Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C(Cl)Cl.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC.CO>[Br:38][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: BrCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To an ice-cooled mechanically stirred solution of 2-benzyloxyethanol (25 mL, 0.18 mole), triphenylphosphine (115.2 g, 0.44 mole) and pyridine (56.9 mL, 0.70 mole) in methylene chloride (1000 mL) was added, dropwise, carbon tetrabromide (61.3 g, 0.18 mole). The mixture was stirred overnight at room temperature. Methanol (130 mL) was then added and, after further stirring for 1 hour, the solvents were evaporated. The residue was triturated with hexane and the hexane solution was concentrated to yield an oil which was set aside. The residue remaining after trituration was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution and brine and was concentrated to afford a brown oil. This was triturated with hexane. The resulting hexane solution was combined with the oil from the previous trituration and concentrated. The residue was chromatographed twice on silica gel eluting with hexane and then 5% ethyl acetate/hexane to afford (2-bromoethoxymethyl)benzene as an oil (28.8 g, 76% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8].C(Cl)Cl.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:2][C:3]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[CH2:23][CH2:24][N:25]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:26][CH2:27]2)=[CH:17][C:4]=1[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)NCc2cc(CN3CCNCC3)ccc2Cl)cn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)NCc2cc(CN3CCN(S(C)(=O)=O)CC3)ccc2Cl)cn1
Reaction time: 16 h

Procedure:
In a 20 mL scintillation vial equipped with a stir bar, 1-(2-chloro-5-(piperazin-1-ylmethyl)benzyl)-3-(6-methylpyridin-3-yl)urea hydrochloride salt (367 mg, 654 □mol) and DMAP (2 mg) were sealed with a septum cap and maintained under a positive nitrogen pressure. To the mixture was added 6 mL of anyhydrous CH2Cl2, followed by DIPEA (520 □L, 2.94 mmol) and methanesulfonyl chloride (70 □L, 785 □mol). The reaction mixture was stirred for 16 h. The reaction mixture was diluted with 6 mL of EtOAc. The organic solution was washed with 4 mL each of water and saturated NaCl solution, dried over Na2SO4, filtered and concentrated to afford 1-(2-chloro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)benzyl)-3-(6-methylpyridin-3-yl)urea as beige foam (209 mg).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O>O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:7]2[N:4]=[C:1]([CH3:2])[S:3][CH:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(N)=S
Reactant: COc1cccc(C(=O)CBr)c1
Solvent: O
Product: COc1cccc(-c2csc(C)n2)c1
Temperature: 140 °C
Yield: 82.9 %

Procedure:
A mixture of thioacetamide (8.0 g, 106.0 mmol) and 2-bromo-1-(3-methoxy-phenyl)-ethanone (2.0 g, 8.81 mmol) was heated at 140° C. for 6 h under nitrogen atmosphere. After completion of the reaction mixture (TLC monitoring), water (50 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 2% EtOAc-Hexane) to get the desired product (1.5 g, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:24])[CH2:9][C:10]([N:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][O:14][C:13]2=[O:23])=[O:11])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].CC(C1C=C(C(C)C)C(S([N:50]=[N+:51]=[N-:52])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C.C([O-])(=O)C.[K+]>C1COCC1>[N:50]([C@@H:9]([C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH3:24])[C:10]([N:12]1[C@@H:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][O:14][C:13]1=[O:23])=[O:11])=[N+:51]=[N-:52]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: C[C@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(F)cc1)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of the product from Step B (1.18 g, 3.61 mmol) in anhydrous THF (40 mL) was added potassium hexamethyldisilazide (8.7 mL, 0.5M in toluene, 4.35 mmol) at −78° C. The resultant mixture was stirred at −78° C. for 30 min. A precooled solution of trisyl azide (1.56 g, 5.04 mmol) in THF (30 mL) was added via cannula. After 1.5 min the reaction was quenched with glacial acetic acid (0.95 mL, 16.6 mmol) and potassium acetate (1.77 g, 18.1 mmol). The cooling bath was removed, and the reaction was stirred at room temperature for 12 h. The solution was partitioned between ethyl acetate and brine. The aqueous phase was extracted with three portions of ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated in vacuo. Purification by flash chromatography (silica gel, 80:20 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:6][C:7]=1[C:8](Cl)=[O:9].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:6][C:7]=1[C:8]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=1[Cl:17])=[O:9]
Reactant: O=C(Cl)c1cc(-c2ccncc2)nnc1Cl
Reactant: NCc1ccc(Cl)cc1Cl
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)nnc1Cl

Procedure:
The title compound was prepared by treating the dichloride (6) with 2,4-dichlorobenzylamine according to Scheme I. DCI-MS m/z 392 (m+H+). 1H NMR (CDCl3) δ 8.83 (d, J=6 Hz, 2H), 8.33 (a, 1H), 8.00 (d, J=6 Hz, 2H), 7.5 (m, 2H), 7.3 (m, 3H), 4.76 (d, J=6 Hz, 2H).
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@H:19]([O:24]C(=O)C(C)(C)C)[CH2:18][CH2:17]2)C.Cl[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=O>>[CH3:45][N:44]([CH3:46])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1-c1ccc2c(c1)CC[C@@H](OC(=O)C(C)(C)C)C2
Reactant: CN(C)C(=O)CCl
Product: COc1cc(NCCCc2ccc(OCCN(C)C)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 69.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N,N-dimethylacetamide (6.6 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.3 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([N:16]1[CH2:21][CH2:20][C:19]([OH:22])([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(Br)cc1
Product: Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
The starting material can be produced in the following manner: In a manner analogous to that described in Example 6, 100 g of p-bromotoluene and 110 g of N-benzyl-4-piperidone are reacted to give N-benzyl-4-hydroxy-4-(4-methylphenyl)-piperidine, b.p.0.05 =185°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:18]C)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.B(Br)(Br)Br>C(Cl)Cl.C(OC)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc(F)c2c1C1(CCCCC1)NC(=O)N2
Agent: BrB(Br)Br
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O=C1Nc2c(F)ccc(O)c2C2(CCCCC2)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
To a stirred solution of 8′-fluoro-5′-methoxy-1′H-spiro[cyclohexane-1,4′-quinazolin]-2′(3′H)-one (2.34 g, 8.84 mmol) in DCM (250 mL) at 0 to 5° C. was added boron tribromide (11.07 g, 44.2 mmol) dropwise over 20 minutes under N2. The mixture was stirred at 5° C. for 10 mins and gradually allowed to warm up to ambient temperature. Stirring was continued at ambient temperature for 18 h and a further portion of BBr3 (5 g, 20 mmol) was added. The mixture was left to stir for a further 24 hours and quenched with saturated NaHCO3 solution (500 mL) at 10° C. over 30 minutes. The mixture was stirred at ambient temperature for 1 hour and the aqueous layer was separated from dichloromethane and extracted with ethyl acetate (2×500 mL). The organic layers were washed with saturated NaHCO3 solution (200 mL), water (300 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo at 40° C. to give the crude product. The crude material was slurred in tert-butylmethylether (10 mL) at 18 to 20° C. for 5 minutes, filtered and dried in vacuo at 40° C. to give 8′-fluoro-5′-hydroxy-1′H-spiro[cyclohexane-1,4′-quinazolin]-2′(3′H)-one (1.5 g, 68%) as a light-brown solid, purity (99.9%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH2:17])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].C(=O)(O)[O-].[Na+].Cl.C1(C(=N[O:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=O)C#N)C=CC=CC=1>O.O1CCCC1.C(N(CC)CC)C>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)-2-(2-aminoethoxyimino)acetic acid (syn isomer, 0.80 g.) and triethylamine (0.45 g.), in a solution of a saturated aqueous solution of sodium bicarbonate (4 ml.), tetrahydrofuran (35 ml.) and water (25 ml.) was adjusted to pH 8.5 with hydrochloric acid. 2-Phenyl-2-(tert-butoxycarbonyloxyimino)acetonitrile (0.77 g.) was added to the stirred solution and stirred at room temperature for 3 hours. After distilling off tetrahydrofuran from the resultant solution, the aqueous solution was washed with diethyl ether, and adjusted to pH 1.5 with 85% phosphoric acid. The solution was extracted with ethyl acetate (50 ml.), and the extract was washed with a saturated aqueous solution of sodium chloride (10 ml.), dried over magnesium sulfate and concentrated under reduced pressure to give 2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 0.40 g.).
Reaction SMILES: CS(C)=O.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)([CH3:8])([CH3:7])[CH3:6].[OH-].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.C1(C)C=CC=CC=1>[CH2:21]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]([CH3:8])([CH3:6])[CH3:7])=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
A reactor was charged with DMSO (6 L), followed by 4-tert-butyl-2-nitrophenylamine (Preparation 108, 3.0 kg, 15.4 mol) and potassium hydroxide (1.32 kg, 23.5 mol). The mixture was stirred at room temperature for twenty minutes. Toluene (12 L) was added and the mixture stirred for another twenty minutes. After cooling to 10° C., benzyl bromide (3.16 kg, 18.5 mol) was added slowly and the reaction mixture was stirred for 4 hours. Water (30 L) was added, the mixture stirred for 30 minutes and the layers allowed to settle. The aqueous layer was extracted with toluene (2×10 L), followed by ethyl acetate (10 L), and the combined organic extracts concentrated under vacuum at <50° C. Isopropanol (4 L) was added and the mixture cooled to −5° C. The slurry was stirred for 1 hour before collecting the solids by filtration, washing with isopropanol (2×1.5 L) and drying at 55-60° C. to provide 2.8 kg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(N(C)C)=O>[CH3:23][O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][O:21][C:19]1[CH:18]=[CH:17][C:9]2[C:10]([CH3:16])([CH3:15])[C:11]3[NH:12][C:13]4[C:5]([C:6]=3[C:7](=[O:22])[C:8]=2[CH:20]=1)=[CH:4][CH:3]=[C:2]([Br:1])[CH:14]=4
Reactant: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)CCCOc1ccc2c(c1)C(=O)c1c([nH]c3cc(Br)ccc13)C2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ2, 20 mg, 0.056 mmol), 4-bromo-butyric acid methyl ester (7.0 μl, 0.056 mmol) and cesium carbonate (36.6 mg, 0.112 mmol) were dissolved in DMA (0.09 ml), and then stirred at room temperature for 1 hr. Thereafter, 4-bromo-butyric acid methyl ester (7.0 μl, 0.056 mmol) was added thereto and the mixture was stirred at room temperature for 3 hr, followed by further stirring at 45° C. for 30 min. The reaction solution was added with water, extracted with diethyl ether and dried over anhydrous magnesium sulfate. After the concentration under reduced pressure, the resulting residues were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain 4-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-9-yl oxy)-butyric acid methyl ester. This compound was dissolved in MeOH (0.50 ml), added with aqueous solution of sodium hydroxide (6 mol/l), and then stirred at room temperature for 10 min. The reaction solution was added with hydrochloric acid (3 mol/l), extracted with diethyl ether, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain white solid. This white solid was washed with methylene chloride to obtain the title compound (6.1 mg, 25%).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH3:27])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[NH2:26].[I-].[Na+]>CN(C=O)C>[NH2:26][C:17]1[C:16]2=[N:15][N:14]([CH3:27])[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:25]2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: CS(N)(=O)=O
Reactant: Cn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc2c(N)nc3ccccc3c2c1CCCCNS(C)(=O)=O
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 38.4 %

Procedure:
Methanesulfonamide (1.5 g, 16.5 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 0.660 g, 16.5 mmol) in DMF (10 mL); the reaction was stirred for five minutes. 1-(4-Chlorobutyl)-2-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.952 g, 3.3 mmol) in DMF (1 mL) and sodium iodide (123 mg, 0.825 mmol) were sequentially added. The reaction was heated at 80° C. for four hours, allowed to cool to ambient temperature, and poured into ice water (70 mL). The resulting mixture was extracted with dichloromethane (6×50 mL), and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified twice by chromatography using a HORIZON HPFC system (40+M cartridge, eluting with 0-30% CMA in chloroform first and 5-10% methanol in dichloromethane second) followed by recrystallization from acetonitrile to provide 440 mg of N-[4-(4-amino-2-methyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]methanesulfonamide as light tan crystals, mp 188-189° C.
Reaction SMILES: [C:1]([C:3]1[CH:44]=[CH:43][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4C(OC(C)(C)C)=O)[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)CC(OC)=O)N(COCC[Si](C)(C)C)C=2C=1)#N.CO.[OH-].[NH4+]>Cl>[C:1]([C:3]1[CH:44]=[CH:43][C:6]2[NH:7][C:8]([CH:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][NH:20]4)[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)CC(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COC(=O)CC(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: COC(=O)CC(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Temperature: 65 °C

Procedure:
A mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-3-methoxy-3-oxopropyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-3-methoxy-3-oxopropyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 145-B) (400 mg, 0.646 mmol) was dissolved in 1.25M HCl in MeOH (20 mL, 25.00 mmol) and heated at 65° C. for 22 hrs. The reaction mixture was cooled down to 0° C. and neutralized with ammonium hydroxide. The layers were separated and the aqueous layer was extracted with AcOEt/heptanes (4:1) (3 x). The combined organic layers were dried over MgSO4, filtered and concentrated to give crude product that was purified via FCC with Heptane/AcOEt (100/0 to 0/100) to obtain the title compound. MS (ESI+) m/z 389.36 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[C:12]([C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1.CO.CCOC(C)=O>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][S:24]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:26])=[O:25])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(/C=C/S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CCS(=O)(=O)Nc2ccccc2S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
2-Aminobenzenesulfonamide (0.057 g, 0.33 mmol) was dissolved in pyridine (2.5 mL) followed by addition of (E)-2-(4-tert-butylphenyl)ethenesulfonyl chloride (0.078 g, 0.30 mmol) and the reaction was stirred at RT overnight. The solvent was then removed under reduced pressure and the pale yellow oily residue was used in the next step without further purification. The crude material (0.118 g, 0.3 mmol) was dissolved in MeOH (5 mL) with a few drops of EtOAc and was subjected to reduction using the H-cube instrument. The reaction mixture was eluted through the Pd/C (10%) cartridge using full hydrogen (1 atm) at 1 ml/min. The mixture was subjected to the H-cube once again using the same conditions for full conversion of the starting material and purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (56 mg, 47%) as a white solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:8][C:9]([F:13])([F:12])[CH:10]=[CH2:11]>C1(C)C=CC=CC=1>[CH3:7][O:6][C:4](=[O:5])[CH2:3][CH2:2][S:1][CH2:11][CH2:10][C:9]([F:13])([F:12])[F:8]
Reactant: C=CC(F)(F)F
Reactant: COC(=O)CCS
Solvent: Cc1ccccc1
Product: COC(=O)CCSCCC(F)(F)F
Temperature: 20 °C
Yield: 94 %

Procedure:
A 100 mL stainless steel Parr reactor was charged with methyl 3-mercaptopropionate (4.15 g, 34.5 mmol), toluene (30.3 g), and 2,2′-azobis(4-methoxy-2,4-dimethyl) valeronitrile (V-70, 0.531 g, 1.72 mmol) and the reactor was cooled with a dry ice/acetone bath, purged with nitrogen, and pressure checked. 3,3,3-Trifluoropropene (3.40 g, 35.4 mmol) was added via transfer cylinder and the reaction was allowed to warm to 20° C. After 23 hours the reaction was heated to 50° C. for 1 hour to decompose any remaining V-70 initiator. The reaction was allowed to cool to room temperature. The solution was concentrated to provide the title compound (7.01 g, 66%, 70.3 wt % linear isomer by GC internal standard assay, 4.93 g active, 66%, 24:1 linear:branched by GC, 18:1 linear:branched by fluorine NMR).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33][OH:34])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[H-].[Na+]>CCOC(C)=O>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][C:10]=1[CH2:33][O:34][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1COCc1ccccc1
Temperature: -10 °C
Reaction time: 5 h
Yield: 57.8 %

Procedure:
A 100 mL round bottomed flask was charged with 3-[4-(tert-butyldiphenylsilanyloxy)-2-hydroxymethylphenyl]propionic acid tert-butyl ester (1.52 g, 3.10 mmol), anhydrous DMF (15 mL), and then benzyl bromide (1.84 mL, 15.5 mmol) under a nitrogen atmosphere. The solution was cooled to −10° C., and NaH (0.124 g, 3.10 mmol, 60% oil dispersion) was added. The mixture was stirred for 5 h, and was poured into EtOAc (150 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated to a brown oil. The crude oil was purified using radial chromatography (EtOAc:hexanes 2:98 to 5:95) to give a pale yellow oil (1.04 g, 58%). MS (ES) m/e 598 (M+NH4).