Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.[NH3:21]>CCO>[F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:21])[NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1
Reactant: N
Reactant: N#CCCCCn1ccc(NC(=S)NCC(F)(F)F)n1
Solvent: CCO
Product: N#CCCCCn1ccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
The above thiourea (12.5 g.) was dissolved in 8M ammonia in EtOH (120 ml.). Mercuric oxide (12.8 g.) was added and the mixture was stirred at 20° for 30 minutes. The resulting mixture was filtered and the filtrate was evaporated in vacuo to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)pyrazol-1-yl]valeronitrile as an oil. A sample of the oil was dissolved in acetone and 5 molecular equivalents of maleic acid was added. Ether was added to the resulting clear solution to produce the crystalline maleate, m.p. 123°-125°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2c1ccc(OCc1ccccc1)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-(benzyloxy)-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.123 g, 0.217 mmol) in methylene chloride (10 mL) was added with a 4 N solution of hydrogen chloride in 1,4-dioxane (10 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate (20 mL), and the precipitated solid was collected by filtration. The resulting solid was washed with water, and then dried under reduced pressure to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-(benzyloxy)-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0720 g, 71%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21]O)=[C:4]([O:23]C)[CH:3]=1.[I:25]I>C1([Si](C)(C)C)C=CC=CC=1.Cl>[F:1][C:2]1[CH:3]=[C:4]([OH:23])[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][I:25])=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO
Reactant: II
Agent: C[Si](C)(C)c1ccccc1
Agent: Cl
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CI)c(O)cc1F
Temperature: 25 °C

Procedure:
A solution of [4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol (71.5 mg, 0.209 mmol) and iodine (610 mg, 2.40 mmol) in phenyltrimethylsilane (877 μL) was heated at 110° C. in a sealed tube overnight. The reaction was cooled to room temperature, diluted with 1N HCl (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were washed with 10% Na2S2O3 (20 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to afford 4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-ol. Rf=0.65 (20% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.69 (d, J=11.1 Hz, 1H), 4.82 (s, 1H), 4.41 (d, J=9.4 Hz, 1H), 4.23 (d, J=9.3 Hz, 1H), 3.27-3.19 (m, 1H), 1.27 (br s, 6H).
Reaction SMILES: [Na].[NH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[NH2:3].[C:10](#[N:14])/[CH:11]=[CH:12]/[CH3:13]>C(O)C>[NH2:14][C:10]1[CH2:11][CH:12]([CH3:13])[N:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[N:3]=1
Reactant: C/C=C/C#N
Reactant: NNc1ccccn1
Agent: [Na]
Solvent: CCO
Product: CC1CC(N)=NN1c1ccccn1

Procedure:
A 0.3 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 5.45 g. of 2-hydrazinopyridine is added, followed by 3.35 g. of crotononitrile (mixture of cis or trans isomers). The reaction mixture is refluxed for 3 hours, then the solvent is removed in vacuo. Water is added and the solid is collected by filtration. The solid is recrystallized from dichloromethane-hexane, then acetone-hexane to give 3.1 g. of the product of the Example as yellow crystals, m.p. 154°-157° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>S([O-])([O-])(=O)=O.[Cu+2].ClCCl>[CH3:19][C:20]([S@:23]([NH:25][C@@H:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=[O:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N[C@@H](c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
A mixture of 4-formyl-piperidine-1-carboxylic acid, benzyl ester (0.96 g), (R)-2-methyl-2-propanesulfinamide (0.51 g), anhydrous copper(II) sulphate (1.5 g) and dichloromethane (20 mL) was stirred at room temperature for 48 h. Copper(II) sulphate was filtered off and the filtrate concentrated. The residue was treated with dry dichloromethane (15 mL) and cooled to −78° C. A solution of phenylmagnesium bromide in diethyl ether (3M, 4 mL) was added dropwise. The mixture was slowly warmed to 0° C., then quenched with sat. aqueous NH4Cl solution. The mixture was stirred for 15 min and extracted into dichloromethane. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified (SiO2 chromatography eluting with iso-hexane:ethyl acetate (0-100%)) to give the title compound (623 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][NH:25][CH3:26])[C:21]([O:27]COC)=[C:20]([C:31]([O:33]C)=[O:32])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].Cl.[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][NH:25][CH3:26])[C:21]([OH:27])=[C:20]([C:31]([OH:33])=[O:32])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cc(CNC)c(OCOC)c(C(=O)OC)c3)cs2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(-c2nc(-c3cc(CNC)c(O)c(C(=O)O)c3)cs2)cc1OCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
In 20 ml of methanol was dissolved 150 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-methylaminomethylphenyl)thiazole. Thereto was added 0.2 ml of 10% hydrochloric acid. The mixture was stirred at 60° C. for 30 minutes. 2 ml of 10% sodium hydroxide was added, and the mixture was refluxed for 1 hour with heating. The reaction mixture was made neutral with 10% hydrochloric acid and the solvent was removed by distillation. The residue was mixed with ethanol. The insoluble was collected by filtration, washed with water, dried and recrystallized from dimethylformamide to obtain 35 mg of 2-(3,4-diethoxyphenyl-4-(3-carboxy-4-hydroxy-5-methylaminomethylphenyl)thiazole.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.C(N(CC)CC)C.[CH2:20]([O:22][C:23](=[O:37])[CH:24]([CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:25](=O)[CH3:26])[CH3:21].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:20]([O:22][C:23]([C:24]1[CH:28]=[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N:4]([CH3:12])[CH3:3])[CH:6]=2)[C:25]=1[CH3:26])=[O:37])[CH3:21]
Reactant: CN(C)c1cccc(N)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(N(C)C)c2)c1C

Procedure:
N,N-dimethyl-1,3-phenylenediamine dihydrochloride (5 mmol, 1.09), triethylamine (10 mmol, 1.4 mL), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol (25 mL), then heated under reflux (12 hrs). The solvents were removed under vacuum, the resulting oil was redissolved in methylene chloride, then applied to a silica column. The purified product was collected as a translucent oil. The named compound was identified by 1H-NMR (CDCl3, ppm) 1.28 t (3H) , 2.35 s (3H) , 2.77 s (6H) , 4.2 q (2H) , 6.3-6.7 m (4H), and 7.0-7.3 m (5H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([S:8]([C:11]1[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=1[C:13]([N:15]1[CH2:21][CH2:20][CH2:19]C[CH2:17][C:16]1=[O:22])=[O:14])(=[O:10])=[O:9])[CH2:5][CH2:6][CH3:7].C1(=O)NCCCC1>>[CH3:1][CH2:2][CH2:3][CH:4]([S:8]([C:11]1[CH:26]=[CH:25][CH:24]=[CH:23][C:12]=1[C:13]([N:15]1[CH2:21][CH2:20][CH2:19][CH2:17][C:16]1=[O:22])=[O:14])(=[O:9])=[O:10])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(CCC)S(=O)(=O)c1ccccc1C(=O)N1CCCCCC1=O
Agent: O=C1CCCCN1
Product: CCCC(CCC)S(=O)(=O)c1ccccc1C(=O)N1CCCCC1=O

Procedure:
Synthesized as for N-[(4-heptylsulfonyl)benzoyl]caprolactam (Example VII) using valerolactam (Aldrich) in place of caprolactam.
Reaction SMILES: [CH3:1][P:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[OH:11]O>C(Cl)Cl>[CH3:1][P:2]([CH3:10])([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)=[O:11]
Reactant: OO
Reactant: Cc1ccc(P(C)C)cc1
Solvent: ClCCl
Product: Cc1ccc(P(C)(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl-p-tolyl phosphane (25 g, 0.165 mol) (1a) in diclholoromethane (DCM) (50 mL) was added an aqueous solution of hydrogen peroxide (10%, 60 mL, 0.176 mol) in drops. This is an exothermic reaction so the flask was cooled in ice water during the addition. After the addition the reaction was allowed to stir at rt overnight until the HPLC showed no starting material (18h). From the resulting reaction mixture the organic phase was separated and the aqueous phase was extracted with additional dichloromethane (3×60 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were washed with a solution of sodium bisulfite (10 mL) followed by water (10 mL) and dried over Na2SO4 and concentrated on a rotary evaporator. The desired product was purified by Crystallization from ethyl acetate/hexane (18.8 g). m.p. 90-92° C. 1H NMR (300 MHz, CDCl3) δ (ppm)) 1.469 (d, J=13 Hz, 6H), 2.16 9 (s, 3H), 7.04 (d, J=5.5 Hz, 2H), 7.38 (m, 2H). 31P NMR (121 MHz, CDCl3) δ 34.327.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12](O)=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[N:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([N+:39]([O-:41])=[O:40])=[C:32]2O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.P(Cl)(Cl)([Cl:45])=O>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([Cl:45])=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[N:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([N+:39]([O-:41])=[O:40])=[C:32]2[Cl:45])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1cnc2cc(Cc3ccccc3)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccc(Cc3ccccc3)cc2c1O
Product: O=[N+]([O-])c1cnc2cc(Cc3ccccc3)ccc2c1Cl
Product: O=[N+]([O-])c1cnc2ccc(Cc3ccccc3)cc2c1Cl

Procedure:
The method described in Part E of Example 10 was used to treat 7-benzyl-3-nitroquinolin-4-ol or 6-benzyl-3-nitroquinolin-4-ol with phosphorous oxychloride to provide 7-benzyl-4-chloro-3-nitroquinoline as a light yellow powder or 6-benzyl-4-chloro-3-nitroquinoline as a tan powder, respectively.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[Cl:32][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:31])[C:25]=1[NH:24][C:18]1[C:17]2[C:22](=[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:14]([O:33][CH3:34])=[CH:15][CH:16]=2)[O:21][C:20](=[O:23])[CH:19]=1
Reactant: C1COCCN1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCN1CCOCC1

Procedure:
The title compound was prepared from morpholine and 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 25) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6; HCl salt): δ 10.67 (br, 1H), 9.65 (br s, 1H), 8.82 (s, 2H), 8.01 (d, 1H), 7.22 (d, 1H), 4.64 (s, 1H), 4.01 (t, 2H), 3.93 (s, 3H), 3.92 (m, 2H), 3.76 (t, 2H), 3.42 (d, 2H), 3.20 (m, 2H), 3.05 (m, 2H), 1.97 (m, 2H), 1.74 (m, 2H); MS (ESI): 494.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[CH2:22][OH:23])=[O:16])=[CH:10][C:9]=1[O:24][CH3:25].N1C=CC=CC=1.Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH:14][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[C:11]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[CH2:22][OH:23])=[O:16])=[CH:10][C:9]=1[O:24][CH3:25]
Reactant: COC(=O)CCCOc1cc(N)c(C(=O)N2CCCC2CO)cc1OC
Reactant: C=CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)Nc1cc(OCCCC(=O)OC)c(OC)cc1C(=O)N1CCCC1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A batch of the amine 15 (22.5 g, 61.5 mmol) was dissolved in anhydrous DCM (300 mL) in the presence of anhydrous pyridine (10.9 mL, 134 mmol) at 0° C. Allyl chloroformate (7.17 mL, 67.5 mmol) diluted in anhydrous DCM (200 mL) was added dropwise at 0° C. The resulting solution was allowed to stir overnight at room temperature. It was then washed with cold 1N aqueous HCl (200 ml), water (200 mL), saturated aqueous NaHCO3 (200 mL), and brine (200 mL). The solution was then dried (MgSO4), and the solvent was removed in vacuo to provide 16, slightly contaminated by the product of diacylation (27 g, quantitative yield). A sample was columned (EtOAc/Hexane) to provide the analytical data. 1H NMR (CDCl3) δ 8.78 (1H, bs), 7.75 (1H, s), 6.82 (1H, s), 5.97 (1H, m), 5.38-5.34 (1H, dd, J=1.5, 17.2 Hz), 5.27-5.24 (1H, dd, J=1.3, 10.4 Hz, 1H), 4.63 (2H, m), 4.40 (2H, bs), 4.11 (2H, t, J=6.3 Hz), 3.82 (3H, s), 3.69 (4H, m), 3.61-3.49 (2H, m), 2.54 (2H, t, J=7.4 Hz), 2.18 (2H, p, J=6.7 Hz), 1.92-1.70 (4H, m); 13C NMR (CDCl3) δ 173.4, 170.9, 153.6, 150.5, 144.0, 132.5, 132.0, 118.1, 115.4, 111.6, 105.6, 67.7, 66.6, 65.8, 61.1, 60.4, 56.6, 51.7, 30.5, 28.3, 25.1, 24.3; MS (FAB+) m/z 50 (451, M+H); IR (golden gate) vmax 2949, 2359, 1728, 1596, 1521, 1433, 1202, 1173, 1119, 998, 844, 652 cm−1; [α]26D=−67° (c=0.45, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:32])[C:17]([C:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][O:37][C:35](=[O:36])[CH2:34][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]([C:17]([C:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])[CH3:32])=[CH:13][CH:14]=2)=[CH:3][C:2]=1[Br:1]
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(O)c(Br)c2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OCC(=O)OC)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-N-methyl-1-benzofuran-3-carboxamide (1.01 g, 2.04 mmol), prepared in step 7 of Example 6, methyl bromoacetate (213 μL, 2.25 mmol) and potassium carbonate (1.41 g, 10.2 mmol) in 20 ml of DMF was stirred under nitrogen at room temperature for 23 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give methyl[(3-bromo-4′-{[[(2-butyl-1-benzofuran-3-yl)carbonyl](methyl)amino]methyl}-1,1′-biphenyl-4-yl)oxy]acetate (1.07 g, 93%) as a yellow oil, MS (ESI) m/z 564 [M+H]+. Elemental Analysis for C30H30BrNO5. Calc'd: C, 63.83; H, 5.36; N, 2.48. Found: C, 63.42; H, 5.40; N, 2.39.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13]O>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:13])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)/C=C/c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-bromocinnamic acid (16 g) in methanol (150 mL), thionyl chloride (30 mL) was added at 0° C. The reaction mixture was warmed to room temperature and refluxed for 3 hours. After cooling to room temperature, the solvents were evaporated to dryness. The crude compound obtained was used as such for the next step.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][C:18]1[C:28]2[C:29]3[C:21]([C:22](=O)[C:23](=O)[C:24]=3[CH:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=1.[OH-].[K+]>CO>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2=[C:29]3[C:28]=1[CH:27]=[CH:26][CH:25]=[C:24]3[C:23]1[C:22]2=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8](=[O:9])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C(=O)c2ccc(Br)c3cccc1c23
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(c2ccccc2)=C2C(=C1c1ccccc1)c1ccc(Br)c3cccc2c13
Temperature: 65 °C

Procedure:
1,3-Diphenylacetone (17.5 g, 83 mMole) was dissolved in methanol (240 mL) and heated to 65° C. To the solution was added 5-bromoacenaphthenequinone (2), (20 g, 75 mMole). The resulting well-stirred suspension was then treated with 1M-methanolic KOH (100 mL, 100 mMole) at a fast drip rate, whereupon the dark colored product precipitated immediately. The mixture was then stirred at 65° C. for 1 hour, cooled and filtered. The black solid was washed well with methanol, ether and dried. Yield of product (3), (31 g).
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[CH:20]=[O:21]>CN(C=O)C>[CH2:1]([N:8]([CH2:9][CH2:10][O:11][C:22]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[C:19]=1[CH:20]=[O:21])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CN(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCOc1cccc(Cl)c1C=O)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of N-benzyl-N-methylethanolamine (13.4 g) in dry DMF (30 ml) was added dropwise with stirring to a suspension of sodium hydride (4.75 g, 60% dispersion in mineral oil) in DMF (60 ml) at ambient temperature under nitrogen over 20 minutes. The mixture was stirred and heated at 50° C. for 1 hour until the evolution of hydrogen ceased. The mixture was cooled at ambient temperature and a solution of 2-chloro-6-fluorobenzaldehyde (15.8 g) in DMF (15 ml) was added over 30 minutes. The mixture was heated at 70° C. for 2 hours and then cooled and poured onto ice/water (1 l). The mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with 2M sodium hydroxide solution and then brine, dried and evaporated to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-6-chlorobenzaldehyde as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)=O)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4]>C1COCC1.O.[Fe].CC(O)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]3[N:16]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=4)[CH2:21][C:20](=[O:32])[NH:19][C:12]=3[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cccn1-c1ccc([N+](=O)[O-])c(NC(=O)CC(=O)c2cccc(C#N)c2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccn1-c1ccc2c(c1)NC(=O)CC(c1cccc(C#N)c1)=N2

Procedure:
The title compound was prepared from 1-{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-nitro-phenyl}-1H-pyrrole-2-carboxylic acid methyl ester (Example M15) by reductive cyclization with Fe/HOAc in THF/H2O at 80° C. according to the general procedure J (method d). Obtained as a brown solid (323 mg).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][C:7]#[N:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.C1COCC1>[S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][NH2:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: N#CCc1csc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCc1csc2ccccc12
Yield: 24.4 %

Procedure:
Reduce benzo[b]thiophen-3-yl-acetonitrile (350.9 mg, 2.0 mmol) in Et2O (6.0 mL) with 1.0 M LAH in THF (6.0 mL) at 0-10° C. for 1 hour. Carry out Fieser work-up to remove the LAH. Concentrate and pass through an SCX column washing with MeOH and then eluting with 2.0 M NH3 in MeOH. Concentrate the eluant and purify twice by chromatography, eluting with 75:20:5 EtOAc/hexanes/2.0 M NH3 in MeOH and then with 70:20:10 EtOAc/hexanes/2.0 M NH3 in MeOH to yield the title compound (86.5 mg, 24%): MS ES+ 178.2 (M+H)+, 161.2 (base peak); 1H NMR (DMSO-d6) δ 7.94 (d, J=7.3 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.40-7.33 (m, 3H), 3.32 (br s, 2H), 2.88 (br s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[C:12]([NH:16][C:17]([C:19]1[N:20]=[C:21]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[S:22][CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([CH2:24][C:21]3[S:22][CH:23]=[C:19]([C:17]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[N:20]=3)[CH2:26][CH2:27]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: CC(C)(C)NC(=O)c1csc(CN2CCNCC2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1csc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)n1
Yield: 45.8 %

Procedure:
To a solution of 4-amino-3-fluorobenzoic acid (0.703 g, 4.53 mmol), N-tert-butyl-2-(piperazin-1-ylmethyl)thiazole-4-carboxamide (1.28 g, 4.53 mmol) and triethylamine (0.459 g, 4.53 mmol, 0.630 mL) in dichloromethane was added 1-propanephosphonic acid cyclic anhydride (2.88 g, 4.53 mmol, 2.70 mL, 50% solution in ethyl acetate). The reaction was concentrated under reduced pressure and the residue was taken up in ethyl acetate, washed with sodium bicarbonate (×3) and brine. The organic phase was concentrated under reduced pressure to afford the title compound (0.87 g). MS (ESI) m/z 420.3 [M+H]+