Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:29]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: CCOC(=O)C1=Cc2cc(Cl)cc(-c3cccc(OC)c3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottomed flask under nitrogen, ethyl 6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 73, Step 2) (1.00 g, 2.31 mmol) and 3-methoxyphenylboronic acid (0.369 g, 2.43 mmol) were dissolved in 1-propanol (50 mL). The mixture was stirred at room temperature for 0.5 hours, allowing for the solids to dissolve. The resulting solution was treated with palladium (II) acetate (0.016 g, 0.0693 mmol), triphenylphosphine (0.055 g, 0.208 mmol), sodium carbonate (0.294 g, 2.77 mmol), and deionized water (10 mL). The reaction mixture was heated to reflux for 3 hours. After cooling to room temperature the mixture was extracted with ethyl acetate (1×150 mL, 2×25 mL). The combined organic phases were washed with saturated aqueous NaHCO3 (50 mL) and brine (2×50 mL), dried over MgSO4, filtered, and concentrated in vacuo to yield a yellow oil. The crude material was purified by flash chromatography in 0.5% ethyl acetate in hexane yielding a white solid. The solid was recrystallized from hexane yielding the desired ester as a white solid (0.60 g, 63%): mp 93.7–95.1° C. 1H NMR (CDCl3/300 MHz) 7.69 (s, 1H), 7.35–7.32 (m, 2H), 7.22 (d, 1H, J=2.6 Hz), 7.05–7.03 (m, 2H), 6.96–6.93 (m, 1H), 5.72 (q, 1H, J=6.7 Hz), 4.34–4.31 (m, 2H), 1.35 (t, 3H, J=7.1 Hz). FABLRMS m/z 413 (M+H). ESHRMS m/z 413.0765 (M+H, Calc'd. 413.076747). Anal. Calc'd. for C20H16ClF3O4: C, 58.19; H, 3.91; Cl, 8.59. Found: C, 58.33; H, 4.10; Cl, 8.61.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1[C:24]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]=2[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:21]1[C:22]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:15]4[C:24]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: OC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride (3.06 mL, 35.1 mmol, 2 eq) in methylene chloride (100 mL) under nitrogen was added distilled dimethylsulfoxide (5.00 mL, 70.2 mmol, 4 eq). After 10 min 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl) piperidin-4-ol (described above) (17.5 mmol) was added as a methylene chloride solution (10 mL). The reaction was stirred at -78° C. for 30 min prior to the addition of triethylamine (19.6 mL, 140 mmol, 8 eq). The cooling bath was removed and the reaction warmed to room temperature over 1.5 h. The reaction mixture was poured into 2.5N NaOH (100 mL) and the aqueous phase extracted with methylene chloride (3×100 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The crude reaction mixture was purified by flash chromatography over silica gel (400 mL, eluent:20% ethyl acetate in hexane) to yield the title compound in 80% yield as a white solid. TLC analysis (Rf 0.31, 2% methanol in methylene chloride). MS (Cl, CH4) m/z 304 (M+1,100), 332 (M+29,21)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])(C)(C)C.O.Br[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CCOCC.C1COCC1.[Cl-].[Cl-].[Zn+2].[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)#[N:19]
Reactant: N#Cc1ccccc1Br
Reactant: Cc1ccc(Br)cc1
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A solution of 4-bromotoluene (310 g, 1.81 moles) in 1500 ml of anhydrous ether was cooled to an internal temperature of -65° C. (slurry forms at ~-6° C.) under nitrogen. A solution of t-butyllithium (1.7 M in pentane, 2.2 L, 3.74 moles) was added over a period of ~90 minutes (internal temperature maintained below -55° C.). The cooling bath was then replaced with water baths which brought the reaction mixture up to +20° C. over 45 minutes and the white slurry was stirred an additional 2 hours at room temperature (most solids dissolved). The contents of this flask were then transferred under nitrogen pressure via a 1/8" plastic cannula to a stirred solution of ZnCl2 in ether (1M, 1.86 L) and THF (3.7 L) over 25 minutes (a cool water bath was used to maintain an internal temperature of 25° C.). The reaction mixture was stirred at room temperature for 2 hours. The appearance may vary from a clear solution with white flocculent precipitate to a mixture with heavy white solids. The reaction mixture was then transferred via a 1/4" cannula under vacuum) to a solution of 2-bromobenzonitrile (220 g, 1.2 moles) and bis(triphenylphosphine) nickel (II) chloride (22 g, 0.0337 moles) in THF (3.1 L) at room temperature over 20 minutes. The internal temperature rose to 35° C. during additions but subsided when complete. The dark red solution was stirred at room temperature overnight. The reaction mixture was then added carefully in portions to ice cold 1N HCl (~15 L) stirred rapidly in a large extractor. The organic layer was separated and the aqueous phase extracted with ether (3×2 L). The organic layers were combined and washed with water (2×2 L), brine, dried over MgSO4 and filtered through a plug of silica gel. The solution was concentrated to give the crude product as an oily solid (275 g). The material was then purified on a silica gel column (3 kg of E. Merck SiO2 60, 70-230 mesh) using methylene chloride-hexane (1:4 ) to give 196 g (85%) of the title compound as a low melting (46°-49.5° C.) solid. NMR (CDCl3): 2.22 (s, 3H), 7.24-7.78 (8H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:17][CH2:18][CH2:19]Cl)[C:9]=3[CH:8]=2)=[N:4][N:3]=1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:24][C:23]=2[O:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:17][CH2:18][CH2:19][N:33]4[CH2:32][CH2:31][CH:30]([C:25]5[CH:26]=[CH:27][C:28]6[O:29][CH2:21][O:22][C:23]=6[CH:24]=5)[CH2:35][CH2:34]4)[C:9]=3[CH:8]=2)=[N:4][N:3]=1
Reactant: c1cc2c(cc1C1CCNCC1)OCO2
Reactant: Cc1nnc(-c2cc3c(OCCCCl)cccc3o2)o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(-c2cc3c(OCCCN4CCC(c5ccc6c(c5)OCO6)CC4)cccc3o2)o1
Temperature: 80 °C
Yield: 62.9 %

Procedure:
5-Methyl-2-(4-(3-chloropropyloxy)benzo(b)furan-2-yl)-1,3,4-oxadiazole (1.0 g), 4-(3,4-methylenedioxyphenyl) -piperidine (0.7 g), potassium carbonate (1.5 g) and potassium iodide (1.0 g) were dissolved in a mixed solvent (50 ml) of DMF-toluene (2:1) and the solution was stirred with refluxing under heating at 80° C. for 4 hr. The reaction mixture was poured into water, extracted with ethyl acetate and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (0.99 g) as white crystals, melting point 125-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([O:32][CH2:33][C:34]([NH2:36])=O)=[CH:24][CH:23]=1.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]2[C:15](=[O:20])[CH:16]=[C:17]([CH3:18])[N:36]=[C:34]2[CH2:33][O:32][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]([Cl:21])=[CH:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: NC(=O)COc1ccc(Cl)c2ccccc12
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(Cl)c2)c(COc2ccc(Cl)c3ccccc23)n1
Temperature: 165 °C
Reaction time: 24 h
Yield: 56.4 %

Procedure:
A mixture of N-(3-chloro-4-morpholinophenyl)-3-oxobutanamide (0.59 g, 2.0 mmol), 2-((4-chloronaphthalen-1-yl)oxy)acetamide (0.94 g, 4.0 mmol) and titanium tetraisopropanolate (4.8 mL) in xylene (10 mL) was stirred at 165° C. for 24 h. The mixture was cooled to rt and 60 mL of toluene and 60 mL of saturated NH4Cl aqueous solution were added. The resulting mixture was stirred at rt overnight and filtered and the filtrate was extracted with DCM (20 mL×4). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (0.56 g, 56%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[S:14][CH:15]=[C:16](/[CH:18]=[CH:19]/[C:20](Cl)=[O:21])[N:17]=1>O.CC(C)=O.O1CCOCC1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[S:14][CH:15]=[C:16](/[CH:18]=[CH:19]/[C:20]([N:1]=[N+:2]=[N-:3])=[O:21])[N:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=NC(=O)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a cooled (0° C.) solution of NaN3 (6.2 g, 95 mmol) in water (100 mL) and acetone (100 mL) was added a solution of (E)-3-(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)acryloyl chloride (5.7 g, 19 mmol) in dioxane (100 mL) dropwise over 15 minutes. After addition, the resulting mixture was stirred for another 1 hour at 0° C. The reaction was quenched with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic extract was washed brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography, eluting with EtOAc/petroleum ether (1:8) to give the desired product as a yellow solid (5.3 g, 90% yield). LCMS (ESI) m/z: 309.0 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]([F:48])([F:47])[O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:43]([C:40]4[CH:39]=[CH:38][C:37]([O:36][C:35]([F:34])([F:47])[F:48])=[CH:42][CH:41]=4)(=[O:45])=[O:44])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.12 mmol) and triethylamine 24.2 mg (0.24 mmol) in DCM (6 ml) was added 4-(trifluoromethoxy)benzene-1-sulfonyl chloride (46.8 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:23])[CH2:11][CH2:12][C@H:13]([C:20](=[O:22])[NH2:21])[NH:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:24]1(=[O:41])[N:28]([CH2:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])[C:27](=[O:36])[C:26]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:25]12.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:2]([O:9][C:10](=[O:23])[CH2:11][CH2:12][C@H:13]([C:20](=[O:22])[NH2:21])[NH:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH:17][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:24](=[O:41])[C:25]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:26]2[C:27]1=[O:36])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](N)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reactant: O=C(O)CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)CCCCN1C(=O)c2ccccc2C1=O)C(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
L-alanyl-D-isoglutamine benzyl ester hydrochloride (548 mg, 1.6 mmoles) and 5-phthalimidopentanoic acid (400 mg, 1.6 mmoles) were dissolved in N,N-dimethylformamide (8 ml). The solution was cooled to 0° C. and diphenylphosphoryl azide (495 mg, 1.8 mmoles) and triethylamine (323 mg, 3.2 mmoles) were added thereto. The reaction mixture was stirred for 1 hour at 0° C. and for 24 hours at room temperature. The reaction mixture was diluted by ethyl acetate (40 ml) and the organic phase was washed successively with citric acid (0.52M; 3×10 ml), water (3×10 ml), saturated NaCl solution (3×10 ml), saturated NaHCO3 solution (3×10 ml), water (3×10 ml) and saturated NaCl solution (3×10 ml). The organic phase was dried with MgSO4 and filtered, the filtrate was evaporated and the product was precipitated from n-hexane/diethyl ether. The compound was filtered off and crystallized from acetone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:10](=[O:30])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[C:19](=O)[NH:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:10]1[O:30][C:19](=[N:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[C:13]2[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cccc(Cl)c1C(=O)Nc1cc(F)cc(F)c1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2c(=Nc2cc(F)cc(F)c2)o1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
100-mL, three-neck, round bottomed flask equipped with a magnetic stirrer and thermometer was purged with nitrogen and charged with compound 168 (3.30 mmol), anhydrous methylene chloride (25 mL), N,N-diisopropylethylamine (4.60 g, 35.7 mmol) and triphenylphosphine (3.98 g, 15.2 mmol). The reaction mixture was then cooled to 0-5° C. in an ice/water bath. Iodine (3.61 g, 14.2 mmol) was then added portion-wise to the reaction mixture over 1 h. Once the addition was complete, the cooling bath was removed, and the mixture was stirred at room temperature for an additional 30 min. The reaction was then quenched with 10% aqueous potassium carbonate (25 mL), the organic layer separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography of the resulting solid (silica gel, EtOAc/hexanes) gave a 52% yield of compound 169 as a white solid. m.p. 117-118° C.; 1H NMR (DMSO-d6) δ (ppm) 7.72-7.60 (m, 2H), 7.42 (dd, 1H, J=7.6 Hz, 1.3 Hz), 7.31 (d, 1H, J=7.0 Hz), 6.95 (t, 1H, J=9.3 Hz), 6.82 (m, 2H), 4.27 (m, 1H), 1.33 (s, 9H), 1.28 (d, 3H, J=7.2 Hz); m/z=436 (M+H). The reaction described above and compound 169 are shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)(Cl)Cl)=[CH:4][CH:3]=1.Cl.[NH2:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[OH:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:15]3[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1
Agent: Cl
Product: O=[N+]([O-])c1ccc2oc(-c3ccc(Cl)cc3)nc2c1

Procedure:
Compound XV was prepared as in Example 12 at 180°-200° C from p-chlorobenzotrichloride and 2-amino-4-nitrophenol hydrochloride, and purified through a preheated Al2O3 column: 3.4 g of raw product melting at 205°-210° C (12% of the theory). After recrystallization from benzene: melting point 217°-218° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:27])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=3[CH3:26])=[N:13]2)=[O:8])[N:6]=1.[CH3:28][NH:29][CH3:30].C1COCC1>N1C=CC=CC=1>[Cl:25][C:19]1[C:18]([CH3:26])=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([N:29]([CH3:30])[CH3:28])[S:3][CH:4]=3)=[O:8])[CH3:27])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: CNC
Reactant: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(Br)n3)n2)ccc(C#N)c1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(N(C)C)n3)n2)ccc(C#N)c1Cl
Temperature: 120 °C
Yield: 63.2 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)thiazole-4-carboxamide (0.247 g, 0.531 mmol) was added into a microwave test tube with dry pyridine. The mixture was bubbled with nitrogen and dimethylamine 2 M in THF (1.329 ml, 2.66 mmol) was added. The reaction mixture was heated with microwaves at 120° C. for 10 h. The crude product was evaporated, diluted with DCM, washed with 1M Na2CO3 and water. The product was purified with Flash-chromatography. Yield 63.2%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.53 (s, 3H), 3.00 (s, 6H), 4.32 (dd, 1H), 4.41 (dd, 1H), 4.55 (m, 1H), 6.41 (d, 1H), 7.30 (d, 1H), 7.52 (m, 3H), 7.74 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][O:16][C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)=[O:18]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:20][CH:21]=2)=[O:24])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
320 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 400 mg of 4-(methoxycarbonyl)benzoic acid via Procedure G to give methyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate. 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was then hydrolyzed via Prodedure M to give 550 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-aminopyridine via Procedure G. The organic layer was evaporated to dryness and purified on reverse phase HPLC to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-3-yl)terephthalamide. MS (Q1) 429 (M)+.
Reaction SMILES: [CH3:1][N:2]1[CH:8]2[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2.[CH3:9][NH2:10].[Cl-].[NH4+].[OH-].[Na+]>>[CH3:9][NH:10][C@@H:8]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:2][CH3:1]
Reactant: CN1C2CCCCC21
Reactant: CN
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CN[C@@H]1CCCC[C@H]1NC
Temperature: 99 °C
Yield: 39 %

Procedure:
7-Methyl-7-azabicyclo[4.1.0]heptane (36.1 g prepared by the method detailed in Example 1), methylamine (162 ml of a 23-30% aqueous solution) and 0.5 g of ammonium chloride were heated in an oil bath at 94°14 99° C. for 21.5 hours. After cooling to 0° C. the mixture was treated with 10 g of solid sodium hydroxide and extracted four times with 100 ml portions of ether. The combined ether extracts were dried over anhydrous magnesium sulfate, the ether evaporated, and the residue distilled to yield 18 g (39%) of trans-N,N'-dimethylcyclohexane-1,2-diamine, bp 78° C. (at a pressure of 1866 Pascal) which solidified upon standing to a solid which melted at 17° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[S:12])[N:8]([CH3:13])[C:7]2=[O:14].[C:15]([O-])([O-])=O.[K+].[K+].CI>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:15])[N:8]([CH3:13])[C:7]2=[O:14]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=S)[nH]c2c(I)cccc2c1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nc2c(I)cccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
At RT, to a mixture of 8-iodo-3-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (11.2 g g, 35.3 mmol) and K2CO3 (9.76 g, 70.6 mmol) in THF (100 mL) was added MeI (6.58 mL, 106 mmol). The reaction was heated to reflux for 6 h, and then cooled to RT. The mixture was poured into ice/water (300 mL) and stirred for 10 min. The suspension was filtered and the solid was washed with cold water (20 mL) followed by cold ether (20 mL). The solid was dried to give 8-iodo-3-methyl-2-(methylthio)quinazolin-4(3H)-one (700a; 11.4 g, 97% yield) as an off-white solid. Crude material was used in the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (1H, dd, J=7.6, 1.4 Hz), 8.08 (1H, dd, J=7.8, 1.4 Hz), 7.19 (1H, t, J=7.7 Hz), 3.51 (3H, s), 2.73 (3H, s). m/z (ES, +ve) 332.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.Br[CH2:16][C:17]#[C:18][CH3:19].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[N:6]([CH2:16][C:17]#[C:18][CH3:19])[C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[N:3]=1
Reactant: COC(=O)c1nc(Br)[nH]c1C(=O)OC
Reactant: CC#CCBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCn1c(Br)nc(C(=O)OC)c1C(=O)OC
Yield: 75 %

Procedure:
A solution of 15.0 g (57.0 mmol) of dimethyl 2-bromo-imidazole-4,5-dicarboxylate, 5.15 ml (57.0 mmol) of 1-bromo-2-butyne and 50 ml of N,N-diisopropylethylamine in 280 ml of tetrahydrofuran was refluxed for one hour. The mixture was concentrated by evaporation, the residue combined with approx. 100 ml of water and extracted three times with 70 ml of ethyl acetate. The extracts were washed with 50 ml of water, dried and evaporated down. The crude product thus obtained was purified by column chromatography (silica gel; eluant:dichloromethane with 0–2% ethanol).