Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:13]2[CH:4]([N:5]3[CH:10]([CH2:11][C:12]2=[O:14])[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[CH2:7][CH2:6]3)[CH2:3][CH2:2]1.[C-]#[C-].[Li+].[Li+].[CH2:23](N)[CH2:24]N.[ClH:27]>O1CCCC1.CCOCC>[ClH:27].[C:23]([C:12]1([OH:14])[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=32)[CH:4]2[CH2:3][CH2:2][CH2:1][CH:13]12)#[CH:24]
Reactant: NCCN
Reactant: O=C1CC2c3ccccc3CCN2C2CCCC12
Agent: Cl
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC1(O)CC2c3ccccc3CCN2C2CCCC21

Procedure:
According to the general procedure of J. W. Huffman and P. G. Arapakos, J. Org. Chem. 30, 1604 (1965) 10.0 g (0.042 mole) of 1,2,3,3a,5,6,10b,11,12,12a-decahydrobenzo[a]cyclopenta[f]quinolizin-12-one in 50 ml of tetrahydrofuran is reacted with an excess of lithium acetylide-ethylenediamine. The resulting material is dissolved in ether and treated with excess ethereal hydrochloric acid, and the precipitate is recrystallized from butanone-methanol to give 12-ethynyl-1,2,3,3a,5,6,10b, 11,12,12a-decahydrobenzo[a]cyclopenta[f]quinolizin-12-ol hydrochloride, M.P. 230°-240° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:23]([CH3:22])[CH2:24][CH2:25][OH:26])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CNCCO
Product: CN(CCO)CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and 2-(methylamino)ethanol were converted to yield 2-[[3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-methyl-amino]-ethanol, MS: 422 (MH+, 1Br).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[N:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)nc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a mixture of ethyl 3-{[(5-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridin-2-yl)carbonyl](methyl)amino}propanoate (318 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (262 mg, 87%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:30][OH:31].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:31][NH:30][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
To a solution of compound 12f (125 mg, 0.287 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (199 mg, 2.87 mmol) and a freshly prepared solution of sodium methoxide in methanol (99 mg, 4.30 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13f (20 mg, yield 16%). HPLC 85.42% (Rt=14.11 min).
Reaction SMILES: NC1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[H-].[Na+].IC.CC(O)=O.[CH3:17][N:18]([CH:20]=O)[CH3:19]>CCOC(C)=O>[I:8][C:5]1[CH:6]=[CH:7][C:20]([N:18]([CH3:19])[CH3:17])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Nc1ccc(I)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CI
Product: CN(C)c1ccc(I)cn1
Reaction time: 14 h

Procedure:
To a solution of 2-amino-5-iodopyridine (1.00 g; 4.55 mmol) in 10 mL of DMF was added 545 mg of 60% NaH (13.6 mmol) and 0.85 mL of iodomethane (13.6 mmol). The mixture was stirred for 14 h, and the mixture was neutralized with 1M HOAc. The mixture was extracted with Et2O, the extract was washed with water and brine, dried with MgSO4, filtered, and concentrated. Chromatography (0–25% EtOAc in hexanes) provided 700 mg (2.82 mmol) of (5-iodo-pyridin-2-yl)-dimethyl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:16]1[C:24]([CH3:25])=[C:23]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:21][C:17]=1[CH:18]=[N:19][OH:20].C(=O)([O-])[OH:30].[K+].O>O1CCCC1>[CH:16]([O:30][CH:9]([CH3:10])[CH3:11])([CH3:24])[CH3:17].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:11]([F:14])([F:12])[F:13])[O:20][N:19]=[C:18]([C:17]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[C:24]([CH3:25])[CH:16]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: O=C([O-])O
Reactant: Cc1c([N+](=O)[O-])ccc(C=NO)c1Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a solution of 1.31 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 3 and 1.17 g of -chloro-3-methyl-4-nitrobenzaldoxime in 10 ml of tetrahydrofuran, 1.15 g of potassium hydrogen carbonate and 1.50 g of water were added, and stirred at room temperature for 18 hours. After the completion of the reaction, tetrahydrofuran was removed from the reaction mixture, 3 ml of water was added, and stirred under colloing with ice for further 30 minutes. Precipitated crystal was filtered off, washed with 5 ml of water and then 5 ml of diisopropyl ether to obtain 1.29 g of the aimed product as white crystal.
Reaction SMILES: C([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]1=[O:23])(=O)C1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>>[OH:9][C:10]1([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH3:24])[CH:27]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]1=[O:23]
Reactant: COc1cccc(CCl)c1
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: CCCN1C(=O)C(O)(Cc2cccc(OC)c2)c2cc(C)ccc21

Procedure:
This compound was made in an analogous fashion to 11-ethyl-3-hydroxy-5-methyl-3-(3,4,5-trimethoxybenzyl)indolin-2-one using 5-methyl-2-oxo-1-propylindolin-3-yl benzoate and 3-methoxy benzyl chloride (purchased from Fisher Scientific). 1H NMR δ 7.12 (s, 1H), 7.04 (m, 2H), 6.69 (d, 1H), 6.55 (t, 2H), 6.43 (s, 1H), 3.61 (m, 4H), 3.29 (m, 2H), 3.16 (d, 1H), 2.89 (bs, OH), 2.32 (s, 3H), 1.39 (m, 2H), 0.74 (t, 3H). Calculated mass for C20H23NO3, 325.17. Observed 348.1 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[Zn:22](OC(C(C)(C)C)=O)[O:23][C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25]>C1COCC1>[C:24]([O-:25])(=[O:23])[C:26]([CH3:29])([CH3:28])[CH3:27].[C:1]([O:5][C:6]([O:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[Zn+:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cccc(OC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)C(=O)O[Zn]OC(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)[O-]
Product: CCOC(=O)c1cccc(OC(=O)OC(C)(C)C)c1[Zn+]
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, ethyl 3-((tert-butoxycarbonyl)oxy)benzoate (266 mg, 1.00 mmol) was dissolved in dry THF (3.0 mL). TMPMgCl.LiCl (1.00 mL, 1.2 M in THF, 1.20 mmol) was added dropwise and the mixture was stirred for 4 h at 0° C. A solution of Zn(OPiv)2.2 LiCl (529 mg, 1.50 mmol) in 1.5 mL of dry THF was added and the mixture was slowly warmed to 22° C. The solvent was removed in vacuo and (2-((tert-butoxycarbonyl)oxy)-6-(ethoxycarbonyl)phenyl)zinc pivalate was obtained as a orange solid.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: CC(C)NCC(=O)c1ccc(OC(=O)c2cccnc2)c(O)c1

Procedure:
Following a procedure similar to that described above in Example 58A but using 3,4-dihydroxyphenyl isopropylamino-methyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride, and nicotinoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(nicotinoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(nicotinoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.I[CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:9][CH2:14][CH3:15])=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc([N+](=O)[O-])c(O)cc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOc1cc(F)c(C)cc1[N+](=O)[O-]
Yield: 60.6 %

Procedure:
4-Methyl-5-fluoro-2-nitrophenol (11.1 g, 65.0 mmol) and iodoethane (12.2 g, 78.0 mmol) were dissolved in 100 mL of DMSO with stirring. K2CO3 (13.5 g, 97.5 mmol) was added. The reaction was stirred for 3 h and then diluted with DCM and filtered. The filtrate was poured into H2O and extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound of step A (8.0 g, 39.4 mmol) as a pale yellow crystalline solid. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.1 Hz, 1H), 6.70 (d, J=11.0 Hz, 1H), 4.10 (q, J=7.0 Hz, 2H), 2.22 (s, 3H), 1.45 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]\[CH2:4][OH:5].[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C[O:20]CC1>>[CH2:9]([O:5][CH:4]([OH:20])/[CH:3]=[CH:2]\[CH2:1][OH:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: BrCc1ccccc1
Reactant: OC/C=C\CO
Agent: [H-]
Agent: [Na+]
Product: OC/C=C\C(O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Cis-2-Butene-1,4 diol (10 g, 0.113 mol) was dissolved in THF (50 mL) and added to a slurry containing THF (100 mL) and NaH (5.9 g, 0.246 mol, 60% dispersion). The mixture was stirred 15 minutes then benzyl bromide (14.8 mL, 0.124 mole) was added and the mixture was stirred 1.5 hours at room temperature then refluxed 3 hours and finally cooled to room temperature. The reaction mixture was quenched with 20 mL water and concentrated in vacuo to an orange oil. The oil was dissolved in ethyl acetate (100 mL), washed with 10% NaCl (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 15 g of the title compound as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]([CH3:36])[CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)=[O:20])=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14]2>C(O)C.[C].[Pd]>[ClH:8].[CH3:36][N:27]([CH:24]1[CH2:23][CH2:22][N:21]([C:19]([C:12]2[CH:11]=[CH:10][CH:9]=[C:17]3[C:13]=2[CH2:14][C:15](=[O:18])[NH:16]3)=[O:20])[CH2:26][CH2:25]1)[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2ccc(Cl)c3c2CC(=O)N3)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cccc3c2CC(=O)N3)CC1
Product: Cl
Reaction time: 6 h
Yield: 22 %

Procedure:
0.88 ml of triethylamine, 0.1 g of 10% palladium carbon were added to 20 ml of a solution of 0.86 g of 7-chloro-4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinylcarbonyl}oxindole in ethanol. The mixture was subjected to hydrogenation at normal pressure at room temperature for 6 hours. The catalyst was removed by filtration. The filtrate was subjected to distillation to remove the solvent. The residue was dissolved in methylene chloride. The solution was water-washed, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silical gel column chromatography (eluant:methylene chloride/methanol=30/1). The product was converted into a hydrochloride in ethanol to obtain 0.19 g of 4-{4-[N-methyl-N-(2-phenylethyl)amino]-1-piperidinylcarbonyl}oxindole hydrochloride as a colorless amorphous.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[Cl:37])[C:17]([CH:19]1[C:24](=O)[C@@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[Cl:37][C:31]1[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@@H:20]3[C:26]([CH3:27])([CH3:28])[C@@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1cc(Cl)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cc(Cl)ccc3Cl)c(=O)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
Trifluoroacetic acid (100 mL) was added slowly to a cooled (0° C.) solution of N′-(2,5-dichloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜46.9 mmol) in dichloromethane (100 mL), and the resulting solution was stirred at 0° C. for 10 min and then at room temperature for 2 h. The solvent was evaporated and dichloromethane (200 mL) was added. The solution was washed with water (4×80 mL) and brine (80 mL), dried (magnesium sulfate), filtered, and evaporated to give a brown foam. This was triturated with 10% ethyl acetate/hexane (100 mL) and the mixture was stirred at room temperature for 20 min and then cooled in an ice-bath at 0° C. for 1 h. The solid was filtered off, washed with hexane, and dried to give (4S,7R)-2-(2,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (13.55 g, 86%) as a tan solid.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.[S:8]1[CH:12]=[CH:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:16]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)O)[C:9]1=2.O>C(#N)C>[CH3:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:17][C:16]2[C:9]3[S:8][CH:12]=[CH:11][C:10]=3[CH:13]=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: Cc1ccc(C(O)c2cccc3ccsc23)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(Cc2cccc3ccsc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a suspension of sodium iodide (2.0 g) in acetonitrile was added chlorotrimethylsilane (1.5 g) at room temperature. After the mixture was stirred at room temperature for 15 minutes, benzo[b]thiophen-7-yl-p-tolylmethanol (0.68 g) was added to the mixture, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, and the mixture was extracted with hexane. The organic layer washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (0.57 g) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:1][C:2]1[CH:9]=[C:8]([O:10][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C:7]([CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1cc(C=O)c(C)cc1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
To a stirring solution of 2,5-dimethyl-4-hydroxy-benzaldehyde (0.43 g, 2.86 mmol) in DMF (8 mL) at room temperature was added imidazole (0.43 g, 6.29 mmol) and chloro-triisopropyl-silane (0.74 mL, 3.43 mmol). The mixture was stirred at room temperature for 16 hrs. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (15:75) to afford 2,5-dimethyl-4-triisopropylsilanyloxy-benzaldehyde as a colorless oil (0.7 g, 80%): 1H NMR (300 MHz, DMSO-d6): δ 10.07 (s, 1H), 7.65 (s, 1H), 6.69 (s, 1H), 2.55 (s, 3H), 2.21 (s, 3H), 1.35 (m, 3H), 1.10 (d, J=6.9 Hz, 18H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=5% ethyl acetate in hexanes; Rf=0.68.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[C:15]1([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[C:23]2[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=2)[NH:17][C:16]1=[O:25].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([NH:1][C:2]3[C:10]([O:11][CH2:12][CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=3[C:4]([OH:6])=[O:5])([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: CCOc1cccc(C(=O)O)c1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cccc(C(=O)O)c1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 8 h
Yield: 26 %

Procedure:
At room temperature, 2-Amino-3-ethoxy-benzoic acid (0.59 g, 3.26 mmol), 3-Bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (1.21 g, 3.26 mmol) and DIPEA (0.68 ml) were mixed in about 6 ml CH2Cl2. After stirred overnight, the solution was concentrated and the crude product was purified by chromatography to obtain 400 mg solid rac-2-[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-3-ethoxy-benzoic acid. MS: 471 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][C:11]([CH3:52])=[CH:12][C:13]=1[C:14]([CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH:19]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([O:46]C(C)(C)C)=[O:45])[CH:39]=2)=[O:36])[C:18]1=[O:51])=[O:15]>C(Cl)Cl>[CH3:8][C:9]1[S:10][C:11]([CH3:52])=[CH:12][C:13]=1[C:14]([CH2:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH:19]([NH:34][C:35](=[O:36])[NH:37][C:38]2[CH:39]=[C:40]([CH:41]=[CH:42][CH:43]=2)[C:44]([OH:46])=[O:45])[C:18]1=[O:51])=[O:15]
Reactant: Cc1cc(C(=O)CN2C(=O)C(NC(=O)Nc3cccc(C(=O)OC(C)(C)C)c3)CN(C3CCCCC3)c3ccccc32)c(C)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)CN2C(=O)C(NC(=O)Nc3cccc(C(=O)O)c3)CN(C3CCCCC3)c3ccccc32)c(C)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 1-[1-(2,5-dimethylthiophen-3-yl)carbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-tert-butoxycarbonylphenyl)urea (450 mg) in anhydrous methylene chloride (10 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, ethanol was added to the residue, crystals were collected by filtration, to thereby obtain 202 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][N:10]([CH3:12])[CH3:11].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH2:9][N:10]([CH3:12])[CH3:11])[CH:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)Cc1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)Cc1cc(OCc2ccccc2)ccc1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A mixture of 4-bromo-3-((dimethylamino)methyl)phenol (4 g, 17.4 mmol), benzylbromide (2 eq.), and potassium carbonate (3 eq.) in DMF (100 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford 1-(5-(benzyloxy)-2-bromophenyl)-N,N-dimethylmethanamine (709) (98%).
Reaction SMILES: [I:1]Cl.[CH2:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[CH2:5][O:4]1.C(=O)(O)[O-].[Na+]>ClCCl.CO>[I:1][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][O:4][CH2:3]2)=[CH:7][C:8]=1[NH2:12]
Reactant: Nc1ccc2c(c1)COC2
Reactant: ClI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc2c(cc1I)COC2
Reaction time: 1 h

Procedure:
Dropwise, add a 1.0 M solution of iodine monochloride (64 mmol) to a solution of 1,3-dihydro-isobenzofuran-5-ylamine (64 mmol) in dichloromethane (200 mL), methanol (50 mL) and sodium bicarbonate (96 mmol). After stirring for 1 h, quench the reaction with aqueous sodium metabisulfite (100 mL). Separate the organic phase and wash the aqueous with dichloromethane (2×100 mL). Combine the organics and dry over sodium sulfate. Filter the reaction and remove solvent under vacuum. Chromatograph (0-20% ethyl acetate/hexane) the crude mixture over silica gel to give the title compound as a tan solid. 1H NMR (CDCl3, 400 MHz): δ 4.10 (bs, 2H), 4.97 (s, 4H), 6.63 (s, 1H), 7.49 (s, 1H).