CCNc1nc(C)ccc1C(=O)OC

Procedure:
To a cold solution of 5.4 g. (0.12 mole) of anhydrous ethyl amine in 5 ml. of ethanol was added 11.1 g. (0.06 mole) of 2-chloro-6-methylnicotinic acid methyl ester. The mixture was heated in a glass autoclave over a steam bath for 5 hours. The mixture was then evaporated in a rotary evaporator and the residue was added to 100 ml. of water and was basified with concentrated ammonium hydroxide. The mixture was then extracted with 100 ml. of chloroform. The chloroform layer was dried over magnesium sulfate, filtered and was evaporated to give 2-ethylamino-6-methylnicotinic acid methyl ester as an oil which was used without further purification.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[O:30][CH3:31])=[CH:8]2)=[O:4].[NH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:32])[C:5]([C:3]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3cc(F)ccc3OC)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(F)cc1-c1cc2c(O)c(C(=O)NCCC(=O)O)ncc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A mixture of 1-benzyl-3-(5-fluoro-2-methoxy-phenyl)-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (27 mg, 0.062 mmol), β-alanine (737 mg, 8.3 mmol) and NaOMe solution (12 mL, 6.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 23 mg of the title compound as a white solid. MS: (+) m/z 492.25 (M+1).
Reaction SMILES: [C:1](=[O:8])([O-])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[C:9](=[O:16])([O-])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][NH:36][CH2:35][CH2:34][NH:33]2)=[CH:28][CH:27]=1)#[N:25]>O1CCCC1>[C:24]([C:26]1[CH:27]=[CH:28][C:29]([C@H:32]2[CH2:37][N:36]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:16])[CH2:35][CH2:34][N:33]2[C:1]([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:8])=[CH:30][CH:31]=1)#[N:25]
Reactant: N#Cc1ccc([C@H]2CNCCN2)cc1
Reactant: CC(C)(C)OC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(C#N)cc2)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-Chloroethyl chloroformate (2.7 g, 18.9 mmol) was added to a solution of 4-((2S)-1,4-dibenzylpiperazin-2-yl)benzonitrile (1.4 g, 3.81 mmol) in dichloroethane (30 ml). The reaction mixture was vigorously stirred at room temperature for 10 hours. The solvent was evaporated under reduced pressure and methanol (40 ml) was added to the residue. The mixture was heated at 80° C. for one hour and the solvent was evaporated under reduced pressure to afford (2S)-2-(4-cyanophenyl)piperazine as white crystals. Di-tert-butyl di-carbonate (1.9 g, 8.71 mmol) was added to a solution of triethylamine (1.2 g, 11.9 mmol) and (2S)-2-(4-cyanophenyl)piperazine in tetrahydrofuran (50 ml) at room temperature and the mixture was stirred at 50° C. for one hour. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 10-20% ethyl acetate in hexane to furnish di-tert-butyl
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][N:16]=[N:17][N:8]2[C:7]1=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>C(#N)C>[Br:19][C:12]1[NH:11][C:10]2[C:9]3=[N:15][N:16]=[N:17][N:8]3[C:7](=[O:18])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c(=O)n2nnnc2c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCCCCn1c(=O)n2nnnc2c2[nH]c(Br)nc21
Temperature: 70 °C

Procedure:
The mixture of 6-pentyl-6,9-dihydro-5H-tetrazolo[5,1-i]purin-5-one (0.020 g, 0.081 mmol) and N-bromosuccinimide (10 mg, 8.0 mmol) in acetonitrile (2 mL) in a 5 mL-microwave reaction tube was heated at 70° C. in microwave oven for 12 min. After cooling down to room temperature, the reaction mixture was purified using preparative LCMS to yield the desired product as a white powder. LCMS calculated for C10H13BrN7O (M+H): 326.0, 328.0. found: 326.0, 328.0.
Reaction SMILES: C([N:8]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1)[OH:11])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.O>[OH:11][C@H:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][NH:8][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3ccc(Cl)nc3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3cccnc3)cc2)cc1
Yield: 92.3 %

Procedure:
Methyl 4′-[2-[N-benzyl-N-[(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]ethyl]-1,1′-biphenyl-4-carboxylate (470 mg), ammonium formate (296 mg) and palladium on carbon powder (100 mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 30 minutes. The reaction mixture was filtrated and poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. A mixture of the residue was chromatographed (chloroform-methanol) over silica gel to give methyl 4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]-amino]ethyl]-1,1′-biphenyl-4-carboxylate (326 mg) as a colorless foam.