Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].[C:16]([C:20]1[CH:29]=[CH:28][C:23]([CH2:24][N:25]=[C:26]=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.ClCCl>[C:16]([C:20]1[CH:29]=[CH:28][C:23]([CH2:24][NH:25][C:26](=[O:27])[NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:3]([F:2])[CH:4]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC(C)(C)c1ccc(CN=C=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CNC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride (1.13 g) prepared in step 3 of Example 1 was dissolved in DMF (6 mL) and diluted with dichloromethane (35 mL). To the solution were added 4-t-butylbenzylisocyanate (1.09 g) and TEA (1.2 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with ethylacetate (20 mL) and washed with water and saturated NaCl aqueous solution. The resulting solution was dried over anhydride MgSO4 and the remaining liquid was concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane/ethyl acetate=312) to yield title compound (1.23 g, 53%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5](=O)[C:4]1=[O:14])[CH3:2].P(Br)(Br)([Br:17])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[Br:17][C:5]1[C:4](=[O:14])[N:3]([CH2:1][CH3:2])[C:12]2[C:7]([N:6]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CCn1c(=O)c(=O)[nH]c2ccccc21
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCn1c(=O)c(Br)nc2ccccc21
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To 2 g (10.5 mM) of 1-ethyl-1,4-dihydroquinoxaline-2,3-dione in 20 ml of dichloroethane were added dropwise 3.16 g (11.0 mM) of POBr3. The reaction mixture was refluxed under stirring for 2 h and then treated with ice cold and an aqueous sodium carbonate solution. The mixture was filtered and the filtrate was extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated to give 1.4 g of 3-bromo-1-ethyl-quinoxalin-2(1H)-one as a yellow solid. Yield: 53%.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:25](O)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)O
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(OC(=O)CCCCC)cc3)s2)cc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
In a 200 ml-round-bottomed flask, 2.00 g (5.93 mM) of 2-(4-hexylphenyl)-5-(4-hydroxyphenyl)thiazole, 0.76 g (6.54 mM) of hexanoic acid and 40 ml of dichloromethane were placed and mixed. To the solution, 1.24 g (6.01 mM) of N,N'-dicyclohexylcarbodiimide and 0.10 g of 4-pyrrolidinopyridine were successively added under stirring at room temperature, followed by further stirring for 7 hours at room temperature to precipitate N,N'-dicyclohexylurea. The resultant N,N'-dicyclohexylurea was filtered off and the solvent of the filtrate was distilled-off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized from a mixture solvent of toluene-methanol to obtain 1.81 g of 2-(4-hexylphenyl)-5-(4-hexanoyloxyphenyl)thiazole (Yield: 70.1%). ##STR198##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[CH2:29][C:30]#[N:31]>CN(C=O)C>[C:30]([CH2:29][N:10]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:12][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:9]1)#[N:31]
Reactant: CCOC(=O)c1cc(-c2cccc(F)c2)n[nH]1
Reactant: N#CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccc(F)c2)nn1CC#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of Intermediate 4B (7.0 g, 29.9 mmol) in DMF (45 mL), is added dropwise a solution of LHMDS (31.4 mL, 31.4 mmol, 1M in THF). The reaction mixture is allowed to stir for 5 min. and the ice bath is subsequently removed. 2-Chloroacetonitrile (2.482 g, 32.9 mmol) was added to the reaction mixture. The reaction was allowed to warm to RT and stir for 18 h. The reaction was quenched by the addition of 1.0 mL of a satd. aq. solution of NH4Cl. The reaction was diluted with equal parts water and EtOAc and the resulting mixture was allowed to stir vigorously for 15 min. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The crude reaction mixture was purified by silica gel chromatography (120 g REDISEP® column, eluting with a gradient from 0-40% EtOAc in hexanes). Fractions containing the product were combined and concentrated to afford Intermediate A131A (6.15 g, 75%) as a white solid. MS(ES) m/z=274 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[CH2:17][C:18](=O)[CH2:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.C1CCCCC1.C([O:37]C(NC1C=CC(OC)=CC=1C)=O)(C)(C)C.CON(C)C(C1CC1)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]([CH:18]1[CH2:20][CH2:19]1)=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)Cc1cc(OC)ccc1NC(=O)OC(C)(C)C
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Agent: CON(C)C(=O)C1CC1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)OC(C)(C)C)c(C(=O)C2CC2)c1
Temperature: -55 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
1-[2-(tert-Butoxycarbonylamino)-5-methoxyphenyl]-2-butanone. A solution of 1.3M sec-butyl lithium/cyclohexane (100 mL, 0.13 mol) was added slowly to 15.17 g (0.065 mol) of N-tert-butoxycarbonyl-4-methoxy-2-methylaniline in 230 mL of THF while keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to -20° C. and then the bath was replaced. After the temperature had cooled to -55° C., 8.4 g (0.065 mol) of N-methoxy-N-methylcyclopropylcarboxamide in 20 mL of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 2 hours. It was then poured into 500 mL of water. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The residue was crystallized from hexane to give 15.22 g (77% yield) of [2-(tert-butoxycarbonylamino)-5-methoxyphenyl]cyclopropyl ketone, melting at 96°-97° C.,
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]#[N:14])[CH:8]=[C:9](Cl)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]#[N:14])[CH:8]=[C:9]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([F:15])[CH:21]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1cc(Cl)cc2c(N)ncnc12
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(-c2cccc(F)c2)cc2c(N)ncnc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To an 8 mL vial was added 4-amino-6-chloro-quinazoline-8-carbonitrile (100 mg, 0.49 mmol) followed by (3-fluorophenyl)boronic acid (2 equiv., 1.0 mmol, 0.13676 g), potassium phosphate tribasic (2M in water, 4 equiv., 2.0 mmol, 1 mL), Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.05 equiv., 0.024 mmol, 17 mg) and dioxane (2 mL). The reaction was capped and shaken at 100° C. for 2 h. The reaction was cooled to room temperature, then diluted with 4 mL ethyl acetate and 3 mL water. The resulting precipitate was collected by filtration, yielding 72 mg of desired product. 1H NMR (400 MHz, DMSO) δ 8.94-8.89 (d, J=1.5 Hz, 1H), 8.77-8.72 (d, J=1.4 Hz, 1H), 8.55-8.50 (s, 1H), 8.43-8.13 (s, 2H), 7.83-7.74 (t, J=8.5 Hz, 2H), 7.63-7.55 (dd, J=14.5, 8.0 Hz, 1H), 7.33-7.25 (dd, J=12.5, 4.5 Hz, 1H). LCMS M/Z (M+H)=265.
Reaction SMILES: Br[C:2]1[N:10]=[C:9]2[N:4]([CH:5]=[N:6][C:7]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[C:8]2[CH2:11][CH2:12][CH3:13])[N:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[F:26][C:25]1[C:20]([C:16]2[N:15]([CH2:14][C:7]3[N:6]=[CH:5][N:4]4[N:3]=[C:2]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[N:10]=[C:9]4[C:8]=3[CH2:11][CH2:12][CH3:13])[CH:19]=[CH:18][N:17]=2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(Br)nc12
Reactant: C1CCNC1
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(N3CCCC3)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 175 (77 mg, 0.185 mmol) and pyrrolidine (0.5 ml) is stirred at room temperature for 4 hours. The solvent is removed in vacuo and the residue is partitioned between water (5 ml) and EtOAc (5 ml). The layers are separated and the aqueous layer is extracted with EtOAc (2×5 ml). The combined extracts are washed with brine (5 ml), dried (Na2SO4) and evaporated. PTLC separation of the residue with 5% MeOH in CH2Cl2 gives the title compound 173 as a white solid. H1 NMR (δ, CDCl3): 8.84 (s, 1H), 8.40 (m, 1H), 7.51–7.56 (m, 1H), 7.21–7.31 (m, 2H), 7.18 (s, 1H), 5.76 (s, 2H), 3.53–3.57 (m, 4H), 2.80–2.84 (m, 2H), 1.99–2.02 (m, 4H), 1.58–1.64 (m, 2H), 0.93 (t, 3H). LC-MS (M+1), 407.10.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:47]([O:49][C:50]([C:52]1[C:60]2[N:59]=[C:58]([NH2:61])[NH:57][C:56]=2[CH:55]=[C:54]([O:62][CH2:63][CH3:64])[CH:53]=1)=[O:51])[CH3:48]>CN(C=O)C.[Cl-].[Na+].O>[CH2:47]([O:49][C:50]([C:52]1[C:60]2[NH:59][C:58]([NH:61][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:57][C:56]=2[CH:55]=[C:54]([O:62][CH2:63][CH3:64])[CH:53]=1)=[O:51])[CH3:48]
Reactant: CCOC(=O)c1cc(OCC)cc2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC)cc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Yield: 61.8 %

Procedure:
600 mg (3.0 mmol) of isoquinoline-3-carboxylic acid and 1200 mg (3.1 mmol) of HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and reacted with 500 mg (2.0 mmol) of 2-amino-6-ethoxy-1H-benzoimidazole-4-carboxylic acid ethyl ester as described in general procedure A. Upon completion, the reaction was diluted with brine. The resulting solid was filtered, washed with water and EtOAc, and dried under vacuum to produce 500 mg (62%) of 6-ethoxy-2-[(isoquinoline-3-carbonyl)-amino]-3H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 406 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([O:21]CC3C=CC=CC=3)=[CH:16][C:15]=2[O:29]CC2C=CC=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([OH:21])=[CH:16][C:15]=2[OH:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(F)c(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 29 h
Yield: 147.8 %

Procedure:
A mixture of 860 mg (0.42 mmol, 1 eq) of 4-(2,4-bis(benzyloxy)-5-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester at 35% in 10 ml of ethyl acetate, in the presence of 200 mg of palladium-on-charcoal at 10%, is stirred at ambient temperature under a hydrogen pressure of 5 bar for 17 hours. 5 ml of methanol are added and the reaction medium is stirred at ambient temperature under a hydrogen pressure of 5 bar for 29 hours. The reaction medium is filtered through filter paper and the filtrate is evaporated off. The residue is chromatographed on silica gel, elution being carried out with 60/40 heptane/ethyl acetate. 192 mg of 4-(5-fluoro-2,4-dihydroxyphenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[C:5]([NH2:6])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[C:17](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:11])([F:13])[F:12])[C:5]([NH:6][CH3:17])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1c(OC(F)(F)F)cc(Br)cc1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1c(OC(F)(F)F)cc(Br)cc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 4-bromo-2-nitro-6-(trifluoromethoxy)aniline (1.962 g, 6.52 mmol, commercially available from, for example, Apollo Scientific) in N,N-dimethylformamide (DMF) (80 mL) was cooled with an ice/water bath to ˜0° C. for 10 min. Cesium carbonate (4.25 g, 13.04 mmol) was then added and stirred, and the colour changed from yellow to red. After 10 min, methyl iodide (0.408 mL, 6.52 mmol) was added and the mixture was allowed to return to rt with stirring under nitrogen for 3 h. LCMS showed 90% conversion to the desired product with no starting material remaining, and ˜10% formation of an impurity. The reaction mixture was partitioned using water (400 mL) and EtOAc (400 mL), and the aqueous layer re-extracted with EtOAc (2×400 mL). The combined organics were backwashed with water (400 mL) and then passed through a hydrophobic frit and concentrated in vacuo to give the crude product as a yellow oil. The sample was loaded in dichloromethane and purified on silica (Si) (100 g) using 100% cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the required product (1.368 g, 67%) as an orange solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:17]#[N:18])=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23](B2OC(C)(C)C(C)(C)O2)=[C:24]([NH:26]C(=O)OC(C)(C)C)[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:20]1[CH:21]=[CH:22][C:23]2=[C:2]3[C:3](=[C:17]([NH2:18])[N:26]=[C:24]2[CH:25]=1)[N:4]=[CH:5][C:6]([C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=[CH:7]3
Reactant: Cc1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-5-(p-tolylethynyl)picolinonitrile (from the previous step) (1.0 eq.), tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) (1.2 eq.), tetrakis(triphenylphosphine)palladium (10 mol %), and 2N sodium carbonate aqueous solution (4.0 eq.) in toluene/ethanol (2:1, 0.2 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with 2% MeOH in DCM. The two phases were separated, and the aqueous layer was extracted with 2% MeOH in DCM twice. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in toluene to give 8-methyl-2-(p-tolylethynyl)benzo[f][1,7]naphthyridin-5-amine.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10]3([CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:62]([C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1)([CH3:65])([CH3:64])[CH3:63]>C1COCC1>[C:62]([C:66]1[CH:67]=[CH:68][C:69]([NH:70][C:17]([CH:14]2[CH2:15][CH2:16][C:10]3([O:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11]3)[CH2:12][CH2:13]2)=[O:19])=[CH:71][CH:72]=1)([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(O)C1CCC2(CC1)CC(c1ccccc1)=NO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)C2CCC3(CC2)CC(c2ccccc2)=NO3)cc1
Reaction time: 8 h

Procedure:
3-Phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid (400 mg, 1.5 mmol) was slowly added to a solution of N-ethyldiisopropylamine (662 mg, 4.6 mmol), 1-hydroxybenzotriazole hydrate (206 mg, 1.5 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (496 mg, 1.5 mmol) and 4-tert-butylaniline (230 mg, 1.5 mmol) in abs. THF (11 ml). The reaction mixture was stirred overnight and the solvent removed under vacuum. The residue was taken up in EtOAc (75 ml). The organic phase was washed successively with sat. aq. NaCl solution, sat. aq. NaHCO3 solution, sat. aq. ammonium sulphate solution and sat. aq. NaCl solution, dried over magnesium sulphate and the solvent removed under vacuum. The desired product 3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid-(4-tert-butylphenyl)amide was obtained as a diastereomer mixture in a yield of 220 mg (37% of the theoretical amount).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH3:11])(=[O:9])[C:7]#[CH:8].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1.CCOCC.CCCCCC.CCOCC>[OH:18][CH:17]([C:16]1[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([O:13][CH3:12])[CH:15]=1)[C:8]#[C:7][C:6]([O:10][CH3:11])=[O:9]
Reactant: C#CC(=O)OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C#CC(O)c1cc(OC)c(OC)c(OC)c1
Reaction time: 1.5 h

Procedure:
71.6 ml of n-butyllithium solution (1.6M in hexane) were added to a solution of 9.6 ml (0.115 mol) of methyl propiolate in 195 ml of tetrahydrofuran/ether/hexane (4:2:1) at -110° . The mixture was stirred at -110° for 20 minutes, whereupon 15.0 g (76.4 mmol) of 3,4,5 -trimethoxybenzaldehyde in 15 ml of ether were added within 20 minutes. The reaction mixture was stirred at -78° for a further 90 minutes, then brought slowly to room temperature and thereupon treated with 100 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and evaporated. Chromatography on silica gel with ethyl acetate/hexane (1:2) yielded methyl 4-hydroxy-4-(3,4,5 -trimethoxyphenyl)-2-butynoate.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[S:34][C:33](B(OC(C)C)OC(C)C)=[CH:32][CH:31]=2)[CH2:24][CH2:23]1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[F:20])[NH:13][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:33]3[S:34][C:30]([CH2:29][CH2:28][N:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)=[CH:31][CH:32]=3)[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: CC(C)OB(OC(C)C)c1ccc(CCN2CCOCC2)s1
Reactant: Fc1ccc(Nc2ncnc3ccc(Br)cc23)cc1Cl
Agent: Cl
Product: Fc1ccc(Nc2ncnc3ccc(-c4ccc(CCN5CCOCC5)s4)cc23)cc1Cl
Temperature: 25 °C
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 5 except that the reaction mixture was heated to reflux for 4 hours, 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt was reacted with di-isopropyl 5-(2-morpholinoethyl)thien-2-ylboronate. The reaction mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was triturated under a mixture of hexane and ethyl acetate to give 4-(3-chloro-4-fluoroanilino)-6-[5-(2-morpholinoethyl)thien-2-yl]quinazoline in 27% yield; NMR Spectrum: 2.6-2.7 (t, 2H), 3.0 (t, 2H), 3.65 (t, 4H), 7.0 (d, 1H), 7.45 (t, 1H), 7.55 (d, 1H), 7.8 (m, 2H), 8.1 (m, 1H), 8.2 (m, 1H), 8.6 (s, 1H), 8.75 (d, 1H), 9.95 (broad s, 1H); Elemental Analysis: Found C, 59.0; H, 4.9; N, 11.3; C24H22ClFN4OS 1H2O requires C, 59.2; H, 5.0; N, 11.5%.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]2[O:19][C:20]3[CH:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[CH:23][C:21]=3[N:22]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:30]([C:33]1[CH:34]=[C:35]([NH:39]C(C2C=CC3OC(CCNS(C4C=CC(CCCCC)=CC=4)(=O)=O)=NC=3C=2)=O)[CH:36]=[CH:37][CH:38]=1)([CH3:32])[CH3:31].C(C1C=CC(S(NCCC2OC3C=CC(C(O)=O)=CC=3N=2)(=O)=O)=CC=1)CCCC>>[CH:30]([C:33]1[CH:34]=[C:35]([NH:39][C:27]([C:25]2[CH:24]=[CH:23][C:21]3[N:22]=[C:18]([CH2:17][CH2:16][NH:15][S:12]([C:9]4[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=4)(=[O:13])=[O:14])[O:19][C:20]=3[CH:26]=2)=[O:29])[CH:36]=[CH:37][CH:38]=1)([CH3:32])[CH3:31]
Reactant: CCCCCc1ccc(S(=O)(=O)NCCc2nc3ccc(C(=O)O)cc3o2)cc1
Reactant: CCCCCc1ccc(S(=O)(=O)NCCc2nc3cc(C(=O)Nc4cccc(C(C)C)c4)ccc3o2)cc1
Agent: CCCCCc1ccc(S(=O)(=O)NCCc2nc3cc(C(=O)O)ccc3o2)cc1
Product: CCCCCc1ccc(S(=O)(=O)NCCc2nc3ccc(C(=O)Nc4cccc(C(C)C)c4)cc3o2)cc1

Procedure:
The title compound was prepared from the product of Step 3 in a manner similar to that described for the preparation of the title compound of Example 11 from the product of Example 11, Step 1. MS m/e 534; HPLC retention time 4.19 min.
Reaction SMILES: C(OO)(=[O:3])C.[C:6]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[C:11]=1[CH3:17])(=[O:8])[CH3:7]>C(O)(=O)C>[C:6]([NH:9][C:10]1[CH:15]=[CH:14][N+:13]([O-:3])=[C:12]([CH3:16])[C:11]=1[CH3:17])(=[O:8])[CH3:7]
Reactant: CC(=O)OO
Reactant: CC(=O)Nc1ccnc(C)c1C
Solvent: CC(=O)O
Product: CC(=O)Nc1cc[n+]([O-])c(C)c1C
Temperature: 50 °C
Reaction time: 12 h

Procedure:
200 mL 30% peracetic acid in acetic acid was slowly added to a solution of 50 g 4-acetylamino-2,3-dimethylpyridine in 100 mL glacial acetic acid at 60° C. The solution was held at 70° C. for 12 hours then reduced under vacuum heated by a 50° C. water bath. Yield, 58 g N-oxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[CH3:11][O:12][CH2:13][CH2:14]Cl>>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][O:12][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9]
Reactant: COCCCl
Reactant: CCc1ccc(O)cc1Br
Product: CCOCOc1ccc(CC)c(Br)c1

Procedure:
In a manner similar to that of Example 1(e), by reacting 13 g (65 mmol) of 3-bromo-4-ethylphenol with 6.7 ml (72 mmol) of methoxyethyl chloride, and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (90/10), 12 g (76%) of the expected product are obtained in the form of a yellow oil.