Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.[C:10](O)(=O)[CH:11](C)[CH3:12].N>OS(O)(=O)=O.[N+]([O-])([O-])=O.[Ag+]>[CH:11]([C:2]1[NH:1][CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=1)([CH3:12])[CH3:10]
Reactant: CC(C)C(=O)O
Reactant: COC(=O)c1c[nH]cn1
Agent: [Ag+]
Agent: N
Agent: O=S(=O)(O)O
Product: COC(=O)c1c[nH]c(C(C)C)n1
Temperature: 25 °C

Procedure:
A solution of methyl 1H-imidazole-4-carboxylate (5.0 g, 39.68 mmol), AgNO3 (4.0 g, 23.81 mmol), isobutyric acid (10.4 g, 119.1 mmol) in 10% H2SO4 (150 ml) was heated at 80° C. for 15 min. An aqueous solution of (NH4)2S2O8 (28.0 g, 119.1 mmol) was added to the mixture dropwise in 15 min at 80° C. The reaction mixture was cooled to RT and poured into ice. The mixture was basified with aqueous ammonia (pH 9) and extracted with EtOAc (500 ml). The organic layer was concentrated and the residue was purified by flash chromatography. Yield 1.5 g. 1H-NMR (400 MHz; CDCl3): δ 1.36 (d, 6H), 3.05-3.14 (m, 1H), 3.87 (s, 3H), 7.62 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:20]([OH:22])=[O:21])[C:3]=1[CH3:31].[Si](C=[N+]=[N-])(C)(C)[CH3:33].BrC1C2C(=CC=CC=2)C(C2C=CC(Cl)=CC=2)=C(C(O[Si](C(C)(C)C)(C)C)C=O)C=1C>C(Cl)Cl.CO>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([CH:19]([O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])[C:20]([O:22][CH3:33])=[O:21])[C:3]=1[CH3:31]
Reactant: Cc1c(C(O[Si](C)(C)C(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1Br
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Cc1c(C(C=O)O[Si](C)(C)C(C)(C)C)c(-c2ccc(Cl)cc2)c2ccccc2c1Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(O[Si](C)(C)C(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
Crude 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)acetic acid 0.740 g, 1.4 mmol)was dissolved in 20 mL DCM-MeOH (50-50, v/v) and combined with TMS-diazomethane solution (7.0 mL, 2.0 M in hexanes) and allowed to stir 6 hrs at 23° C. The reaction was cooled on ice and quenched by the slow addition of TFA (500 μL) which simultaneously removed the yellow color from the reaction mixture. Mixture was diluted with DCM and washed with brine, then dried and concentrated in vacuo. Purification by silica gel chromatography with EtOAc in hexanes provided purified material (537.8 mg, 78% yield) from the 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)acetaldehyde. 1H-NMR: (400 MHz, MeOH-d4): δ 8.39 (d, J=8.0 Hz, 1H); 7.58-7.54 (m, 1H); 7.50-7.47 (m, 2H); 7.37-7.33 (m, 2H); 7.27-7.21 (m, 2H); 5.31 (s, 1H); 3.69 (s, 3H); 2.67 (s, 3H); 0.83 (s, 9H); −0.04 (s, 3H); −0.27 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.P(Cl)(Cl)([Cl:15])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Oc1ncnc2ccc(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc2ncnc(Cl)c2c1

Procedure:
Preparation D2, Step 2: 6-fluoroquinazolin-4-ol (1.00 g, 6.09 mmol, 1 eq.), phosphorus oxychloride (3.41 mL, 36.6 mmol, 6 eq.) and triethylamine (5.09 mL, 36.6 mmol, 6 eq.) were mixed at room temperature and then refluxed for 2 hours. Worked up by stripping 3 times from methylene chloride. The residue was dissolved in methylene chloride (25 mL) and rinsed 3 times with saturated sodium bicarbonate (25 mL) and 1× with brine (25 mL). The organic layer was dried (sodium sulfate) and stripped to give a crude oil. Purified over silica gel in 9:1 to 3:1 hexanes/ethyl acetate. Obtained 4-chloro-6-fluoroquinazoline (0.96 g) as a tan solid. Yield=86%. LCMS detects (M+H)+=183.16.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[C:6](=[O:26])[N:7]([CH2:20][C:21]([O:23]CC)=[O:22])[CH:8]=[CH:9][C:10]=1[S:11](=[O:19])(=[O:18])[NH:12][CH2:13][CH:14]1[CH2:17][CH2:16][CH2:15]1.Cl>O.CO.C1COCC1>[NH2:4][C:5]1[C:6](=[O:26])[N:7]([CH2:20][C:21]([OH:23])=[O:22])[CH:8]=[CH:9][C:10]=1[S:11](=[O:18])(=[O:19])[NH:12][CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)Cn1ccc(S(=O)(=O)NCC2CCC2)c(N)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(S(=O)(=O)NCC2CCC2)ccn(CC(=O)O)c1=O
Reaction time: 2 h

Procedure:
Lithium hydroxide hydrate (40 mg, 0.952 mmol) was added to a stirred solution of 3-amino-4-(N-cyclobutylmethylsulfamoyl)-1-ethoxycarbonylmethyl-2-pyridinone (170 mg, 0.476 mmol) in 1:3:3 water/methanol/THF (14 mL). After 2 h, the reaction was acidified with 1M HCl and the mixture was partitioned between chloroform and brine. The organic layer was dried (Na2SO4) and evaporated to give the title compound as a solid;
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:22]4[CH:23]=[CH:24][S:20][CH:21]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Reactant: OB(O)c1ccsc1
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4ccsc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and thiophene-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by chromatography on silica gel (7% methanol in CH2Cl2) afforded 1-isobutyl-8-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 235–236° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C@@H:8]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@H:10]([C@@H:11]([O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[CH2:12][C@@H:13]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:23])[CH2:19][CH2:20][CH:21]=O)[CH2:9]1.O1C[CH2:43][CH2:42][CH2:41]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C@@H:8]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@H:10]([C@@H:11]([O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39])[CH2:12][C@@H:13]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:23])[CH:19]=[CH:20][CH:21]=[C:42]([CH3:43])[CH3:41])[CH2:9]1
Reactant: COCCOCO[C@@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCC=O)CC[C@H]4[C@@H]3C[C@H](OCOCCOC)[C@@H]2C1
Reactant: C1CCOC1
Product: COCCOCO[C@@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)C=CC=C(C)C)CC[C@H]4[C@@H]3C[C@H](OCOCCOC)[C@@H]2C1

Procedure:
1.4 g of 3α,6α-bis(β-methoxyethoxymethoxy)-5β-cholan-24-al (prepared as described in my U.S. patent application Ser. No. 236,160) was dissolved in 5 ml of tetrahydrofuran, and this solution was added dropwise to the deep red ylid solution (as described in Example I), and the chain extension reaction carried out in the same manner as in Example I. The residue remaining after evaporation of petroleum ether was the 3α,6α-bis(β-methoxyethoxymethoxy)-5β-cholest-24-ene.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([CH3:16])([CH3:15])[CH2:6][C:5]1=O)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([CH3:16])([CH3:15])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)CC(C)(C)c2cc(N)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N1CCC(C)(C)c2cc(N)ccc21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(1-Isopropyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amine (Compound 1, 1.3 g, 5.6 mmol) was dissolved in tetrahydrofuran (80 mL) and the solution was cooled to 0° C. under argon. The solution was treated with 1M lithium aluminum hydride (15.0 mL, 15.0 mmol) and the reaction stirred at 0° C. to room temperature for 16 hours. The reaction was cooled to 0° C., poured onto ice and extracted with ether (2×). The combined organic extracts were washed with brine and dried (MgSO4). The filtered solution was concentrated under reduced pressure and the crude product was purified by silica gel chromatography (5% ethyl acetate in hexanes) to give the title compound as an oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[C:13]([I:25])[CH:12]=[CH:11][N:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:8][C:9]1[C:14]([CH2:15][CH2:16][NH2:17])=[C:13]([I:25])[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)NCCc1c(I)ccnc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1c(I)ccnc1F
Reaction time: 4 h

Procedure:
TFA (0.677 ml, 8.79 mmol) was added into a solution of tert-butyl 2-(2-fluoro-4-iodopyridin-3-yl)ethylcarbamate (1.61 g, 4.40 mmol) in DCM (6.28 ml, 4.40 mmol). After 4 h, LCMS showed mainly starting material. 1 mL of TFA was added. After 16 h, the reaction was diluted with DCM, neutralized with sat. NaHCO3. The product was extracted with DCM. The organic layer was washed with brine, dried over MgSO4, and concentrated to afford a creamy colored solid, 2-(2-fluoro-4-iodopyridin-3-yl)ethanamine MS Calcd for C7H8FIN2: [M]+=266. Found: [M+H]+=267. HRMS Calcd for C7H8FIN2: [M+H]+=266.9789. Found: [M+H]+=266.9802.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:7])[F:1])(=[O:19])=[O:18]
Reactant: OCCCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC(F)(F)F
Reaction time: 0.5 h
Yield: 988 %

Procedure:
A stirred solution of 4,4,4-trifluorobutanol (35 g; 0.027 mol) and triethylamine (28.3 g; 0.280 mol) in 200 ml of dichloromethane was treated dropwise at 0° C. with a solution of methanesulphonyl chloride (32.1 g; 0.280 mol) in 100 ml of dichloromethane. After the end of the addition, the mixture was stirred for a further 30 min, then poured onto ice and the phases were subsequently separated. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. 55 g of crude 4,4,4-trifluorobutyl methanesulphonate were obtained as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[NH:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:37](Cl)([CH3:39])=[O:38].O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[N:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[N:11]([C:37](=[O:38])[CH3:39])[CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: O=C1N(c2cc(Cl)nc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCNN12
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCCC2(Cc3ccc(Br)cc3)C(=O)N(c3cc(Cl)nc(Cl)c3)C(=O)N12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the compound from Example 100 (80 mg) in dry THF (2 mL) under N2 was added DIEA (0.073 mL) followed by AcCl (0.024 mL) and the reaction mixture stirred at room temperature for 18 hours. Water (10 mL) and EtOAc (10 mL) were added and the mixture was shaken. The aqueous phase was then separated and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel; EtOAc/hexanes; chromatotron) to give the titled compound (71 mg). MS (m/z) 513 (MH+); mp. 91° C.
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:14])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)=[O:3].[CH3:15][Zn]C>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:14])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:15]
Reactant: COC(=O)C1(C)CCC(C(=O)Cl)CC1
Reactant: C[Zn]C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C1(C)CCC(C(C)=O)CC1
Temperature: 38 °C

Procedure:
To a deoxygenated solution of methyl 4-(chlorocarbonyl)-1-methylcyclohexanecarboxylate (7.282 g, 33.3 mmol) and palladium (II) acetate (374 mg, 1.665 mmol) in 1,4-dioxane (200 mL) was added dimethylzinc (2.0 M in toluene, 16.65 mL, 33.3 mmol). The black reaction mixture was heated under an inert atmosphere at 38° C. for 15 hours before being diluted with water (30 mL). The resulting suspension was filtered twice through CELITE. The filtrate was dried over magnesium sulfate and concentrated under reduced pressure. The resiude was purified by chromatography on silica gel (5-45% ethyl acetate/hexanes) to afford methyl 4-acetyl-1-methylcyclohexanecarboxylate. MS ESI calc'd. for C11H18O3 [M+H]+ 199. found 199.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25](Cl)=[O:26].O>ClCCl>[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH:13][C:25]([C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)=[O:26]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1ccc2ccccc2c1
Temperature: 2 °C
Yield: 9560.7 %

Procedure:
Dichloromethane (66 mL) and then triethylamine (14.6 mL, 105 mmol, 2.0 eq.) were added to glycine methyl ester hydrochloride (6.61 g, 52.5 mmol, 1.0 eq.). A white precipitate appeared on the addition of the triethylamine, and the solution became a lot thicker. The mixture was stirred and cooled to 2° C. using an ice/water bath. A solution of 2-naphthoyl chloride (10.07 g, 52.5 mmol, 1.0 eq.) in dichloromethane (33 mL) was added over 15 minutes. The pale brown mixture was stirred for 25 hours at 5° C. Water (100 mL) was added and the mixture was stirred rapidly for 30 minutes at room temperature. The layers were separated. The organic layer was washed with sodium hydroxide (1 M, 100 mL) and then evaporated to dryness using a rotary evaporator to give an off-white solid (1221 g, 96%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1B(O)O.[Na+].[Na+].[Na+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.C(NC(C)C)(C)C>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cncc(-c2ccc(F)cc2F)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 111.4 %

Procedure:
To a solution of 5-bromonicotinic acid (0.5 g, 2.48 mmol) in DMF (7.4 mL) and water (2.5 mL) were added (2,4-difluorophenyl)boronic acid (0.43 g, 2.72 mmol), palladium acetate (27.8 mg, 0.12 mmol), 3,3′,3″-phosphinidynetris (benzensulfonic acid) trisodium salt (0.21 g, 0.37 mmol) and diisopropylamine (1.23 mL, 8.66 mmol). The mixture was heated to 80° C. After 1.5 h, the mixture was cooled to ambient temperature and filtered. The filtrate was purified by reverse chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid). The product was converted to hydrochloride salt by adding HCl (2.0 M in ether) and concentrated to give the hydrochloride salt of the title compound (0.65 g). MS 236.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].B.C1COCC1.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CCc1ccc(F)c(Cl)c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1ccc(F)c(Cl)c1
Yield: 55.6 %

Procedure:
To a solution of (3-chloro-4-fluoro-phenyl)-acetonitrile (1 g, 5.9 mmol) in THF (30 mL) was slowly added BH3-THF (8.26 ml). After the addition, the reaction mixture was heated to reflux for 3 hours. MeOH was added to quench the reaction and volatiles were removed under reduced pressure. The crude product was first dissolved in aq. HCl solution (30 mL) and impurities were removed by exaction with EtOAc (2×30 mL). The pH of the aqueous solution was adjusted to 8 using K2CO3 and the mixture was then extracted with DCM (3×30 mL). The combined organic layers were then washed with brine, dried with anhy. Na2SO4, filtered and concentrated in vacuo to give the title compound (570 mg, 55.8%) as an oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]3[CH:14]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[CH:12]=[N:11][C:9]=3[NH:10][C:6]=2[CH:5]=[N:4][C:3]=1[C:21]#[N:22].[H-].[Na+].Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.O>[Br:1][C:2]1[C:7]2[C:8]3[CH:14]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[CH:12]=[N:11][C:9]=3[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:6]=2[CH:5]=[N:4][C:3]=1[C:21]#[N:22]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cn1cc(-c2cnc3[nH]c4cnc(C#N)c(Br)c4c3c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cnc3c(c2)c2c(Br)c(C#N)ncc2n3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.9 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (547 mg, 1.55 mmol) in DMF (25 ml) under a flow of nitrogen was added sodium hydride (93 mg, 60% dispersion in mineral oil, 2.39 mmol). After 20 min, a yellow solution had formed and (2-chloromethoxyethyl)-trimethyl-silane (358 μL, 2.02 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 days, then diluted with water and sonicated. The resultant solid was collected by filtration and triturated with methanol to afford the title compound as a yellow solid (404 mg, 54%). 1H NMR (CDCl3, 300 MHz): δ 9.13 (s, 1H), 9.04 (d, J=2.2 Hz, 1H), 8.95 (d, J=2.1 Hz, 1H), 7.93-7.88 (m, 1H), 7.83-7.77 (m, 1H), 6.06 (s, 2H), 4.06 (s, 3H), 3.70-3.59 (m, 2H), 1.03-0.92 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[O:16][C:15]([C:17](=[NH:21])OCC)=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:22](N)[CH2:23][NH2:24]>C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[O:16][C:15]([C:17]3[NH:21][CH2:22][CH2:23][N:24]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: NCCN
Reactant: CCOC(=N)c1ccc(-c2ccc(OC)c(OC)c2)o1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2ccc(C3=NCCN3)o2)cc1OC
Reaction time: 8 h
Yield: 66.8 %

Procedure:
A mixture of 51 g (0.16 mole) of ethyl 5-(3,4-dimethoxyphenyl)-2-furimidate hydrochloride, 11 g (0.18 mole) of ethylenediamine, and 850 ml of absolute ethanol was refluxed for 5 hrs and then kept overnight at room temperature. The solid was recrystallized from acetic acid, washed with ether, and air dried to yield 33 g (65%) of 2-[5-(3,4-dimethoxyphenyl)-2-furyl]imidazoline hydrochloride. An analytical sample was prepared by recrystallizing a sample from methanol and drying in the vacuum pistol at the temperature of refluxing CHCl3, m.p. 291°-293°.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]([C:10]1[C:14]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[C:21]([I:23])[CH:20]=[N:19][C:18]=2[O:24][CH2:25][CH2:26][CH3:27])=[C:13]([CH2:29][CH3:30])[NH:12][N:11]=1)=[O:9].I[CH:32]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]1>CN(C)C=O>[NH2:7][C:8]([C:10]1[C:14]([NH:15][C:16]([C:17]2[C:18]([O:24][CH2:25][CH2:26][CH3:27])=[N:19][CH:20]=[C:21]([I:23])[CH:22]=2)=[O:28])=[C:13]([CH2:29][CH3:30])[N:12]([CH:32]2[CH2:33][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35]2)[N:11]=1)=[O:9]
Reactant: CCCOc1ncc(I)cc1C(=O)Nc1c(C(N)=O)n[nH]c1CC
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1ncc(I)cc1C(=O)Nc1c(C(N)=O)nn(C2CN(C(=O)OC(C)(C)C)C2)c1CC
Temperature: 80 °C

Procedure:
Cesium carbonate (3.59 mmol) was added to a stirred solution of the product from stage b) (1.79 mmol) and the product from stage c) (2.15 mmol) in N,N-dimethylformamide (10 ml) under a nitrogen atmosphere. The mixture was heated at 80° C. for 24 h. The mixture was cooled and extracted from water with ethyl acetate. The organics were dried (MgSO4) and concentrated to give a brown oil. Purification by flash column chromatography (gradient elution from 100% dichloromethane to 90% dichloromethane/MeOH) gave the title product; 1H NMR (400 MHz, DMSO): δ=0.95 (t, 3H), 1.05 (t, 3H), 1.40 (s, 9H), 1.78-1.88 (m, 2H), 2.68 (q, 2H), 4.22-4.35 (m, 4H), 4.40 (t, 2H), 5.3 1H), 7.35 (bs, 1H), 7.52 (bs, 1H), 8.40 (s, 1H), 8.55 (s, 1H), 10.10 (s, 1H); LRMS (TSP—positive ion) 373.2 (MH+—BOC and I); Anal. Found C, 45.11; H, 5.07; N, 13.56 Calcd for C23H31O5N6I. 0.2 DCM: C, 45.28;H, 5.14; N, 13.66.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:23][CH2:24][CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1>>[NH:28]1[CH:27]=[C:26]([CH2:25][CH2:24][NH:23][C:2]2[N:11]=[C:10]([N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:30]=[CH:29]1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: NCCc1c[nH]cn1
Agent: Cl
Product: COc1ccc(N(C)c2nc(NCCc3c[nH]cn3)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methylamine (10 mg, 0.033 mmol) and histamine hydrochloride (16 mg, 0.10) by a procedure similar to example 10 and was isolated as white solid (7 mg, 70%). 1H NMR (CDCl3): 7.52 (s, 1H), 7.49 (brd, J=3.9 Hz, 2H), 7.20-7.15 (m, 2H), 7.03-6.96 (m, 3H), 6.83 (ddd, J=8.4, 4.5 and 3.9 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 3.88 (s, 3H), 3.85 (t, J=6.6 Hz, 2H), 3.63 (s, 3H), 3.03 (t, J=6.6 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[N:8][N:7]([CH2:19][CH3:20])[C:6](=[O:21])[C:5]=1[N+:22]([O-])=O)(=[O:3])[CH3:2].N[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[N:8][N:7]([CH2:19][CH3:20])[C:6](=[O:21])[C:5]=1[NH:22][C:30]1[C:31]2[C:26](=[CH:2][CH:1]=[CH:4][CH:5]=2)[CH:27]=[CH:28][CH:29]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2cccc([N+](=O)[O-])c2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1ccccc1
Product: CCn1nc(-c2cccc([N+](=O)[O-])c2)c(C(C)=O)c(Nc2cccc3ccccc23)c1=O

Procedure:
The title compounds were synthesized from 5-acetyl-2-ethyl-4-nitro-6-(3-nitrophenyl)pyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) and the corresponding aniline following the procedure of Example 49. The ESI/MS data and HPLC retention times are summarized in Table 10.