Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:33]([OH:35])=[O:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].I[CH2:42][CH3:43].O>CN(C=O)C>[CH2:42]([O:34][C:33](=[O:35])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:28])([F:29])[F:27])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH3:43]
Reactant: CCI
Reactant: Cc1cc(C(F)(F)F)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.5 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (145 mg, 0.275 mmol) and sodium bicarbonate (185 mg, 2.2 mmol) in DMF (2 mL) was added iodoethane (343 mg, 2.2 mmol) at room temperature. The mixture was stirred for 72 h at room temperature. Then, the reaction mixture was poured into water (30 mL) and was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine solution (60 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate gave 129 mg (85% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine ethyl ester as a crystalline white solid: mp 86-91° C. ES-HRMS m/e calcd for C26H23Cl2F3N2O4 (M+Na) 577.0876. found 577.0887.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[CH:6]=1.[CH3:29]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:29])[CH:11]=2)[CH:6]=1
Reactant: CB(O)O
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(Br)cc23)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(C)cc23)nc1
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of [6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (30 mg, 0.07 mmol, methyl ester of example 12-1), methylboronic acid (7 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.007 mmol), potassium phosphate (45 mg, 0.21 mmol) and toluene (0.5 mL) was stirred at 115 overnight under an argon atmosphere. The resulting mixture was diluted with water (5 mL), and then extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (20% ethyl acetate in petroleum ether) to give [4-(5-ethanesulfonyl-pyridin-2-yloxy)-6-methyl-naphthalen-2-yl]-acetic acid methyl ester (20 mg) as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:34])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]2=[O:34])[CH2:12][CH2:13]1
Reactant: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2ccncc2)c2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2 mL of a chloroform solution containing 280 mg of tert-butyl(1-(2-(7-methoxy-5-(pyridin-4-yl)-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.84 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, chloroform and water were added thereto, the resultant solution was adjusted to pH about 12 with a 2 mol/L aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 230 mg of a yellow oily substance, 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-5-(pyridin-4-yl)quinoxalin-2(1H)-one.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Cl)[CH:18]=1>CCO>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[NH:3][CH:2]=[N:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)[CH:18]=1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: CCO
Product: c1cncc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)c1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.418 mL, 3.0 mmol) and (pyridin-3-yl)methylchloride hydrochloride (0.246 g, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:14])[CH:7]=[CH:6]2)[CH3:2].[CH2:21](O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:21]1[CH2:22][O:23][C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[CH:4]=3)[CH:9]=2)([CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[O:14]1
Reactant: OCCO
Reactant: CCc1ccc2cc(C(=O)Cn3ccnc3)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCc1ccc2cc(C3(Cn4ccnc4)OCCO3)ccc2c1

Procedure:
A mixture of 0.7 g. of 1-[(6-ethyl-2-naphthoyl)methyl]imidazole, 4 ml of ethylene glycol and 1.3 g. of anhydrous p-toluenesulfonic acid in 50 ml. of toluene is heated overnight under reflux through a Dean-Stark trap. The trap is then replaced by a separatory funnel containing 4 A molecular sieves and heating is continued for a further day. After cooling, the mixture is treated with 100 ml. of ethyl acetate, neutralized by pouring into excess aqueous potassium carbonate and the organic phase separated, washed with water, dried (MgSO4) and separated to afford 1-[2,2-ethylenedioxy-2-(6-ethyl-2-naphthyl)ethyl]imidazole. This is purified by chromatography on silica gel eluting with 10% methanol/dichloromethane and the hydrochloride salt prepared by dropwise addition of ethereal hydrogen chloride until precipitation is complete. Filtration and recrystallization from acetone/methanol gives 0.38 g. pure hydrochloride, m.p. 251° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH2:16])[CH:15]=1.[N:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)=[C:20]=[S:21]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([O:17][CH3:18])=[C:14]([NH:16][C:20](=[S:21])[NH:19][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[CH:15]=1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NC(=S)Nc1ccc(S(N)(=O)=O)cc1

Procedure:
The product from Example 1, Step B, 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.12 g, 0.1 mmol) was reacted with 4-isothiocyanatobenzene sulfonamide (0.108 g, 0.1 mmol) according to the procedure for Example 2 to give the product (0.14 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccc(Sc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(Cl)cc3)cc2)c1C
Yield: 37.9 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(4-chlorophenylsulfanyl)-benzene (0.25 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(4-chloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.094 g, 37%) as a solid. MS calcd. for C26H21ClFO2S [(M+H)+] 451, obsd. 451.0.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.1 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.66 g (56%); off white solid; mp 210° C.; MS: 432 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12]O)=[CH:2]1.[Na].O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH2:12])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:2]1
Reactant: ON=C(Cc1c[nH]c2ccccc12)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: NC(Cc1c[nH]c2ccccc12)c1ccccc1
Yield: 92 %

Procedure:
2-(1H-indol-3-yl)-1-phenylethanone-oxime (0.2 g, 0.75 mmol) dissolved in ethanol (10 ml) was mixed in portions with sodium pieces (500 mg, 21 mmol) in the boiling heat. This reaction mixture was stirred with reflux until the metal was fully dissolved. After cooling in an ice bath, water (15 ml) was carefully added to the reaction solution. The volatile constituents were then removed in a vacuum. The aqueous residue was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried with sodium sulphate, filtered and all the volatile constituents removed in a vacuum. The residue (163 mg) obtained after distilling off the solvent was purified by column chromatography [silica gel 60 (30 g); methanol (500 ml)].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.C([Li])CCC.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:12]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: c1cocn1
Reactant: O=C1CCCC1
Agent: B
Agent: [Li]CCCC
Product: OC1(c2ncco2)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
An ambient solution of oxazole (1.00 g, 14.5 mmol) and borane●tetrahydrofuran complex (14.5 mL, 14.5 mmol, 1 M in tetrahydrofuran) was stirred for 30 min. The reaction was cooled to −78° C., and n-butyllithium (9.5 mL, 15.2 mmol, 1.6 M in hexane) was added dropwise. After 30 minutes, cyclopentanone (1.42 mL, 16.0 mmol) was added dropwise. After 30 minutes, the cold (−78° C.) reaction was quenched by the addition of 5% acetic acid in ethanol (70 mL) and warmed to room temperature. The solution was diluted with diethyl ether (10.0 mL) and saturated NaHCO3 (50 mL). Layers were separated, and the organics were washed with brine (1×50 mL), dried over Na2SO4, concentrated under reduced pressure, and purified by chromatography on SiO2 gel, eluting with 50% ethyl acetate in hexane, to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.59-1.71 (m, 2 H), 1.72-1.84 (m, 2 H), 1.84-1.96 (m, 2 H), 1.98-2.09 (m, 2 H), 5.40 (s, 1 H), 7.11 (s, 1 H), 8.02 (s, 1 H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([O:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[CH3:14].Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:28]1[C:29]([CH3:31])=[CH:30][C:26]([O:25][C:18]2[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=2)=[N:27]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: CCOc1cc(Oc2cc(C)[nH]n2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2ccc([N+](=O)[O-])c(OCC)c2)cc1C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
Triethylamine (0.07 g, 0.7 mmol) and ethyl isocyanate (0.12 g, 0.7 mmol) were added to a solution of 3-(3-ethoxy-4-nitrophenyloxy)-5-methylpyrazole (0.16 g, 0.6 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 5 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow solid of N-ethyl-3-(3-ethoxy-4-nitrophenyloxy)-5-methylpyrazole-1-carboxamide (0.13 g, yield: 61.8%). mp: 110-112° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (t, J=7.3 Hz, 3H), 1.49 (t, J=7.0 Hz, 3H), 2.63 (d, J=0.5 Hz, 3H), 3.40 (dq, J=6.0 and 7.3 Hz, 2H), 4.14 (q, J=7.0 Hz, 2H), 5.80 (q, J=0.5 Hz, 1H), 6.73 (dd, J=2.4 and 9.0 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.92 (br s, 1H), 7.92 (d, J=9.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[C@@H:14]3[C@@H:20]([N:23]=[N+]=[N-])[CH2:21][CH2:22][N:13]3[C:12]2=[O:26])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H][H]>CCO.[Pt](=O)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:18])([F:19])[F:17])[C@@H:14]3[C@@H:20]([NH2:23])[CH2:21][CH2:22][N:13]3[C:12]2=[O:26])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)N3CC[C@H](N=[N+]=[N-])[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1c(N2C(=O)N3CC[C@H](N)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To 69B (15.0 mg, 0.0391 mmol) in EtOH (1 mL) was added platinum (IV) oxide (5 mg) and hydrogen was bubbled through the system for 10 min. The hydrogen outlet was removed and the system was stirred under a hydrogen atmosphere. After 2 h, the reaction was filtered through celite and concentrated. The resulting residue was purified via preparative HPLC (YMC ODS C-18, 21×100 mm, eluting with 50-100% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 10 min; Flow rate at 40 mL/min; UV detection at 220 nm) to provide the title compound (6.00 mg) as a clear film. MS: m/z 419 [M+HCO3]−
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15](NC(=O)OCC)[NH:16][C:17](=[O:21])OCC)=[CH:11][CH:10]=1)#[N:8]>C1C=CC=CC=1>[Cl:2][CH:15]([N:16]=[C:17]=[O:21])[C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)NC(NC(=O)OCC)c1ccc(C#N)cc1
Solvent: c1ccccc1
Product: N#Cc1ccc(C(Cl)N=C=O)cc1

Procedure:
Phosphorous pentachloride (83.3 g, 400 mmol) is added to a suspension of diethyl (4-cyanophenyl)methylenedicarbamate (intermediate 1, 53.0 g, 182 mmol) in benzene (200 mL) and the mixture is heated at reflux for 2 h. The benzene is evaporated and the mixture is then purified by distillation under reduced pressure. The first fraction (ca. 40° C., ca. 0.01 mbar) is discarded. The second fraction (ca. 110° C., ca. 0.6 mbar) is collected. Yield: 28.4 g; ESI mass spectrum: [M+MeOH−HCl+H]+=189; Retention time HPLC: 0.65 min (Z003_004).
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:8]=12.CC1(C)[C@]23C4(ON4S(=O)(=[O:34])C2)C[C@H]1CC3.[Cl-].[NH4+]>C1COCC1>[F:6][C:7]1[C:12]([OH:34])=[CH:11][N:10]=[C:9]2[N:13]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:18])[CH3:19])[CH:14]=[CH:15][C:8]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Reactant: CC1(C)[C@@H]2CC[C@@]13CS(=O)(=O)N1OC13C2
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
sec-Butyl lithium (8.06 mL, 11.3 mmol, 1.4 M in cyclohexane) was added dropwise to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.5 g, 5.13 mmol, prepared as described in L′Heureux, et al., Org. Lett., 5(26) p. 5023 (2003)) in THF (100 mL) at −78° C. The reaction was stirred for 30 minutes. (1R)-(−)-(10-camphorsulfonyl)oxaziridine (2.94 g, 12.8 mmol) in THF (10 mL) was added rapidly, and the reaction was stirred at −78° C. for 30 minutes. A solution of saturated ammonium chloride (50 mL) was added, and the reaction mixture was allowed to reach room temperature. After one hour, the aqueous phase was extracted with AcOEt, dried over MgSO4 and concentrated to a solid, which was triturated in ether. The solid (most of the camphor side product) was filtered off, and the filtrate concentrated and purified by chromatography (25M, toluene/AcOEt 95/5) to yield a paste. The paste was triturated with hexanes, and the filtrate was concentrated to dryness to yield 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (820 mg, 51.8% yield) as an oil, which solidified upon standing.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:69][C:70]1[S:71][CH:72]=[CH:73][N:74]=1>CN(C=O)C>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([NH:69][C:70]3[S:71][CH:72]=[CH:73][N:74]=3)=[O:33])=[CH:34][CH:35]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:37]
Reactant: Nc1nccs1
Reactant: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2ccc(C(=O)Nc3nccs3)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To the compound 4-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (28 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2-aminothiazole (8.26 mg, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (5.8 mg, 18%). LC-MS m/z 590 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=C1C2C=CN=NC=2OC1.[CH2:13]([O:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]2[O:23][CH2:24][C:25](=O)[C:17]=12)[CH3:14]>>[CH3:1][O:2][N:3]=[C:25]1[C:17]2[C:18](=[N:19][C:20]([CH3:22])=[CH:21][C:16]=2[O:15][CH2:13][CH3:14])[O:23][CH2:24]1
Reactant: CCOc1cc(C)nc2c1C(=O)CO2
Reactant: CON=C1COc2nnccc21
Product: CCOc1cc(C)nc2c1C(=NOC)CO2

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 4-ethoxy-6-methylfuro[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as white solid;
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].CC(C)=[O:35].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:35])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16](=[O:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of betulin (1, 1.0 g, 2.26 mmol) in acetone (50 mL), cooled to 0° C., freshly prepared Jones' reagent was added dropwise. The resulting mixture was stirred for about 1.5 hours at 0° C., quenched with methanol (25 mL), stirred for an additional 5 minutes, then water (40 mL) was added. The acetone was removed under vacuum and the aqueous residue was extracted two times with 40 mL of ethyl acetate (EtOAc). The ethyl acetate layer was separated from the aqueous layer, then the ethyl acetate layer was washed first with water (20 mL) and then with brine (15 mL). The ethyl acetate layer was dried over magnesium sulfate (MgSO4), then filtered, and finally the ethyl acetate was removed under vacuum. The residue was column chromatographed over silica gel (60-200 mesh) using petroleum ether/EtOAc (4:1 volume ratio) to yield 770 mg of betulonic acid, having a melting point (mp) of 247°-249° C. (literature mp 246°-2470° C.). The reaction provided a 75% yield of betulonic acid.