Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([NH:28][C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2

Procedure:
80 mg (0.29 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 90 mg (0.26 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-4-methyl-3H-benzoxazol-2-one and 0.15 mL (0.87 mmol) DIPEA in 1.5 mL DMF were stirred at 150° C. After the reaction of the reactants the reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and evaporated down. The residue was dried.
Reaction SMILES: [CH3:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[NH:33])SC)[N:25]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8].[NH3:34].CO>>[CH3:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[NH:33])[NH2:34])[N:25]=3)[N:23]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH3:8]
Reactant: CCOc1ccc(-c2nc(-c3cccc(C(=N)SC)n3)cs2)cc1OCC
Reactant: N
Agent: COS(=O)(=O)O
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cccc(C(=N)N)n3)cs2)cc1OCC

Procedure:
0.81 g of 2-(3,4-diethoxyphenyl)-4-[6-(1-imino-1-methylthiomethyl)-2-pyridyl]thiazole monomethylsulfate and a saturated ammonia-methanol solution were refluxed at 100° C. for 3 hours in a sealed tube. The solvent was removed by distillation. The residue was recrystallized from chloroform-diethyl ether to obtain 0.44 g of 2-(3,4-diethoxyphenyl)-4-(6-amidino-2-pyridyl)thiazole monomethylsulfate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:20][OH:21])[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([O:8][CH2:9][C:10]1([CH:20]=[O:21])[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1(COCc2ccccc2)CCC2(CC1)OCCO2
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1(COCc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.7 %

Procedure:
To a solution of (8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)methanol (Reference Example 85) (183 mg, 0.625 mmol) in dimethyl sulfoxide (2.1 mL), 50% sulfur trioxide-pyridine complex (596 mg, 1.87 mmol) and triethylamine (0.522 mL, 3.75 mmol) were added, and the obtained solution was stirred at room temperature for 20 minutes. The reaction was quenched by adding water to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed sequentially with 20% aqueous citric acid solution, saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (172 mg, 0.592 mmol, 95%) as a colorless oily compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:37])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32]([O:34]CC)=[O:33])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:37])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32]([OH:34])=[O:33])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(Br)ccc3c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
To a solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxylate (1.338 g, 2.396 mmol) in tetrahydrofuran (48 mL) and methanol (16 mL) at room temperature was added a solution of lithium hydroxide hydrate (0.402 g, 9.58 mmol) in water (10 mL). The resulting solution was stirred at room temperature for 1.5 hr, and then concentrated under vacuum to a volume of about 10 mL. The residue was diluted with water (5 mL) and neutralized with 1 N HCl solution to pH 5-6. The precipitating product (1.177 g, 2.219 mmol, 93% yield) was collected as a beige solid by suction filtration and dried over Drierite under vacuum.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)(=[O:5])=[O:4].ClC1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:27]=[C:26]([N:36]2[C:40]3[CH:41]=[CH:42][CH:43]=[C:44]([O:45][CH3:46])[C:39]=3[N:38]=[C:37]2[CH:47]([F:49])[F:48])[N:25]=1.CCN(C(C)C)C(C)C>CO.C1COCC1.[Pd]>[F:49][CH:47]([F:48])[C:37]1[N:36]([C:26]2[N:27]=[C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:29]=[C:12]([N:9]3[CH2:8][CH2:7][CH:6]([S:3]([N:2]([CH3:1])[CH3:22])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[N:25]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([O:45][CH3:46])[C:39]=2[N:38]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CN(C)S(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(S(=O)(=O)N(C)C)CC2)n1
Yield: 86 %

Procedure:
The above carbamate was hydrogenated over 5% Pd on carbon in MeOH. After removal of the solvent, the residue was combined with 0.19 g (0.48 mmol) 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) and DIPEA in THF. The mixture was heated under reflux for 30 min and the solvent was removed. After dilution with water, the resulting solid was collected and dried. Chromatography on silica, eluting with CH2Cl2/EtOAc (93:7), gave 0.227 g (86% yield) of 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N,N-dimethyl-4-piperidinesulfonamide: mp (MeOH) 260-264° C.; 1H NMR (CDCl3) δ 7.88 (dd, J=8.4, 0.6 Hz, 1H), 7.46 (t, JHF=53.5 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H), 4.91 (br d, J=13.5 Hz, 2H), 4.05 (s, 3H), 3.88 (m, 4H), 3.78 (m, 4H), 3.27 (tt, J=11.8, 3.8 Hz, 1H), 2.95 (s, 6H), 2.17 (dd, J=12.7, 2.2 Hz, 2H), 1.85 (dq, J=12.6, 4.2 Hz, 2H); Anal. Calcd. for C23H30F2N8O4S: C, 50.0; H, 5.5; N, 20.3. Found: C, 49.9; H, 5.5; N, 20.4%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[C:17]#[N:18])=[CH:10][C:8]=2[CH:9]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]3[CH:21]=[CH:20][CH:19]=[C:16]([C:17]#[N:18])[CH:15]=3)=[CH:10][C:8]=2[CH:9]=1)(=[O:25])=[O:24]
Reactant: N#Cc1cccc(-c2ccc3oc(CCCO)cc3c2)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCc1cc2cc(-c3cccc(C#N)c3)ccc2o1

Procedure:
The product from Example 170B and methanesulfonyl chloride is processed as described in Example 112D to provide the title compound.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:36][CH2:37][CH2:38][C@@H:39]([O:61][CH2:62][O:63][CH3:64])[C@H:40]([C:52]1[CH:57]=[C:56]([F:58])[C:55]([F:59])=[C:54]([F:60])[CH:53]=1)[C:41]([NH:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:42])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.[Cl-].[NH4+]>C1COCC1>[OH:36][CH2:37][CH2:38][C@@H:39]([O:61][CH2:62][O:63][CH3:64])[C@H:40]([C:52]1[CH:57]=[C:56]([F:58])[C:55]([F:59])=[C:54]([F:60])[CH:53]=1)[C:41]([NH:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:42]
Reactant: COCO[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](C(=O)NNC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCO[C@H](CCO)[C@@H](C(=O)NNC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
TBAF (1.36 mL; 1 M solution in THF) was added to a solution of tert-butyl N′-[(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate (600 mg) in THF (10 mL). The reaction solution was stirred at room temperature for one hour. Then, ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 383 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6](Br)[CH:5]=1)([O-:3])=[O:2].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC.O>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH3:24])[CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Temperature: 115 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Methyl 4-nitro-2-bromobenzoate (11.40 g, 43.85 mmol) was dissolved in 100 mL of DMF. Air was removed and the system was flushed with nitrogen. To this solution was added Pd(PPh3)4 (1.63 g, 3.1% eq). The pale yellow solution was stirred for 15 min until the color changed to deep brown. 2-Tolylboronic acid (6.6 g, 48.5 mmol) was added followed by anhydrous K2CO3 (18.2 g, 3.0 eq). The mixture was heated at 115° C. for 18 hr and then cooled down. This mixture was diluted with 100 mL of ether and 50 mL of water. The aqueous solution was extracted with ether. The ether solution was washed with 1N hydrochloric acid and then dried and evaporated. The residue was purified by flash column chromatography (10:1=hexane/ethyl acetate) to give a pale yellow oil which slowly solidifies (11.53 g, 97% yield). 1H NMR (CDCl3) δ 8.28 (d, J=8.7 Hz, 1H), 8.06-8.13 (s and d, 2H), 7.22-7.34 (m, 3H), 7.07 (d, J=7.3 Hz, 1H), 3.66 (s, 3H), 2.10 (s, 3H), 13C NMR (CDCl3) δ 165.7, 148.6, 143.5, 138.5, 135.9, 134.7, 130.5, 129.3, 127.9, 127.7, 125.1, 121.5, 51.8, 19.3; HRMS (EI) calcd for Cl5H13O4N 271.0844, obsd 271.0842.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1>CCO.CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[C:10]3[CH:9]=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:23][CH:24]=1
Reactant: COc1cnc2c(c1)cc(/C=C/C(=O)O)n2Cc1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cnc2c(c1)cc(CCC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
To a solution of (E)-3-[1-(4-Chloro-benzyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl]-acrylic acid (Example 1; 95 mg, 0.277 mmol) in a mixture of EtOH (2 mL) and EtOAc (2 mL) was added Pd/C (˜20 mg) and maintained under an atmosphere of H2 for 12 hrs. The resulting slurry was filtered through celite eluting with EtOAc, and the solvent evaporated to afford the title acid as a colorless solid. LCMS (ESI) M+H 345.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[NH2:22][C@@H:23]([CH2:29][CH:30]1[CH2:32][CH2:31]1)[C:24]([N:26]([CH3:28])[CH3:27])=[O:25]>>[CH:30]1([CH2:29][C@H:23]([NH:22][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:24](=[O:25])[N:26]([CH3:27])[CH3:28])[CH2:32][CH2:31]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CN(C)C(=O)[C@@H](N)CC1CC1
Agent: Cl
Product: CN(C)C(=O)[C@H](CC1CC1)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-2-amino-3-cyclopropyl-N,N-dimethylpropanamide hydrochloride (Example 222 b) as starting materials. MS (EI): m/e=423.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:4]([C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1])=[O:6])[CH2:47][CH2:48][CH3:49]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,4-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.86-0.92 (m, 3 H) 1.25-1.35 (m, 2 H) 1.67-1.77 (m, 2 H) 2.50 (s, 3 H) 4.14 (t, 2 H) 6.21 (s, 1 H) 7.45-7.50 (m, 1 H) 7.56 (d, 1 H) 7.63-7.65 (m, 1 H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13]>>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:18]3[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=3)[C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1CCc2cc(Br)ccc21
Product: N#Cc1cccc(-c2ccc3c(c2)CCC3=O)c1

Procedure:
The title compound was prepared from 5-bromo-1-indanone and 3-cyanophenyl boronic acid according to the coupling procedure as described in example 6. MS m/z 234; HRMS: calcd for C16H11NO+H+, 234.09134; found (ESI, [M+H]+), 234.0905;
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH:15]=[O:16])[N:12]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:9]2=[N:10][CH:11]=1)([O-:5])=[O:4].O.C(OCC)(=O)C>C1COCC1.CO>[N+:3]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH2:15][OH:16])[N:12]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:18])=[O:19])[C:9]2=[N:10][CH:11]=1)([O-:5])=[O:4]
Reactant: O=Cc1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)cc(CO)n2S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 42.3 %

Procedure:
NaBH4 (0.084 g, 2.21 mmol) was added to a solution of 5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (611 mg, 1.844 mmol) in THF (18.3 mL) and methanol (1.8 mL) at 0° C. The reaction mixture was stirred for 1 hour. It was then treated with water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford (5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)methanol (0.26 g, 42% yield).
Reaction SMILES: [CH3:1][N:2]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9]OS(C2C=CC(C(F)(F)F)=CC=2)(=O)=O)[CH2:5][CH2:4]1.Cl.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][SH:42].[H-].[Na+].[Na+].[I-].OS([O-])(=O)=O.[K+].C([O-])(O)=O.[Na+].CCOCC>CN(C=O)C>[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][S:42][CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[CH2:4][CH2:5]1
Reactant: CN([C@H]1CC[C@H](COS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CN(C)CCS
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)CCSC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 280 mg (0.5 mmol) of trans-4-Trifluoromethyl-benzenesulfonic acid 4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexylmethyl ester and 78 mg (0.55 mmol) of 2-dimethylaminoethanethiol hydrochloride in 4.5 ml DMF was treated at 0° C. with 48 mg (1.1 mmol) of 55% NaH, stirred for 20 h at RT. After cooling (0° C.) and treatment with a catalytic amount of NaI followed by 78 mg (0.55 mmol) of 2-dimethylaminoethanethiol hydrochloride and 48 mg (1.1 mmol) of 55% NaH the reaction mixture was stirred for 18 h at RT. The reaction was neutralized (aqueous 10% KHSO4, at 0° C.) and poured into aqueous sat. NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl solution, dried over Na2SO4 and evaporated. Purification by flash column chromatography on silica gel with CH2Cl2/MeOH (95:5) yielded 138 mg (63%) of trans-N-[4-(2-Dimethylamino-ethylsulfanylmethyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 439 (MH+).
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: O
Solvent: C1CCOC1
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: [CH2:1]([NH:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:21](OC(=O)C)(=[O:23])[CH3:22]>C([O-])(=O)C.[Na+].O>[CH2:1]([NH:11][C:12]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:21](=[O:23])[CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)CCCOCCO
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCNC(=O)CCCOCCOC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
In a glass reaction vessel 17.7 grams (0.0616 mole) of N-decyl-4-(2-hydroxyethoxy)butyramide was admixed with 25.3 grams (0.25 mole) of acetic anhydride in the presence of 4 grams sodium acetate catalyst. This mixture was heated to 100° C. on a steam bath until a reaction was completed within a period of 3 hours. The mixture was then drowned in water, salted out and phase separated. The upper liquid phase was dried to 17.8 grams of liquid product having a refractive index η d25 =1.4586 and an IR of 6.09 mu.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[O:4][N:3]=1.[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21]O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][O:1][C:2]1[CH:6]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[O:4][N:3]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cc(-c2cccs2)on1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2cccs2)on1
Yield: 81.8 %

Procedure:
3-Hydroxy-5-(2-thienyl)isoxazole (0.42 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.63 g, 82%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:45]([OH:47])=[O:46])[CH2:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[NH:23][C:24]([CH3:44])=[C:25]([C:40]([O:42][CH3:43])=[O:41])[CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:48](O)[CH3:49].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[NH:23][C:24]([CH3:44])=[C:25]([C:40]([O:42][CH3:43])=[O:41])[CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(COCCNC(=O)CC[C@H](NC(=O)OCc2ccccc2)C(=O)O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCCNC(=O)CC[C@H](NC(=O)OCc2ccccc2)C(=O)OCC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 81.6 %

Procedure:
A mixture of 2-[2-(-(S)-4-benzyloxycarbonylamino-4-carboxybutanamido)ethoxymethyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (1.0 g), ethanol (0.27 g), N,N'-dicyclohexylcarbodiimide ("DCCD") (0.34 g) and 4-dimethylaminopyridine (50 mg) was stirred in dichloromethane (10 ml) at room temperature for 18 hours. The resulting N,N'-dicyclohexylurea was then removed by filtration and the filtrate evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0→2% methanol as the eluant. Appropriate fractions were combined and evaporated to give 2-[2-(-(S)-4-benzyloxycarbonylamino-4-ethoxycarbonylbutanamido)ethoxymethyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.85 g) as an essentially pure oil.