Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[C:11]([C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[CH2:18][OH:19])([CH3:14])([CH3:13])[CH3:12]>>[C:24]([C:21]1[CH:20]=[C:17]([CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:22]=1[OH:23])[CH:18]=[O:19])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1O
Agent: C1N2CN3CN1CN(C2)C3
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Yield: 92.1 %

Procedure:
A 12-liter reaction flask fitted as previously described was charged with 2280 ml (2477 g) of the initial filtrate from the above described reaction. With stirring, the reaction flask was charged with 106.5 g (0.76 mole) of hexamethylenetetramine. As the amine dissolved, there was a small exothermic response. To this solution was added 179.6 g (0.76 mole) of 3,5-ditert.butyl-4-hydroxybenzyl alcohol. There was no apparent reaction and when external heating had increased the pot temperature to 65°-70° , the slurry formed a clear solution. With controlled heating, reflux (108°) was attained after 1.25 hours with product precipitation and gas evolution recorded beginning at 104°. After two hours at reflux, the reaction mixture was cooled to 25°. The product was separated from the mother liquor and washed as described above. After drying in the vacuum oven, there was obtained 164 g of light yellow crystalline 3,5-ditert.butyl-4-hydroxybenzaldehyde, m.p. 191°-93°. The product was submitted for GLC analysis and found to be equivalent to the analytical standard (100%). The yield was 92.1%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([F:19])=[C:13]([F:18])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[N:26]=1.C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[Br:24][C:25]1[N:26]=[C:27]([CH2:31][N:9]2[C:10]3[C:15](=[CH:14][C:13]([F:18])=[C:12]([F:19])[CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:20]=[CH:21][C:22]([CH3:23])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH:28]=[CH:29][CH:30]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc(F)c(F)cc3c2=O)cc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3cc(F)c(F)cc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 74 mg (0.24 mmol) of 3-(3,4-dimethyl-benzoyl)-6,7-difluoro-1H-quinolin-4-one, 71 mg (0.28 mmol) of 2-bromo-6-bromomethyl-pyridine, 0.57 mL of 0.5M toluene solution of potassium bis(trimethylsilyl)amide and 2 mL of THF. Yield: 73 mg of a white solid: LC-MSD, m/z for C24H17BrF2N2O2 [M+H]+=483.4, 485.4; HPLC retention time: 2.6 min.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl)(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C.CCOC(C)=O>[C:1]([O:4][C@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@@H:18]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[O:17][C@@H:6]1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:34]=[N+:35]=[N-:36])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@H](OCCOCCOCCCl)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@H](OCCOCCOCCN=[N+]=[N-])[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A solution of 36 (2.9 g, 5.8 mmol), sodium azide (1.89 g, 29.1 mmol) and nBu4NI (4.3 g, 11.6 mmol) in anhydrous DMF (20 mL) was stirred at 90° C. for 24 h. The solution was cooled to rt then diluted with EtOAc (300 mL). The organic layer was washed with water (3×200 mL), dried (Na2SO4), filtered and evaporated. The oily residue was purified by flash silica gel column chromatography (PE then PE/EtOAc 1:1) to afford 37 (2.54 g, 86%) as a pale yellow oil. 1H NMR (CDCl3, 300 MHz): δ 1.96, 2.02, 2.08, 2.13 (4s, 4×3H, 4×CH3CO), 3.37 (t, 2H, J=5.0 Hz, CH2N3), 3.60-3.72 (m, 9H, OCH2CH2O), 3.74-3.84 (m, 1H, OCH2), 4.00-4.15 (m, 2H, H-5, H-6), 4.27 (dd, 1H, J6′,5=5.1 Hz, J6′,6=12.4 Hz, H-6′), 4.85 (d, 1H, J1,2=1.5 Hz, H-1), 5.20-5.37 (m, 3H, H-2, H-3, H-4). 13C NMR (CDCl3, 75 MHz): δ 20.62, 20.63, 20.7, 20.8 (4s, 4×CH3CO), 50.6 (CH2N3), 62.3 (C-6), 66.0, 68.3, 69.0, 69.5 (4s, C-2 to C-5), 67.2, 69.97, 70.02, 70.6, 70.7 (5s, 5×CH2O), 97.6 (C-1), 169.6, 169.8, 170.0, 170.6 (4s, 4×CH3CO). [α]D=+34 (c=1/CH2Cl2). ESIMS (positive mode) m/z: 528 [M+Na]+. HRESIMS (positive mode) m/z: calcd for C20H31N3O12Na1 [M+Na]+528.1805, found 528.1801.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5][CH:4]([OH:20])[C:3]1=[O:21].N1C=CC=CC=1.[CH2:28]([CH:31]([CH2:35][CH2:36][CH3:37])[C:32](Cl)=[O:33])[CH2:29][CH3:30]>CN(C)C=O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=2[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5][CH:4]([O:20][C:32](=[O:33])[CH:31]([CH2:35][CH2:36][CH3:37])[CH2:28][CH2:29][CH3:30])[C:3]1=[O:21]
Reactant: CN1C(=O)C(O)N=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CCCC(CCC)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCC(CCC)C(=O)OC1N=C(c2ccccc2)c2cc(Cl)ccc2N(C)C1=O
Reaction time: 4 h

Procedure:
A solution of 15 g of 1-methyl-7-chloro-3-hydroxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one (Temazepam) and 5 g of absolute pyridine is cooled in 40 ml of freshly distilled dimethyl formamide to -5° and is mixed drop by drop with 10.5 g of dipropyl acetic acid chloride with the exclusion of atmospheric moisture. The mixture is stirred for an additional 4 hours at -5° and is allowed to stand over night at 0°, and then the mixture is poured on ice. The separated oil crystallizes while rubbed on with ethanol. By recrystallization from petroleum ether or isopropanol using activated charcoal, one will obtain the 1-methyl-7-chloro-3-dipropylacetoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one as a colorless powder with a melting point of 134°-136°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11]>N12CCN(CC1)CC2.C(Cl)(Cl)Cl>[OH:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:10](=[CH2:11])[C:9]([O:13][CH3:14])=[O:12]
Reactant: C=CC(=O)OC
Reactant: O=Cc1ccccn1
Agent: C1CN2CCN1CC2
Solvent: ClC(Cl)Cl
Product: C=C(C(=O)OC)C(O)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
A 250-mL single-neck round-bottomed flask was charged with chloroform (100 mL), picolinaldehyde (10.7 g, 0.10 mol), methyl acrylate (8.60 g, 0.10 mol), and 1,4-diazabicyclo[2.2.2]octane (0.560 g, 5.00 mmol). The reaction mixture stirred at room temperature for 48 h. After this time the reaction was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 127a as a dark yellow oil (11.6 g, 60%). MS-ESI: (M+H)+ 194.2. 1H NMR (500 MHz, CDCl3) δ 8.54 (d, J=5.0 Hz, 1H), 7.69-7.66 (m, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.22-7.20 (m, 1H), 6.36 (s, 1H), 5.97 (s, 1H), 5.62 (s, 1H), 4.85 (s, 1H), 3.74 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:14])=[C:9](\[CH2:12][CH3:13])/[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH2:15]([O:17][C@@H:18]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH3:14])=[C:9](\[CH2:12][CH3:13])/[CH2:10][O:11][C:28]2[CH:27]=[CH:26][C:25]([CH2:24][C@H:18]([O:17][CH2:15][CH3:16])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:30][CH:29]=2)=[CH:6][CH:7]=1
Reactant: CC/C(CO)=C(/C)c1ccc(Br)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C(CC)=C(\C)c2ccc(Br)cc2)cc1)OCC
Yield: 88.7 %

Procedure:
The title compound (843 mg, 89%) was prepared from (E)-3-(4-bromophenyl)-2-ethyl-but-2-en-1-ol (510 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[Br:8][C:9]1[CH:10]=[C:11]2[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])(O)[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([I:30])[CH:20]=3)[O:15][C:12]2=[N:13][CH:14]=1>C1(C)C=CC=CC=1>[N:1]([C:22]1([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:11]2[C:12](=[N:13][CH:14]=[C:9]([Br:8])[CH:10]=2)[O:15][C:16]2[C:21]1=[CH:20][C:19]([I:30])=[CH:18][CH:17]=2)=[N+:2]=[N-:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)CC1(O)c2cc(I)ccc2Oc2ncc(Br)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(N=[N+]=[N-])c2cc(I)ccc2Oc2ncc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Azidotrimethylsilane (1.102 ml, 8.32 mmol) was added to a suspension of ethyl 2-(3-bromo-5-hydroxy-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate (2.33 g, 4.75 mmol) in toluene (31.7 ml). The reaction mixture was cooled to 0° C. and (diethyloxonio) trifluoroborate (0.753 ml, 5.94 mmol) was added slowly. The reaction mixture was allowed to warm to RT. After 30 min, the reaction mixture was quenched with MeOH (5 mL) followed by aqueous, saturated NaHCO3 solution (10 mL). The reaction mixture was extracted twice with EtOAc. The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford ethyl 2-(5-azido-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27]([NH2:29])=[S:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O>[F:31][C:15]1[CH:16]=[C:17]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27]([NH2:29])=[S:28])[O:22][C:21]2=[O:30])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@H](CNC(N)=S)OC3=O)cc2F)CC1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reaction time: 96 h

Procedure:
A solution of 649 mg 4-[2-fluoro-4-{(5S)-2-oxo-5-thio-ureidomethyl-oxazolidin-3-yl}-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (1.43 mmol) in a mixture of 6 ml of a 1.25 M solution of hydrochloric acid in methanol and 1 drop water was stirred for 4 days. The solvent was evaporated, and the residue was neutralized at pH 7 with a saturated solution of sodium bicarbonate. The water was evaporated and the residue was digested in a 95/5 dichloromethane/methanol mixture and the solid filtered. The filtrate was purified by chromatography using a 95/5 dichloromethane/methanol mixture with 1% acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C(#N)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:3]([CH3:10])[CH:4]=1)=[O:7]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1ccc(C=O)cc1C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 4-hydroxy-3-methylbenzaldehyde (8 g, 58.8 mmol) in an hydrous acetonitrile (300 mL), under nitrogen at 0° C., was added caesium carbonate (21 g, 64.6 mmol) and ethyl bromoacetate (6.52 mL, 58.8 mmol). The resulting mixture was allowed to come to room temperature and stirred for 16 h. The reaction mixture was diluted with water (400 mL) and extracted with EtOAc (2×500 mL). The combined organic extracts were dried (MgSO4) and the solvents removed in vacuo, to afford the title compound as brown solid (11.5 g).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.[C:22]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH2:31])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1>[C:22]([O:26][C:27](=[O:32])[NH:28][CH2:29][CH2:30][NH:31][C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCNc1nnc(C#N)c(N2CCc3ccccc3CC2)n1

Procedure:
In analogy to the procedure described in example 4 the 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile was reacted with (2-aminoethyl)-carbamic acid tert-butyl ester in dioxane at 120° C. overnight to give {2-[6-cyano-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazin-3-ylamino]-ethyl}-carbamic acid tert-butyl ester as a white solid; MS: 410 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)C.O.Cl>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCCCCCCc2ccccc2)cc1

Procedure:
A mixture of 5 g. of ethyl p-[(7-phenylheptyl)amino]benzoate (prepared as described in Example 34), 5 g. of KOH and 50 ml. of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture is acidified while hot with concentrated hydrochloric acid, diluted with H2O, chilled and filtered. The solid is washed with H2O to give off-white crystals, m.p. 123°-126° C. Recrystallization from ethanol gives tan crystals, m.p. 123.5°-125° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:11]3[N:16]=[C:15]([CH:17]=[O:18])[S:14][C:12]=3[N:13]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4]=1)[CH3:2].CO.[BH4-].[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:11]3[N:16]=[C:15]([CH2:17][OH:18])[S:14][C:12]=3[N:13]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)sc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CO)sc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a solution of 5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (1.2 g, 3.04 mmol) in DCE (30 mL) was added MeOH (3 mL) and NaBH4 (119 mg, 3.15 mmol) and the resulting mixture stirred at r.t. for 4 h. The reaction mixture was concentrated in vacuo and the resulting residue triturated with H2O. The resulting solid was collected by filtration and dried in vacuo affording the title compound (1.18 g, 98%). LCMS (method H): RT 2.42 min, [M+H]+ 397.4
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:17][CH2:18][C:19](Br)=[O:20]>C(Cl)Cl>[C:2]1([NH:1][C:19](=[O:20])[CH2:18][Br:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Br)CBr
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CBr)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of aniline (7.40 mmol) in methylene chloride (25 mL) at −50° C. was added successively N,N-diisopropylethylamine (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl bromide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed 40° C. On completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether (70 mL) and poured into 1 N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[S:10]([NH2:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[S:10]([NH2:13])(=[O:11])=[O:12])[CH:3]=[CH:2]1
Reactant: NS(=O)(=O)c1cccc2c1NCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a slurry of activated manganese dioxide (20 g) in methylene chloride (200 ml) was added indoline-7-sulfonamide (4.3 g). The mixture was stirred at 25° C. for 24 hours. The solid was removed by filtration and the filtrate concentrated and hexane added until crystallization occurred. The pure product (TLC) was isolated by filtration (2.9 g, m.p. 125°-127° C.
Reaction SMILES: [C:1]([C:3]1[O:4][CH:5]=[CH:6][CH:7]=1)#[CH:2].[Li]CCCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH:18]=[O:19]>C1COCC1>[O:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:1]#[C:2][C:18]([C:17]1[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:15]([O:14][CH3:13])[CH:16]=1)=[O:19]
Reactant: C#Cc1ccco1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)C#Cc2ccco2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
2-Ethynylfuran (200 mg, 2.17 mmol) was dissolved in dry THF (10 ml) and cooled to −78° C. under N2 atmosphere. BuLi (1.2 ml, 2.4 mmol) was added slowly and stirred at −78° C. for 10 min and then 3,4,5-trimethoxybenzaldehyde (500 mg, 2.6 mmol) was added and reaction mixture was stirred for 1 h at −78° C. and then reaction temp raised to room temp. The reaction was quenched by addition of aqueous NH4Cl solution and extracted with EtOAc. The colorless oil was dissolved in dichloromethane and excess of MnO2 was added to it and stirred overnight at room temp. The reaction mixture was filtered through celite plug and evaporated to dryness. 3-(2-furyl)-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-one was precipitated from ether by slow addition of hexane as off-white powder (65%). 1H NMR (300 MHz, CDCl3) δ 3.93 (s, 9H), 6.50-6.52 (m, 1H), 7.01 (d, J=3.6 Hz, 1H), 7.45 (s, 2H), 7.24 (s, 1H), 7.55 (d, J=1.5 Hz).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].[BrH:23]>>[Br:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: Br
Reactant: OCCCCCCCCCCCCCCCCCCCCO
Product: OCCCCCCCCCCCCCCCCCCCCBr

Procedure:
20-Bromo-icosan-1-ol was synthesized according to Uneyama et al, Tetrahedron Letters, 1991, 32(11), 1459-1462. Briefly, 400 ml petrolether were heated before 240 ml petrolether, 20.34 g icosane-1,20-diol and 280 ml HBr (48% in H2O) were added. The mixture was refluxed over night and incubated at room temperature for another day. The precipitate was then removed by filtration and dissolved in 300 ml dichloromethane. The solution was dried over Na2SO4 and filtered through silica gel. The solvent was removed and the crude product finally recrystallized from petrolether. Purity of the product was judged by 1H-NMR.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][OH:22])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([CH2:21][O:22][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:29])[CH:17]=4)[C:12]3=[O:30])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccc2c(c1)OCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(COCc2ccccc2)n1Cc1ccc2c(c1)OCO2

Procedure:
To a solution (2.5 ml) of 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-3-hydroxymethyl-4-phenyl-2H-isoquinolin-1-one (250 mg) in THF was added sodium hydride (26 mg) at 0° C. with stirring. The mixture was stirred at room temperature for 10 min., benzylbromide (71 μl) was added, and the mixture was further stirred for 2 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (210 mg) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>ClCCl>[CH2:39]([O:38][C:36](=[O:37])[NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OCc3ccccc3)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl), phenyl)-3-methoxybenzamide (50 mg, 136 μmol) and triethylamine (0.038 mL, 0.27 mmol) in dichloromethane was added benzyl chloroformate (26 mg, 150 μmol), dropwise at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with dichloromethane (3×20 mL) and dried over anhydrous MgSO4. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography. (EtOAc/Hexane=50-90%). {2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamic acid benzyl ester was obtained as white solid in 37% yield. LCMS m/z (%)=501 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 3.5 (q, J=5.4 Hz, 2 H), 3.7 (s, 3 H), 3.9 (s, 3 H), 4.0 (t, J=5.1 Hz, 2 H), 4.9 (t, J=5.8 Hz, 1 H), 5.1 (s, 2 H), 6.3 (d, J=2.0 Hz, 1 H), 7.0 (d, J=8.6 Hz, 1 H), 7.1 (m, 1 H), 7.3 (m, 5 H), 7.4 (m, 1 H), 7.5 (m, 2 H), 7.7 (dd, J=8.8, 2.8 Hz, 1 H), 7.8 (s, 1 H).