Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>>[Br-:1].[CH2:2]1[N+:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:4][CH2:3]1
Reactant: BrCCCBr
Reactant: C1CCNC1
Product: C1CC[N+]2(C1)CCC2
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-dibromopropane (287 ml) was heated to 45° C. and pyrrolidine (23.4 ml) added over 4 hours. The mixture was then cooled to room temperature and evaporated to dryness on a rotary evaporator. To the residual oil was added water (200 ml) and the small organic lower layer separated. The solution was washed with dichloromethane (20 ml). The aqueous layer was basified by the addition of potassium carbonate (42.8 g) and extracted with dichloromethane (2×80 ml). The combined organic extracts were dried over magnesium sulphate and evaporated to dryness on a rotary evaporator. The residue was triturated by the addition of acetone (30 ml) and stirred overnight. The solid was filtered, washed with acetone (30 ml) and dried in a vacuum oven at 40° C.
Reaction SMILES: [I:1]I.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)([O-:28])(=[O:27])=[O:26].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[I+:1][C:22]1[S:25][CH:19]=[CH:24][CH:23]=1
Reactant: c1ccsc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: II
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: c1csc([I+]c2cccs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.2 %

Procedure:
Iodine (862 mg, 3.39 mmol), m-CPBA (1.48 g, 8.62 mmol) and thiophene (1 g. 11.88 mmol) were combined in dry dichloromethane (66 mL). p-Toluene sulfonic acid (2.19 g, 11.56 mmol) was added to the solution at room temperature, and the mixture was stirred for 16 hours at room temperature. The solution was evaporated to dryness, and the resulting crude product was subjected to flash chromatography (5-10% MeOH/CH2Cl2)) to yield dithienyliodonium tosylate (11.2%) as a brown colored sticky mass.
Reaction SMILES: O[C:2]1([CH:12]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[C:13]2[N:17]=[CH:16][NH:15][N:14]=2)[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.S(Cl)(Cl)=O>ClCCl>[CH:3]12[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]([CH2:8]3)[C:2]1=[C:12]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[C:13]1[N:17]=[CH:16][NH:15][N:14]=1)[CH2:4]2
Reactant: N#Cc1ccc(C(c2nc[nH]n2)C2(O)C3CC4CC(C3)CC2C4)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(C(=C2C3CC4CC(C3)CC2C4)c2nc[nH]n2)cc1
Reaction time: 2 h
Yield: 62.2 %

Procedure:
9 g of crude 4-[2-hydroxyadamant-2-yl-1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved at 0° in 50 ml of dichloromethane and stirred at 0° with 24 ml of thionyl chloride for 1 hour. Then the mixture is concentrated to dryness in an oil pump vacuum, dissolved in 50 ml of dichloromethane, stirred for 2 hours with 32 ml of triethylamine, diluted with water, extracted three times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, yielding 5.3 g of 4-[2-adamantylidene-1-(1,2,4-triazolyl)methyl]benzonitrile as the free base, mp 130°, which is converted with hydrochloric acid into the hydrochloride, mp 105°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]=[O:15])[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:22]C)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[CH2:34]1COC[CH2:35]1.[CH2:39]([Mg]Br)C>C(OCC)C.[Ti+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C:14]3([OH:15])[CH2:35][CH2:34]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][C:21]([CH3:39])([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:25]=3)[CH3:22])=[O:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC=O)c1=O)c1cccc(C(F)(F)F)c1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Solvent: CCOCC
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC2(O)CC2)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
72 mg (0.14 mmol) of 2-[3-(4-chlorophenyl)-4-(2-oxoethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 401 together with 4 mg (0.014 mmol) of titanium(IV) isopropylate are dissolved in 0.45 ml of diethyl ether and 0.3 ml of THF and treated at RT within 1 hr with 108 μl (0.32 mmol) of ethylmagnesium bromide (3 M solution in diethyl ether), diluted with 0.4 ml diethyl ether. This is stirred for a further 10 mins at RT. For the workup, the mixture is poured into 10 ml of ice-cold 10% sulphuric acid and extracted twice with 10 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 5 mg (7% of theory) of the target compound are thus obtained
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[N:9]1C=CC=C[CH:10]=1>>[C-:3]#[N:4].[Br:1][C:2]1[C:3]([C:10]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Br)c1
Reactant: c1ccncc1
Product: N#Cc1ncccc1Br
Product: [C-]#N

Procedure:
In Scheme I is described the preparation of pyridine intermediates (5), (6), and (7). In Scheme I, Step 1,3-bromopyridine (1) is oxidized to 3-bromo-pyridine-N-oxide (2). In Scheme I, Step 2, cyanide substitution gives 3-bromo-pyridine-2-carbonitrile (3). The nitrile of formula (3) is hydrolyzed in Step 3 to the carboxylic acid and esterified with acid catalysis to the ester of formula (4). In Scheme I, Step 4, the ester is reduced to the pyridinylmethanol of formula (5) using sodium borohydride. The pyridinylmethanol is converted to the mesylate of formula (6) with methanesulfonyl chloride (Step 5) or to the pyridinylmethyl chloride of formula (7) using thionyl chloride (Step 6).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]2[C:14]3[C:15]([OH:30])=[C:16]4[C:23](=[O:24])[C:22]5[C:25]([OH:29])=[CH:26][CH:27]=[CH:28][C:21]=5[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[C@@H:12]([C:31]([O:33][CH3:34])=[O:32])[C@@:11]([OH:36])([CH3:35])[CH2:10]2)[CH2:5][C@H:4]([N:37]([CH3:39])[CH3:38])[C@@H:3]1[O:40][C@@H]1O[C@@H](C)[C@@H](O[C@@H]2O[C@@H](C)C(=O)CC2)[C@@H](O)C1.Cl.CO.[OH-].[Na+].O>CC(C)=O.CO>[CH3:1][CH:2]1[O:7][CH:6]([O:8][CH:9]2[C:14]3[C:15]([OH:30])=[C:16]4[C:23](=[O:24])[C:22]5[C:25]([OH:29])=[CH:26][CH:27]=[CH:28][C:21]=5[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[CH:12]([C:31]([O:33][CH3:34])=[O:32])[C:11]([OH:36])([CH3:35])[CH2:10]2)[CH2:5][CH:4]([N:37]([CH3:39])[CH3:38])[CH:3]1[OH:40]
Reactant: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@H](O)[C@H](O[C@H]5CCC(=O)[C@H](C)O5)[C@H](C)O4)[C@H](C)O2)C[C@@]1(C)O)C(=O)c1c(O)cccc1C3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: COC(=O)C1c2cc3c(c(O)c2C(OC2CC(N(C)C)C(O)C(C)O2)CC1(C)O)C(=O)c1c(O)cccc1C3=O
Yield: 61.8 %

Procedure:
To a solution of 100 mg of auramycin A in 20 ml of acetone and 1 ml of methanol was added 1 ml of 0.2 N hydrochloric acid-methanol with stirring and reacted at room temperature for 40 minutes. The reaction mixture was neutralised by dilute sodium hydroxide solution and 20 ml of water was added and extracted with 20 ml of chloroform twice. The extracts were combined and concentrated to a small volume in vacuo. The concentrate was chromatographed by a column packed with silica gel (chloroform:methanol, 95:5). The fractions containing auramycin D were concentrated in vacuo to give 43 mg of auramycin D.
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].CC#N.CCN(CC)CC.[Cl:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=1>O>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][NH:5][CH2:4][C:3]([F:7])([F:6])[F:2])=[CH:21][CH:20]=1
Reactant: NCC(F)(F)F
Reactant: ClCc1ccc(Cl)nc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)CNCc1ccc(Cl)nc1
Temperature: 0 °C
Yield: 92.7 %

Procedure:
In 15 ml of water was dissolved 12.55 g of 2,2,2-trifluoroethylamine hydrochloride, followed by addition of 68 ml of CH3CN, and further 9.35 g of Et3N and then 3.00 g (0.0185 mole) of 6-chloro-3-pyridylmethyl chloride under cooling with ice-water and stirring. The mixture was stirred at room temperature for one hour, at 50° C. for one hour and at 70° C. for 90 hours. The CH3CN was distilled off, and the residue was followed by addition of NaHCO3 and then extracted with CH2Cl2 (100 ml×3). The extract was dried over MgSO4 and distilled to remove CH2 Cl2 . To the residue was added 100 ml of Et2O and the resulting unsoluble matter was filtered off. The filtrate was concentrated to give 3.85 g of the title compound as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][CH2:16][CH:10]3[C:9]2=[O:17])=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:38])[C:20]([C:22]1[N:31]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:25]2[N:26]=[C:27](Cl)[N:28]=[CH:29][C:24]=2[CH:23]=1)=[O:21]>>[CH3:18][N:19]([CH3:38])[C:20]([C:22]1[N:31]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:25]2[N:26]=[C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]5[CH2:14][CH2:15][CH2:16][CH:10]5[C:9]4=[O:17])=[CH:6][N:7]=3)[N:28]=[CH:29][C:24]=2[CH:23]=1)=[O:21]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCC1
Reactant: Nc1ccc(N2CCN3CCCC3C2=O)cn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN5CCCC5C4=O)cn3)nc2n1C1CCCCC1
Yield: 64.7 %

Procedure:
Following general N—C coupling procedure 1, 2-(6-amino-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-one (0.050 g, 0.215 mmol) was combined with 2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.066 g, 0.215 mmol, 1.0 eq), and gave 7-Cyclohexyl-2-[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as a beige solid (75 mg, 0.139 mmol), in 65% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.52 (m, 4H) 1.72-1.90 (m, 2H) 1.90-2.00 (m, 6H) 2.00-2.18 (m, 2H) 2.21-2.39 (m, 1H) 2.52-2.82 (m, 3H) 2.95-3.14 (m, 3H) 3.15-3.27 (m, 8H) 3.42 (t, J=8.28 Hz, 1H) 3.66 (dt, J=11.54, 4.02 Hz, 1H) 3.95 (ddd, J=11.80, 9.29, 4.52 Hz, 1H) 4.27-4.41 (m, 1H) 6.45 (s, 1H) 7.69 (dd, J=9.03, 2.51 Hz, 1H) 8.11 (5, 1H) 8.25 (d, J=2.51 Hz, 1H) 8.65 (d, J=9.03 Hz, 1H) 8.73 (s, 1H); HRMS calc for m/z=503.2883. Found m/z=503.2892 (M+H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36](OC)=[C:37]([OH:39])[CH:38]=1.[CH2:42]1COCC1>>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])[CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:42]
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Reactant: COc1ccc(N)cc1O
Reactant: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(C)c(O)c2)C(=O)N3)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (as prepared in Example 1, 30 mg, 0.072 mmol) and THF (1 mL). To the resulting solution was added 5-amino-2-methoxyphenol (13.3 mg, 0.1082 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 67% (25 g, 0.048 mmol) of the title compound.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1.[C:22]1(C)C=CC=C[CH:23]=1>COCCO[AlH2-]OCCOC.[Na+]>[NH:8]1[CH2:9][CH2:10][O:11][CH2:6][CH2:7]1.[C:12]1([CH:5]([O:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=2[CH:22]=[CH2:23])[CH:6]2[O:11][CH2:10][CH2:9][NH:8][CH2:7]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccccc1OC(c1ccccc1)C1CNCCO1
Reactant: Cc1ccccc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Product: C1COCCN1
Product: C=Cc1ccccc1OC(c1ccccc1)C1CNCCO1
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
To a solution of morpholinone 2 (0.255 g, 0.825 mmol) in toluene (10 mL), Red-Al (65% solution in toluene (0.8 mL, 2.55 mmol), was added dropwise at 0° C. over 20 min. The reaction mixture was stirred at 0-5° C. for 2.5 h. Excess Red-Al was destroyed by dropwise addition of 2 M NaOH solution (2.7 mL). The layers were separated and the aqueous layer was diluted with water (20 mL) and extracted with toluene (2×15 mL). The combined organic extract was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified on a column of silica gel using 10% methyl alcohol in ethyl acetate to give morpholine compound 3 (2-[Phenyl-(2-vinyl-phenoxy)-methyl]-morpholine) as a viscous colorless oil (0.154 g, 63%). 1H NMR (CDCl3) δ: 7.46-7.18 (m, 7H), 7.01 (m, 1H), 6.84 (t, 1H), 6.68 (d, 1H), 5.78 (dd, 1H), 5.29 (dd, 1H), 5.12 (d, 1H), 3.98-3.86 (m, 2H), 3.64 (dt, 1H), 2.86-2.72 (m, 2H), 2.66-2.54 (m, 2H); MS (ES) 296.1 [C19H21NO2+H]+; HPLC purity (94.3%); Analysis: Calcd. C19H21NO2.0.5H2O: C, 74.91; H, 7.23; N, 4.60. Found: C, 75.41; H, 7.09; N, 4.95.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:7]=12
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Reactant: BrCC1CC1
Product: Cc1c(C)n(CC2CC2)c2c(Cl)nccc12
Yield: 92 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and (bromomethyl)cyclopropane, the titled compound was obtained as a white solid. (Yield: 92%)
Reaction SMILES: [CH2:1]=[C:2]([CH:10]([OH:15])[C:11]([Cl:14])([Cl:13])[Cl:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(=O)C.[Na+]>C([O-])(=O)C.[Na+].C(O)(=O)C>[CH2:1]=[C:2]([CH:10]([O:15][C:16](=[O:18])[CH3:17])[C:11]([Cl:14])([Cl:13])[Cl:12])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C(=O)OCCCC)C(O)C(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C=C(C(=O)OCCCC)C(OC(C)=O)C(Cl)(Cl)Cl
Temperature: 120 °C
Yield: 91.4 %

Procedure:
To 1173.0 g of butyl 2-methylene-3-hydroxy-4,4,4-trichlorobutyrate (91% pure) charged in a 2-liter, 3-neck round bottom flask equipped with a mechanical stirrer, thermometer, and a condenser were added 520.0 g of acetic anhydride and 7.0 g of sodium acetate. The reaction mixture was heated at 120° C. for three hours. Unreacted acetic anhydride and formed acetic acid were stripped off under vacuum at <80° C./0.6 mm Hg. After cooling to room temperature, the solid sodium acetate that had settled to the bottom of the flask was separated. 1236.1 g of acetylated product was obtained, 91.3% purity (GC analysis), 91.4% yield. The product structure was confirmed by NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.[OH:18][CH2:19][C:20]1[C:21](B(O)O)=[CH:22][S:23][CH:24]=1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:21]3[C:20]([CH2:19][OH:18])=[CH:24][S:23][CH:22]=3)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2n1-c1cccc(I)c1
Reactant: OCc1cscc1B(O)O
Product: Nc1nc2ccccc2n1-c1cccc(-c2cscc2CO)c1
Yield: 56 %

Procedure:
2-Amino-1-[3-(3-hydroxymethyl-4-thienyl)-phenyl]-benzimidazole was synthesized as above with amino-1-(3-iodophenyl)-benzimidazole and 4-hydroxymethyl-3-thienylboronic acid as starting materials. Yield 56%, mp. 106°-108° C.
Reaction SMILES: CN1CC2C(NCC2)C1.[CH3:10][N:11]1[CH2:18][CH:17]2[CH:13]([N:14]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[CH2:15][CH2:16]2)[CH2:12]1.[C:26]([N:33]1[CH:37]=[CH:36]N=[CH:34]1)(N1C=CN=C1)=[O:27].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]2CCNC[CH2:46]2)=[CH:41][CH:40]=1>>[CH3:10][N:11]1[CH2:18][CH:17]2[CH:13]([N:14]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:33]4[CH2:34][CH2:46][CH:45]([C:42]5[CH:43]=[CH:44][C:39]([Cl:38])=[CH:40][CH:41]=5)[CH2:36][CH2:37]4)=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:16]2)[CH2:12]1
Reactant: CN1CC2CCN(c3ccc(N)cc3)C2C1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN1CC2CCNC2C1
Product: CN1CC2CCN(c3ccc(NC(=O)N4CCC(c5ccc(Cl)cc5)CC4)cc3)C2C1

Procedure:
5-Methyloctahydropyrrolo[3,4-b]pyrrole (EP 0 393 424) was initially converted as described in Example 3 into 4-(5-methylhexahydropyrrolo[3,4-b]pyrrol-1-yl)-phenylamine and then reacted with carbonyldiimidazole and subsequently with 4-(4-chlorophenyl)piperidine. The product with the molecular weight of 439.01 (C25H31ClN4O); MS (ESI): 439 (M+H+) was obtained in this way.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12]>COCCOC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][Br:12]
Reactant: BrP(Br)Br
Reactant: OCc1cc(F)ccc1Br
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-bromo-5-fluorophenyl)methanol (11, 4.10 g, 20.0 mmol) in dry DME (40 mL) at 0° C. was added a solution of PBr3 (3.25 g, 12.0 mmol) in dry DME (40 mL) dropwise. The mixture was then slowly warmed up to RT and stirred at for another 3 h. The mixture was diluted with water (100 mL), and extracted with 1:1 petroleum-ether-EtOAc (100 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated to give 1-bromo-2-(bromomethyl)-4-fluorobenzene (12).
Reaction SMILES: C(OCC)C.[NH2:6][C:7]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[C:21]([N:28]=C(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=2)=[O:18])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[Cl:42]CCl>CO>[ClH:42].[NH2:6][C:7]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[C:21]([NH2:28])[N:20]=2)=[O:18])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc(C(=O)c2nc(N=C(c3ccccc3)c3ccccc3)c3ccccn23)ccc1N
Reactant: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cc(C(=O)c2nc(N)c3ccccn23)ccc1N
Product: Cl
Reaction time: 1 h
Yield: 84 %

Procedure:
8 ml of hydrochloric ethyl ether (1 M) are added to the solution of 1.92 g (4.05 mmol) of the imine obtained in stage A above in a mixture of 40 ml of dichloromethane and 8 ml of methanol. The clear orange medium becomes dark red and then a precipitate forms. After 1 hour at ambient temperature, the precipitate is filtered and then washed with dichloromethane and dried under vacuum at 50° C., to give 1.18 g (84%) of the hydrochloride in the form of an ochre powder.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]([NH:5][CH2:6][C:7]([O:9][CH:15]1[CH2:16][C:17](=[O:18])[NH:13][C:14]1=[O:19])=[O:8])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CNC(=O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1CC(OC(=O)CNC(=O)C(F)(F)F)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Trifluoroacetylglycine (684 mg) and N-hydroxysuccinimide (480 mg) in 5 ml of dry CH2Cl2 at 50° C. are treated with a solution of 915 mg dicyclohexylcarbodiimide (4.43 mmol) in 5 ml of CH2Cl2. The mixture is stirred at room temperature overnight, is then filtered and evaporated to produce the named compound which can be used in subsequent reactions without further purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:26]1OCCOCCOCCOCCOC1.Cl[S:42]([C:45]1[O:49][C:48]([C:50]([O:52][CH3:53])=[O:51])=[CH:47][CH:46]=1)(=[O:44])=[O:43]>O1CCCC1>[O:51]1[CH2:26][CH2:53][O:52][CH:50]1[C:48]1[O:49][C:45]([S:42]([N:14]2[C:10]([C:9]3[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=3)=[C:11]([F:25])[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13]2)(=[O:44])=[O:43])=[CH:46][CH:47]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: C1COCCOCCOCCOCCO1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccc(C3OCCO3)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a suspension of sodium hydride (60% in oil, 155 mg) in tetrahydrofuran (10 mL) was added tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (1.04 g) under ice-cooling and the mixture was stirred for 15 min. 15-Crown-5 (354 mg) and a solution of methyl 5-(chlorosulfonyl)-2-furoate in tetrahydrofuran (2 mL) were added dropwise and the mixture was further stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1) to give the title compound as a brown oil (yield 1.33 g, 78%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=2[C:19]([OH:21])=O)=[CH:5][CH:4]=1.[O:22]=[C:23]1[CH:28]([N:29]2C(=O)C3C(=CC=CC=3NCCOC)C2=O)[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1>>[O:22]=[C:23]1[CH:28]([N:29]2[C:19](=[O:21])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][C:10]=3[NH:9][CH2:8][C:6]3[O:7][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)[C:13]2=[O:15])[CH2:27][CH2:26][C:25](=[O:45])[NH:24]1
Reactant: COCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1cccc(NCc2ccc(CO)o2)c1C(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4ccc(CO)o4)c3C2=O)C(=O)N1

Procedure:
3-[(5-Hydroxymethyl-furan-2-ylmethyl)-amino]-phthalic acid (3.04 mmol) was treated in the same manner as described above for the synthesis of 2-(2,6-Dioxo-piperidin-3-yl)-4-(2-methoxy-ethylamino)-isoindole-1,3-dione. The solid yellow residue was purified by chromatography (SiO2, 60% ethyl acetate/hexanes) to give 0.40 g of solid which was dissolved in methylene chloride (70 ml) and washed with saturated NaHCO3 (2×100 ml), brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated leaving 0.32 g (27%) of product as a yellow solid: mp 172-174° C.; 1H NMR (DMSO-d6) δ 11.11 (s, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.06 (d, J=7.0 Hz, 1H), 6.99 (t, J=6.0 Hz. 1H), 6.27 (d, J=2.9 Hz, 1H), 6.20 (d, J=2.9 Hz, 1H), 5.18 (t, J=5.7 Hz, 1H), 5.07 (dd, J=5.2 and 12.5 Hz, 1H), 4.54 (d, J=5.9 Hz, 2H), 4.33 (d, J=5.7 Hz, 2H), 2.96-2.82 (m, 1H), 2.63-2.46 (m, 2H), 2.06-1.99 (m, 1H); 13C NMR (DMSO-d6) δ 172.80, 170.07, 168.80, 167.24, 155.00, 151.10, 145.79, 136.08, 132.12, 117.57, 111.04, 109.71, 108.06, 107.60, 55.63, 48.60, 39.05, 30.98, 22.13; Anal. Calcd. For C19H17N3O6: C, 59.53; H, 4.47; N, 10.96. Found: C, 59.30; H, 4.54; N, 10.70.