Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([NH2:41])[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([NH:41][C:36]2[CH:35]=[C:34]([CH:31]3[CH2:30][CH2:29][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:33][CH2:32]3)[CH:39]=[CH:38][C:37]=2[F:40])=[O:16])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(N)c2)CC1
Reactant: O=C(O)CCc1ccc(Oc2ccc(F)c(F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(NC(=O)CCc3ccc(Oc4ccc(F)c(F)c4)cc3)c2)CC1
Reaction time: 12 h
Yield: 25.1 %

Procedure:
A 25-mL RB-flask was charged with 3-[4-(3,4-difluorophenoxy)phenyl]propanoic acid (180 mg, 0.650 mmol), tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidine carboxylate (180 mg, 0.610 mmol), 1-[3-(Dimethylamino) propyl]-3-ethylcarbodimide hydrochloride (1.22 mmol, 190 mg), 4-dimethylaminopyridine (20 mg) in DMF:DCM (0.4:4.0 mL) at room temperature. The reaction mixture was stirred for 12 h and water (10.0 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with CHCl3 (3×10 mL) The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by chromatography (silica gel, hexanes:EtOAc 6:1) to afford tert-butyl 4-[3-({3-[4-(3,4-difluorophenoxy)phenyl]propanoyl}amino)-4-fluorophenyl]-1-piperidinecarboxylate (85.0 mg, 25.0%): 1H NMR (400 MHz, CDCl3) δ 8.32-8.15 (m, 1H), 7.47-6.45 (m, 10H), 4.41-4.07 (br, 2H), 3.17-2.96 (m, 2H), 2.90-2.67 (m, 4H), 2.67-2.56 (m, 1H), 1.91-1.69 (m, 2H), 1.68-1.48 (m, 2H), 1.47 (s, 9H); ESMS m/e 553.3 (M−H+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[O:31][C:14]4=[C:15]([NH2:30])[N:16]=[CH:17][C:18]([C:19]5[CH:20]=[N:21][N:22]([CH:24]6[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]6)[CH:23]=5)=[C:13]4[CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:30][C:15]1[N:16]=[CH:17][C:18]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:25][CH2:26][N:27]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:28][CH2:29]3)[CH:23]=2)=[C:13]2[CH:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)[O:31][C:14]=12
Reactant: COCC(=O)Cl
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3cccc4cnccc34)oc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6cnccc56)cc34)cn2)CC1
Yield: 59.2 %

Procedure:
A solution of 2-isoquinolin-5-yl-4-(1-piperidin-4-yl-1H-pyrazol-4-yl)-furo[2,3-c]pyridin-7-ylamine (30 mg, 0.07 mmol), methoxyacetyl chloride (8.02 μL, 0.0877 mmol), and DIPEA (28.0 μL, 0.161 mmol) in DCM (0.94 mL) stirred overnight at RT. The reaction was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography (10% 7 N NH3/MeOH:EtOAc) afforded 20 mg (60%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.97-2.21 (m, 4 H) 2.31 (br s, 2 H) 2.81-2.94 (m, 1 H) 3.17-3.32 (m, 1 H) 3.41-3.51 (m, 3 H) 4.06-4.25 (m, 3 H) 4.46 (tt, J=11.34, 4.07 Hz, 1 H) 4.76 (d, J=12.88 Hz, 1 H) 5.01 (br s, 2 H) 7.22 (s, 1 H) 7.69-7.80 (m, 2 H) 7.84-7.91 (m, 1 H) 8.03 (s, 1 H) 8.08-8.18 (m, 2 H) 8.22 (d, J=6.06 Hz, 1 H) 8.61-8.70 (m, 1 H) 9.37 (s, 1 H); MS (ESI): 483.11 [M+H]+; HPLC tR=0.89 min (TOF, polar—3 min).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[CH3:6].[CH2:14]=[O:15]>>[CH3:1][O:2][CH2:3][O:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][OH:15])=[N:11][CH:12]=1)[CH3:6]
Reactant: COCOC(C)c1ccc(C)nc1
Reactant: C=O
Product: COCOC(C)c1ccc(CCO)nc1
Yield: 31.9 %

Procedure:
The mixture of 5-(1-methoxymethoxyethyl)-2-methylpyridine (21.0 g) and formalin (37% aq. HCHO, 14.1 g) was heated at 150° to 160° C. for 8 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure and then the residue was subjected to silica gel column chromatography. A fraction eluted with chloroform-methanol (25:1, v/v) gave 2-[5-(1-methoxymethoxyethyl)-2-pyridyl]ethanol (7.8 g, yield: 32%) as oil.
Reaction SMILES: [C:1]([C:3]1[C:12](I)=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([CH3:14])[CH:4]=1)#[N:2].C([C:17]1[C:26]([OH:27])=[CH:25][C:20](C(OC)=O)=C(C)C=1)#N.C1([OH:35])C=CC=CC=1.BrC(CC)C>>[NH2:2][C:1]([C:3]1[C:12]([O:27][CH:26]([CH3:17])[CH2:25][CH3:20])=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:14])[CH:4]=1)=[O:35]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1cc(I)c(C#N)cc1C
Reactant: COC(=O)c1cc(O)c(C#N)cc1C
Solvent: CCC(C)Br
Product: CCC(C)Oc1cc(C(=O)O)c(C)cc1C(N)=O

Procedure:
Synthesized according to the method of reagent preparation 41 by replacement of step 6 with the conversion of methyl 4-cyano-5-iodo-2-methylbenzoate to methyl 4-cyano-5-hydroxy-2-methylbenzoate according to the method described in Chemical & Pharmaceutical Bulletin (2007), 55(9), 1361-1364 followed by phenol alkylation with 2-bromobutane then proceeding with steps 7 and 8. MS (EI) for C13H17NO4: 252 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20]N(CCN(C)C)C.C([Li])(CC)C.COS(OC)(=O)=O>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH:13]1[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCCC2)CC1
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: CC1CC(N2CCCCC2)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1′-tert-Butoxycarbonyl-[1,4′]-Bipiperidine 1 (5.1 g, 19.0 mmol), TMEDA (19 ml) in dry Et2O (40 ml) at −78° C. is slowly added a solution of sec-butyllithium (19.0 ml, 24.7 mmol, 1.3 M in cyclohexanes) over a period of 30 min. The mixture is stirred at −78° C. for 3 hr, and then is treated with a solution of Dimethylsulfate (3.6 g, 28.5 mmol) in Et2O (5 ml). The cooling bath is removed and the reaction mixture is stirred at ambient temperature for 16 hr. After cooling to 0° C., the reaction mixture is quenched with water, extracted with Et2O (5×100 ml), and the combined ether layers is dried over K2CO3. The solvent is removed in vacuo and the residue is purified on silica gel chromatography (eluting 40% ethyl acetate in hexane) to give 2.51 g of 1′-tert-Butoxycarbonyl-2′-methyl-[1,4′]-Bipiperidine, 2.
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([CH2:14][O:15][CH:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:17][OH:18])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>>[ClH:1].[C:2]1([C:8]2([CH2:14][O:15][CH:16]([C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:20]=3)[CH2:17][O:18][CH2:36][CH:33]3[CH2:35][CH2:34]3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: OCC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: FC(F)(F)c1cc(C(COCC2CC2)OCC2(c3ccccc3)CCNCC2)cc(C(F)(F)F)c1

Procedure:
This was prepared in a similar manner to Example 2 using the compound of Example 1 (d) and cyclopropyl methyl bromide. 1H NMR (360MHz, d6 -DMSO) δ 7.91 (1H, s), 7.66 (2H, s), 7.35-7.19 (5H, m), 4.58 (1H, t, J=4.7 Hz), 3.50-3.06 (6H, m), 2.76-2.61 (2H, m), 2.33-2.17 (2H, m), 2.08-1.94 (2H, m), 0.84-0.77 (1H, m), 0.36-0.30 (2H, m), 0.01-0.06 (2H, m). MS (Cl+) 502 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][CH:27](C)[CH:28]2N.[CH2:37]([N:39](CC)CC)C>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:39]([CH3:37])[CH:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[O:22][CH3:21])[CH2:28]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: COc1ccc2c(c1OC)CCC(C)C2N
Reactant: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3c(ccc(OC)c3OC)C1)CC2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane, triethylamine and 5,6-dimethoxy-2-methyl-amino-1,2,3,4-tetrahydronaphthalene. Mp: 216°-217° C. (decomp.).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([OH:16])=[O:15].S(=O)(=O)(O)O>>[N+:14]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)=[CH:6][CH:5]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=c1cnc(-c2ccccc2)c[nH]1
Agent: O=S(=O)(O)O
Product: O=c1cnc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Phenyl-2-(1H)-pyrazinone (5 g) was added in portions during 30 minutes to a stirred mixture of fuming nitric acid (30 ml) and sulphuric acid (5 ml) at -5° C. The mixture was stirred in the cold for 30 minutes, and the temperature of the mixture was then allowed to rise to 10° C. The mixture was then poured into ice-water (250 ml) to give 5-(4-nitrophenyl)-2(1H)-pyrazinone recrystallised from dimethylformamide, m.p. 336°-8° C., δ(DMSO-d6) 8.15 and 8.30 (2d, 3- and 6- protons of pyrazinone ring), 8.18 (m, phenyl); νmax (Nujol mull) 3200-2500 (NH), 1690, 1675, 1545, 1510, 1349, 860 and 750 cm-1.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[C:15]([CH2:17][CH3:18])[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:19])[C:5]=2[CH:4]=1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([C:3]1[CH:16]=[C:15]([CH2:17][CH3:18])[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([OH:19])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(CC)c2sc3ccccc3c(=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCc1cc(CC)c2c(c1)C(O)c1ccccc1S2
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a stirred solution of 2,4-diethyl-9H-thioxanthen-9-one (20 g, 74.5 mmol) in methanol (400 ml) cooled in an ice bath was added sodium borohydride (8 g, 0.2 mole) portionwise. After 1 hour at room temperature, water (100 ml) was added to the reaction mixture and the precipitate collected and washed with water to give the title compound as a white solid (20 g).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:21])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([OH:20])=O)=[CH:7]1.[NH2:22][C:23]1[NH:27][N:26]=[N:25][N:24]=1>CN(C)C=O>[CH3:21][N:3]([CH3:2])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([NH:22][C:23]2[NH:27][N:26]=[N:25][N:24]=2)=[O:20])=[CH:7]1
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(CCN(C)C)c2n1
Reactant: Nc1nnn[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(CCN(C)C)c2n1
Reaction time: 36 h

Procedure:
1(2-Dimethylaminoethyl)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride (4.6 g) and N,N'-carbonyldiimidazole (2.75 g) in dimethylformamide (40 ml) were stirred and heated to 90° for 2 hours. 5-Amino-1H-tetrazole (1.45 G) was added and the mixture was heated to 40° and stirred for 36 hours. The solid was collected, m.p. 305°-307° (d). (39%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH:18]=[O:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC[OH:22]>C1COCC1.O.[N+]([O-])([O-])=O.[Ag+]>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:22])=[O:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=Cc1cc2ccccc2c(-c2cccc(I)c2)n1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccccc2c(-c2cccc(I)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-iodophenyl)-3-methylisoquinoline (5.733 g, 16.62 mmol), N-bromosuccinimide (NBS) (7.399 g, 41.57 mmol), and benzoyl peroxide (BPO) (0.48 g) in CCl4 (100 mL) was heated to reflux while being illuminated by a flood lamp for 5 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with saturated NaHCO3 aqueous solution (40 mL), dried (Na2SO4), then filtered. The filtrate was concentrated in vacuo, thereby affording crude 1-(3-iodophenyl)-3-dibromomethylisoquinoline (8.327 g) as a yellow oil. It was used directly in next step without any purifications. To a refluxing solution of crude dibromide (8.327 g) in EtOH (110 mL) and THF (60 mL) was added dropwise a solution of AgNO3 (7.994 g) in H2O (10 mL). The mixture was refluxed for 1 h and filtered while hot. The filter cake was washed with hot THF (2×30 mL). The combined filtrate was concentrated in vacuo to give crude 1-(3 -Iodophenyl)-3-isoquinoline-carboxaldehyde as an dark yellow oil (11.62 g, containing H2O). This oil was used without further purification. To a solution of crude aldehyde (11.62 g) in absolute EtOH (80 mL)was slowly added a solution of AgNO3 (7.28 g) in H2O (10 mL). To this stirred solution was added dropwise a solution of NaOH (5.80 g) in H2O (100 mL). The resulting black slurry was stirred at room temperature for 2 h. Then the mixture was filtered through a small Celite column. The filter cake was washed with ether. The ether was evaporated and the aqueous solution was made slightly acidic with concentrated HCl. The precipitate was collected by filtration, then washed with H2O. It was recrystallized from CH3CN, thereby affording 1-(3-iodophenyl)-3-isoquinolinecarboxylic acid as a yellow crystalline (2.22 g, 36%). mp 145-146° C. 1H NMR (DMSO-d6) d 7.37 (t, J=6.0 Hz, 1 H, aromatic), 7.65-7.71(m, 2 H, aromatic), 7.80 (t, J=4.8 Hz, 1 H, aromatic), 7.91 (d, J=6.6 Hz, 1 H, aromatic), 7.95 (d, J=6.3 Hz, 1 H, aromatic), 8.01 (s, 1 H, aromatic), 8.14 (d, J=6.0 Hz, 1 H, aromatic), 8.44 (s, 1 H, aromatic). HRMS Calcd for C16H10INO2 : 374.9756. Found: 374.9741.
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:16](OC)=[O:17])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][OH:17])[CH:3]=1
Reactant: COC(=O)c1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(CO)cc1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 108.9 %

Procedure:
A solution (80 mL) of methyl 5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (7.1 g) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L solution (42 mL) of diisobutylaluminum hydride in toluene was added dropwise over 30 min and the mixture was further stirred at −78° C. for 1 hr. 1 mol/L hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (yield 7.1 g, about 100%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:10][C:6]=2[CH:5]=[C:4]([C:29]#N)[CH:3]=1.CC(C[AlH]CC(C)C)C.CC[O:42]C(C)=O.O>C1COCC1>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:12](=[O:28])[NH:13][CH:14]=[CH:15][C:16]=3[NH:17][CH2:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[OH:20])[NH:10][C:6]=2[CH:5]=[C:4]([CH:29]=[O:42])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1cc(Br)c2nc(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)[nH]c2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Br)c2nc(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)[nH]c2c1
Temperature: -40 °C
Reaction time: 10 h
Yield: 43 %

Procedure:
To a solution of (S)-7-Bromo-2-{4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzimidazole-5-carbonitrile (150 mg, 0.31 mmol) in THF (50 mL) was added DIBAL-H (1 M toluene solution, 1.55 mL, 1.55 mmol) at −78° C. The reaction mixture was stirred at −40° C. for 10 h and cooled to −78° C. EtOAc (0.5 mL) was added. The reaction mixture was stirred for 30 min at −78° C. before water (1 mL) was added. The reaction mixture was warmed to room temperature and concentrated. The residue was passed through a small pad of celite. The filtrate was concentrated and purified by prep. HPLC to give the titled compound (67 mg, 43%). 1H NMR (400 MHz, CD3OD) δ 9.45 (1H, s), 7.62 (1H, s), 7.56 (1H, narrow d, J=1.6 Hz), 7.44 (1H, narrow d, J=1.0 Hz), 7.32–7.42 (2H, m), 7.24–7.30 (3H, m), 6.24 (1H, d, J=7.6 Hz), 5.01 (1H, m), 3.65–3.76 (2H, m). LCMS (M+H)+ m/z 487 (t=1.76 min.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([CH2:9][CH2:10][CH3:11])[CH2:4][C:5](=[O:8])[NH:6][N:7]=1.BrBr>CC(O)=O>[CH3:1][C:2]1[C:3]([CH2:9][CH2:10][CH3:11])=[CH:4][C:5](=[O:8])[NH:6][N:7]=1
Reactant: CCCC1CC(=O)NN=C1C
Agent: BrBr
Solvent: CC(=O)O
Product: CCCc1cc(=O)[nH]nc1C
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methyl-5-propyl-4,5-dihydropyridazin-3-one (16.7 g, 108 mmol) in HOAc (200 ml) heated to 85° C., is added Br2 (5.5 ml, 108 mmol) dropwise. After the addition, the mixture is stirred at 85° C. for 1 hour. The solvent is removed in vacuo and the residue is dissolved in EtOAc (250 ml) and washed with NaHCO3 (200 ml) followed by Na2S2O3 saturated solution (50 ml) and brine (200 ml). The organic phase is dried (Na2SO4) and evaporated. The resulting yellow solid is used in next step without further purification.
Reaction SMILES: [C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:8]([C:10]2[S:21][C:13]3[N:14]=[C:15]([CH2:18]OC)[N:16]([CH3:17])[C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(N(C(C)C)C(C)C)C.[NH2:41][C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1>C(Cl)Cl.N.C(Cl)Cl.C(O)C>[C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:8]([C:10]2[S:21][C:13]3[N:14]=[C:15]([CH2:18][NH:41][C:42]4[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=4)[N:16]([CH3:17])[C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COCc1nc2sc(C(=O)N(CCC(=O)OC)c3ccccc3)cc2n1C
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(C(=O)c1cc2c(nc(CNc3ccc(C#N)cc3)n2C)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.73 g (1.88 mmol) of 1-methyl-2-methoxymethylthieno[2,3-d]imidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide in 30 mL of methylene chloride were added dropwise at 5° C. 2.9 mL (2.9 mmol) of a 1-molar solution of boron tribromide in methylene chloride. After 16 hours stirring at ambient temperature, the mixture was washed with 20 mL of saturated sodium hydrogen carbonate solution, the organic phase was separated off, dried with sodium sulfate and filtered. The filtrate was mixed with 14 mL of N-ethyldiisopropylamine and 0.43 g (3.64 mmol) of 4-aminobenzonitrile. Then the methylene chloride was distilled off in vacuo, the residue obtained was heated to 50° C. for 1 hour and then the residual solvent was distilled off in vacuo. After chromatography (silica gel; methylene chloride/ethanol=99:1 to 97:3), a yellow oil was obtained which slowly solidified. Yield: 0.37 g (42% of theory); Rf value: 0.29 (silica gel; methylene chloride/ethanol=50:1+a few drops of ammonia).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:19][N:20](C(OCC2C=CC=CC=2)=O)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[CH3:29])[C@@H:14]([OH:18])[C:15]#[C:16][CH3:17])[C:9]1=[O:40])(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)C(C)C)(C)C.[F:58][C:59]([F:70])([F:69])[C:60]1[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=1)[C:63]([OH:65])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][CH2:19][C@H:13]([N:10]1[CH2:11][CH2:12][C@H:8]([NH:7][C:63](=[O:65])[C:62]2[CH:66]=[CH:67][CH:68]=[C:60]([C:59]([F:58])([F:70])[F:69])[CH:61]=2)[C:9]1=[O:40])[C@@H:14]([OH:18])[CH2:15][CH2:16][CH3:17]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CC#C[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)N1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Reaction time: 3 h

Procedure:
A solution of {(3S)-1-[(1S,2S)-(1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pent-3-ynyl)]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (1.16 g, 1.74 mmol) was dissolved in CH2Cl2 (16 mL) and treated with TFA (8 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo; this procedure was repeated. A portion (0.22 mmol) of the product amine was dissolved in CH2Cl2 (4 mL). The resultant solution was charged sequentially with N, N-diisopropylethylamine (0.16 mL, 0.88 mmol), 4-dimethylaminopyridine (24 mg, 0.22 mmol), meta-trifluoromethylbenzoic acid (41 mg, 0.22 mmol), and BOP (96 mg, 0.22 mmol). The reaction was stirred for 12 h and partitioned between EtOAc and sat. NH4Cl. The organic phase was washed with sat. NaHCO3 and brine, and then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in MeOH (6 mL). The resultant solution was charged with 5% Pd/C, Degussa style (50 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was purified by reverse-phase HPLC to afford the title compound as a white powder after lyopholization. MS found: (M+H)+=506.6.