Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].O>CN(C=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])=[C:4]([I:9])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Oc1cnc(F)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCOc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Cool a suspension of 6-fluoro-4-iodo-pyridin-3-ol (1.5 g, 6.28 mmol) and K2CO3 (4.38 g, 31.4 mmol) in DMF (10 mL) to 0° C. in an ice bath under nitrogen. Add 2-(2-bromo-ethyl)-isoindole-1,3-dione (3.19 g, 12.55 mmol). Stir the mixture at RT overnight. Add water. Extract with ethyl acetate. Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (hexane to 30% ethyl acetate in hexane) to afford the title compound as a yellow oil (1.51 g, 58%). MS (ES) m/z 413 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:13]1=[O:21].[H][H]>C1COCC1.[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([N:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:13]2=[O:21])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: [H][H]
Reactant: CCCc1cccn(-c2ccc([N+](=O)[O-])cc2OC)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cccn(-c2ccc(N)cc2OC)c1=O

Procedure:
130 mg (0.45 mmol) of the product from example 52A are initially charged in 4 ml of THF. To this are added 50 mg of 10% palladium on activated carbon, and hydrogenation is effected at standard pressure in a hydrogen atmosphere for 1 h. The reaction solution is then filtered through Celite which is rinsed with ethyl acetate. The mixture is concentrated under reduced pressure to obtain 115 mg (99% of theory) of the crystalline title compound.
Reaction SMILES: [Li].N.C([S:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C.[Cl-].[NH4+].Br[CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>CCOCC>[CH:6]([S:5][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OCC(O)CBr
Reactant: CCCCCC=CSCC
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: CCOCC
Product: CCCCCC=CSCC(O)CO
Reaction time: 0.08 h

Procedure:
Lithium (1.61 g., 0.234 eq.) cut into small pieces is added to 150 ml. of dry liquid ammonia with stirring. After 5 minutes, 100 ml. of dry ether is added followed by the dropwise addition of 1-ethylthio-1-heptene (18.6 g., 0.117 moles). At the end of the addition, the blue color of the solution disappears and the reaction mixture is a white milky suspension. Ammonium chloride (6.26 g., 0.117 moles) is added cautiously followed by 1-bromo-2,3-propanediol (19.9 g., 0.128 moles). After stirring for 30 minutes, the ammonia is allowed to evaporate and water and ether are added to the residue. The aqueous layer is extracted once with ether and the ether extracts are combined and dried over MgSO4. The residue obtained after concentration of the ether is distilled (bp 129°-133° C, 0.15 mm.) to afford 6 g. of a yellow liquid. The liquid is further purified by column chromatography on SilicAR, CC-7, eluting with acetone:chloroform (1:5) to afford 3-(1-heptenylthio)-1,2-propanediol as a colorless liquid (5.7 g., 23.9%); nD24.1 1.5091.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH2:8])[CH2:6][OH:7])=[O:4].Cl.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][O:2][C:3](=[O:4])[CH:5]([NH:8][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17])[CH2:6][OH:7]
Reactant: COC(=O)C(N)CO
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Product: COC(=O)C(CO)NS(=O)(=O)c1ccccc1

Procedure:
In analogy to example 1, DL-serinemethylester hydrochloride was reacted with benzenesulfonyl chloride to give 2-benzenesulfonylamino-3-hydroxy-propionic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cncc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1cncc(CCc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.5 %

Procedure:
To a solution of 3,4-bis(benzyloxy)-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 16, 1.5 g) in methanol (10 ml) was added 10% palladium on carbon (0.04 g) slowly under nitrogen and the reaction mixture was stirred for 30 minutes at room temperature under a hydrogen atmosphere. The resulting mixture was filtered through a “Celite” (trade mark) diatomaceous earth bed under nitrogen atmosphere and washed with methanol before the filtrate was concentrated under vacuum to afford crude 3,4-bis(benzyloxy)-6-(2-(5-(trifluoromethyl)pyridin-3-yl)ethyl)pyridazine (0.4 g, 0.86 mmol). This was taken up in methanol (10 ml) at room temperature and 10% palladium on carbon (0.04 g) was added slowly under nitrogen atmosphere. The mixture was then stirred under hydrogen (200 psi) at room temperature overnight before being filtered through a bed of “Celite” diatomaceous earth under nitrogen and washed with methanol. The organic layer was concentrated in vacuo to afford the crude product (0.2 g) which was purified by the preparative HPLC to afford homogeneous 4-hydroxy-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethyl})pyridazin-3(2H)-one (0.03 g, 81.6% yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1)[CH2:12][CH:13]([CH3:15])[CH3:14].[C:28]([O:32][C:33](=[O:36])[CH2:34]Br)([CH3:31])([CH3:30])[CH3:29].[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([CH2:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:36])[C:24]([O:26][CH3:27])=[O:25])=[CH:21][CH:22]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)Cc1ccc(OCCC(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.06 M in THF; 9.43 mL, 10.0 mmol) was added dropwise over 10 min to a stirred solution of methyl [4-(isopentyloxy)phenyl]acetate (2.15 g, 9.10 mmol) in THF (30 mL) at −78° C. under nitrogen. On completion of addition stirring was continued at −78 ° C. for 30 min then t-butylbromoacteate (2.12 g, 1.61 mL, 10.9 mmol) was added dropwise over 5 min. The reaction was allowed to warm slowly to room temperature over 4 h then saturated ammonium chloride solution (30 mL) was added and the resulting suspension extracted with ethyl acetate (3×50 mL). The organic phases were combined, dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (20% diethyl ether: cyclohexane) to give the title compound as a colourless oil (2.69 g, 85%). LC/MS: 3.80 min; z/e 351, calcd (M+1) 351. 1H NMR (400 MHz: CDCl3): 7.20 (2H), 6.85 (2H), 3.95 (3H), 3.65 (3H), 3.05 (1H), 2.55 (1H), 1.85 (1H), 1.70 (2H), 1.40 (9H), 0.95 (6H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>O>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:33])([CH3:34])[C:28]([OH:30])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cnn(C(C)(C)C(=O)O)c3)cc1OCC2

Procedure:
Ethyl 2-(4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate was treated with lithium hydroxide in water to give 216. LC/MS (ESI+): m/z 448 (M+H). 1H NMR (400 MHz, DMSO) δ 8.44 (s, 1H), 8.38 (d, J=8.4, 1H), 7.98 (s, 1H), 7.92 (s, 2H), 7.45 (dd, J=8.4, 1.8, 1H), 7.36 (d, J=1.7, 1H), 5.90 (dt, J=13.2, 6.6, 1H), 4.53 (q, J=6.0, 4H), 1.77 (s, 6H), 1.50 (d, J=6.6, 6H)
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:15].BrN1C(=O)CCC1=O.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:32][CH2:31][CH2:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1
Reactant: NCCc1ccccc1
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(F)c(CNCCc2ccccc2)c1
Yield: 64.6 %

Procedure:
According to the procedure of Preparation 4 (b), except using tert-butyl 4-fluoro-3-methylbenzoate (6.25 g, 29.7 mmole), N-bromosuccinimide (5.75 g, 32.3 mmole), benzoyl peroxide (375 mg, 1.6 mmole), CCl4 (50 mL), and 2-phenethylamine (19 mL, 151 mmole), the title compound (6.32 g, 64%) was prepared as a yellow oil following flash chromatography on silica gel (gradient: 20-40% EtOAc/hexanes): MS (ES) m/e 330.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:15][C:16](=O)[CH3:17].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:17][C:16]1[N:13]=[C:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[O:12][CH:15]=1
Reactant: NC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1coc(Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 8.3 %

Procedure:
A mixture of 2-(4-nitrophenyl)acetamide (15.0 g), 1-bromo-2-propanone (19.03 g), and N,N-dimethylformamide (2 mL) was stirred at 120° C. for 3 hrs. Water, potassium carbonate and ethyl acetate were added to basify the reaction mixture and the mixture was extracted with ethyl acetate. Insoluble materials were filtered off, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-methyl-2-(4-nitrobenzyl)-1,3-oxazole as orange crystals (1.50 g, yield 8.2%) from a fraction eluted with hexane-ethyl acetate (2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 67-68° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][O:13][C@H:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:8][C@H:9]1[CH2:14][O:13][C@H:12]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:10]1
Reactant: NC(=O)[C@@H]1CC[C@@H](N(Cc2ccccc2)Cc2ccccc2)CO1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)[C@@H]1CC[C@@H](N)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.8 %

Procedure:
The compound (490 mg, 1.51 mmol) obtained in Step 2 above was dissolved in ethanol (10 ml), 20% palladium hydroxide (100 mg) was added and the resulting mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The catalyst was removed by filtration through celite, then the solvent in the filtrate was evaporated under reduced pressure and the residue was dried to give 215 mg (99%) of the title compound as a solid.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pt]>[Cl:20][C:16]1[CH:15]=[C:14]([C:13]2[C:7]3[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=3[CH:10]=[CH:11][CH:12]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3cccc(Cl)c3)c2O1
Agent: [Pt]
Product: NCC1Cc2cccc(-c3cccc(Cl)c3)c2O1
Yield: 74 %

Procedure:
Treatment of (±)-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (3.6 g, 8.66 mmol) with sodium azide (2.25 g, 34.65 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.125 g, 5 wt. %) generally according to the procedure described for Example 1 provided 1.91 g (74%) of (±)-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a tan solid, hydrochloride salt. mp 150-154° C.; Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 59.17; H, 5.12; N, 4.38.
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(=O)([O-])[O-].[K+].[K+].[Cl:18][CH:19](Cl)[CH3:20]>CC(=O)CC>[Cl:18][CH2:19][CH2:20][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: CC(Cl)Cl
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 70 %

Procedure:
2-Amino-3-nitrophenol (10.0 g, 64.9 mmol, commercially available from Aldrich) was dissolved in 200 mL 2-butanone, potassium carbonate (18.0 g, 0.13 mol) and dichloroethane (15 mL) were added. The suspension was refluxed for 20 hours. The reaction was allowed to cool to room temperature and filtered through a plug of Celite and the retained solid residue was washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The crude material was redissolved in 200 mL of ethyl acetate, washed with water, 1N sodium hydroxide solution water, saturated sodium chloride solution dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure to give 9.8 g of 2-(2-Chloroethoxy)-6-nitroaniline (70% yield), which was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.80 (d, 1H), 6.95 (d, 1H), 6.61 (dd, 1H), 6.42 (b, 2H), 4.30 (t, 2H), 3.90 (t, 2H). MS (EI): 217 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH2:18][OH:19])[CH:8]=[C:9](C(C)(C)C)[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH2:18][OH:19])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CCCO)cc(C(C)(C)C)c1O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(CCCO)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A stirred solution of III (12.5 Kg) in trifluoroacetic acid (60.0 L) was heated 40° C. for 6 hrs. After completion of reaction on TLC, reaction mixture was quenched in ice-water and extracted 3 times with dichloromethane (25.0 L). Total organic layers were combined and evaporated to dryness at atmospheric pressure. A solution of sodium hydroxide (3.0 Kg) in methanol (50.0 L) was added to the residue and stirred at room temperature for 1 hr. The solution was neutralized with 1N HCl and extracted 3 times with dichloromethane (25.0 L). All the organic layers were combined and washed with saturated sodium carbonate solution (10.0 L), DM Water (10.0 L), brine (10.0 L) and evaporated to dryness under reduced pressure to give the title compound (7.5 Kg)
Reaction SMILES: [Li].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:12]([O:15][CH2:16][CH3:17])(=[O:14])[CH3:13].[Br:18][C:19]1[C:28]([CH2:29]Br)=[C:27]([O:31][CH3:32])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[O:33][CH3:34]>C1COCC1.O.C(Cl)Cl>[Br:18][C:19]1[C:28]([CH2:29][CH2:13][C:12]([O:15][CH2:16][CH3:17])=[O:14])=[C:27]([O:31][CH3:32])[C:26]2[C:21]([C:20]=1[O:33][CH3:34])=[CH:22][CH:23]=[CH:24][CH:25]=2
Reactant: CCOC(C)=O
Reactant: COc1c(Br)c(CBr)c(OC)c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Li]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(Br)c(OC)c2ccccc2c1OC
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
Following a modified procedure of Clegg et al.,28 lithium hexamethyldisilizade (LiHMDS, 1 M in THF, 1.5 ml, 1.5 mmol) was added to a flame-dried round bottom flask containing THF (20.0 mL) at 78° C. Ethyl acetate (0.15 ml, 1.5 mmol) was then added slowly at 78° C. and stirred at 78° C. for 30 minutes. 36 (0.415 g, 1.15 mmol) was then dissolved in THF (10.0 mL) and added at 78° C., at which point the reaction was allowed to warm to room temperature, and was stirred at room temperature for 4 h. The reaction was monitored by TLC (CH2Cl2) for disappearance of the less polar starting material. More LiHMDS (2.0 mL, 2.0 mmol) and EtOAc (0.70 mL, 0.70 mmol) were added and the reaction was monitored for the disappearance of starting material. When no starting material was present, 10 hours, the reaction was then poured into water, extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and condensed. The product was the purified by column chromatography (CH2Cl2 to 1:19 EtOAc:CH2Cl2) to provide 67a (0.361 g, 0.983 mmol, 86%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Brc1ccc2ncccc2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ncccc3c2)CCN(C)C1

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.5 mmol), 6-bromoquinoline (0.135 mL, 1 mmol), K3PO4 (0.318 g, 1.5 mmol), CuI (9.5 mg, 0.05 mmol) and L-Proline (11.5 mg, 0.1 mmol) in dry DMF (5 mL) was stirred at 150° C. for 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-quinolin-6-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (8 mg). 1H NMR (Oxalate salt, CD3OD) δ (ppm): 8.92 (d, 1H), 8.43 (d, 1H), 8.2 (dd, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 7.6 (dd, 1H), 7.38 (d, 1H), 7.18 (d, 1H), 7.0 (dd, 1H), 4.42 (s, 2H), 3.5 (m, 2H), 3.1 (m, 5H), 2.4 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:18])[C:15]=2[O:16][CH3:17])=[C:12]([OH:19])[CH:11]=[C:10]([O:20][CH3:21])[CH:9]=3)=[CH:4][C:3]=1[O:24][CH3:25].[C:26]([O-])(=[O:28])[CH3:27].[Na+].C(OC(=O)C)(=O)C>>[C:26]([O:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:18])[C:15]=2[O:16][CH3:17])=[C:12]([OH:19])[CH:11]=[C:10]([O:20][CH3:21])[CH:9]=3)=[CH:4][C:3]=1[O:24][CH3:25])(=[O:28])[CH3:27]
Reactant: COc1cc(O)c2c(=O)c(OC)c(-c3ccc(O)c(OC)c3)oc2c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1cc(O)c2c(=O)c(OC)c(-c3ccc(OC(C)=O)c(OC)c3)oc2c1
Temperature: 100 °C
Yield: 89.1 %

Procedure:
A mixture of 250 mg of 4',5-dihydroxy-3,3',7-trimethoxyflavone, 60 mg of sodium acetate and 70 mg of acetic anhydride was heated at 100° C. for 2 hours. The reaction mixture was evaporated under reduced pressure, and the residue was extracted with 30 ml of chloroform. Removal of the solvent from the extract and subsequent recrystallization of the residue from methanol gave 250 mg (90% yield) of 4'-acetoxy-5-hydroxy-3,3',7-trimethoxyflavone as yellow crystals: m.p. 168°-169° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]1[CH2:23][CH2:22][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]1>[N+]([O-])([O-])=O.[Ag+]>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:13]2[CH2:23][CH2:22][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:14]2)=[C:3]([C:4]#[N:5])[CH:6]=1)([O-:12])=[O:11]
Reactant: CCOC(=O)C1CCNCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Temperature: 25 °C
Yield: 102.9 %

Procedure:
2-Chloro-5-nitrobenzonitrile (10 g), ethyl isonipecotate (60 g) and silver nitrate (11.1 g) were stirred at 120° C. for 3 h. The reaction mixture was cooled to room temperature and the solid was filtered off. To the filtrate was added dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous diisopropyl ether to give ethyl 1-(4-nitro-2-cyanophenyl)piperidin-4-ylcarboxylate (17.1 g).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:10]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[NH:12][C:11]1=[O:20].CCOC(C)=O>C1COCC1.O>[Cl:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:20])[C:10]2([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28]
Reactant: COC(=O)CO
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)COC1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Under nitrogen atmosphere, to a solution of 12.9 g of methyl glycolate in THF (250 ml), under room temperature, was added 3.43 g of NaH, and the reaction mixture was stirred for 10 minutes at the same temperature. Under room temperature, 22.0 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one was added to the reaction solution and the reaction mixture was stirred for 10 minutes. To the reaction solution was added EtOAc and water and the mixture was stirred for 5 minutes. Liquid separation was performed, the aqueous layer was extracted with EtOAc, the combined organic layer was washed with 1 mol/L hydrochloric acid and saturated brine, then, was dried over MgSO4, the drying agent was separated by filtration, then, the solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc) to obtain 9.30 g of an orange solid. The obtained solid was crystallized from Et2O to obtain 8.18 g of the title compound (pale yellow crystal).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[CH2:27]([SH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][S:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=1)[CH3:2]
Reactant: SCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSCc2ccccc2)c1

Procedure:
As described for Example 10, [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and benzyl mercaptan were reacted to provide [3-(2-benzylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-benzylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and then treated with 4-chlorobenzoyl chloride to provide {3-[2-benzylsulfanylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided Compound 18.