Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10](B(O)O)[CH:9]=[N:8][C:7]=12)[CH3:2].O1CCOCC1.Br[C:22]1[S:23][C:24]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[C:29]([C@H:38]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:28]([CH3:49])=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:45]([O:44][C@@H:38]([C:29]1[C:28]([CH3:49])=[CH:27][C:25]2[N:26]=[C:22]([C:10]3[CH:9]=[N:8][C:7]4[N:6]([N:5]=[CH:4][C:3]=4[CH2:1][CH3:2])[CH:11]=3)[S:23][C:24]=2[C:30]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40])([CH3:46])([CH3:47])[CH3:48]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CCc1cnn2cc(B(O)O)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(CC)cnn4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of the crude 3-ethylpyrazolo[1,5-a]pyrimidin-6-ylboronic acid in dioxane (˜0.18M, 0.68 mL, 0.123 mmol) was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50 mg, 0.101 mmol), Pd(PPh3)4 (12 mg, 0.010 mmol) and 2M potassium carbonate (0.20 mL, 0.404 mmol) was heated in a microwave at 110° C. for 1 h. Reaction mixture was stored overnight at rt, diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 30% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C30H32ClN4O3S: 563.2 (M+H+); Found: 563.3 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH2:18]([NH:25][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:17])[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc2scc(-c3ccccc3)c2c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cc2scc(-c3ccccc3)c2c(NCc2ccccc2)n1
Temperature: 220 °C
Yield: 61.8 %

Procedure:
A microwave reaction vessel was charged with 4-chloro-6-methyl-3-phenyl-thieno[3,2-c]pyridine (254 mg, 0.982 mmol), benzylamine (642 μl, 5.886 mmol), triethylamine (137 μl, 0.982), solvated in NMP (3 ml), and set to stir in a Biotage microwave reactor. The reaction was heated at 220° C. for 6 h. The crude reaction was next partitioned between ethyl acetate (25 ml) and distilled water (25 ml). The organic phase was dried (MgSO4) and the solvent removed in vacuo. Purification by flash column chromatography (petroleum spirit 40-60° C.:ethyl acetate, 5:1, Rf 0.5) afforded the title compound as a yellow solid (200.4 mg, 62%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C@@H:8]([C@H:36]([CH3:44])[CH2:37][CH:38]([CH3:43])[CH2:39][CH2:40]C=C)[C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17](=[O:35])[NH:18][C@:19]1([C:24](=[O:34])[NH:25][S:26]([C:29]2([CH2:32][F:33])[CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH2:21][C@H:20]1[CH:22]=[CH2:23])=[O:10])([CH3:4])([CH3:3])[CH3:2]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:1]([O:5][C:6](=[O:45])[NH:7][C@@H:8]1[C:9](=[O:10])[N:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]2[C:17](=[O:35])[NH:18][C@:19]2([C:24](=[O:34])[NH:25][S:26]([C:29]3([CH2:32][F:33])[CH2:31][CH2:30]3)(=[O:27])=[O:28])[CH2:21][C@H:20]2[CH:22]=[CH:23][CH2:40][CH2:39][CH:38]([CH3:43])[CH2:37][C@H:36]1[CH3:44])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(CF)CC2)C[C@H]1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CC1CC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(CF)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Solvent: ClCCCl
Product: CC1CCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(CF)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 80 °C

Procedure:
A solution of tert-butyl((2S,3R)-1-((2S,4R)-2-(((1R,2S)-1-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-hydroxypyrrolidin-1-yl)-3,5-dimethyl-1-oxonon-8-en-2-yl)carbamate (7.5 g, 22.84 mmol) in DCE (2855 ml) was spurged with nitrogen for 30 min. and then Hoveyda-Grubbs Catalyst 2nd Generation (0.718 g, 1.142 mmol) was added and the reaction was heated to 80° C. for 2 hrs. The reaction was concentrated and purified by flash chromatography on silica gel (20-60% Acetone in hexanes) to give tert-butyl((2R,6S,7R,13aS,14aR,16aS,Z)-14a-(((1-(fluoromethyl)cyclopropyl)sulfonyl)carbamoyl)-2-hydroxy-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)carbamate (4 g, 6.36 mmol, 27.9% yield). MS: MS m/z 629.3 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[N:5]=[C:6]=[O:7].[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17]>>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH:5][C:6]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C=O
Reactant: CC(C)(C)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 99.5 %

Procedure:
To 60.9 g of the N-carbonyl-L-phenylalanine methyl ester, 66.0 g of t-butanol was added and the reaction was conducted under reflux for eight hours. Then, the unreacted t-butanol was distilled off at 65° C. under reduced pressure from the reaction solution to obtain 82.5 g of a crude oily N-t-butoxycarbonyl-L-phenylalanine methyl ester. The reaction yield was 99.5%. The optical purity of the N-t-butoxycarbonyl-L-phenylalanine methyl ester preparation was 97.5%ee.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([O:16]COCCOC)[CH:9]=2)=[CH:4][CH:3]=1.Cl>C1COCC1>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([OH:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COCCOCOc1cc(NCc2ccc(F)cc2)ccc1C#N
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(NCc2ccc(F)cc2)cc1O
Yield: 20.6 %

Procedure:
To a solution of 4-(4-fluoro-benzylamino)-2-(2-methoxy-ethoxymethoxy)-benzonitrile (15 mg; 0.05 mmol) in THF (1 mL) was added 4 M HCl (aq.; 0.5 mL). The mixture was refluxed for 2 h, cooled and the precipitate filtered off. Purification by flash column chromatography (SiO2—MeOH/CH2Cl2=0:1 to 5:95) yielded 2.5 mg pure product.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][Mg]Br.O>O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:14])[CH3:38])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(C)O)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.30 g) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (0.9 M tetrahydrofuran solution, 1.3 mL) at 0° C., and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-{1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-1-ethanol as colorless crystals (0.27 g, yield 87%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 105-106° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:15][C@H:16](O)[CH3:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>ClCCl.O.CCOCC>[CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:15][CH:16]([N:31]=[N+:32]=[N-:33])[CH3:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2cnn(C[C@@H](C)O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1ccc2cnn(CC(C)N=[N+]=[N-])c2c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a stirred solution of the product from Step B (1.8 g, 7.6 mmol) in dichloromethane (10 mL) was added triethylamine (1.3 mL, 9.2 mmol) followed by methanesulfonyl chloride (0.72 mL, 9.2 mmol) at 0° C. After 30 min, ether (50 mL) was added followed by water (50 mL). The organic layer was separated and the aqueous was extracted with ether (2×50 mL). The combined organic layers were washed with brine (30 mL), dried and evaporated. The residue was taken up in DMF (20 mL) and sodium azide (0.99 g, 15.2 mmol) was added. The reaction mixture was heated at 70° C. for 14 h, poured into water, and extracted with ether (3×50 mL). The combined extracts were washed with brine, dried and evaporated. The residue was purified by chromatography (silica, hexane to 10% ethyl acetate in hexane) to give an oil (1.75 g, 83%): MS (ES) m/z 274 (M+); 1H NMR (CDCl3) 8.22 (1H, s), 8.09 (1H, s), 7.84 (1H, d, J=1.2 Hz), 7.78 (1H, d, J=1.2 Hz), 4.45 (4H, m), 4.24 (1H, m), 1.46 (3H, t, J=7.2 Hz). 1.35 (3H, d, J=6.8 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]=[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:10]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH3:40][C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[CH2:42]>CCCCCCC>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:41]([CH3:42])([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH3:40])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1
Reactant: C=C(C)c1ccccc1
Reactant: Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CCCCCCC
Product: CC(C)(c1ccccc1)c1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)cc1O
Temperature: 160 °C
Reaction time: 26 h
Yield: 65.9 %

Procedure:
To a 500 mL three-necked, round-bottomed flask equipped with a magnetic stirrer, dropping funnel, condenser, thermometer, and a nitrogen atmosphere are charged 5.00 g (14.7 mmol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-phenyl-s-triazine and 300 mg of aluminum isopropoxide. The mixture is heated to 160° C. and 17.3 g of α-methylstyrene are added all at once. After stirring at this temperature for 26 hours the mixture is allowed to cool and a portion of heptane is added. Vacuum filtration affords 4.45 g of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])C(=O)[NH:8]2)=[CH:4][CH:3]=1.[OH-:13].[Na+].Cl>OO>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[C:6]([OH:12])=[O:13]
Reactant: [OH-]
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Nc1cc(Br)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
To a 500 mL round bottom flask, 6-bromo-1H-indole-2,3-dione (50 g, 0.2192 mol) and NaOH (20 g in 250 mL water) were added and cooled the reaction vessel to 0° C. To this reaction mixture 30% hydrogen peroxide (50 mL) was slowly added. The reaction mixture was stirred at 0° C. for 2 h. Subsequently, the reaction mixture was acidified with 2N HCl [pH-6] at 0° C. to afford the solid compound. The solid material was collected by filtration and dried to obtain the title compound [10 g, 21%]. 1H NMR (300 MHz, DMSO-d6): δ 7.59 (d, J=8.7 Hz, 1H), 6.96 (d, J=2.1 Hz, 1H), 6.65 (dd, J′=8.7 Hz, J″=1.8 Hz, 1H) LC-MS (ESI): Calculated mass: 215.0; Observed mass: 215.9 [M+H]+ (RT: 0.83 min).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9][CH:10]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:4][C:3]=1[CH3:27].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH2:47]([O:49][C:50](=[O:54])[CH2:51][CH2:52][NH2:53])[CH3:48]>ClCCl.O>[CH2:47]([O:49][C:50](=[O:54])[CH2:51][CH2:52][NH:53][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([CH:10]([S:9][C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:27])[CH:4]=2)[CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:15])[F:16])=[CH:19][CH:20]=1)[CH3:48]
Reactant: Cc1cc(SC(CCCC(F)(F)F)c2ccc(C(=O)O)cc2)cc(C)c1Br
Reactant: CCOC(=O)CCN
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CCOC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Racemic 4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoic acid (0.190 g, 0.410 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.0747 g, 0.430 mmol) and 4-methylmorpholine (0.050 mL, 0.430 mmol) are combined in anhydrous dichloromethane (2.0 mL) under nitrogen. The reaction is allowed to stir under nitrogen at room temperature overnight. The beta alanine ethyl ester hydrochloride (0.0695 g, 0.450 mmol) and 4-methylmorpholine (0.100 mL, 0.860 mmol) is added to the reaction mixture and allowed to stir at room temperature. Some water (<10% volume) is added to help solubility. The reaction is monitored by HPLC, and upon complete consumption of the acid, the reaction is diluted with dichloromethane. The reaction is diluted with water and rinsed with 1N hydrochloric acid. Upon acidification, the two layers are separated. The organic layer is washed with brine, dried over anhydrous sodium sulfate, and concentrated. Flash column chromatography gave the title compound (0.200 g, 0.360 mmol).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:25]=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[CH:22][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][C:15]=1[O:16]C)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([S:5][CH2:6][C:7]1[CH:25]=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[CH:22][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][C:15]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Oc1cc(CC(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (0.953 g, 2.07 mmol) in CH2Cl2 was cooled to 0° C. Boron tribromide (1M in CH2Cl2; 6.21 mL, 6.21 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction was quenched, and after aqueous work-up, the crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: O1C2C(=CC=CC=2)/C(=[N:11]/[OH:12])/CC1.[CH2:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=O)[CH3:14]>>[CH2:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[N:11][OH:12])[CH3:14]
Reactant: CCC1Cc2ccccc2C1=O
Reactant: O/N=C1\CCOc2ccccc21
Product: CCC1Cc2ccccc2C1=NO

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting (+/−)-2-ethyl-2,3-dihydro-1H-inden-1-one and making non-critical variations provided the title compound as a colorless syrup. MS (ESI+) for m/z 176.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[C:12](=O)([O-:14])[O-:13].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[F:11][C:4]1[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=[C:2]([C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: Fc1cc(Br)cc2[nH]cnc12
Reactant: O=C([O-])[O-]
Agent: [Mo]
Agent: [C-]#[O+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(F)c2nc[nH]c2c1
Temperature: 155 °C
Reaction time: 0.01 h
Yield: 63 %

Procedure:
To a 2.5-5 mL microwave tube, was added 6-bromo-4-fluoro-1H-benzo[d]imidazole (160 mg, 0.744 mmol) suspended in de-gassed 1,4 dioxane (1.5 mL). To this was added trans-di(u-acetato)bis[o-(di-o-tolylphino)benzyl]di-palladium (II) (26 mg, 0.043 mmol) and molybdenum hexacarbonyl (100 mg, 0.38 mmol), along with sodium carbonate (237 mg, 2.23 mmol) dissolved in de-gassed water (2 mL). The mixture was stirred for 20 seconds and then heated at 155° C. in the microwave for 10 minutes, keeping the pressure under 16 bar. The vessel was vented before handling and left to stand overnight at room temperature. Water (2 mL) and ethyl acetate (3 mL) were added to the reaction, and then the mixture was filtered through Celite®. The filtrate was partitioned with ethyl acetate and separated. The aqueous fraction was washed with ethyl acetate once more and the combined organic layers were set aside. Another portion of water (5 mL) was added to the aqueous layer and acidified with 0.5 M HCl to pH 3; a brown precipitate was formed. The mixture was allowed to stand in the refrigerator at 4° C. for 1 hour. The mixture was filtered and washed with water to give 4-fluoro-1H-benzo[d]imidazole-6-carboxylic acid as a grey solid, (63% yield). 1H NMR (500 MHz, DMSO-d6) □ ppm 1299 (br. s., 1H) 8.47 (s, 1H) 8.02 (s, 1H) 7.52 (d, J=11.71 Hz, 1H).
Reaction SMILES: [CH:1](=[N+:8]([O-:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH2:18]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:18][CH:17]([P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])[O:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CP(=O)(OCC)OCC
Reactant: [O-][N+](=Cc1ccccc1)Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C1CC(c2ccccc2)N(Cc2ccccc2)O1
Yield: 30.6 %

Procedure:
A solution of 2.11 g (10 mmol) of N-benzylidenebenzylamine N-oxide and 1.64 g (10 mmol) of diethyl vinylphosphonate in 30 ml of toluene under a nitrogen blanket is heated at reflux temperature for 5 days. The solvent is removed under reduced pressure to give 4.45 g of crude product which is then purified by preparative HPLC (Waters Prep 500A, silica gel, 3:2 heptane:ethyl acetate eluent) to give 1.15 g (31% yield) of a caramel-colored liquid.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(C)cc2)ccn1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccnc(N(CCCCCCC(=O)NO)c3ccccn3)c2)cc1
Reaction time: 17 h
Yield: 38 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (43 mg, 0.10 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 17 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish IV as a colourless oil (16 mg, 38%).
Reaction SMILES: O=S(Cl)[Cl:3].CN(C=O)C.[CH3:10][O:11][C:12]1[CH:32]=[CH:31][C:15]([CH2:16][N:17]2[CH:22]=[C:21]([CH2:23]O)[C:20]([C:25]([O:27][CH3:28])=[O:26])=[C:19]([Cl:29])[C:18]2=[O:30])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:10][O:11][C:12]1[CH:32]=[CH:31][C:15]([CH2:16][N:17]2[CH:22]=[C:21]([CH2:23][Cl:3])[C:20]([C:25]([O:27][CH3:28])=[O:26])=[C:19]([Cl:29])[C:18]2=[O:30])=[CH:14][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1c(CO)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1c(CCl)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
SOCl2 (0.1 ml, 1.370 mmol) and DMF (0.1 ml, 1.291 mmol) were each slowly added in sequence to a suspension of compound (11) (360 mg, 1.066 mmol) in CHCl3 (10 ml) and the reaction was stirred at 70° C. for about 3 h. The solvent was removed and the resulting mixture was deposited onto silica gel, loaded onto a silica gel column and eluted with MeOH/DCM (1:100) to afford the title compound (110 mg, 0.309 mmol, 29.0% yield). 1H-NMR (CDCl3, 400 MHz): δ=3.80 (s, 3H), 3.98 (s, 3H), 4.37 (s, 2H), 5.09 (s, 2H), 6.89 (d, 2H, J=8.0 Hz), 7.28 (d, 2H, J=8.0 Hz).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:5](=[O:24])[NH:6][CH:7]1[CH2:16][C:15]2[C:10](=[C:11]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:23].Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][CH:2]([CH3:33])[CH2:3][C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:5](=[O:24])[NH:6][CH:7]1[CH2:16][C:15]2[C:10](=[C:11]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:8]1=[O:23]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2NC1=O
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccccn2)C1=O
Reaction time: 1 h

Procedure:
tert-Butyl (2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylcarbamate (320 mg) was dissolved in N,N-dimethylformaldehyde (4.0 mL), and 2-bromomethylpyridine hydrobromide (216 mg) and sodium hydride (67 mg) were added thereto under cooling on ice, followed by stirring for one hour. The resultant mixture was subjected to extraction with saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (ethyl acetate:methanol=20:1), whereby the title compound (315 mg) was yielded.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]2[CH2:9][CH:10]([CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[C:11](=[O:12])[C:6]2=[CH:5][C:4]=1[O:27][CH3:28].C(O)(C(O)=O)=O.[Cl:35]CCl.N>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[CH2:9][CH:10]([CH2:13][CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:18][CH2:19]3)[C:11](=[O:12])[C:6]2=[CH:5][C:4]=1[O:27][CH3:28].[ClH:35]
Reactant: ClCCl
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Agent: N
Agent: O=C(O)C(=O)O
Solvent: O
Product: Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Donepezil oxalate (purified, example 2), 5 gms, was dissolved in water 50 ml under heating at 50° C. Stirring was continued for 1 hour with gradual cooling. At room temperature, dichloromethane 50 ml was added and stirred for 10 mins. Liquid Ammonia 5 ml was added slowly with stirring. The dichloromethane layer was separated and 50 ml water was added to it. Analytical grade concentrated hydrochloric acid 1.5 ml was slowly added and stirred for 10 mins. Dichloromethane was distilled off under vacuum at 45° C. to obtain Donepezil hydrochloride in water, which was kept for lyophilyzation for 24 hours at −35° C. to give Donepezil hydrochloride amorphous with a yield of 3.9 gms (95%).