Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]=[C:24]=[O:25])[CH:19]=[C:20]([Cl:22])[CH:21]=1.O.Cl>N1C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][C:24](=[O:25])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:13][CH:14]=2)[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(Oc1ccc(N)cc1)C(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(Oc1ccc(NC(=O)Nc2cc(Cl)cc(Cl)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 4.95 g (0.025 mole) of 2-(4-aminophenoxy)-2-methylpropionic acid in 50 ml dry pyridine, 4.95 g (0.025 mole) of 3,5-dichlorophenyl isocyanate were added. After 1 hour stirring at room temperature, 150 ml water was added and the mixture was acidified with concentrated HCl. The precipitate was filtered, washed several times with cold water and dried. Recrystallization from aqueous acetone gave small plates 1.81 g (94%) MP 182°-184°.
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[NH:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:6]=[CH:5][C:4]=2[CH:3]=1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:7]2[N:8]=[C:9]3[C:4]([CH:3]=[C:2]([CH3:1])[C:11](=[O:12])[NH:10]3)=[CH:5][CH:6]=2)[CH2:29][CH2:28]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: Cc1cc2ccc(OCCCC=O)nc2[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]c1=O
Reaction time: 0.08 h
Yield: 19.4 %

Procedure:
To a solution of crude 4-(6-methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.65 g, 2.24 mmol, 1.0 equiv) in anhydrous methanol (40 mL) cooled to 0° C. was added 2,3-dichlorophenylpiperazine (1.2 g, 4.0 mmol, 2.0 equiv). The mixture was stirred for 5 min and NaBH(OAc)3 (2.3 g, 11.2 mmol, 5.0 equiv) was added. The reaction mixture was brought to room temperature and stirred overnight. The reaction was quenched with water and was concentrated to remove methanol completely. The resultant pale green residue was dissolved in ethyl acetate and washed with 0.5 N HCl (1×10 mL), saturated NaHCO3 solution (1×10 mL) and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, 2% MeOH/CH2Cl2) to afford the title compound as a white foamy solid (0.2 g, 30%). MS: ES+ 461.03, 463.03 (Exact Mass: 460.14).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:31]([O:35][N:36]1N=NC2C=CC=C[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CN(C)O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:13]([N:36]([O:35][CH3:31])[CH3:37])=[O:15])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H](CCCCCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (S)-2-(((benzyloxy)carbonyl)amino)-8-(tert-butoxy)-8-oxooctanoic acid (prepared as described in WO2006/061638), HBTU (1.1 eq.) and DIPEA (2 eq.) in DMF (0.7 M) was stirred at room temperature for 10 min. Then, dimethylhydroxylamine hydrochloride (1.1 eq.) was added. The reaction mixture was stirred at room temperature for a further 16 h then diluted with EtOAc. Organic phase was washed with sat. aq. NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue that was purified by column chromatography (eluent: petroleum ether/EtOAc from 85:15 to 1:4) to give the title compound as a pale yellow oil. MS (ES+) C22H34N2O6: 423 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:8][CH2:7]1.C(N(CC)CC)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([C:40](Cl)=[O:41])[N:39]=2)[CH:36]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:40]([C:38]3[N:39]=[C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][N:35]4[CH:37]=3)=[O:41])[CH2:14]2)[CH2:8][CH2:7]1
Reactant: O=C(Cl)c1cn2cc(F)ccc2n1
Reactant: Clc1ccc(OC2CCN(CC3CNCCO3)CC2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cn2cc(F)ccc2n1)N1CCOC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 2 h
Yield: 8.2 %

Procedure:
The product of Example 2, Step (c) (0.2 g) was dissolved in dichloromethane (4 ml) and triethylamine (0.16 ml) added. The product of Step (c) (0.12 g) was then added and the reaction stirred for 2 hrs. Saturated aqueous NaHCO3 solution was added and the product was extracted with dichloromethane. The combined organic extracts were dried with MgSO4 and concentrated. Purification by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH3(aq) (0.1%) to 95% MeCN/NH3(aq) (0.1%)) gave the title compound (0.024 g).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[CH:27](=[O:29])[CH3:28].S(=O)(=O)(O)O.C(OO)(C)(C)C>FC(F)(F)C(O)=O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].C(O)(=O)C>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[C:15]([C:27]([CH3:28])=[O:29])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[N:22]=1)[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: CC=O
Agent: [Fe+2]
Agent: CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2C(C)=O
Yield: 75 %

Procedure:
Camptothecin (5 g, 14.36 mmols) was dissolved in trifluoroacetic acid: acetic acid (60 mL; ratio, 1:1) and added deionized water (15 mL) and freshly distilled acetaldehyde (20 mL; excess) followed by dropwise addition of concentrated sulfuric acid (5 mL) at 0° C. using an ice bath over a period of 15 min. To the above stirred reaction medium is then introduced 70% aqueous solution of t-butylhydroperoxide (3 mL) followed by iron sulfate heptahydrate (7.8 g, 28 mmol) in 1 mL water. The reaction mixture was then stirred at 0° C. to 25° C. for an additional 24 hours. The reaction mixture was then diluted with water and extracted with diethyl ether (500 mL×1), chloroform (250 mL×1) and then using n-butanol (250 mL×4). The organic portions were extracted out using diethyl ether and chloroform and discarded as fractions lacking desired product, while the n-butanol portion was concentrated to dryness at 40° C. and the crude product was recrystallized from a 90% chloroform-methanol mixture to furnish 4.2 gm of the title compound (75% yield).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][N:4]=1)=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.[I-].[Na+]>CN(C=O)C>[CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[N:4]=1)=[O:2]
Reactant: COc1ccc(CBr)cc1
Reactant: COC(=O)c1cccc2[nH]nc(C=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c(C=O)nn2Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
To a solution of methyl 3-formyl-1H-indazole-4-carboxylate (49.5 g, 242 mmol) was added cesium carbonate (158 g, 485 mmol) in DMF (750 mL) at 0° C. The mixture was stirred under an atmosphere of nitrogen for 15 min. To this solution were added 4-methoxybenzyl bromide (41.6 g, 267 mmol) and sodium iodide (7.3 g, 48.5 mmol). The resulting mixture continued to stir for 10 min and then warmed to room temperature and stirred for 2.5 h. The mixture was filtered to remove solid cesium carbonate and the filtrate was quenched with sat. aqueous sodium chloride (200 mL) and extracted with diethyl ether (3×500 mL). The combined organic layers were washed with brine (3×200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 10 to 25% ethyl acetate in hexanes) to afford methyl 3-formyl-1-(4-methoxybenzyl)-1H-indazole-4-carboxylate (41.8 g, 53%): 1H NMR δ (300 MHz, CDCl3) 10.53 (s, 1H), 7.77 (dd, J=7.2, 1.0 Hz, 1H), 7.58 (d, J=9.0, 1.0 Hz, 1H), 7.44 (dd, J=9.0, 7.20, Hz, 1H), 7.20 (dd, J=6.6, 2.1 Hz, 2H), 6.89 (dd, J=6.9, 2.1 Hz, 2H), 5.68 (s, 2H), 4.01 (s, 3H), 3.77 (s, 3H); MS (ESI+) m/z 325 (M+H). In addition, methyl 3-formyl-2-(4-methoxybenzyl)-2H-indazole-4-carboxylate (24.2 g, 31%) was also isolated: 1H NMR δ (300 MHz, CDCl3) 10.88 (s, 1H), 8.10 (t, J=7.2 Hz, 2H), 7.42 (dd, J=9.0, 1.0 Hz, 1H), 7.36 (dd, J=9.0, 7.20, Hz, 2H), 6.82 (dd, J=6.6, 2.1 Hz, 2H), 6.07 (s, 2H), 4.01 (s, 3H), 3.77 (s, 3H); MS (ESI+) m/z 325 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.O.O.[Sn](Cl)Cl>C1COCC1.C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1
Reactant: N#Cc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: N#Cc1ccccc1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 69.2 %

Procedure:
To a stirred suspension of 2′-fluoro-5′-nitrobiphenyl-2-carbonitrile (18.71 g, 77.2 mmol) in THF (150 ml) and ethanol (150 ml) was added tin(II) chloride dihydrate (52.42 g, 232.4 mmol) and the mixture was stirred at room temperature for 22.5 h. The mixture was evaporated in vacuo and the residue was treated with ice-cold 2 N aqueous NaOH (800 ml). The resulting mixture was stirred for 1.5 h, then extracted with dichloromethane (2×800 ml). The combined organic extracts were washed with saturated aqueous NaCl (200 ml), dried (MgSO4), and evaporated in vacuo. The residue was recrystallised from hot toluene (100 ml) to afford 11.33 g (69%) of 5′-amino-2′-fluorobiphenyl-2-carbonitrile as a white solid: 1H NMR (360 MHz, CDCl3) δ 3.65 (2H, br s), 6.67-6.73 (2H, m), 7.00 (1H, t, J 9.0 Hz), 7.46 (1H, td, J 7.6, 1.1 Hz), 7.49 (1H, d, J 7.4 Hz), 7.64 (1H, td, J 7.7, 1.3 Hz), 7.76 (1H, dd, J 7.7, 0.7 Hz).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6](O)[C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1.FC1C=CC(O)=CC=1>C1COCC1.ClCCl>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1
Reactant: CN1CCC(O)c2ccc(-c3cccnn3)cc2C1
Agent: Oc1ccc(F)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCCc2ccc(-c3cccnn3)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a solution of the 2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ol (170 mg, 0.67) from Step H above in THF (5 mL) was added 4-fluorophenol (98 mg, 0.87 mmol), tributylphosophine (176 mg, 0.52 mmol) and 1,1′-(azodicarboyl)dipiperidine (220 mg, 0.87 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane and washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (98:2 to 95:5 ethyl acetate/methanol), followed by preparative HPLC to give 544-fluorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (120 mg, 51%) as a gum-like solid. This compound was resolved using Chiralcel OJ column (eluente:80 Hep:20 EtOH:0.1 DEA) to give (+)-enantiomer (36 mg)) and (−)-enantiomer (37 mg).
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)C2=CC=CC=C2C1=O.OO>C(#N)C>[C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: OO
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 75 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
A mixture of 5 mmol of benzhydrol, 0.5 mmol of N-hydroxyphthalimide, and 5 ml of acetonitrile was stirred at 75° C. in an air atmosphere (1 atm) for 24 hours. An iodometric analysis of a reaction mixture revealed that hydrogen peroxide was formed in yield of 41% (selectivity: 76%). Separately, a gas chromatographic analysis of the reaction mixture revealed that the conversion rate from benzhydrol was 54%, and benzophenone was formed in yield of 52%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][CH:12]=[C:11]([CH2:14]O)[CH:10]=2)=[CH:5][CH:4]=1.C(P(CCCC)CCCC)CCC.[CH2:31]([O:33][C:34](=[O:45])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([SH:43])=[CH:39][C:38]=1[CH3:44])[CH3:32]>O1CCCC1>[CH2:31]([O:33][C:34](=[O:45])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43][CH2:14][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=3)[O:13][CH:12]=2)=[CH:39][C:38]=1[CH3:44])[CH3:32]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: OCc1coc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (0.15 g) in tetrahydrofuran (15 ml) stirred at 0° C. was treated with tributylphosphine (0.2 ml), as solution of ethyl(4-mercapto-2-methylphenoxy)acetate (0.150 g) in tetrahydrofuran (2 ml) and finally azodicarbonyldimorpholide (0.204 g). The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The solvent was evaporated and the residue subjected to an aqueous work up using ethyl acetate and water. The organic phase was dried over magnesium sulfate. The product isolated after evaporation of the solvent was further purified by flash column chromatography using a cyclohexane:ethyl acetate (5:1) as eluent to give the title compound.
Reaction SMILES: [C@H:1]12[CH2:9][C@H:5]([O:6][C:7]1=[O:8])[CH2:4][O:3][CH2:2]2.[OH-:10].[Na+].Cl>CO>[OH:10][C@H:5]1[CH2:4][O:3][CH2:2][C@@H:1]([C:7]([OH:6])=[O:8])[CH2:9]1
Reactant: O=C1O[C@@H]2COC[C@H]1C2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)[C@@H]1COC[C@H](O)C1

Procedure:
A solution of 25.5 mmol of (cis)-3,6-dioxabicyclo[3.2.1]-octan-7-one in 500 ml of methanol is adjusted to pH 9 with 0.1M NaOH. The solution is stirred at constant pH until conversion is complete, and is adjusted to pH 6.5 with 0.1 M HCl before the methanol is evaporated off. The title compound is identified from the aqueous solution by means of the Rf by ion exchange chromatography (Amberlite XAD-2 resin).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]1[CH:13]=[CH:14][C:15]([CH2:23][OH:24])=[N:16][C:17]=1[O:18][CH2:19][CH:20]([CH3:22])[CH3:21].Cl[C:26]1[N:31]=[CH:30][N:29]=[C:28]([CH:32]([CH:39]2[CH2:41][CH2:40]2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=1.Cl>C1COCC1>[CH:39]1([CH:32]([C:28]2[CH:27]=[C:26]([O:24][CH2:23][C:15]3[CH:14]=[CH:13][C:12]([C:5]4[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=4[F:3])=[C:17]([O:18][CH2:19][CH:20]([CH3:21])[CH3:22])[N:16]=3)[N:31]=[CH:30][N:29]=2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:41][CH2:40]1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2OCC(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 57.7 %

Procedure:
60% Sodium hydride (34 mg) was added to a solution of (5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methanol (200 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (167 mg) in THF (6.0 mL) at 0° C., and the mixture was stirred at room temperature for 30 min and at 50° C. for 4 hr. 1N Hydrochloric acid was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (198 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16](Br)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2].[CH2:37]([N:39]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40]1)[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.ClCCl.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[N:30]=[CH:29][C:28]3[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=3)[C:22]2=[O:36])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:44][C:41]2[CH:42]=[CH:43][N:39]([CH2:37][CH3:38])[N:40]=2)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CCn1ccc(N)n1
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCn1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a 1-dram vial was added 142c (40 mg, 0.074 mmol), 1-ethyl-1H-pyrazol-3-amine (1.2 equiv), cesium carbonate (1.5 equiv), Xantphos (10 mol %) and tris(dibenzylideneacetone) dipalladium(0) (5 mol %) in dry 1,4-dioxane (0.2 M). The reaction was then stirred at 80° C. for 3 hours. After cooling to room temperature, the reaction was then diluted with dichloromethane (3 mL) and washed with water (2×3 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product 142d was then carried on to the subsequent step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[F:14])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccccc1CCl
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccccc1F)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 2-fluorobenzyl chloride (1.2 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 291 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: O=S(=O)(Nc1ccccc1Br)N1CCCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3NS(=O)(=O)N3CCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 571 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and N-(2-bromophenyl)pyrrolidine-1-sulfonamide MS (ESI): mass calcd. for C20H20FN5O2S, 413.13; m/z found, 414.4 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 2H), 7.59 (d, J=8.4, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.32-7.29 (m, 2H), 7.24-7.22 (m, 1H), 7.22-7.15 (m, 1H), 6.87-6.79 (m, 2H), 6.36 (s, 1H), 3.37-3.26 (m, 4H), 1.94-1.83 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1>[Pd].CO>[F:20][C:2]([F:1])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Agent: [Pd]
Solvent: CO
Product: OC1CCN(C2=Nn3c(nnc3C(F)(F)F)CC2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
1-[3-(Trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (5 g, 17.41 mmol) and 5% palladium on carbon (50% wet, 0.963 g, 0.23 mmol) in MeOH (50 mL) were stirred under an atmosphere of hydrogen at 5 bar and 50° C. for 16 hours. The reaction was incomplete and further 5% palladium on carbon (50% wet, 0.963 g, 0.23 mmol) was added and the mixture was stirred at 50° C. for a further 16 hours. The catalyst was removed by filtration and washed with MeOH/DCM mixtures. The solvents were evaporated to give 1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (4.93 g, 98%) as a solid.
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]([CH3:21])[C@@H:7]([O:19]C)[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.C[C@H]1[C@@H]2CC[C@]3(C)OO[C@]42[C@H]([C@@H](C)C(O[C@@H]4O3)=O)CC1>CO.[BH4-].[Na+]>[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]([CH3:21])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1
Reactant: CO[C@H]1O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Agent: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: 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

Procedure:
A process for the preparation of artemether from artemisinin comprising the steps of (a) dissolving the artemisinin in methanol, (b) reducing the artemisinin dissolved in methanol with sodium borohydride in a reaction vessel to produce a reaction mixture comprising dihydroartemisinin, (c) without isolating the dihydroartemisinin from the reaction mixture, adding an acid catalyst to the reaction mixture to cause conversion of the dihydroartemisinin to artemether, said steps (b) and (c) being conducted in a solvent consisting essentially of the methanol, and (d) recovering and purifying the artemether.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH2:4]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].O>C(Cl)Cl>[CH3:16][S:17]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[C:3]([CH3:15])([CH3:2])[CH2:4]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1(C)CN(S(C)(=O)=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of 3,3-dimethyl-6-nitroindoline hydrochloride (2.9 g, 12.8 mmol) in CH2Cl2 (75 mL) was added TEA (4.48 mL, 32.2 mmol) and methanesulfonyl chloride (1.1 mL, 13.5 mmol) at 0° C. The resulting mixture was stirred at RT for 4 h and water was added. Mixture was extracted with CH2Cl2, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford 1-Methanesulfonyl-3,3-dimethyl-6-nitro-2,3-dihydro-1H-indole as a yellow solid.