Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH2:35][C@H:36](O)[CH2:37][CH3:38].[O:40]1CCOCC1>>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:35][CH2:36][C@H:37]([OH:40])[CH3:38])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: CC[C@H](N)O
Reactant: C1COCCO1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Product: C[C@@H](O)CNc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in example 300 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (110 mg, 0.211 mmol), (R)-(−)-1-aminopropanol (79 mg, 1.056 mmol) in 1,4-dioxane (2 mL), the title compound was obtained as a yellow foam (48 mg, 0.081 mmol, 38.6%). 1H NMR (400 MHz, DMSO-d6) ppm 0.93-1.12 (m, 3H), 1.75 (qd, J=12.13, 4.29 Hz, 2H), 2.02 (d, J=1.77 Hz, 1H), 3.00-3.24 (m, 2H), 3.24-3.33 (m, 1H), 3.40-3.59 (m, 2H), 3.78 (dt, J=10.67, 5.65 Hz, 1H), 3.93 (dd, J=11.24, 2.15 Hz, 2H), 4.69 (d, J=1.26 Hz, 1H), 5.79-6.06 (m, 1H), 6.66 (d, J=1.26 Hz, 1H), 7.13 (t, J=5.81 Hz, 1H), 7.20-7.40 (m, 2H), 7.40-7.53 (m, 1H), 7.81 (t, J=1.77 Hz, 1H), 8.08 (d, J=5.05 Hz, 1H), 8.27 (s, 1H), 10.30 (br. s., 1H); MS (ESI): 560.1 [M+H]+.
Reaction SMILES: [Cl-].[Na+].Cl[C:4]([O:6][CH2:7][CH3:8])=[O:5].[OH:9][OH:10].[OH-].[Na+].[C:13]([O:22][C:23]([CH2:31]C)(CC)CCCCC)(=[O:21])CCCCC([O-])=O>O>[C:4]([O:9][O:10][C:13]([O:22][CH2:23][CH3:31])=[O:21])([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)Cl
Reactant: OO
Reactant: CCCCCC(CC)(CC)OC(=O)CCCCC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)OOC(=O)OCC
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Into a 1000-l stirred reactor cooled below 10° C. are introduced 622 kg of an aqueous solution of sodium chloride containing 180 g/kg (that is 510 kg of demineralized water and 112 kg of NaCl), precooled to 5° C. 20.4 kg of ethyl chloroformate and 8.5 kg of aqueous solution of hydrogen peroxide containing 350 g/kg are then introduced successively into the stirred aqueous solution, and finally, very slowly, 36.1 l of aqueous solution of sodium hydroxide containing 200 g/kg, so as to maintain the temperature below 10° C. The density of the aqueous reaction mixture rises to 1.11. 10 minutes after the end of the introduction of the NaOH solution 34.5 kg of diethylhexyl adipate are introduced, precooled to 5° C. After the reaction mixture has been kept stirred for 15 minutes while being cooled to 5° C., the stirring is stopped. The aqueous phase (dense phase) is then separated off after settling out and the organic phase is recovered. The solution of diethyl peroxydicarbonate in diethylhexyl adipate which is thus produced is stored at 5° C. with a view to its subsequent use. Its diethyl peroxydicarbonate content (determined by analysis) is 287 g/kg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1>C(N)C(C)C>[CH3:14][N:13]([CH3:15])[C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:10][CH2:9][CH:16]([CH3:17])[CH3:21])[N:7]=2)=[C:9]([C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:10]=1
Reactant: CN(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(N(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)n1
Temperature: 35 °C
Yield: 66 %

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(dimethylamino)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.1 g, 0.2 mmol) was taken up in 2 mL isobutylamine and heated to 35° C. overnight. The solvent was removed under reduce pressure and the residue taken up in EtOAc and washed with 2 mL of 0.1N HCl (aq). The organic layer was dried over Na2SO4 and evaporated to afforded the title compound (36 mg, 0.066 mmol, 33.6% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.01 (s, 1H), 7.74 (d, J=5.3 Hz, 1H), 7.67 (ddd, J=14.6, 8.4, 6.1 Hz, 1H), 7.28-7.35 (m, 1H), 7.18-7.28 (m, 4H), 7.12 (d, J=7.7 Hz, 1H), 7.07 (t, J=5.5 Hz, 1H), 5.68 (s, 1H), 3.06 (s, 6H), 3.02 (t, J=6.3 Hz, 2H), 1.82 (dt, J=13.4, 6.7 Hz, 1H), 0.86 (d, J=6.8 Hz, 6H). MS (ESI): 545 [M+H]+.
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:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[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(O[N:46]1N=N[C:48]2[CH:49]=CC=C[C:47]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CC>CN(C=O)C>[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:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:46][CH2:47][CH2:48][CH3:49])=[O:32])[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)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCCN
Product: CCCNC(=O)c1cccc(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and propylamine (7.40 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20.8 mg, 63%). LC-MS m/z 549 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1Cl.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1COCC1>[Br:1][C:2]1[C:3]([NH2:14])=[N:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[N:6][C:7]=1[S:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Sc1ccccc1
Reactant: Nc1nc(-n2cccn2)nc(Cl)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(-n2cccn2)nc(Sc2ccccc2)c1Br

Procedure:
To a solution of 0.1 g (0.36 mmol) of 5-bromo-6-chloro-2-(1H-pyrazol-1-yl)pyrimidin-4-amine (Intermediate 5) in 4 ml of THF, 74 μl (0.73 mmol) of thiophenol and 0.178 g (0.55 mmol) of Cs2CO3 were added. The mixture was allowed to react under microwave conditions 15 min. at 100° C. Afterwards the reaction mixture was put on 10 ml of cool water. The formed white precipitate was filtered, washed several times with cold water and dried.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].CI>C1COCC1.CN(C=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)o1
Reaction time: 18 h
Yield: 100.2 %

Procedure:
To a stirred solution of 25.0 g (198 mmol) 5-methyl-2-furoic acid in 160 ml THF and 100 ml DMF were added 110 g (793 mmol) potassium carbonate and 49 ml (787 mmol) methyl iodide and stirring continued for 18 hours at room temperature. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was then partitioned between ether and water, the phases separated, and the aqueous phase further extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Chromatography (hexane then ethyl acetate/hexane 1/9) afforded 27.8 g (100%) methyl 5-methyl-2-furoate as a yellow oil. EI-MS m/e (%): 140 (M+, 44), 109 ([M—OMe]+, 100).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].[Cl:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[C:14]1([CH2:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[ClH:29]>CCOCC>[OH2:2].[ClH:6].[ClH:29].[N:9]1([CH2:8][CH2:7][N:26]2[CH2:27][CH2:28][CH:23]([CH2:22][CH2:21][CH2:20][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=C([O-])O
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: ClCCn1ccnc1
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O
Product: c1ccc(CCCC2CCN(CCn3ccnc3)CC2)cc1

Procedure:
Sodium bicarbonate (2.9 g) was added to a solution of 1-(2-chloroethyl)imidazole (4.0 g) and 4-(3-phenylpropyl)piperidine (6.2 g) in industrial methylated spirits (100 ml) and the reaction mixture heated under reflux for 96 hours. The reaction mixture was then filtered and the filtrate concentrated to give an oil, which was purified by flash chromatography eluting with ethylacetate/methanol/triethylamine (88:10:2). The solid obtained was dissolved in ether, ethereal hydrogen chloride acid was added and the solid precipitated was collected and recrystallised from ethanol/ether to give 1-[2-(imidazol-1-yl)ethyl]-4-(3-phenylpropyl)piperidine, dihydrochloride monohydrate, m.p. 178°-179° C.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[CH:6][C:7](OS(C2C=CC=CC=2S(N(C)C2CCN(C)CC2)(=O)=O)(=O)=O)=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15](=[NH:17])[NH2:16].CC1C=CC([O:64][S:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[S:74]([N:77]([CH3:85])[CH:78]2[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]2)(=[O:76])=[O:75])(=[O:67])=[O:66])=C(C=1)OCCCOC1C=CC=C2C(NC(=O)C=12)=O.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:64][S:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[S:74]([N:77]([CH3:85])[CH:78]2[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]2)(=[O:75])=[O:76])(=[O:67])=[O:66])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c(OCCCOc2cccc3c2C(=O)NC3=O)c1
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c(OCCCONC(=N)N)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c1
Yield: 76 %

Procedure:
N-{3-[5-Methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl) phenylsulfonyloxy]phenoxy]propoxy}guanidine dihydrochloride: The title compound was prepared in 76% yield from N-{3-[5-methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl) aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 8.25 (d, J=7.9 Hz, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.02 (t, J=7.6 Hz, 1H), 7.89 (t, J=7.7 Hz, 1H), 7.37 (br s, 4H), 6.75 (s, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 4.07 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.22 (m, 2H), 3.17 (s, 3H), 2.79 (s, 3H), 2.72 (t, J=12.0 Hz, 2H), 2.22 (s, 3H), 1.99 (pentet, J=6.3 Hz, 4H), 1.60 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C24H35N5O7S2: 570.2 (M+H), 592.2 (M+Na). Found: 570.1, 592.1.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:1][CH2:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CO)c3ccccc32)cc1
Solvent: c1ccncc1
Product: CC(=O)OCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 5-hydroxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.40 g) are added acetic anhydride (4.0 ml) and pyridine (0.5 ml), and the mixture is stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution is poured into ice-water and extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is recrystallized from ethyl acetate/n-hexane to give 5-acetyloxymethyl-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.43 g) as colorless needles, m.p. 155-156° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:27]([CH2:28][CH3:29])[CH2:26][C:25](=[O:30])[NH:24][N:23]=4)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1)(=O)=O.[CH2:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:28]([CH:27]1[C:22]([C:20]2[CH:19]=[CH:18][C:16]3[N:17]=[C:13]([C:10]4[CH:9]=[CH:8][C:7]([CH:33]=[CH:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:12][CH:11]=4)[O:14][C:15]=3[CH:21]=2)=[N:23][NH:24][C:25](=[O:30])[CH2:26]1)[CH3:29]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3)oc2c1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(C=Cc4ccccc4)cc3)oc2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
60 mg (128 μmol) 4-[6-(4-ethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-yl]-phenyl trifluoro-methanesulphonate, 14.7 μl (128 μmol) styrene, 2.9 mg (13 μmol) palladium-(II)-acetate, 4.1 mg (13 μmol) tri-o-tolylphosphine, 72 μl (513 μmol) triethylamine and 2 ml acetonitrile are combined and stirred overnight at 80° C. Then a further 7.5 μl styrene, 2.9 mg palladium-(II)-acetate and 4 mg tri-o-tolyphosphine are added and the mixture is stirred for 5 days at 80° C. Then it is diluted with DCM and extracted successively with 10% sodium carbonate solution and sat. saline solution. The org. phase is evaporated down completely i.V. and the residue is purified through silica gel (eluant: DCM/methanol). The residue obtained is crystallised from cyclohexane/EA.
Reaction SMILES: [N:1]1[N:2]2[CH:13]=[CH:12][N:11]=[C:3]2[N:4]=[C:5]([C:7]([OH:10])([CH3:9])[CH3:8])[CH:6]=1.C([O-])(=O)C.[Na+].[Br:19]Br>C(O)(=O)C>[Br:19][C:13]1[N:2]2[N:1]=[CH:6][C:5]([C:7]([OH:10])([CH3:9])[CH3:8])=[N:4][C:3]2=[N:11][CH:12]=1
Reactant: CC(C)(O)c1cnn2ccnc2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(O)c1cnn2c(Br)cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.2 %

Procedure:
To a stirred solution of 2-(imidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (5.55 g, 31.1 mmol) in acetic acid (100 ml) was added sodium acetate (3.83 g, 46.7 mmol), then, dropwise over 5 min, a solution of bromine (1.77 ml, 34.4 mmol) in acetic acid (12 ml). The solution was stirred at room temperature for 25 min, then partitioned between saturated aqueous NaHCO3 (2 l) and ethyl acetate (1 l). The aqueous layer (pH 7) was further extracted with ethyl acetate (1 l), and the combined organic extracts were dried (Na2SO4) and evaporated iii, vacuo. The residue was purified by flash chromatography (silica gel, 2% MeOH/CH2Cl2) to afford 6.17 g (77%) of the title compound as a yellow solid: 1H NMR (360 MHz, CDCl3) δ 1.70 (6H, s), 3.12 (1H, br s), 7.95 (1H, s), 8.80 (1H, s).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3].[BH4-].[Na+]>CO.C(O)(C)C>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[CH:19]([OH:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCC(O)C(OC)C2)C(C)C(O)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.1 %

Procedure:
To a stirred solution of 17-allyl- 1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (300 mg, 0.374 mmol) in 9 ml MeOH was added dropwise at RT a solution of NaBH4 (0.12 mmol) in 2 ml isopropanol. After stirring at RT for 15 minutes the reaction was quenched by pouring into 1.5 ml acetic acid in ice and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with sat. NaHCO3 (1×50 ml) and water (1×50 ml) and dried over MgSO4. Evaporation of solvent gave 320 mg of crude product which was purified by prep TLC (10% i-PrOH/CH2Cl2) to give 127 mg (42% yield) of the title compound (with NMR and mass spectra consistent with the structure).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].C[C@H]1[C@@H]2CCC3(C)O[O:39][C@:32]42[C@H:27]([C@@H:28](C)[C@@H:29]([OH:41])[O:30][C@@H]4O3)CC1.C1(=O)OC(=O)CC1>O1CCOCC1.O.O1CCCC1>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@H:7]([O:8][C:32]([CH2:27][CH2:28][C:29]([OH:41])=[O:30])=[O:39])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: 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
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
Agent: O=C1CCC(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1[C@H](OC(=O)CCC(=O)O)O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
In the process of the present invention, artemisinin and the catalyst, polyhydroxy compound or cation exchange resin were stirred in 1,4-dioxan or tetrahydrofuran for 5 minutes. Sodium borohydride was added slowly at room temperature (20-35° C.) and the reaction mixture was stirred for about 0.5-2 hours at room temperature. After completion of the reduction of artemisinin, without workup or the isolation of the dihydroartemisinin, succinic anhydride was added in the presence of a base at room temperature (20-35° C.). The reaction mixture was stirred further for about 1-3 hours at room temperature (20-35° C.). After completion of the esterification reaction, cold water was added. The Applicants experimentally found that if the pH of the solution is maintained between 6-7, it is conducive for extraction with ethyl acetate n-hexane mixture. Hence, the pH of the solution is adjusted between 6 to 7 by adding acetic acid. The solution having pH of 6-7 was then extracted with mixture of ethyl acetate n-hexane (3-4 times). The combined extract was washed with water. The ethyl acetate-hexane extract was dried over anhydrous sodium sulphate and removal of the solvent furnished impure artesunic acid. Silica gel column chromatography (1:4-5 ratio) of the impure artesunic acid using 20-30% ethyl acetate in n-hexane as an eluant furnished pure artesunic acid in 85-96% w/w yield.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][NH:21][C:22]([C@@H:24]3[CH2:28][CH2:27][C@@H:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.O=S(Cl)Cl>O1CCOCC1>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:22]([C@@H:24]4[CH2:28][CH2:27][C@@H:26]([NH2:29])[CH2:25]4)=[N:21][N:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@@H]4CC[C@@H](NC(=O)OC(C)(C)C)C4)cnc32)cc1
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@@H](N)C4)n23)cc1
Temperature: 80 °C
Yield: 68.3 %

Procedure:
To tert-butyl (1R,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclo-pentylcarbamate (5.03 g, 9.78 mmol) in 1,4-dioxane (103 mL) was added DIEA (7.2 mL, 41 mmol) and SOCl2 (2.3 mL, 31 mmol). The reaction mixture was heated at about 80° C. for about 1 h. The solvent was removed under reduced pressure and the residue was purified using silica gel chromatography (330 g) eluting with a gradient of 0-20% MeOH in DCM to give (1R,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (2.65 g, 68%): LC/MS (Table 1, Method b) Rt=1.55 min; MS m/z: 397 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:28]C(=O)C(F)(F)F.I[CH3:40].[Na+].[Cl-]>CC(N(C)C)=O>[ClH:3].[NH2:28][CH:9]1[CH:8]([CH2:7][C:6]2[CH:35]=[CH:36][C:37]([Cl:38])=[C:4]([Cl:3])[CH:5]=2)[C:17]2[CH:16]=[C:15]([O:18][CH2:19][CH2:20][N:21]([CH3:40])[S:22]([CH2:25][CH2:26][CH3:27])(=[O:23])=[O:24])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CI
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(NC(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCS(=O)(=O)N(C)CCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N)CC2
Product: Cl
Reaction time: 14 h

Procedure:
NaH (3.38 mg, 0.078 mmol, 55% in oil) was suspended in DMA (5 ml) and N-(1-(3,4-dichlorobenzyl)-7-(2-(propylsulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-2,2,2-trifluoroacetamide (40 mg, 0.07 mmol) dissolved in DMA (4 ml) was added dropwise. After stirring for 1 h iodomethane (10.5 mg, 0.074 mmol) dissolved in DMA (1 ml) was added. After stirring for another 14 h the reaction mixture was added to a halfconcentrated solution of NaCl. Extraction with ethyl acetate, washing of the organic layers with water and saturated NaCl solution followed by drying with Na2SO4 gave a residue that was washed with diisopropyl ether. Cleavage of the amide bond was achieved by stirring the residue with concentrated NaOH in water and subsequent extraction with ethyl acetate. The organic layer was dried with MgSO4 and evaporated. The residue was purified by preparative HPLC (RP-18, acetonitrile/water, 0.01% TFA). After transferring the product into the HCl salt a yellow solid (11.0 mg, 0.021 mmol, 30%) was obtained.