Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:20]([CH3:22])[CH3:21])=[CH:10][C:11]=2/[C:13](/[CH2:18][CH3:19])=[C:14](/[F:17])\[CH2:15][OH:16])[C:6]([CH3:24])([CH3:23])[CH2:5][CH2:4]1)[CH3:2].C[N+]1([O-])CCOCC1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:20]([CH3:22])[CH3:21])=[CH:10][C:11]=2/[C:13](/[CH2:18][CH3:19])=[C:14](/[F:17])\[CH:15]=[O:16])[C:6]([CH3:24])([CH3:23])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC/C(=C(\F)CO)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C
Agent: C[N+]1([O-])CCOCC1
Product: CC/C(=C(\F)C=O)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C

Procedure:
Following General Procedure G, (E)-3-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-2-fluoro-pent-2-en-1-ol (Intermediate 19, 2.45 g, 6.28 mmol) and N-methylmorpholine N-oxide (1.73 g, 12.6 mmol) were reacted to give the title compound as a bright yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[O:12]([CH2:19][CH2:20]CS([O-])(=O)=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[O:12]([CH2:19][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)([O-])CCCOc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCOc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
1.19 g of 4-hydroxybenzaldehyde were dissolved in 30 ml of DMF, and 0.41 g of 60% NaH were further added to the resultant solution while cooling it with ice. The solution was then stirred for 1 hour after elevating the temperature of the solution up to room temperature. The solution was again cooled with ice, then added with 2.0 g of 2-phenoxyethyl-methane sulfonate, and stirred for 1 hour at room temperature and subsequently for a night at 50-60° C. The solution reacted was poured into ice-water and extracted with ethyl acetate, then the organic layer resulted was dried with anhydrous magnesium sulfate. The solvent used was then removed by distillation under reduced pressure, and the residue obtained was washed with a mixture of ether and hexane, thereby affording 1.45 g of 4-(2-phenoxyethyloxy)benzaldehyde.
Reaction SMILES: C(OC([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[C:8]([C:15]1[C:16]([Cl:20])=[N:17][S:18][N:19]=1)=[C:9]([Cl:14])[CH2:10]2)=O)C.[Cl-].[Cl-].[Cl-].[Al+3].O>C1(C)C=CC=CC=1>[Cl:14][C:9]1[CH2:10][CH:11]2[NH:6][CH:7]([CH2:13][CH2:12]2)[C:8]=1[C:15]1[C:16]([Cl:20])=[N:17][S:18][N:19]=1
Reactant: CCOC(=O)N1C2CCC1C(c1nsnc1Cl)=C(Cl)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: ClC1=C(c2nsnc2Cl)C2CCC(C1)N2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-ethoxycarbonyl-3-chloro-2-(3-chloro-1,2,5-thiadiazol-4-yl)-8-azabicyclo[3.2.1]oct-2-ene (1.7 g, 5 mmol) (PCT/DK91/00236) in dry toluene (50 ml) was added aluminium trichloride (2.6 g, 20 mmol). The reaction mixture was heated to 80° C. and kept at this temperature for 10 min. After cooling water was carefully added to the reaction mixture. The water solution was extracted with methylene chloride (2×50 ml), then made basic with 4N sodiumhydroxide solution. The alkaline solution was extracted with diethylether (3×100 ml). The organic extracts from the basic extractions were dried over magnesium sulfate and evaporated. The residue was crystallized as the oxalate salt from acetone in 1.60 g yield.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:16])[C:9]([F:17])=[C:8](F)[C:7]=1[F:19]>CC(C)=O.O>[N:1]([C:8]1[C:7]([F:19])=[C:6]([F:5])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:16])[C:9]=1[F:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1F
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1c(F)c(F)c(N=[N+]=[N-])c(F)c1F
Yield: 94.3 %

Procedure:
All reaction steps were carried out with protection from light due to the sensitive nature of the azido group. First, a mixture of NaN3 (300 mg, 4.6 mmol) and methyl pentafluorobenzoate (0.972 g, 4.3 mmol) in acetone (8 mL) and water (3 mL) was refluxed for 8 hours. The mixture was cooled, diluted with 10 mL of water, and then extracted with diethyl ether (3×10 mL). The extract was dried (anhydrous Na2SO4) and evaporated to give methyl 4-azido-2,3,5,6-tetrafluorobenzoate (1.01 g, 94%), as off-white flakes, mp 53.6-54.3° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([NH:21][S:22]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)(=[O:24])=[O:23])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[C:40]1(=[O:50])[O:45][C:43](=[O:44])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12>C1COCC1>[Cl:30][C:27]1[S:26][C:25]([S:22]([NH:21][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:40]([C:41]4[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=4[C:43]([OH:45])=[O:44])=[O:50])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:24])=[O:23])=[CH:29][CH:28]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)c2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a solution of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 4) (0.046 g, 0.1 mmol) in THF (0.5 ml) was added N,N-diisopropylethylamine (0.035 ml, 0.2 mmol), followed by phthalic anhydride (0.014 g, 0.1 mmol). The solution was stirred for 18 hours at room temperature, concentrated in a blow-down unit and the residue was dissolved in DMSO (0.5 ml) and purified by mass directed auto-preparative HPLC (Method E) to give the title compound (35 mg, 51%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][C:7]2[C:8]([N:18]=1)=[N:9][CH:10]=[C:11]([C:13](OCC)=[O:14])[CH:12]=2)([CH3:3])[CH3:2].CC(C[Al]CC(C)C)C>C1(C)C=CC=CC=1.C1COCC1>[CH:1]([NH:4][C:5]1[S:6][C:7]2[C:8]([N:18]=1)=[N:9][CH:10]=[C:11]([CH2:13][OH:14])[CH:12]=2)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc2nc(NC(C)C)sc2c1
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)Nc1nc2ncc(CO)cc2s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 2-(isopropylamino)thiazolo[4,5-b]pyridine-6-carboxylate (0.278 g, 1.05 mmol) in toluene (10 mL) and THF (5 mL) was introduced Dibal-H (5.8 mL, 5.8 mmol) at −78° C. over 10 min. The resulting mixture was allowed to warm to rt and stirred for 4 hr. Additional Dibal-H (1.2 mL, 1.2 mmol) was added at rt, and the mixture was stirred for additional 1.5 hr before it was poured into ice-cold water (100 mL). The mixture was stirred at rt for 30 min, and then filtered through Celite® 545. The organic layer of filtrate was separated. The aqueous layer was basified with saturated NaHCO3 solution and extracted with AcOEt. The combined organic phase was washed with brine and dried over anhydrous MgSO4. Evaporation of solvent under vacuum gave the title compound as a viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)#[N:21].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.[I-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][N:25]2[CH2:26][CH2:27][CH:22]([C:20]#[N:21])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: N#CC1CCNCC1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 130 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
2.13 g of 1-bis(4-fluorophenyl)methoxy-2-chloroethane and 0.95 g of 4-cyanopiperidine were dissolved in 15 ml of dimethylformamide. After this, 4.00 g of anhydrous sodium carbonate and 0.08 g of sodium iodide were added to the resulting solution, and the mixture was stirred for 4 hours at 130° C. At the end of this time, the mixture was poured into ice water and extracted with ethyl acetate. The oily extract obtained was purified by silica gel chromatography. Elution with a 2:1 by volume mixture of ethyl acetate and hexane afforded 2.36 g (yield 88%) of the title compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([N:11]([CH3:18])[C:12]2[CH:17]=[N:16][CH:15]=[N:14][CH:13]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: CI
Reactant: Clc1cc(Br)cc(Nc2cncnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cncnc1)c1cc(Cl)cc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
NaH (24 mg, 1.0 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (2.2 mL) was added. The slurry was cooled to 0° C. and compound 34 (255 mg, 0.896 mmol, 1.00 eq) was added as a solution in THF (2.2 mL). After stirring at 0° C. for 30 minutes methyl iodide (61.5 μL, 1.00 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 248 mg (93%) of the title compound as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.64 (s, 1H), 7.25 (t, J=1.7 Hz, 1H), 7.16 (t, J=1.9 Hz, 1H), 7.07 (t, J=1.9 Hz, 1H), 3.32 (s, 3H); ES-MS [M+1]+: 298.1.
Reaction SMILES: C(OC(=O)CN1C=C([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18](=[O:35])[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])=[CH:21][C:20]=3[Cl:34])[CH:12]=2)N=N1)C.[N:37]([C:40]1C=CC(C)=[C:44]([C:46](C2C=CC(NC3C=CC(F)=CC=3F)=CC=2Cl)=[O:47])[CH:45]=1)=[N+:38]=[N-:39].C(O)CC#C>>[Cl:34][C:20]1[CH:21]=[C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[CH:23]=[CH:24][C:19]=1[C:18]([C:13]1[CH:12]=[C:11]([N:37]2[CH:40]=[C:45]([CH2:44][CH2:46][OH:47])[N:39]=[N:38]2)[CH:16]=[CH:15][C:14]=1[CH3:17])=[O:35]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCOC(=O)Cn1cc(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Agent: C#CCCO
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 110, using compound 434 (6.87 mmol) and 3-butyne-1-ol (8.24 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 50:50 to 100:0 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20](OS(C(F)(F)F)(=O)=O)[CH:21]=[N:22][CH:23]=1.C(OCC)(=O)C>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:19]=1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1ccc(C#Cc2cncc(Cl)c2)cc1
Temperature: 60 °C
Yield: 65 %

Procedure:
Add 4-fluorophenylacetylene (1.0 g, 8.35 mmol), triethylamine (4 mL, 30 mmol), copper (I) iodide (76 mg, 0.40 mmol), and bis(triphenylphosphine)palladium (II) dichloride (140 mg, 0.20 mmol) to a solution of trifluoromethanesulfonic acid 5-chloropyridin-3-yl ester, (prepared as described in PREPARATION 25) in ethyl acetate (1.95 g, 7.5 mmol), (7 mL) under nitrogen and heat at 60° C. for 12 h. Concentrate and purify the residue by silica gel chromatography, eluting with dichloromethane to give the title compound as a white solid (1.12 g, 65%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][C@@H:34]([CH3:38])[CH2:33]2)=[CH:28][CH:27]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)[CH2:33][C@@H:34]2[CH3:38])=[O:48])[C:44]=1[CH3:45]
Reactant: C[C@H]1CN(c2ccc(Cl)cc2)CCN1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)C[C@@H]1C

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chlorophenyl)-3-(S)-methylpiperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 300 MHz) 7.25 (d 2H), 6.83 (d, 2H), 4.91 (m, 3H), 4.28 (m, 1H), 3.80-3.10 (m, 4H), 2.86 (m, 1H), 2.71 (m, 1H), 2.29 (s, 3H), 1.40 (m, 3H) ppm; MS (ES) M+H expected=435.1, found=435.0.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.Cl[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]Cl>ClC1C=CC=CC=1Cl>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: ClCCNCCCl
Reactant: Nc1ccccc1C1=CCCCCCC1
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: C1=C(c2ccccc2N2CCNCC2)CCCCCC1
Temperature: 200 °C
Reaction time: 9 h
Yield: 53.2 %

Procedure:
To a solution of 2-cyclooct-1-enylphenylamine (140 mg, 0.695 mmol) in 1,2-dichlorobenzene (2 mL) was added bis(2-chloroethyl)amine hydrochloride (149 mg, 0.835 mmol), and the mixture was stirred at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was blown into the reactor to remove the hydrogen chloride gas in the reactor. This procedure was repeated several times. After 9 hours, the mixture was air-cooled to room temperature. Aqueous solution of potassium carbonate, ethyl acetate and methanol were added to the reaction mixture and extraction was performed three times with ethyl acetate. The obtained organic layers were dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 100 mg of the title compound as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][N:6]=[C:5]2[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([CH3:31])[CH:27]=3)[N:22]([CH3:32])[C:21]2=[O:33])[CH2:16][CH2:15]1.[CH2:34](I)[CH2:35][CH3:36]>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:4]([C:5]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:29](=[O:30])[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH3:31])[CH:27]=5)[N:22]([CH3:32])[C:21]4=[O:33])[CH2:16][CH2:15]3)=[N:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[O:1][CH2:34][CH2:35][CH3:36]
Reactant: CCCI
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1O
Product: CCCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2cc1OC
Yield: 64 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 100.0 mg (0.22 mmol) of Compound 90 obtained in Example 80 was used in place of Compound 24 and propyl iodide was used in place of methyl iodide. As a result, 69.0 mg (yield: 64%) of Compound 92 was obtained as white crystals.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH3:6][CH:7]1[C:13]2[NH:14][C:15](=O)[CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:8]1>CN(C=O)C>[Br:3][C:15]1[CH:16]=[CH:17][C:12]2[CH2:11][CH2:10][N:9]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:8][CH:7]([CH3:6])[C:13]=2[N:14]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(=O)[nH]c21
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Br)nc21
Temperature: 90 °C
Yield: 55.6 %

Procedure:
TFA (9.20 mmol, 0.709 ml) was slowly added to a stirred solution of tert-butyl 4-hydroxy-9-methyl-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (0.541 g, 1.84 mmol) in DCM (20 ml) at room temperature. The reaction solution was stirred until all starting materials are consumed. The solvent was removed under reduced pressure and the resulting residue was dissolved in DCM (20 ml). Addition of Et3N (18.4 mmol, 2.56 ml) and TFAA (3.86 mmol, 0.511 ml) was followed by stirring for 8 h at room temperature. The reaction mixture was parted between sat. aq. NaHCO3 and DCM. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified to provide 277 mg (52%, two steps) of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 291 [M+1]+. POBr3 (0.533 mol, 153 mg) was added to a stirred solution of 4-hydroxy-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (77 mg, 266 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 2 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 47 mg (50%) of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one. MS (ESI) m/z 353/355. A mixture of 4-bromo-9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (47 mg, 134 μmol), EtOH (2 ml) and 10% Pd/C was stirred for 5 minutes under H2 atmosphere (1 atm). The reaction was filtered through Celite and 35 mg (99%) of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one was obtained. MS (ESI) m/z 275. POBr3 (256 μmol, 73.5 mg) was added to a stirred solution of 9-methyl-7-(trifluoroacetyl)-1,5,6,7,8,9-hexahydro-2H-pyrido[2,3-d]azepin-2-one (35 mg, 128 μmol) in DMF (1 ml). The mixture was heated at 90° C. for 5 h, quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography to furnish 24 mg (56%) of 2-bromo-9-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 337/339. Deprotection was carried out at 60° C. for 10 minutes using MeOH (1 ml), H2O (200 μl) and K2CO3 (30 mg) to render 15 mg (87%) of 2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (DMSO-d6) δ 7.42 (d, 1H), 7.35 (d, 1H), 4.25 (m, 2H), 3.86 (m, 2H), 3.18 (m, 2H), 2.84 (dd, 1H), 1.21 (d, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.Cl[CH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[O:10][CH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: ClCc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ncccn2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 4-nitro-m-cresol (0.25 g, 1.6 mmol), 2-(chloromethyl)pyrimidine hydrochloride (0.40 g, 2.4 mmol) and potassium carbonate (0.50 g, 4.0 mmol) in N,N-dimethylformamide (6.0 mL) was stirred at 70° C. for 18 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford 2-[(3-methyl-4-nitrophenoxy)methyl]pyrimidine as crude material (0.32 g, y. 81%) as solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C:11]#[N:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:13].[C:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[ClH:13].[C:1]1([CH2:7][C:8]([NH:10][C:11]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=2)=[NH:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: N#CNC(=O)Cc1ccccc1
Agent: Cl
Product: CC(C)(C)c1ccc(NC(=N)NC(=O)Cc2ccccc2)cc1
Yield: 69 %

Procedure:
Synthesis of this compound was achieved by the method set forth in Example 1, Part II above with the use of phenylacetylcyanamide in place of 4-methylbenzoylcyanamide and using 4-t-butylaniline hydrochloride instead of 4-isopropylaniline hydrochloride respectively. Yield 69%; m.p. 182–186° C.; Purity 86% (HPLC); 1H-NMR (CD3OD) δ 1.38 (s, 9H, CH3), 3.84 (s, 2H, CH2), 7.3 (d, 2H, ArH), 7.3–7.45 (m, 5H, ArH), 7.6 (d, 2H, ArH).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]1[O:6][C@@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[NH3:15]>CO>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:5]2[O:6][C@@H:4]2[C:3]([NH2:15])=[O:2])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H]1O[C@@H]1c1ccc(C)cc1
Reactant: N
Solvent: CO
Product: Cc1ccc([C@H]2O[C@@H]2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a mixture of (2S,3R)-3-(4-methylphenyl)-2,3-epoxypropionic acid methyl ester (3.84 g) and methanol (25 ml) is added dropwise a solution of 28% aqueous ammonia (6.1 g) in methanol (10 ml) under ice-cooling. The reaction mixture is gradually warmed to room temperature, and stirred for two hours, and further stirred for one hour under ice-cooling. The precipitated crystals are collected by filtration, washed, and dried at 50° C. to give (2S,3R)-3-(4-methylphenyl)-2,3-epoxypropionamide (2.71 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1.O>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[C:6]3[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]3=[O:5])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(COc2ccc(C=O)cc2)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ccc(C=C3C(=O)OC(C)(C)OC3=O)cc2)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Condensation with Meldrum's acid is carried out according to the procedure of DeWolf et al. (1989) Biochemistry 28: 3833-3842. A solution of Meldrum's acid (18 g, 124 mmol) compound 12.1 (30 g, 124 mmol) in toluene (100 mL) was treated with glacial acetic acid (4 mL) and piperidine (2 mL). The reaction mixture was stirred and heated at reflux until the removal of water with a Dean-Stark trap was complete. The reaction mixture was cooled to room temperature and the resulting solid was filtered and washed with cold toluene to yield 28 g (62%) of 12.2 as a bright yellow powder. 1H NMR(400 MHz)(DMSO-d6) δ8.32 (s, 1H); 8.24 (d, 2H, J=8.9 Hz); 7.42 (d, 2H, J=8.6 Hz); 7.17 (d, 2H, J=9.0 Hz); 6.97 (d, 2H, J=8.7 Hz); 5.18 (s, 2H) 3.75 (s, 6H) 1.75 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C(O)=O)[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:22]2C=CC=C[C:21]=2N=N1.C(Cl)Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]1[CH:21]=[CH:22][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Nc1cccc(C(=O)O)n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: c1ccn2ccnc2c1

Procedure:
In Scheme 2, 2-amino-6-pyridine carboxylic acid 8 is reacted with an amine 9 using a coupling agent such as, but not limited to, BOP or DMC in an organic solvent such as DCM or DMF in the presence of an organic base such as Hunig's base. The resulting amide 10 is reacted with alpha halocarbonyl 11 to give the imidazo[1,2-a]pyridine 12. Alternatively 10 can be reacted with the alpha haloaldehyde 13 to give the imidazo[1,2-a]pyridine 14.