Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[S:12]1[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[CH:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[S:12]1[CH:16]=[C:15]([CH2:17][O:18][C:2]2[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=2)[N:14]=[CH:13]1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: OCc1cscn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OCc2cscn2)cn1
Temperature: 40 °C
Reaction time: 72 h
Yield: 42.2 %

Procedure:
A RBF was charged with methyl 5-chloropyrazine-2-carboxylate (1.239 g, 7.18 mmol, Ark Pharm), thiazol-4-ylmethanol (0.8266 g, 7.18 mmol), cesium carbonate (0.689 ml, 8.61 mmol, Alfa Aesar) and DMF (20.51 ml). The reaction mixture was stirred at 40° C. for 3 days. The reaction mixture was allowed to cool to rt and was diluted with water and extracted with EtOAc. The organic extract was washed with water, satd NaCl, dried over MgSO4, and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and purified by silica gel flash chromatography, eluting with a gradient of 10% to 100% EtOAc in hexane, to provide methyl 5-(thiazol-4-ylmethoxy)pyrazine-2-carboxylate (0.7606 g, 3.03 mmol, 42.2% yield). MS m/z=252.1 [M+H]+. Calculated for C10H9N3O3S: 251.036. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (s, 2H) 5.60 (s, 1H) 7.86 (d, J=1.96 Hz, 1H) 8.46 (d, J=1.37 Hz, 1H) 8.86 (d, J=1.37 Hz, 1H) 9.14 (d, J=1.96 Hz, 1H)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CN(C)C=O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Clc1nccnc1N1CCOCC1

Procedure:
A mixture of 2,3-dichloropyrazine (5 g., 0.034 mmole), morpholine (5.8 g., 0.067 mmole), and 50 ml. of dimethylformamide are heated at 90°-120° C. for 6-14 hours, in an atmosphere of nitrogen. The reaction mixture is cooled and evaporated to dryness at a water-bath temperature of 55° C. A chloroform solution of the residue is extracted twice with 0.1 M sodium hydroxide, dried over magnesium sulfate and evaporated to leave the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=C(C=C)[CH:8]=[CH:7]2.C[N+]1([O-])CC[O:18]CC1.[CH3:22][C:23]([CH3:25])=[O:24].O>ClCCl.O=[Os](=O)(=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:22]([CH:23]([OH:24])[CH2:25][OH:18])[CH:8]=[CH:7]2
Reactant: C=Cc1ccc2cccc(Br)c2n1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: ClCCl
Product: OCC(O)c1ccc2cccc(Br)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 8-bromo-2-vinylquinoline (0.886 g, 3.78 mmol) in acetone/H2O (8 mL/2 mL) was added 4-methylmorpholine N-oxide (1.06 g, 4.54 mmol) followed by OsO4 (0.5 mL, 2.5% in t-BuOH). The reaction mixture was stirred for two hours at ambient temperature then diluted with dichloromethane. The organic layer was washed with saturated sodium sulfate and brine and concentrated to give crude product.
Reaction SMILES: C(O)C.[OH-].[K+].[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[CH:22][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([O:36]CC)=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH2:16][OH:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]>O>[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[CH:22][N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([OH:36])=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH2:16][OH:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nn(-c3ccccc3C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
Ethanol (1.5 ml), ion-exchanged water (0.3 ml), and potassium hydroxide (42 mg) were added to 2-butyl-4-chloro-1-[2-(2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-5-(hydroxymethyl)-1H-imidazole (116 mg, 0.248 mmol) as obtained in Example 3, and the mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated in an evaporator, and partitioned by ion-exchanged water (2.5 ml) and diethyl ether (5 ml). The water layer was separated and conc. hydrochloric acid was dropwise added thereto to adjust its pH to 2. The resultant solid was filtered off and washed three times with ion-exchanged water (1 ml). The solid was dried in vacuo at 37° C. overnight to give 58 mg of 2-butyl-4-chloro-1-[2-(2-carboxyphenyl)-2H-indazol-5-yl]methyl-5-(hydroxymethyl)-1H-imidazole.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[C:9](=O)([O:17]C1C=CC([N+]([O-])=O)=CC=1)[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>C1COCC1>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:9]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:2][CH2:3]1
Reactant: OCC1CCNCC1
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.5 g of 4-piperidinylmethanol were dissolved in 170 ml of THF. 25.8 g of 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate and 15.9 ml of N,N-diisopropylethylamine were successively added thereto. The mixture was stirred at room temperature for 1 h and then the solvent was removed in vacuo. The residue was taken up in 400 ml of ethyl acetate and washed once with 300 ml of 0.5 N HCl and twice with 250 ml of 1 N NaOH each time. The organic phase was dried with MgSO4, the solvent was removed in vacuo, and the residue was purified by chromatography on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([Cl:9])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.4 %

Procedure:
A mixture of 4-bromoaniline (2.58 g 14.99 mmol) in dry methylene chloride (100 mL) was treated with 4-chloro-3-nitrobenzoyl chloride (3.60 g, 17.99 mmol) and N,N-diisopropylethylamine (3.14 mL, 17.99 mmol), and the resulting mixture stirred at room temperature for 17 hours. The solvent was removed by rotary evaporation in vacuo, the residue taken up in ethyl acetate (100 mL) and washed with water (2×50 mL) and brine. Dried the organic extract over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the product as a tan solid (5.132 g, 14.45 mmol, 96%)
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.Cl[C:23]1[N:28]=[C:27]([NH:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[N:25][CH:24]=1>C1COCC1>[CH:30]([NH:29][C:27]1[CH:26]=[N:25][CH:24]=[C:23]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[N:28]=1)([CH3:32])[CH3:31]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)Nc1cncc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncc(NC(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
To a solution of tributyl tin hydride (8.5 mL, 29.23 mmol, Aldrich) in THF (50 mL) was added LDA (2.0 M) (THF/heptane/ethyl benzene) (18.3 mL, 29.23 mmol, Aldrich) at 0° C. and the mixture was stirred for 10 min at RT. To the mixture at 0-5° C. was added 6-chloro-N-isopropylpyrazin-2-amine (2.5 g, 14.61 mmol) and the mixture was stirred for an additional 3 h at RT. The reaction was quenched with 10% aq KF (25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was further purified with basic alumina column chromatography (eluent: 10% EtOAc in petroleum ether) to give N-isopropyl-6-(tributylstannyl)pyrazin-2-amine (2 g, 26.5%) as a colorless liquid. MS (ESI, pos. ion) m/z: 428.2 (M+1); 1H-NMR (400 MHz, CDCl3): δ 7.77 (s, 1H), 7.64 (s, 1H), 4.28-4.23 (m, 1H), 4.09-3.98 (m, 1H), 1.63-1.54 (m, 7H), 1.39-1.23 (m, 14H), 1.12-1.08 (m, 6H), 0.91-0.88 (q, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[NH3:6].[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)=[C:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: COC(Cc1cc(Br)ccc1N)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(Cc1cc(Br)ccc1NC1CCOCC1)OC
Product: N
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.7 %

Procedure:
Compound 67 (300 mg, 1.153 mmol) and dihydro-2H-pyran-4(3H)-one (231 mg, 2.306 mmol) were stirred in acetic acid (10 mL) under Argon in the presence of anhydrous sodium sulfate (1.638 g, 11.530 mmol) at room temperature for 30 minutes. Sodium triacetoxyborohydride (733 mg, 3.459 mmol) was then added and the mixture stirred for 19 hours at room temperature. After dilution with a mixture of 8:1 ethyl acetate:Hexanes, the reaction is quenched with saturated sodium bicarbonate. The mixture was transferred to a separatory funnel and the organic layer separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure and the residue purified via chromatography on silica gel (EtOAc: Hexanes, 1:4 then 2M NH3 in methanol:CH2Cl2, 3:7 then 100% methanol) to yield a pale yellow oil, 87 (168 mg, 42.3%). 1H NMR (DMSO-d6) δ 1.34-1.47 (m, 2H), 1.86 (d, 2H, J=12.3 Hz), 2.75 (d, 2H, J=5.3 Hz), 3.27 (s, 6H), 3.35-3.49 (2×m, 3H), 3.77-3.91 (2×m, 2H), 4.52 (t, 1H, J=5.3 Hz), 4.89 (d, 1H, J=7.6 Hz), 6.60 (d, 1H, J=9.4 Hz), 7.10-7.20 (m, 2H); ESI-MS (m/z, %): 344/346 (MH+, 5%), 280/282 (cyclized product, 100%).
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:21](I)[CH3:22].O>CS(C)=O.C1COCC1>[CH3:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:21][CH3:22])[C:8]#[N:9]
Reactant: CCI
Reactant: CC(C#N)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5 g (38 mmol) of 2-phenylpropionitrile in 50 mL of DMSO was added 42 mL of a 1M solution of NaHMDS in THF. After 15 minutes, the reaction was cooled to 0° C. and 4.6 mL of ethyl iodide was added. The reaction was monitored by TLC. After 30 minutes, the mixture was poured into water and extracted with diethyl ether. The combined organics were washed with four portions of water, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6.1 g of 2-methyl-2-phenylbutyronitrile as an oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[CH2:7].ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl.O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]1[O:25][CH2:7]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1cc(C2CO2)cc(C(F)(F)F)c1

Procedure:
A solution of 3,5-bis(trifluoromethyl)styrene (13.3 g) and m-chloroperbenzoic acid (21 g) in dichloromethane (100 ml) was stirred at room temperature for 16 hours. The resulting suspension was diluted with water (100 ml) and dichloromethane (100 ml), and the organic phase was washed further with water (2×100 ml) and saturated brine (100 ml). After drying (MgSO4) the solvent was removed in vacuo and the residue purified by chromatography on silica (eluting with isohexane followed by 10% ethyl acetate in isohexane) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 2.79 (1H, dd J 6.0 Hz and 2.7 Hz), 3.23 (1H, dd J 5.9 Hz and 4.5 Hz), 3.99 (1H, dd J 4,4 Hz and 2.7 Hz), 7,74 (2H,s), 7.82 (1H, s).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[Br:19].C([O-])(=O)C.[Na+].[N:34]#[C:35]Br.O>C(O)C>[Br:19][C:10]1[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]=1[CH2:8][N:7]([CH2:6][C:5]1[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=1)[C:35]#[N:34]
Reactant: FC(F)(F)c1cc(CNCc2cc(C(F)(F)F)ccc2Br)cc(C(F)(F)F)c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1Br
Reaction time: 0.33 h

Procedure:
To the product of step B (873 g, 1.82 mol) in ethanol (4.6 L) was added sodium acetate (452 g, 5.46 mol). The resulting mixture was stirred for 20 minutes and then cyanogen bromide (386 g, 3.64 mol) was added. This mixture was stirred for 2 hours at which point the reaction was complete as evidenced by LC analysis. Water (4 L) was added and volatiles were removed in vacuo. Toluene (4 L) was added and the mixture was stirred until 2 clear layers formed. The layers were separated and the aqueous layer was washed with toluene (2 L). The combined organics were washed with brine (1 L), dried over sodium sulfate, filtered, and concentrated (910 g yield). 1H-NMR (CDCl3) δ 7.83 (s, 1H), 7.71 (m, 3H), 7.54 (d, 1.7 Hz, 1H), 7.46 (dd, 2.1 Hz, 8.3 Hz, 1H), 4.38 (s, 2H), 4.34 (s, 2H). Mass Spec (ESI): M+1=505.0
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:11][NH2:12].CCO>CC(C)=O>[CH3:11][NH:12][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CN
Solvent: CC(C)=O
Solvent: CCO
Product: CNc1nc2ccccc2[nH]1
Temperature: 160 °C
Yield: 51.4 %

Procedure:
2-Chloro-1H-benzo[d]imidazole (20 g, 131.08 mmol) was charged to high pressure autoclave PV10832 (Hastelloy 450 ml) with methylamine (260 mL, 131.08 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 11 bar. The solvent was removed under reduced pressure to afford a brown oil. EtOH was added and the solvent again removed to afford a brown foam. The foam was dissolved in a minimum of hot acetone. This was then allowed to cool. The resultant solid was filtered affording N-methyl-1H-benzo[d]imidazol-2-amine (9.91 g, 51%); 1H NMR (400 MHz, DMSO-d6) 2.83 (3H, s), 6.87-7.00 (2H, m), 7.05-7.25 (2H, m), 7.49 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[C:13]4[CH:25]=[CH:24][CH:23]=[N:22][C:14]=4[NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:11]3=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:5]=[CH:4][C:3]=1[C:33]1([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35][CH2:34]1.[ClH:45]>ClCCl.O1CCOCC1>[ClH:45].[F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[C:13]4[CH:25]=[CH:24][CH:23]=[N:22][C:14]=4[NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:11]3=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:5]=[CH:4][C:3]=1[C:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1
Reactant: Cc1ccccc1-c1nc2n(c1-c1ccc(C3(NC(=O)OC(C)(C)C)CCC3)c(F)c1)-c1cccnc1Nc1ccccc1-2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccccc1-c1nc2n(c1-c1ccc(C3(N)CCC3)c(F)c1)-c1cccnc1Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (1-(2-fluoro-4-(2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.035 g) in dichloromethane (0.5 mL) was added 4.0 M HCl in dioxane (0.05 mL). The reaction was stirred at room temperature for 3 hours. The product was removed by filtration under reduced pressure and dried to give 1-(2-fluoro-4-(2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutanamine hydrochloride as a yellow solid (0.025 g, 74% based on tris HCl salt). 1H NMR (DMSO-d6) 400 MHz δ 8.77 (br. s, 1 H), 8.73 (br. s, 3H), 8.19 (d, J=4.4 Hz, 1H), 7.91 (dd, JA=7.6 Hz, JB=1.2 Hz, 1H), (7.41 (t, J=6.8 Hz, 1H), 7.36-7.31 (m, 3H), 7.30-7.25 (m, 2H), 7.24-7.18 (m, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.89-6.84 (m, 3H), 2.68-2.57 (m, 2H), 2.54-2.44 (m, 2H), 2.36-2.25 (m, 1H), 2.17 (s, 3H), 1.88-1.74 (m, 1H); LCMS: 488 [M+H]; Calc. for C31H26N5F.2.59HCl.1.05 dioxane: C, 62.68; H, 5.53; N, 10.38. Found C, 62.69; H, 5.67; N, 10.39.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(NC(C)C)(C)C.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([OH:26])=[O:25].C1C[O:30][CH2:29]C1>O.C(#N)C1C=CC=CC=1>[C:8]1([C:29]([C:23]2[S:19][C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH:22]=2)=[O:30])[CH:7]=[CH:6][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCC
Reactant: C1CCOC1
Reactant: O=C(O)c1cccs1
Agent: [Li]CCCC
Solvent: N#Cc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=C(O)c1ccc(C(=O)c2ccccc2)s1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A 1.6M solution of n-butyllithium in n-hexane (51.0 ml, 81.3 mmol) is added dropwise to diisopropylamine (11.6 ml, 82.2 mmol) in 150 ml of absolute THF at -70° C. After stirring at -70° C. for 15 minutes, thiophene-2-carboxylic acid (5.00 g, 39.0 mmol) is added and the mixture is held at -70° C. After 45 minutes benzonitrile (5.0 ml, 49 nunol) is added dropwise and the mixture is stirred at -70° C. for 90 minutes. After equilibration to room temperature, the reaction mixture is poured into 200 ml of water and subjected to extraction with 200 ml of ether, and this organic phase is discarded. The aqueous phase is adjusted to a pH of 2 using a 6N HCl solution and is subjected to extraction with 2×200 ml of ether. The combined organic phases are dried over magnesium sulfate and the solvent is distilled off. The residue is suspended in 50 ml of 6N HCl solution and the suspension is heated at 80° C. for one hour. The precipitated crystals are filtered off and dried under vacuum overnight.
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:8])[CH2:6][F:7])=[N+:2]=[N-:3].[C:9]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N+:17]([O-:19])=[O:18])#[C:10][CH3:11]>>[F:7][CH2:6][CH:5]([OH:8])[CH2:4][N:1]1[CH:11]=[C:10]([CH2:9][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[N+:17]([O-:19])=[O:18])[N:3]=[N:2]1
Reactant: [N-]=[N+]=NCC(O)CF
Reactant: CC#Cn1ccnc1[N+](=O)[O-]
Product: O=[N+]([O-])c1nccn1Cc1cn(CC(O)CF)nn1
Temperature: 60 °C

Procedure:
To a vial is added fluoroazide 17 (5.79 mmol) and 1-propynyl-2-nitroimidazole (5.79 mmol). The solution is heated at 60° C. overnight. The material is then purified on a silica gel column using EtOAc:Hex as the eluent. The material is then further purified via recrystallization using EtOAc:Hex to afford pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C1(=O)O[CH2:20][CH2:19][O:18]1>CN(C=O)C>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:20][CH2:19][OH:18])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc2cc[nH]c2c1
Temperature: 125 °C

Procedure:
A mixture of 6-hydroxyindole (2.66 g, 20 mmol) and K2CO3 (3.04 g, 22 mmol) was stirred in DMF (10 mL) at 80° C. for 10 min. A solution of ethylene carbonate (1.94 g, 22 mmol) in DMF (4 mL) was added and the mixture was heated at 125° C. for 3 h. The mixture was concentrated, diluted with water, and extracted with toluene. The organic phase was washed with 1 M aqueous Na2CO3 and brine. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica using EtOAc/toluene (1:4→36:65) as eluent. Yield 1.02 g (29%); mp 74-77° C.; HRMS m/z calcd for C10H11NO2 (M)+ 177.0790, found 177.0784. Anal. (C10H11INO2) C, H, N.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][C:14]=2[F:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)[CH2:23][CH2:24]3)=[CH:15][C:14]=2[F:25])=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)cc2F)c1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2F)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-3-fluoro-phenyl]-piperazin-1-yl}-benzoic acid was synthesized by the coupling of N-(3-tert-butyl-phenyl)-2-fluoro-4-piperazin-1-yl-benzamide and 4-bromo benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C28H30FN3O3 (m/e) 475, obsd 476 (M+H).
Reaction SMILES: [CH2:1]([N:11]1[C:15]([Cl:16])=[C:14]([CH3:17])[N:13]=[CH:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl>>[Cl-:16].[CH2:1]([N+:11]1[C:15]([Cl:16])=[C:14]([CH3:17])[N:13]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:19]=2[CH3:18])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Cc1cc(Cl)ccc1CCl
Reactant: CCCCCCCCCCn1cnc(C)c1Cl
Product: CCCCCCCCCC[n+]1cn(Cc2ccc(Cl)cc2C)c(C)c1Cl
Product: [Cl-]
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
25.6 g (0.1 mole) of 1-decyl-4-methyl-5-chloroimidazole were heated to 100° C., 17.7 g (0.1 mole ) of 4-chloro-o-xylyl chloride were added dropwise, and the mixture was stirred for a further 30 minutes at 125° C.
Reaction SMILES: [N+]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][CH2:9][O:10][N:11]2[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[NH:12]2)=[CH:6][CH:5]=1)([O-])=O.COC1C=C(OC)C=CC=1C=O.C(O)CC1C=CC=CC=1.N1C(C)=CC(C)=CC=1C>>[CH2:9]([O:10][N:11]1[N:12]=[C:13]([Cl:18])[CH:14]=[C:15]([Cl:17])[NH:16]1)[CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(CCON2N=C(Cl)C=C(Cl)N2)cc1
Agent: COc1ccc(C=O)c(OC)c1
Solvent: OCCc1ccccc1
Solvent: Cc1cc(C)nc(C)c1
Product: ClC1=CC(Cl)=NN(OCCc2ccccc2)N1
Yield: 52 %

Procedure:
In a manner exactly analogous to the preparation of compound 35, using 4.4 g (0.0024 mole) of cyanuric chloride (1), 2.9 g (0.0024 mole) of phenethyl alcohol and 3.2 ml of collidine, 3.37 g (52% yield) of the desired compound 46 was obtained after plug filtration of the crude product on silica gel using methylene chloride.