Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[CH3:8].S(Cl)([Cl:14])=O>>[ClH:14].[Cl:14][CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCn1cnc(CO)c1C
Product: CCCn1cnc(CCl)c1C
Product: Cl
Temperature: 90 °C

Procedure:
4-hydroxymethyl-5-methyl-1-propylimidazole (4.5 g) was added to thionyl chloride (25 ml) at 0° C., and the mixture was heated for 1 hour at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained residue was washed with ethyl acetate to give 4-chloromethyl-5-methyl-1-propylimidazole hydrochloride (5.79 g) as colorless crystals.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4](=[N:6]/[N:7]=[C:8](/[C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1)\[CH3:9])[NH2:5].CCO.Cl>[Fe].O>[ClH:1].[ClH:1].[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10](/[C:8](=[N:7]/[N:6]=[C:4]([NH2:5])[NH2:3])/[CH3:9])[CH:11]=2)=[O:27])=[CH:23][CH:22]=1
Reactant: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(N)cc2)c1
Yield: 212.2 %

Procedure:
To a refluxing suspension of amide F4 (2.02 g, 5.36 mmol) in 2:1 EtOH:H2O (100 mL) were sequentially added Fe dust (1.20 g, 21.44 mmol) and c.HCl (2 mL), and the resulting suspension was refluxed for 14 h. After this time, the hot reaction mixture was filtered through a pad of Celite, and the solvent was removed under reduced pressure. The residue was re-dissolved in hot H2O, and the resulting suspension filtered through a pad of Celite. Solvent was removed under reduced pressure, and the residue dried via three MeOH-azeotrope cycles. The resulting residue was reprecipitated from acidified MeOH to afford triamine F5 (2.18 g, quantitative) as an amorphous cream solid; 1H NMR (400 MHz, DMSO): δ 11.30 (s, 1H, hydrazonyl-N30—H), 10.05 (s, 1H, ArC(O)NHAr), 8.21 (s, 1H, ArH), 8.20-7.55 (m, 8H, ArH & ═C(NH2)2), 7.36 (t, J=7.90 Hz, 1H, ArH), 6.91 (d, J=7.96 Hz, 1H, ArH), 5.30 (v br s, 3H, ArNH3+), 2.35 (s, 3H, Ar(CH3)═N—); LCMS (APCl+): 311 (100%).
Reaction SMILES: C(Cl)[Cl:2].[Cl:4][C:5]1[CH:10]=[C:9]([C:11](Cl)=[O:12])[CH:8]=[C:7]([Cl:14])[N:6]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CCOCC>[ClH:2].[Cl:4][C:5]1[CH:10]=[C:9]([C:11]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:12])[CH:8]=[C:7]([Cl:14])[N:6]=1
Reactant: CN1CCNCC1
Reactant: ClCCl
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Solvent: CCOCC
Product: CN1CCN(C(=O)c2cc(Cl)nc(Cl)c2)CC1
Product: Cl
Reaction time: 24 h

Procedure:
To methylene chloride (15 mL) was added 2,6-dichloropyridine-4-carbonyl chloride (1.0 g, 4.8 mmol) and 1-methylpiperazine (0.48 g, 4.8 mmol). After stirring for 1 day, the reaction was poured into ether. The resulting solid was filtered to give 1-[(2,6-dichloropyridin-4-yl)-carbonyl]-4-methylpiperazine, hydrochloride.
Reaction SMILES: ClC[C:3]1[N:8]=[CH:7]C=[CH:5][N:4]=1.C(N)C[NH2:11].[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[CH2:19][NH:20][CH2:21][CH2:22][NH2:23].CN=C=S>>[C:5]([NH:4][C:3]([NH:8][CH3:7])=[N:23][CH2:22][CH2:21][NH:20][CH2:19][C:14]1[N:15]=[CH:16][CH:17]=[CH:18][N:13]=1)#[N:11]
Reactant: NCCN
Reactant: NCCNCc1ncccn1
Reactant: ClCc1ncccn1
Agent: CN=C=S
Product: CNC(=NCCNCc1ncccn1)NC#N

Procedure:
Reaction of 2-chloromethylpyrimidine with ethylenediamine by the procedure of Example 34 and reaction of the resulting N-(2-pyrimidylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b) gives, after concentrating and chromatographing, N-methyl-N'-[2-(2-pyrimidylmethylamino)ethyl]thiourea. This thiourea is reactd with lead cyanamide by the procedure of Example 3(b) to give the title compound.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7]([NH:10][CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8].[C:14](#[N:18])[CH:15]([CH3:17])O>C(OCC)C>[CH:7]([N:10]([CH:11]([CH3:13])[CH3:12])[CH:15]([CH3:17])[C:14]#[N:18])([CH3:9])[CH3:8]
Reactant: CC(O)C#N
Reactant: CC(C)NC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C)N(C(C)C)C(C)C#N
Temperature: 51 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Anhydrous magnesium sulfate (12.04 g, 0.1 mol) was added to diisopropylamine (12.14 g, 0.12 mol), followed by lactonitrile (7.73 g of 92% aqueous solution, 0.1 mol) added all at once with stirring. The reaction mixture spontaneously warmed up to 51° C. It was left overnight at room temperature. Diethyl ether (50 ml) was added, and magnesium sulfate was filtered off and washed with ether (50 ml). The product was isolated by distillation, 11.57 g, 75% yield, bp 49°-50° C./0.1 mm Hg. 1H NMR CDCl3 δ ppm, 1.02 (d, J=6.5 Hz, 6H, CH3), 1.17 (d, J=6.5 Hz, 6H, CH3), 1.41 (d, J=6.5 Hz, 3H, CH3, 3.21 (sep, J=6.5 Hz, 2H,=CH) , 3.89 (q, J=6.5 Hz, 1H, CH) .
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:20])[CH2:14][C:15](=[O:19])[CH:16](Br)[CH3:17].C(N(CC)CC)C>CC(C)=O>[CH3:11][O:12][C:13]([CH2:14][C:15](=[O:19])[CH:16]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)[CH3:17])=[O:20]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)CC(=O)C(C)OC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-Chloro-nicotinic acid (10 g, 63.5 mmol) and 4-Bromo-3-oxo-pentanoic acid methyl ester (1.51 g, 7.2 mmol) (14.6 g, 70 mmol) in acetone (100 mL) is added triethyl amine (9.76 mL, 70 mmol) at 0-5° C. After addition, the reaction mixture is warmed to room temperature and stirred overnight, solid is filtered off, the filtrate is concentrated and taken into methylene chloride, washed with water and brine, dried. The residue is purified by column giving 6-chloro-nicotinic acid 3-methoxycarbonyl-1-methyl-2-oxo-propyl ester (16.3 g.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[CH:18]=2)[CH2:13][N:12]1C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:32].CC(O)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[ClH:32].[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[CH:18]=2)[CH2:13][NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OC)CN(C(=O)OC(C)(C)C)[C@H](C(=O)OCc1ccccc1)C2
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C[C@@H](C(=O)OCc1ccccc1)NC2
Temperature: 40 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a suspension of crude (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(tert-butyloxycarbonyl)-3-isoquinolinecarboxylic acid benzyl ester (example 5) (335 g, 0.7836 mol) in ethyl acetate (335 mL) and toluene (335 mL) was added 20% HCl solution in IPA (357 g, 1.959 mol) at 15-20° C. The reaction mixture then was heated to 40° C. over 1-2 h, and stirred at this temperature for 2 h. A 20% HCl solution in IPA (71.4 g, 0.3918 mol) was added, and the stirring was continued for another 2 h. The reaction mixture was cooled to 15-20° C., and stirred at this temperature. The mixture was filtered, and washed with ethyl acetate (2×670 mL). The white solids were dried under vacuum at 40° C. to give 278.6 g (99% yield, ee=98%) of (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-3-isoquinolinecarboxylic acid benzyl ester, hydrochloride. 1H NMR (DMSO-d6) δ: 3.10 (dd, J=16.64, 10.74 Hz, 1H, CHHCHCOOH), 3.24 (dd, J=16.64, 5.10 Hz, 1H, CHHCHCOOH), 3.72 (s, 6H, OCH3), 4.23 (br s, 2H, CH2N), 4.58 (dd, J=10.74, 5.10 hz, 1H, CHCOOH), 5.27 (d, J=12.48 Hz, 1H, PhCHH), 5.33 (d, J=12.48 Hz, 1H, PhCHH), 6.85 (br s, 2H, PhH), 7.35-7.46 (m, 5H, PhHCH2), 10.19 (br s, 2H, NH.HCl).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1.C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:33][CH2:2][CH:3]1[CH2:6][C:5]([CH2:29][C:30]#[N:31])([N:7]2[CH:11]=[C:10]([C:12]3[C:13]4[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[N:8]2)[CH2:4]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)C4)c3)ncnc21
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CBr)C4)c3)ncnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To an ice-cooled mixture of 3-(hydroxymethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (1.0 g, 0.0023 mol) and carbon tetrabromide (1.1 g, 0.0034 mol) in DMF (7 mL) was added triphenylphosphine (0.90 g, 0.0034 mol) and the mixture was stirred at this temp. for 30 min. To the resulting dark brown solution was added saturated aq. NaHCO3 (5 mL) followed by water (5 mL) and the mixture was extracted with dichloromethane. The organic layers were combined, washed with water, dried over Na2SO4, concentrated and purified with combiflash (silica gel, 0-40% EtOAc/Hex) to give the desired product (1.0 g, 87%) as light yellow solid. LCMS calculated for C22H30BrN6OSi(M+H)+: 501.1: Found: 501.3.
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12](F)=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4].[CH3:15][Mg]Cl>O1CCCC1.[Cl-].[Mn+2].[Cl-]>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4]
Reactant: C[Mg]Cl
Reactant: CCCC/N=C/c1c(F)cccc1Cl
Agent: [Mn+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCC/N=C/c1c(C)cccc1Cl
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
This compound was prepared using methodology described in Synthesis 1999, 2138-2144. To a solution of 7.00 g (32.8 mmol) butyl-[1-(2-chloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine in 70 ml tetrahydrofuran at 0° C. was added 0.41 g (3.28 mmol) manganese(II) chloride. 21.8 ml (65.5 mmol) of a 3 M solution of methylmagnesium chloride in tetrahydrofuran was then added dropwise while the temperature of the reaction mixture was maintained at 5-10° C. After the addition was complete, the reaction mixture was stirred for a further 30 minutes, during which time the temperature rose to 40° C. (exotherm). The reaction mixture was then quenched by dropwise addition of water and stirred for a further 30 minutes before being diluted with toluene. The mixture was then filtered and the organic phase of the filtrate was then washed with saturated brine. The phases were separated and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was resuspended in carbon tetrachloride and concentrated in vacuo again to afford 6.90 g (100%) of the title compound as a yellow oil which was used in the next step without further purification. MS (ISP): 212.1 ([M+H]+), 210.1 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]=[CH:6][CH2:5][C@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]1=[O:17].[H][H]>CO.[Pd]>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:3]1=[O:17]
Reactant: [H][H]
Reactant: CN1CC=CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: [Pd]
Solvent: CO
Product: CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Yield: 69.3 %

Procedure:
To a degassed solution of 1,1-dimethylethyl [(3S)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl]carbamate (Example 94) (680 mg, 2.8 mmol) in MeOH (20 mL) was added 10% Pd/C (100 mg) and the resulting suspension was stirred overnight under a balloon of hydrogen. Filtration of the catalyst and concentration of the filtrate under reduced pressure yielded 1,1-dimethylethyl [(3S)-1-methyl-2-oxohexahydro-1H-azepin-3-yl]carbamate (470 mg, 88%). LCMS: (M−tBut)+: 186.2.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[CH:38][C:5]=2[N:4]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:20]1[CH2:19][CH:18]([C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:35]=[CH:36][CH:37]=[CH:38][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)[CH2:21]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CNC3)n(C)c2n1
Reaction time: 2.5 h
Yield: 85 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]azetidine-1-carboxylic acid tert-butyl ester 678 (325 mg, 0.63 mmol) in DCM (4 mL) was added TFA (2 mL) The resulting mixture was stirred for 2.5 h at r.t then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-20%) affording 680 as a cream foam (224 mg, 85%). LCMS (method I): RT 2.30 min, [M+H]+ 419.1. 1H NMR (CDCl3, 400 MHz): δ 8.00-8.00 (1 H, m), 7.75-7.74 (1 H, m), 7.26 (2 H, s), 4.34-4.32 (7 H, m), 3.89-3.88 (6 H, m), 3.71-3.69 (3 H, m), 3.35-3.34 (2 H, m), 1.44-1.43 (3 H, m)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[N:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[N:20]=[C:19]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: COc1cccc(C=O)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cccc(C=C2N=C(c3cccs3)OC2=O)n1
Temperature: 90 °C
Yield: 44.2 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 6-methoxy-2-pyridinecarboxaldehyde (46 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 38 mg of the above-captioned compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:33]2[CH2:34][CH2:35][CH:30]([C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2ccccc2[C@H]1[C@@H](CC=O)c1ccc(Cl)c(Cl)c1
Reactant: c1cncc(C2CCNCC2)c1
Product: CN1C(=O)c2ccccc2[C@H]1[C@@H](CCN1CCC(c2cccnc2)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 164 %

Procedure:
A solution of (3S)-3-(3,4-dichlorophenyl)-3-((1R)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.428 g) was treated with 4-pyrid-3-ylpiperidine (0.20g) as described in Example 8. The resulting material was not purified by chromatography, but was transformed into the hydrochloride to afford the title compound (0.535 g); [α]D =34° (c=1.0 ethanol); mp 170°-210° C. (dec); MS: m/z=494(M+1); NMR: 2.12 (m,4), 3.03 (s,3), 3.69 (m,7), 4.88 (m, 1), 6.75 (m, 1), 6.96 (m, 1), 7.32 (m, 1), 7.49 (m,2), 7.63(m, 1), 7.92 (m,2), 8.37 (m, 1), 8.81 (m,2). Analysis for C28H29Cl2N3O·2 HCl·H2O: Calculated C, 57.45; H, 5.68; N, 7.18; Found: C, 57.22; H, 5.67; N, 7.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)=[CH:7][C:4]=1[C:5]#[N:6].[OH-].[Na+].O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncccc23)cc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2c[nH]c3ncccc23)cc1C#N
Yield: 45.2 %

Procedure:
The nitrile 37 (95.8 mg, 237 μmol) was dissolved in dioxane (5 ml) and treated with 2N sodium hydroxide in water (250 μl, 500 μmol). The reaction was sealed and heated to reflux for 2 hours. The reaction was concentrated to dryness and extracted with ethyl acetate and water. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product (72.3 mg). The crude was purified via flash chromatography and eluted with a gradient from 1:1 ethyl acetate/hexane to 100% ethyl acetate to 4/4/1 ethyl acetate/hexane/7N ammonia in methanol to give 38 (26.7 mg, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:26]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1)[CH2:27][CH3:28]
Reactant: CCCBr
Reactant: CC(=O)NC(C)c1cc2cc(CCc3ccc(O)cc3)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(CCc2ccc3oc(C(C)NC(C)=O)cc3c2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 78.1 %

Procedure:
A suspension of N-(1-{5-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (333 mg, 1.03 mmol) obtained in Example 157, bromopropane (1.08 g, 6.37 mmol) and potassium carbonate (924 mg, 6.68 mmol) in DMF (10 mL) was stirred at 80° C. for 2 days. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solution was applied to silica gel column chromatography (hexane:ethyl acetate=9:11 to 0:1), and recrystallized from hexane-ethyl acetate to give the title compound (294 mg, yield 78%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].Cl.[CH:9]([O:12][C:13](=[O:17])[C@@H:14]([CH3:16])[NH2:15])([CH3:11])[CH3:10].[NH:18]([C:34]([O:36]CC1C=CC=CC=1)=O)[C@H:19]([C:31]([OH:33])=O)[CH2:20][C:21](=[O:30])[O:22]CC1C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl>[CH:9]([O:12][C:13](=[O:17])[C@@H:14]([CH3:16])[NH:15][C:31](=[O:33])[C@H:19]([CH2:20][C:21](=[O:30])[OH:22])[NH:18][C:34](=[O:36])[C@@H:1]([CH3:2])[NH2:3])([CH3:11])[CH3:10]
Reactant: CCN(CC)CC
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)OC(=O)[C@@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N
Reaction time: 1 h

Procedure:
Triethylamine (1.4 ml) was added to a suspension of D-alanine isopropyl ester hydrochloride (1.7 g) in 50 ml of chloroform. To the resulting solution was admixed Z-Asp(OBzl) (3.6 g), a solution of 2.06 g DCC in 10 ml chloroform was added under ice cooling, and the mixture was stirred under ice cooling for one hour and then at room temperature overnight. Precipitated dicyclohexylurea was filtered off, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 150 ml of ethyl acetate. This solution was washed with 2N-HCl, water, 4% aqueous solution of sodium bicarbonate, water and saturated aqueous solution of sodium chloride in that order, and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 ml of 80% acetic acid, and the solution was subjected to catalytic reduction under a hydrogen gas stream at room temperature for four hours using palladium-carbon as catalyst. After filtering off the catalyst, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from water, giving 1.8 g of D-alanyl-α-L-aspartyl-D-alanine isopropyl ester.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:22].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:22])=[O:32])=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nn1nc(-c2ccnc(C(F)(F)F)c2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccnc(C(F)(F)F)c2)c2ccccc2c1=O

Procedure:
The product from Example 76B and 2-(4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.80-11.82 (bs, 1H), 8.96-8.99 (m, 1H), 8.40-8.46 (m, 1H), 8.12 (s, 1H), 7.96-8.04 (m, 3H), 7.71-7.79 (m, 1H), 7.36-7.44 (m, 4H), 3.72 (s, 2H); MS (APCI) M/Z 459 (M+H)+.
Reaction SMILES: [Br:1][C:2]([Br:9])([Br:8])[CH2:3][CH2:4][C:5]([Cl:7])=[O:6].S(Cl)([Cl:12])=O.ClN1C(=O)CCC1=O>>[Cl:12][CH:4]([CH2:3][C:2]([Br:9])([Br:8])[Br:1])[C:5]([Cl:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(Cl)CCC(Br)(Br)Br
Agent: O=C1CCC(=O)N1Cl
Product: O=C(Cl)C(Cl)CC(Br)(Br)Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a solution of 343.2 g (1 mole) of 4,4,4-tribromobutyric acid chloride in 600 g of thionylchloride 266.0 g (2 mole) of N-chlorosuccinimide is added portion wise at 60° C. while the reaction mixture is irradiated with a mercury high-pressure lamp. After addition of the N-chlorosuccinimide the reaction mixture is stirred for 5 hours at 60° C. while irradiation is continued. Then the thionyl chloride is evaporated and the residue is distilled in vacuo. 309.7 (82% of theory) of 2-chloro-4,4,4-tribromobutyric acid chloride, b.p. 59°-63° C./0.05 torr is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C.Cl>O1CCCC1.CCCCCC>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:28]([OH:29])[OH:27])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-bromo-4'-n-butyloxybiphenyl (3.05 g) in tetrahydrofuran (60 ml) was added 1.55M n-butyllithium in n-hexane (7.74 ml) at -60° C. over a period of 10 minutes. The solution was stirred at -30° C. for 1.5 hours and cooled to -60° C. To the solution was added triisopropylborate (3.46 ml) over a period of 5 minutes, and the mixture was stirred for 1.5 hours without cooling. To the solution was added 1N hydrochloric acid (20 ml) and the solution was stirred for 30 minutes and extracted with ethyl acetate. The organic layer was separated and washed with water, brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with n-hexane. The solid was collected by filtration and dried under reduced pressure to give 4-(4-n-Butyloxyphenyl)phenylboronic acid (2.31 g).