Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].C(N(CC)CC)C.[C:13]([O:17][C:18]([N:20]1[CH2:32][C:31]2[S:30][C:29]3[N:28]=[CH:27][NH:26][C:25](=O)[C:24]=3[C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>O>[C:13]([O:17][C:18]([N:20]1[CH2:32][C:31]2[S:30][C:29]3[N:28]=[CH:27][N:26]=[C:25]([Cl:3])[C:24]=3[C:23]=2[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3nc[nH]c(=O)c23)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Temperature: 60 °C
Yield: 25 %

Procedure:
To a of mixture of POCl3 (30 mL) and triethylamine (50 mL) at 0° C. was added 4-oxo-3,5,6,8-tetrahydro-4H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester (10.0 g). The reaction mixture was heated at 60° C. for 3 h. Water was then added, followed by sodium bicarbonate to neutralize the reaction mixture. The resulting mixture was extracted with dichloromethane. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (10:1) to give the title compound (3.1 g, 25%). 1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 4.69 (s, 2H), 3.74 (t, 2H, J=5.6 Hz), 3.14-3.18 (brs, 2H), 1.46 (s, 9H). LC-MS (ESI) m/z 326.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:7])[CH:6]=1.[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C:17]([OH:22])([C:16]([F:24])([F:23])[F:15])[C:6]1[C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[NH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc(-n2[nH]c(C)cc2=O)cc1
Reactant: COC(=O)C(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C)cc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 3-methyl-1-(4-methylphenyl)-5-pyrazolone (94 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (172 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:23])[CH:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1>CS(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:23])[CH:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=2)=[CH:20][CH:21]=1)[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OCCOCc1ccccc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)OCCOCc1ccccc1
Temperature: 90 °C

Procedure:
31.6 g of 2-benzyloxyethyl-2-(4-hydroxyphenoxy)propionate were dissolved in 100 ml of dimethylsulfoxide, 15.2 g of potassium carbonate were added thereto, then the mixture was heated at 90° C. for one hour with stirring. 20.0 g of 2-chloro-5-trifluoromethylpyridine were added dropwise to this solution which was then maintained at 90° C. for a further two hours. After cooling the reaction solution to room temperature, it was poured into ice-water, then extracted with ether. The ether layer was dried and filtered, and the ether was distillated off. The end product of 2-benzyloxyethyl-2-[4-(5-trifluoromethyl-2-pyridyloxy)-phenoxy]propionate (a compound also produced in Example 20) was obtained in a yield of 41.0 g (m.p. 44°-47° C.).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:12][C@H:13]([C:18]([N:20]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15].C([BH3-])#N.[Na+]>>[CH2:8]([O:7][C:5]([C@@H:4]([NH:12][C@H:13]([C:18]([N:20]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][C:22]([OH:24])=[O:23])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])[CH2:3][CH:2]([CH3:11])[CH3:1])=[O:6])[CH3:9]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(CC(=O)O)c1cccnc1
Reactant: CCOC(=O)C(=O)CC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)[C@H](CC(C)C)N[C@H](C(=O)N(CC(=O)O)c1cccnc1)[C@@H](C)CC

Procedure:
Ethyl 4-methyl-2-oxopentanoate and L-isoleucyl-N-(3-pyridyl)-glycine were condensed in the presence of sodium cyanoborohydride to yield N-[1-(S)-ethoxycarbonyl-3-methylbutyl]-L-isoleucyl-N-(3-pyridyl) glycine.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:15]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O:17][CH3:18])=[O:16].N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][N:13]([C:23]3[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH3:18])=[O:16])[CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)c1ccc(-c2c[nH]cn2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(-n2cnc(-c3ccc(C(C)C)cc3)c2)c1
Reaction time: 14 h

Procedure:
A solution of 4-(4-isopropyl-phenyl)-1H-imidazole (190 mg), 3-carbomethoxy-phenylboronic acid (360 mg) and Cu(OAc)2 (300 mg) in dichloromethane (15 mL) is treated with pyridine (160 mg) and 4 Å molecular sieves (500 mg). The mixture is stirred in the presence of air for 14 h then filtered through celite, and the celite pad is washed well with ethyl acetate. The filtrate and washing are combined and evaporated, and the residual material is separated by column chromatography to afford the product, methyl 3-[4-(4-isopropyl-phenyl)-imidazol-1-yl]-benzoate, as a yellow solid (190 mg).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([CH3:11])[C:5]=1[CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.CO>[CH2:18]([O:3][C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([CH3:11])[C:5]=1[CH:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ccc(=O)c(OCc2ccccc2)c1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A solution of NaOH (1.77 g dissolved in 20 mL, 44.4 mmol) in de-ionized water was added dropwise to a suspension of 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (9.00 g, 40.3 mmol) in methanol (100 mL), and followed by benzyl bromide (5.28 mL, 44.4 mmol) at room temperature. The resulting suspension was refluxed for 3.5 h, and then stirred at RT for overnight. Methanol was removed under vacuum using the rotary evaporator, and the residue was diluted with water and extracted two times with CH2Cl2 (2×100 mL). The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel using a mixture of methanol and ethyl acetate (10/90, v/v) as eluant. Fractions rich in the product were pooled together and evaporated to dryness to give 4 g of 3-benzyloxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[O:13]C(=O)[NH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>C(O)C>[NH2:11][CH:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:24][CH:23]=1)[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[OH:13]
Reactant: CC(C)(C)c1ccc(CC2NC(=O)OC2c2cccc(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of (4RS,5SR)-4-(4-tert-butylbenzyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one (9.50 g, 27.6 mmol) in ethanol (70 ml) was added 8N aqueous sodium hydroxide solution (17.3 ml, 138 mmol), and the mixture was stirred at 80° C. overnight. To the reaction solution was added water (20 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the objective substance (8.82 g, 100%).
Reaction SMILES: [OH-].[K+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.Cl>CCO.O.O>[CH2:3]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Yield: 62.3 %

Procedure:
KOH (6.16 g, 109.78 mmol) and benzyl bromide (9.42 g, 55.08 mmol) were added to a stirred solution of 4-hydroxy benzoic acid (6.9 g, 49.96 mmol) in EtOH:H2O (9:1, 176 mL) and the resulting mixture was heated to reflux for 20 hrs. 20% KOH solution (60 mL) was then added the mixture maintained at reflux for 4 hours. The reaction mixture was diluted with water (200 mL) and acidified with 20% HCl. The resulting white precipitate was filtered and washed with water followed by hexane to afford 7.1 g (62.2% yield) of 4-benzyloxy benzoic acid. 1H NMR (DMSO-d6): δ 12.6 (s, 1H), 7.9 (d, 2H), 7.4 (m, 5H), 7.1 (d, 2H), 5.2 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([CH2:21][CH3:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.C([Li])CCC.[CH:28]1([N:34]=[C:35]=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([NH:34][C:35]([C:11]2[N:12]([CH2:21][CH3:22])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C=NC1CCCCC1
Reactant: CCn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-ethylimidazole (43 mg, 0.12 mmol) from Example 41, Step A (lower Rf isomer) in THF (2 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.092 mL, 0.15 mmol). The reaction was stirred for 1 hr and then cyclohexyl isocyanate (0.032 mL, 0.25 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (3×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: ClC1C=C(C(C2(C)C3C(=CC=[C:19]([O:22]C)C=3)C(=O)N2)CC=C)C=CC=1Cl.Cl.[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]([CH:51]2[C:59]3[C:54](=[CH:55][CH:56]=[C:57]([O:60][CH:61]([CH3:63])[CH3:62])[CH:58]=3)[C:53](=[O:64])[N:52]2[CH3:65])[CH2:36]CN2CCC(N3CCCNC3=O)CC2)[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]([CH:51]2[C:59]3[C:54](=[CH:55][CH:56]=[C:57]([O:60][CH:61]([CH3:63])[CH3:62])[CH:58]=3)[C:53](=[O:64])[N:52]2[CH3:65])[CH2:36][CH:19]=[O:22])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: CC(C)Oc1ccc2c(c1)C(C(CCN1CCC(N3CCCNC3=O)CC1)c1ccc(Cl)c(Cl)c1)N(C)C2=O
Reactant: C=CCC(c1ccc(Cl)c(Cl)c1)C1(C)NC(=O)c2ccc(OC)cc21
Agent: Cl
Product: CC(C)Oc1ccc2c(c1)C(C(CC=O)c1ccc(Cl)c(Cl)c1)N(C)C2=O

Procedure:
The intermediate 3-(3,4-dichlorophenyl)-3-(6-isopropoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde was prepared from 3-[1-(3,4-dichlorophenyl)but-3-enyl]-5-methoxy-3-methyl-2,3-dihydro-1H-isoindol-1-one (described at Example 30 sub-part c.) by treating the ether as described in Example 31 sub-part a. to give the corresponding alcohol, followed by a sequence similar to that described in Example 42 sub-parts a.-b.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][O:35][CH:34]=2)=[O:32])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[O:35]1[CH:36]=[CH:37][C:33]([C:31]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([CH3:23])=[C:29]([C:2]3[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=4)=[O:7])=[CH:4][N:3]=3)[CH:28]=2)=[O:32])=[CH:34]1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-(3 -methylsulphonylaminobenzyl)-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.93 min, MH+505. NMR: δH [2H6]-DMSO 9.99, (1H, s), 9.32, (1H, t), 9.15, (1H, d), 8.95, (1H, b), 8.38, (1H, s), 8.33, (1H, dd), 7.81, (2H, d), 7.75, (1H, d), 7.68, (1H, d), 7.33-7.30, (2H, m), 7.21, (1H, s), 7.11, (2H, m), 7.01, (1H, s), 4.51, (2H, d), 2.99, (3H, s), 2.32, (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[OH:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=1[O:39][CH3:40]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:18][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][C:30]([O:29][CH2:28][CH2:27][CH2:26][OH:25])=[C:31]([O:39][CH3:40])[CH:32]=2)[CH:15]([CH3:17])[CH3:16])[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: COc1cc(C(=O)O)ccc1OCCCO
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)C(C)C)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](NC(=O)c3ccc(OCCCO)c(OC)c3)C(C)C)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-amino-3-methylbutoxy)-2-methylquinoline-3-carboxylate (Example 95b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi, P. G. et al. J. Med. Chem. 1999, 42, 5131.) as brown solid (29%). MS 540 (MH+).
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][O:12]P(O)(O)=O)[C@@H:8]([OH:17])[C@H:7]2[OH:18])[C:4]([NH2:19])=[C:3]([C:20]([NH2:22])=[O:21])[N:2]=1.[N:23]([O-])=O.[Na+].N>C(O)C>[C@@H:6]1([N:5]2[C:4]3[N:19]=[N:23][NH:22][C:20](=[O:21])[C:3]=3[N:2]=[CH:1]2)[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:17])[C@H:7]1[OH:18]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c1N
Reactant: O=N[O-]
Agent: N
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]nnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
The AICAR [for preparation see Synthesis, 2003, No 17, 2639] (1 g, 3.87 mmol) was added to a solution of chlorhydrique acid 6N (25 mL) at −30° C. A solution of sodium nitrite 3M (4 ml, 11.62 mmol) was added and the mixture was stirred at −30° for 2 hours. A pre-cooled (−30° C.) solution of ethanol (25 mL) was added. A solution of ammonia (28%) was added at −20° C. to pH=7. The reaction mixture was evaporated to dryness. The crude product was purified on silica gel reverse-phase (C18) using water as eluant to give the title compound (0.81 gr) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]#[N:15])[C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[C:6]2[C:11](=[N:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:14]#[N:15]
Reactant: N#Cc1c[nH]c2ncc([N+](=O)[O-])cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Cl

Procedure:
A mixture of 19.3 g (89.3 mmol) of 6-nitro-4-oxo-1,4-dihydro-[1.8]naphthyridine-3-carbonitrile in 386 ml of phosphorous oxychloride was refluxed for 24 hr. Excess phosphorous oxychloride was removed. The residue is mixed with ethyl acetate and 15 g of potassium hydroxide in 200 ml of ice water. The organic layer was separated and the aqueous layer was extract several more times with ethyl acetate. The combined volume of extracts was 4000 ml. The extracts were dried of magnesium sulfate and the solution was filter through a short silica gel column. The solvent was removed. The residue was stirred with ether and the solid was collected giving 15.7 g of the title compound as an orange solid: mass spectrum (electrospray, m/e): M+H 235.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][C:14]([C:18]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:20])=[C:15]([CH3:17])[N:16]=2)=[CH:10][CH:11]=1
Reactant: C1COCCN1
Reactant: Cc1nc(-c2ccc(OCCCCl)cc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(OCCCCl)cc2)sc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylic acid i106 (1.6 mmol, 1 eq, 0.5 g), triethylamine (3.2 mmol, 2 eq, 0.45 ml) in dichloromethane (20 ml) is added 1-hydroxybenzotriazole (0.32 mmol, 0.2 eq, 43 mg), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (1.76 mmol, 1.1 eq, 0.33 g) and morpholine (1.92 mmol, 1.2 eq, 0.17 g). The mixture is stirred at room temperature overnight. The organic layer is washed with water and with a saturated aqueous solution of ammonium chloride, then dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure. The crude product is purified by flash chromatography over silicagel (eluent: dichloromethane/ethanol 99:1 to 95:5) to afford 380 mg of 4-({2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}carbonyl)morpholine i107.
Reaction SMILES: [CH:1]([O:4][C:5]1[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([Br:28])=[CH:23][N:22]=1>C1COCC1>[Br:28][C:24]1[C:23]([NH:10][C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[NH:9][N:8]=2)=[N:22][C:21]([Cl:20])=[N:26][CH:25]=1
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Reaction time: 16 h

Procedure:
To a solution of 5-isopropoxy-1H-pyrazol-3-amine (11.6 g, 82.1 mmol) in THF (85 ml) was added DIPEA (16 ml) and 2,4-dichloro-5-bromopyrimidine (17 g, 74.6 mmol) and the resulting solution was aged at 40° C. for 16 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure and column chromatography gave the title compound as a solid. m/z: 332.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([OH:19])=O)[C:6]=2[CH:20]=1.C1C=CC2N(O)N=[N:33][C:31]=2C=1.CCN=C=NCCCN(C)C.CN>CN(C=O)C.CCN(CC)CC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([N:21]4[CH2:25][CH2:24][CH2:23][C:22]4=[O:26])[CH:2]=[CH:20][C:6]=3[C:7]=2[C:17]([NH:33][CH3:31])=[O:19])=[CH:11][CH:12]=1
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)c(Br)cc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A solution of 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylic acid (280 mg, 0.67 mmol), HOBT (150 mg, 1.11 mmol) and EDCI (280 mg, 1.47 mmol) in dry DMF (2 mL) was allowed to stir at room temperature for 1 hour. Then Et3N (0.2 mL) and CH3NH2 (HCl salt, 100 mg, 1.48 mmol) was added to the mixture, and the reaction was allowed to stir for about 15 hours. After being concentrated in vacuo, water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried and concentrated in vacuo and the resulting resulting residue was purified using column chromatography (eluted with petroleum ether:EtOAc=1:1) to provide 5-bromo-2-(4-fluorophenyl-N-methyl-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxamide (220 mg, yield: 73%), which was also prepared from 6-amino-5-bromo-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide and 4-chlorobutanoyl chloride using the method described in step 1 above. 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.82˜7.86 (m, 2H), 7.32 (s, 1H), 7.09˜7.14 (m, 2H), 6.29 (s, 1H), 3.75˜3.78 (m, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.56˜2.60 (m, 2H), 2.24˜2.26 (m, 2H). MS (M+H)+: 431/433.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.[CH2:21](OC(OCC)OCC)[CH3:22].O>C(O)C>[CH3:21][CH2:22][O:19][C@H:7]1[O:8][C@@H:9]2[O:15][C:14]3([CH3:18])[O:16][O:17][C@@:10]42[C@@H:5]([CH2:4][CH2:3][C@@H:2]([CH3:1])[C@@H:11]4[CH2:12][CH2:13]3)[C@H:6]1[CH3:20]
Reactant: CCOC(OCC)OCC
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Solvent: O
Solvent: CCO
Product: CCO[C@H]1O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dihydroartemisinin (50 mg) was dissolved in 3 ml dry ethanol with stirring the solution for 10 min. at room temperature and add cation exchange resin (Dowex-50, 50 mg) and triethylorthoformate (4 ml) in the solution. The reaction mixture is stirred for 10 hrs at room temperature (30° C.). Water was added in the reaction mixture and filters the cation exchange resin. The reaction product was extracted by dichloromethane. The organic layer was separated, dried over anhydrous sodium sulphate and evaporated under vacuum to yield pure arteether (50 mg).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:26]2[CH2:25][CH2:24][N:23]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[CH:22]([CH3:21])[CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(C(C)(C)C)n3)CC2C)c1

Procedure:
143 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 2-methyl-1-m-tolylpiperazine (69 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).