Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[CH:22]([C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40](O)=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1.C(C1N=C(C2C=C(OC3CC4C(C(=O)N(C)CCCCC=CC5C(C(NS(C6CC6)(=O)=O)=O)(NC4=O)C5)C3)C3C(=C(C)C(OC)=CC=3)N=2)SC=1)(C)C>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[CH:22]([C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:53][S:50]([CH:47]6[CH2:49][CH2:48]6)(=[O:52])=[O:51])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NCCCCCC=CC5CC5(C(=O)O)NC(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NCCCCCC=CC5CC5(C(=O)NS(=O)(=O)C5CC5)NC(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 18-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-2,15-dioxo-3,14-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (80) and cyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (47): m/z=750 (M+H)+. 1H NMR (CDCl3): 0.90-0.96 (m, 1H), 1.1-1.2 (m, 4H), 1.39 (d, J=6.9 Hz, 6H), 1.4-1.55 (m, 5H), 1.80-1.92 (m, 5H), 2.15-2.25 (m, 1H), 2.30-2.40 (m, 1H), 2.45-2.55 (m, 2H), 2.68 (s, 3H), 2.85-2.92 (m, 1H), 3.15-3.30 (m, 2H), 3.45-3.55 (m, 2H), 3.96 (s, 3H), 4.09 (dd, J=11.5 Hz, J=3.8 Hz, 1H), 4.61 (t, J=7.9 Hz, 1H), 4.99 (t, J=9.0 Hz, 1H), 5.51-5.53 (m, 1H), 5.71 (dd, J=18.6 Hz, J=8.2 Hz, 1H), 6.86 (s, 1H), 7.03 (s, 1H), 7.20 (d, J=9.2 Hz, 1H), 7.50 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 9.40 (br s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:12][CH:13]=3)[C:8](=[O:34])[C:7]=2[CH:6]=1.CC(C)=[O:37].OS(O)(=O)=O.O=[Cr](=O)=O.O>C(OCC)C>[CH2:32]([O:31][C:29]([C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[CH:16]=[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:5]([CH2:4][CH2:3][C:2]([OH:37])=[O:1])=[CH:6][C:7]=3[C:8]2=[O:34])=[CH:13][CH:12]=1)=[O:30])[CH3:33]
Reactant: CC(C)=O
Reactant: CCCCCCCCCCOc1cc2c(cc1CCCO)C(=O)c1cc(C(=O)OCC)ccc1-2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCOc1cc2c(cc1CCC(=O)O)C(=O)c1cc(C(=O)OCC)ccc1-2
Reaction time: 8 h

Procedure:
A solution of 170 mg of 2-(3-hydroxypropyl)-3-decyloxy-7-ethoxycarbonyl-9-oxo-9H-fluorene in diethyl ether were treated with 0.75 ml of Jones reagent (chromic acid solution). The reaction mixture was stirred overnight, poured into water and the layer separated. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo providing 90 mg of material which was taken directly to hydrolysis. NMR.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:16]([C:17]2[S:18][C:19]([C:28]3[N:32]=[CH:31][NH:30][N:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][NH2:15])[CH:10]=[CH:11][N:6]2[N:5]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+].CCOC(C)=O>C1COCC1>[CH3:3][C:4]1[C:16]([C:17]2[S:18][C:19]([C:28]3[N:32]=[CH:31][NH:30][N:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][NH:15][C:33](=[O:35])[CH3:34])[CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nn2ccc(OCCN)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCCOc1ccn2nc(C)c(-c3nc(-c4ccccc4)c(-c4nc[nH]n4)s3)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a suspension of 2-({2-methyl-3-[4-phenyl-5-(1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridin-5-yl}oxy)ethanamine di-hydrochloride (100 mg, 0.20 mmol) obtained in Example 73-B(i) and TEA (0.75 mL) in THF (10 mL), was added acetic anhydride (0.5 mL, 5.3 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 h. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (50 mL) and EtOAc (50 mL), and the mixture was stirred for 30 min. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with EtOAc and diisopropyl ether, and dried to give the title compound (33 mg, 35%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[N:8]([CH3:18])[C:7]2=[O:19].[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][NH:21]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[N:8]([CH3:18])[C:7]2=[O:19]
Reactant: CN1C(=O)C2(CCCCBr)CCCc3cccc1c32
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCCCN3CCc4ccccc4C3)CCCc3cccc1c32

Procedure:
2a-(4-Bromobutyl)-1-methyl-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (120 mg, 0.37 mmol), 1,2,3,4-tetrahydroisoquinoline (55 mg, 0.41 mmol) and potassium carbonate (77 mg, 0.56 mmol) were stirred at room temperature for 18 hours in anhydrous N,N-dimethylformamide (1 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and dried with anhydrous magnesium sulfate, the solvent was removed by evaporation under a reduced pressure, and then the thus obtained material was separated and purified by a silica gel column chromatography to obtain 130 mg (0.34 mmol, 90% in yield) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]([OH:11])=O)[CH:2]=1.[Cl:12][C:13]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20].ClCCl.CO.N>>[Cl:12][C:13]1[CH:26]=[C:25]([NH:27][C:9](=[O:11])[C:8]#[C:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:24]=[CH:23][C:14]=1[O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20]
Reactant: O=C(O)C#Cc1cccnc1
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2cccnc2)cc1Cl

Procedure:
Prepared analogously to Example 2.3.f. from pyridin-3-ylpropynoic acid and [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine. Yield: 0.42 g (66.4% of theory); melting point: 118° C.-120° C.; C20H22ClN3O2 (M=371.86); calc.: molecular ion peak (M+H)+: 372/374; found: molecular ion peak (M+H)+: 372/374; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:19]([O-])=[O:20])([CH3:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:19]([C:12]([CH3:18])([CH3:11])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[O-:20]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(=O)OCC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)OCC(C)(C)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.4 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (428.2 mg, 3.01 mmol), 2-methyl-2-nitro-1-acetoxypropane (467.8 mg, 2.90 mmol) and zinc (321.7 mg, 4.92 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.57 ml, 9.9 mmol) was added dropwise to the mixture and was warmed to room temperature and stirred for 16 hours. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (380.8 mg; 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:41])[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OCC4C=CC=CC=4)[CH2:25]3)=[O:23])[C:17]1=[O:42])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:22](=[O:23])[C@@H:21]([N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][S:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[CH:8]=3)(=[O:14])=[O:13])[C:17]2=[O:42])[CH3:41])[CH2:25]1
Reactant: C[C@@H](C(=O)N1CCC[C@H](NC(=O)OCc2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C(=O)N1CCC[C@H](N)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
Benzyl(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate (0.128 g) was dissolved in DCM (3.5 ml) and treated with trifluoroacetic acid (10.5 ml) and stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and the residue purified by SPE (acid ion-exchange, eluting with ethyl acetate:methanol 9:1) to give the title compound (0.093 g) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8]2)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]>ClCCl>[F:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]([NH:14][CH2:13][CH2:12][CH2:11][N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:16][CH:15]=3)[CH2:8]2)=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: NCCCN1CC(Oc2ccc(F)cc2)C1
Solvent: ClCCl
Product: O=C(NCCCN1CC(Oc2ccc(F)cc2)C1)Nc1ccc(F)c(F)c1

Procedure:
A solution of 3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine (0.04 g, 0.178 mmol) and 3,4-difluorophenylisocyanate (0.020 ml, 0.178 mmol) in dichloromethane (1 ml) is stirred at room temperature for 5 hours. The solvent is evaporated and the crude product purified by flash silica chromatography (elution gradient a 3:97 to 5:95 methanol/dichloromethane) to afford 1-(3,4-difluoro-phenyl)-3-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-urea. [MH]+ 379.9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[F:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:30][C:27]3[CH:26]=[CH:25][C:24]([O:23][C:19]4[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=3)=[C:3]([C:15]#[N:16])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Reactant: Nc1ccc(Oc2cccnc2)cc1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Oc4cccnc4)cc3)c(C#N)cnc2cc1F

Procedure:
Following the procedure of Example 1, a mixture of 635.4 mg (2.68 mmol) 4-chloro-7-fluoro-6-methoxy-quinoline-3-carbonitrile, 500 mg (2.81 mmol) of 4-(pyridin-3-yloxy)phenylamine and 309.8 mg (2.68 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (27 mL) at 100° C. for 12 hours to yield 7-fluoro-6-methoxy-4-[4-(pyridin-3-yloxy)-phenylamino]-quinoline-3-carbonitrile as an off-white solid, mp 235-236° C.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.C1C(=O)N(Cl)C(=O)C1.[Cl:20][C:21]1[C:29]([F:30])=[C:28]2[C:24]([CH:25]=[C:26]([CH:38]3[CH2:40][CH2:39]3)[N:27]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH3:37])[CH:35]=2)=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[C:29]([F:30])=[C:28]2[C:24]([C:25]([S:1][C:2]3[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=3)=[C:26]([CH:38]3[CH2:40][CH2:39]3)[N:27]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH3:37])[CH:35]=2)=[CH:23][CH:22]=1
Reactant: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Reactant: COC(=O)c1cccc(S)n1
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CCn1cc(-n2c(C3CC3)c(Sc3cccc(C(=O)OC)n3)c3ccc(Cl)c(F)c32)cn1
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a stirred solution of methyl 6-mercaptopicolinate 6 (3.15 g, crude) in CH2Cl2 (50 mL) under inert atmosphere was added NCS (2.49 g, 18.63 mmol) at RT and stirred for 1 h. To this, indole 5 (5.6 g, 18.47 mmol) in CH2Cl2 (50 mL) was added at RT and stirred for 16 h. After completion of the reaction (TLC), the reaction mixture was diluted CH2Cl2 (100 mL) washed with water (3×100 mL). The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel column chromatography; 10% EtOAc/hexanes) to afford 9 (2.8 g, 32%) as a pale brown solid. 1H NMR (500 MHz, DMSO-d6): δ 7.79 (d, J=7.5 Hz, 1H), 7.66 (d, J=10.5 Hz, 2H), 7.51 (t, J=7.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.10-7.07 (m, 1H), 6.78 (d, J=8.0 Hz, 1H), 4.28 (q, 2H), 4.00 (s, 3H), 1.75-1.69 (m, 1H), 1.58 (t, J=7.0 Hz, 3H), 1.09-1.08 (m, 2H), 0.87-0.84 (m, 2H); LC-MS: 98.4%; m/z 471.4 (M+H+); (column; X-select CSH C-18, (50×3.0 mm, 3.5 μm); RT 4.25 min. 5.0 mM NH4OAc (Aq): ACN; 0.8 mL/min); HPLC: 98.1%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 3.02 min. ACN: 0.025% TFA (aq); 0.5 mL/min).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH2:15][C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.O.[CH3:20]I>[Na].C(O)(C)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:20])[C:16](=[O:18])[CH3:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: CI
Reactant: CC(=O)Cc1ccc2c(c1)Cc1cccnc1O2
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)C(C)c1ccc2c(c1)Cc1cccnc1O2
Yield: 74.8 %

Procedure:
24 g of 5H-[1]benzopyrano[ 2,3-b]pyridin-7-yl-acetone is dissolved in a solution of 2.5 g of metallic sodium in 120 ml of isopropyl alcohol at 50°-60°C with stirring. The solution is cooled to 40°C with water, 17.2 g of methyl iodide is added, and the mixture is stirred under reflux for 1 hour. The isopropyl alcohol is distilled off under reduced pressure, and the residue is dissolved in chloroform. After water cooling, the solution is dried over anhydrous magnesium sulfate and concentrated, and the residue is recrystallized from isopropyl alcohol to give 19 g of 3-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-2-butanone melting at 136°-136°C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:26][CH3:27])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:26]([N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH3:27]
Reactant: CCN(C1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C1CCNCC1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[ethyl-(4-methoxy-benzenesulfonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (11.1 g, 28 mmol) in CH2Cl2 (50 mL) is cooled at 0° C. and TFA (40 mL) is added. The mixture is stirred at 0° C. for 0.5 h and then evaporated. The residue is dissolved in CH2Cl2 (50 mL) and 1 M aq. NaOH (50 mL) is added. The mixture is stirred for 15 h at r.t., then the phases are separated and the aq. phase is extracted with CH2Cl2 (4×30 mL). The combined org. phases are washed with 1 M aq. NaOH (2×30 mL), dried (Na2SO4), filtered and evaporated to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13](OC(=O)C)[C@@H:12]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C@:10]1(C)[O:36][CH2:37][C@H:38]1[O:45][C@H:42]([O:43][CH3:44])[C@H:41]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:40]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@@H:39]1[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:71][OH:72].C[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([CH2:71][OH:72])[C@@H:12]([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C@@H:10]1[O:36][CH2:37][C@H:38]1[O:45][C@H:42]([O:43][CH3:44])[C@H:41]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@@H:40]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@@H:39]1[O:62][CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CO[C@H]1O[C@H](CO[C@@]2(C)O[C@H](COCc3ccccc3)[C@@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@@H](CO)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Methyl 6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxy-methyl-α-D-glucopyranosyl) -2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.469 g, 2.593 mmol) was dissolved in hot toluene (20 mL) and methanol (80 mL) was added, followed by a few drops of 1M. methanolic sodium methoxide. The mixture was stirred at room temperature during 2 h. The reaction mixture was made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure to afford methyl 6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl -α-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.36 g, 100%) as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:8][CH:7]([C@H:9]([C@@H:11]2[C@@:15]3([CH3:33])[CH2:16][CH2:17][C@@H:18]4[C@@:23]5([CH3:31])[C:24]([CH2:26][C@H:27]([OH:30])[C@H:28]([OH:29])[C@@:22]65[O:32][C@@H:21]6[CH2:20][C@H:19]4[C@@H:14]3[CH2:13][CH2:12]2)=[O:25])[CH3:10])[O:6][C:4](=[O:5])[C:3]=1[CH2:34][O:35][C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.CC1C[C@H]([C@H]([C@@H]2[C@@]3(C)CC[C@@H]4[C@@]5(C)[C@@H](O)C[C@H](O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)[C@H](O)[C@@]65O[C@@H]6C[C@H]4[C@@H]3CC2O)C)OC(=O)C=1CO>>[CH3:1][C:2]1[CH2:8][C@H:7]([C@H:9]([C@@H:11]2[C@@:15]3([CH3:33])[CH2:16][CH2:17][C@@H:18]4[C@@:23]5([CH3:31])[C:24]([CH2:26][C@H:27]([OH:30])[C@H:28]([OH:29])[C@@:22]65[O:32][C@@H:21]6[CH2:20][C@H:19]4[C@@H:14]3[CH2:13][CH2:12]2)=[O:25])[CH3:10])[O:6][C:4](=[O:5])[C:3]=1[CH2:34][OH:35]
Reactant: CC1=C(CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)C(=O)OC([C@@H](C)[C@H]2CC[C@H]3[C@@H]4C[C@H]5O[C@]56[C@@H](O)[C@@H](O)CC(=O)[C@]6(C)[C@H]4CC[C@]23C)C1
Agent: CC1=C(CO)C(=O)O[C@@H]([C@@H](C)[C@H]2C(O)C[C@H]3[C@@H]4C[C@H]5O[C@]56[C@@H](O)[C@@H](O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)C[C@H](O)[C@]6(C)[C@H]4CC[C@]23C)C1
Product: CC1=C(CO)C(=O)O[C@@H]([C@@H](C)[C@H]2CC[C@H]3[C@@H]4C[C@H]5O[C@]56[C@@H](O)[C@@H](O)CC(=O)[C@]6(C)[C@H]4CC[C@]23C)C1
Yield: 28 %

Procedure:
Isolation of withanolides. The combined crude extract from PhytoMyco Research Corporation (4 g) was stirred with n-hexane (500 mL) and filtered. The hexane insoluble portion (3.2 g) was chromatographed on MPLC using CHCl3 and MeOH (v/v) under gradient condition. The fractions collected were I (600 mg CHCl3:MeOH, 9:1), II (500 mg, CHCl3:MeOH, 8:2), III (1.2 g, CHCl3:MeOH, 7:3), and IV (200 mg, CHCl3:MeOH, 1:1). Repeated MPLC of fraction I using hexane-EtOAc (1:1, v/v) yielded pure compounds 6 (120 mg, 0.078%), 7 (50 mg, 0.032%) and a fraction 1 (4.0 mg). This fraction was further purified by PTLC (hexane-EtOAc, 6:4, v/v) to yield the pure compound 9 (2.1 mg, 0.0014%). Purification of fraction II by preparative HPLC using MeOH—H2O (1:1, v/v) afforded compound 10 (20 mg, 0.013%) at 19.5 min and fraction 2 (50 mg) at 24.2–28.1 min. It was further purified on HPLC by using MeOH—H2O (4:6, v/v) and gave compound 11 (40 mg, 0.026%) at 32.96 min. Similarly, fraction III was purified by Prep. HPLC (MeOH—H2O, 6:4, v/v) and yield pure compound 12 (15 mg, 0.0097%) at 112 min and fractions 3 (950 mg) at 20–45 min and 4 (16 mg) at 140–160 min. Fraction 3 was further purified by HPLC (MeOH—H2O, 6:4, v/v) to afford compounds 8 (200 mg, 0.13%) and 5 (10 mg, 0.0065%) at 66.8 and 78.6 min, respectively, and 700 mg of sucrose at 132 min. Fraction 4 was subjected to HPLC (MeOH—H2O, 7:3, v/v) yielded compound 2 (12 mg, 0.0078%) at 81 min. The fraction IV was purified by HPLC (MeOH—H2O, 7:3) and collected fractions 5 (13 mg) at 20–30 min and fraction 6 (30 mg) at 30.1–66 min. The fraction 6 was purified by HPLC (MeOH—H2O, 7:3, v/v) to yield compound 3 (8.5 mg, 0.0055%) at 57.9 min. Fraction 5 was further purified by HPLC using MeOH—H2O (6:4, v/v) and afforded pure compound 1 (10.5 mg, 0.0068%) at 59.3 min and a mixture of compounds 4 and 12 at 96.4 min (5.0 mg, 0.0032%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: O=C([O-])[O-]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To acetone (60 mL) charged with 2-amino-3-nitrophenol (32 mmol, 4.9 g) and K2CO3 (48 mmol, 6.62 g) was added MeI (32 mmol, 1.98 mL). The reaction mixture was stirred rapidly at ambient temperature for 16 h. Acetone was removed under reduced pressure and the residue was partitioned between CH2Cl2 and brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure to provide the product as a brown solid. LC-MS (ESI, Method C) 2.56 min, m/z 169.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1F)[N:10]=[CH:9][N:8]=[C:7]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1)([O-:3])=[O:2].[N:24]1([CH2:30][CH2:31][CH2:32][OH:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.CC(C)([O-])C.[K+].Cl>CS(C)=O.O>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][C:13]([O:33][CH2:32][CH2:31][CH2:30][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Reactant: OCCCN1CCOCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCN1CCOCC1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
6-nitro-4-(3-chloro-4-fluorophenylamino)-7-fluoro-quinazoline (1 eq.) and morpholine-propanol (1.5 eq.) were dissolved in DMSO (10 ml), the solution was stirred for 5 mins with a water bath. A solution of potassium tert-butoxide (3.0 eq.) in DMSO (5 ml) was added slowly to the solution mentioned-above in drops, the mixture was stirred at room temperature for further 30 mins. After the reaction finished, the mixture was diluted with 100 ml water and pH was adjusted to neutral with concentrated hydrochloric acid, then stirred for 30 mins, large amount of yellow solid was precipitated, then filtering, the filter cake was washed with water twice and dried to give yellow solid of N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-6-nitroquinazolin-4-amine (yield 90%).