Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([NH:30][NH2:31])=[O:29].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:12]2=[N:11][C:10]=1[C:21]([NH:31][NH:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][CH:34]=[C:25]([CH3:24])[CH:26]=1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)NN)c1
Reactant: Cc1ccc2nc(C(=O)O)c(OCc3ccccc3)c(=O)n2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)NNC(=O)c2nc3ccc(C)cn3c(=O)c2OCc2ccccc2)c1
Yield: 53 %

Procedure:
To a solution of the product from Example 8.2 (200 mg, 0.644 mmol) in tetrahydrofuran (10 mL), was added 3-methylbenzoyl hydrazine (94.8 mg, 0.632 mmol), 1-hydroxybenzotriazole (6.98 mg, 0.0576 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg, 0.632 mmol) successively at room temperature. After 12 h the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate. The extract was washed with 2N aqueous hydrochloric acid (20 mL), 2N aqueous sodium hydroxide (20 mL) dried (Na2SO4) and concentrated in vacuo to afford the desired compound (53%).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[Cl:12]Cl>C(O)(=O)C>[Cl:12][C:10]1[CH:11]=[C:3]([CH:4]=[C:5]([O:6][CH3:7])[C:8]=1[OH:9])[CH:2]=[O:1]
Reactant: ClCl
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(=O)O
Product: COc1cc(C=O)cc(Cl)c1O
Yield: 58 %

Procedure:
To a solution of 50.0 g (330 mmol) of vanillin in 250 mL of glacial acetic acid was added chlorine gas through a glass tubing over 60 minutes (with a slow gas flow) at 25° C. White solid product was collected by filtration, washed with 300 mL of hexane, and dried in vacuum to give the title compound (36.0 g; 58%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.CCN(CC)CC>C(Cl)Cl>[CH3:11][O:12][C:13]([CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:19]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride (1.40 mL, 12.1 mmol) was added in a dropwise manner to a mixture of L-proline methyl ester hydrochloride (2.00 g, 12.1 mmol) and Et3N (4.20 mL, 30.2 mmol) in CH2Cl2 (40 mL) and the resulting mixture stirred overnight at rt. The mixture was concentrated in vacuo and the residue treated with water and extracted with EtOAc and the combined extracts dried over Na2SO4. Concentration left a residue which was loaded onto a silica gel column and eluted with MeOH/CH2Cl2 which allowed for isolation of 2.76 g (94%) of the title compound as a white solid. MS(ES): (M+1)+ 234.2 m/z.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>CN(C)C(=O)C>[C:20]([O:19][C:17]([N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:13][CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
6-Chloronicotinic acid was dissolved in N,N-dimethylacetamide (10 ml), and tert-butyl piperazine-1-carboxylate (1.2 g) and DIPEA (1.6 g) were added thereto, followed by stirring at 130° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and to the obtained residue was added a 1 M aqueous NaOH solution, followed by washing with CHCl3. The pH of the aqueous layer was adjusted to around 6 to 7 by the addition of 1 M hydrochloric acid, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 6-[4-(tert-butoxycarbonyl)piperazin-1-yl]nicotinic acid (934 mg).
Reaction SMILES: [CH2:1]([N:4]([CH2:36][CH2:37][CH3:38])[CH:5]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=2[CH3:35])[N:22]=1)[CH:6]([CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])OCC)[CH2:2][CH3:3]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:1]([N:4]([CH2:36][CH2:37][CH3:38])[C:5]1[CH:6]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16](=[O:18])[N:22]2[C:21]=1[CH:26]=[CH:25][CH:24]=[C:23]2[C:27]1[C:32]([CH3:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=1[CH3:35])[CH2:2][CH3:3]
Reactant: CCCN(CCC)C(c1cccc(-c2c(C)cc(C)cc2C)n1)C(OCC)C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCN(CCC)c1cc(C(=O)OCC)c(=O)n2c(-c3c(C)cc(C)cc3C)cccc12
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
Diethyl [2-(dipropylamino)-1-ethoxy-2-(6-mesitylpyridin-2-yl)ethyl]malonate (0.65 g, 1.35 mmol), was dissolved in 5 mL of Dowtherm A (1:2 biphenyl:phenyl ether). The solution was placed in a pre-heated oil bath at 220° C. The reaction stirred at this temperature for 20 minutes. The solution was cooled and flash chromatographed (15%-35% ethyl acetate/hexanes) to give 0.28 g (48% yield) of an orange solid.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[CH3:14][O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 95850.1 %

Procedure:
To a solution of sesamol (10.0 g, 0.072 mmol) in DMF (50 ml) was added sodium hydride (2.08 g, 0.087 mol) at room temperature under argon. After stirring for 1 h, the mixture was treated with iodomethane (13.5 ml, 0.216 mol) and stirred for another 18 h. Upon the removal of the solvent the residue was extracted with ethyl acetate and washed with water, dried (Na2SO4) and concentrated to afford the title compound as a dark brown oil (10.5 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([I:8])=[CH:6][N:7]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[CH3:46][NH:47][O:48][CH3:49]>CN(C=O)C.C(N(CC)C(C)C)(C)C>[CH3:49][O:48][N:47]([CH3:46])[C:9]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([I:8])[N:4]=1)=[O:11]
Reactant: CNOC
Reactant: Nc1ncc(I)nc1C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nc(I)cnc1N
Temperature: 80 °C
Yield: 57.4 %

Procedure:
27.50 g (0.104 mol) of 3-amino-6-iodo-pyrazine-2-carboxylic acid, 63.0 g (0.125 mol) of PyBOP (1-benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate) and 18.70 g (0.193 mol) of N,O-dimethylhydroxylamine hydrochloride were placed in a nitrogen flushed flask and then dissolved in a mixture of 100 ml of anhydrous DMF and 27 ml of N,N-di-iso-propylethylamine. The mixture was heated to 80° C. for 16 hours. The solvent was evaporated at 50-60° C. under reduced pressure to afford a dark oil. The oil was extracted three to four times with 300 ml of toluene. The toluene phases were combined and evaporated. The resulting oil was purified via chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 18.40 g (59.72 mmol; 58%) of 3-amino-6-iodo-pyrazine-2-carboxylic acid methoxy-methyl-amide as a yellow solid. 1H-NMR (d6-DMSO) δ: 8.28 [1H] s, 6.78 [2H] s, 3.66 [3H] s, 3.25 [3H] s. MS: m/z 309 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[Li]CCCC.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[CH2:9]([C:4]1[CH:3]=[C:2]([B:16]([OH:19])[OH:17])[CH:7]=[CH:6][C:5]=1[F:8])[CH3:10]
Reactant: COB(OC)OC
Reactant: CCc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(B(O)O)ccc1F
Reaction time: 3 h
Yield: 70.8 %

Procedure:
To a solution of 95A (290 mg, 1.43 mmol) in THF (5 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.86 mL, 2.15 mmol). The mixture was stirred at −78° C. for 30 min before trimethyl borate (0.32 mL, 2.86 mmol) was added. The reaction was left stirring from −78° C. to rt over 3 h. It was quenched with 1.0 N HCl (2 mL), extracted with EtOAc, washed with Na2S2O3, brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was purified by silica gel column chromatography eluting with gradient CH2Cl2 in hexanes (0-15%) to give 95B (170 mg, 71% yield). 1H NMR (400 MHz, Methanol-d4) δ ppm 1.09 (t, J=7.47 Hz, 3H) 2.54 (q, J=7.47 Hz, 2H) 6.81-6.88 (m, 1H) 7.42-7.47 (m, 1H) 7.51 (d, J=9.23 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[C:14]([CH3:21])=[CH:15][C:16]([F:20])=[C:17]([CH:19]=3)[NH2:18])[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].Cl[C:28]([O:30][C:31]([CH3:33])=[CH2:32])=[O:29]>CCOC(C)=O>[CH2:32]=[C:31]([O:30][C:28](=[O:29])[NH:18][C:17]1[CH:19]=[C:13]([C:7]2[C:8]([CH3:12])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([Cl:1])[CH:11]=3)[C:14]([CH3:21])=[CH:15][C:16]=1[F:20])[CH3:33]
Reactant: C=C(C)OC(=O)Cl
Reactant: Cc1cc(F)c(N)cc1-c1cc2cnc(Cl)cc2nc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(Cl)cc3nc2C)c(C)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Treat a solution of 5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylaniline (0.5 g, 1.657 mmol) in EtOAc (10 mL) with satd. NaHCO3 (10 mL) followed by isopropenyl chloroformate (0.199 mL, 1.823 mmol) and stir the bi-phasic mixture at RT overnight. Separate the layers, extract the aqueous with EtOAc (2×), dry the combined organics over MgSO4 and concentrate to dryness to the title compound (646 mg, 101%). MS (ESI) m/z: 386.1 (M+H+).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH3:6])[CH:2]1[C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([CH:2]3[O:1][CH:3]3[CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9]2)=[CH:18][CH:17]=1)[CH3:21]
Reactant: CCCC1OC1[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC1OC1[C@H]1CC[C@H](c2ccc(OCC)cc2)CC1
Reaction time: 24 h

Procedure:
A solution of 1.6 g of p-[trans-4-(1,2-epoxypentyl)cyclohexyl]phenol in 120 ml of acetone was treated with 1.89 ml of ethyl iodide and 3.24 g of powdered potassium carbonate while gassing with argon. The mixture was heated to reflux while stirring for 24 hours, then evaporated on a rotary evaporator and the residue was partitioned in diethyl ether/water. The aqueous phase was extracted three times with diethyl ether. The organic phases were washed twice with water, dried over magnesium sulphate, filtered and evaporated. Chromatographic separation of the resulting, yellowish oil (1.76 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 1.45 g (82%) of 4-ethoxy-1-[trans-4-(1,2-epoxypentyl)cyclohexyl]benzene as an oily liquid.
Reaction SMILES: [C:1]1([C@@H:7]2[C:12]3=[CH:13][C:14]([NH2:26])=[N:15][C:16]4[C@@H:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:18][CH2:19][N:10]([C:11]=43)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[C:1]1([C@@H:7]2[C:12]3=[CH:13][C:14]([NH:26][C:35](=[O:36])[O:37][CH3:38])=[N:15][C:16]4[C@@H:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:18][CH2:19][N:10]([C:11]=43)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: Nc1cc2c3c(n1)[C@@H](c1ccccc1)CCN3CC[C@@H]2c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1cc2c3c(n1)[C@@H](c1ccccc1)CCN3CC[C@@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
To a solution (4R,10R)-4,10-diphenyl-4,5,6,8,9,10-hexahydropyrido[3,2,1-de][1,5]naphthyridin-2-amine (Intermediate 4), (110 mg, 0.322 mmol) in dichloromethane (10 mL) was added two equivalent of triethyl amine (0.090 mL, 0.644 mmol), followed by methyl chloroformate (0.037 mL, 0.483 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give methyl (4R,10R)-4,10-diphenyl-4,5,6,8,9,10-hexahydropyrido[3,2,1-de][1,5]naphthyridin-2-ylcarbamate, (179), (20 mg). 1H NMR (300 MHz, CDCl3) δ ppm 2.00-2.18 (m, 2H) 2.22-2.39 (m, 2H) 3.03-3.22 (m, 4H) 3.50-3.64 (m, 3H) 3.54-3.65 (m, 3H) 4.05-4.23 (m, 2H) 6.61 (br. s., 2H) 7.08-7.38 (m, 10H)
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>N1C=CC=CC=1>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:2]=1[NH:1][S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2C(=O)c2ccccc2F)cc1

Procedure:
A mixture containing 10 g of 2-amino-5-nitro-2'-fluorobenzophenone and 7.5 g of tosyl chloride is refluxed in 50 ml of pyridine for 24 hours. The solvent is evaporated off to dryness, water and ethyl acetate are added, an insoluble material is filtered off and the organic phase is washed with a dilute solution of hydrochloric acid, water and an aqueous solution of sodium chloride and then dried over magnesium sulfate and evaporated. The residue is chromatographed on silica and the expected product is eluted with DCM.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[N:29][N:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 65.8 %

Procedure:
A mixture of 5-chloro-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 64, 775 mg, 1.57 mmol), iron (525 mg, 9.40 mmol) and NH4Cl (62.8 mg, 1.17 mmol) was heated at reflux in ethanol (21 mL) and water (7 mL) for 2 h. The mixture was then cooled and filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and then dissolved into CH2Cl2. This solution was washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 2-6% 7N methanolic ammonia in CH2Cl2 gave the title compound (480 mg, 66%) as a brown gum; 1H NMR: 2.26 (3H, s), 2.52 (4H+DMSO, m), 2.89 (4H, t), 3.68 (3H, s), 4.35 (2H, d), 6.73 (1H, s), 6.99 (1H, d), 7.13 (1H, td), 7.28-7.39 (1H, m), 8.38 (1H, d), 8.39-8.46 (2H, m), 8.82 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 465.5.
Reaction SMILES: [CH:1]1([C:7]#[N:8])[CH2:4][CH2:3][CH:2]1[C:5]#[N:6].[OH:9][CH2:10][C:11](N)([CH3:14])[CH2:12][OH:13]>Cl[Cu]>[CH3:14][C:11]1([CH2:12][OH:13])[CH2:10][O:9][C:5]([CH:2]2[CH2:3][CH2:4][CH:1]2[C:7]2[O:9][CH2:10][C:11]([CH2:12][OH:13])([CH3:14])[N:8]=2)=[N:6]1
Reactant: N#CC1CCC1C#N
Reactant: CC(N)(CO)CO
Agent: Cl[Cu]
Product: CC1(CO)COC(C2CCC2C2=NC(C)(CO)CO2)=N1

Procedure:
53 g of cyclobutane-1,2-dinitrile were heated for 3.5 hours to 100° C. with 150 g of 2-hydroxymethyl-2-amino-1-propanol in the presence of 0.5 g of CuCl. Distillation of the reaction mixture in the same way as described in Example 15 gave 175 g of distillate boiling (79)C./142° - 200° C/0.6 Torr which, when subsequently fractionated in a Vigreux column, gave 117 g (83% of the theoretical) of 1,2-bis-(4-methyl-4-hydroxymethyl oxazolin-2-yl)-cyclobutane boiling at 198° - 204° C./0.05 Torr.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:6]#[N:7].Br[C:13]([CH3:18])([CH3:17])[C:14]([O-:16])=[O:15]>>[C:6]([C:5]1[CH:4]=[C:3]([CH:10]=[C:9]([F:11])[CH:8]=1)[CH2:2][NH:1][C:13]([CH3:18])([CH3:17])[C:14]([O:16][C:3]([CH3:4])([CH3:10])[CH3:2])=[O:15])#[N:7]
Reactant: CC(C)(Br)C(=O)[O-]
Reactant: N#Cc1cc(F)cc(CN)c1
Product: CC(C)(C)OC(=O)C(C)(C)NCc1cc(F)cc(C#N)c1
Yield: 91 %

Procedure:
The title compound was prepared following the general procedure 11, starting from 3-(aminomethyl)-5-fluorobenzonitrile and 2-bromoisobutyrate, affording the title compound as a light yellow liquid (5 g, 91%). 1H NMR (DMSO-d6, 400 MHz): δ 7.67 (d, J=7 Hz, 2H), 7.57 (d, J=9.5 Hz, 1H), 3.67 (d, 2H), 2.67 (t, 1H), 1.40 (s, 9H), 1.19 (s, 6H). LC/MS (Method A) 293.2 (M+H)+. HPLC (Method A) Rt: 2.29 min (Purity: 99.7%).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=1.CI>C(#N)C>[CH3:1][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 5 h

Procedure:
A 2 L round bottom flask equipped with a stir bar and reflux condenser was charged with acetonitrile (1 L), K2CO3 (263 g, 1.9 mol) and 4-hydroxy-2-fluoro-1-nitrobenzene (100 g, 0.64 mol). Methyl iodide (271 g, 1.9 mol) was added to the reaction mixture and heated at reflux temperatures with vigorous stirring for 5 h. The acetonitrile was removed and ethyl acetate (1 L) and H2O (700 mL) were added. The heterogeneous mixture was transferred to a separatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×200 mL). The organic phases were combined and washed with H2O (2×500 mL), brine (500 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product as a slightly yellow solid (107 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.C1COCC1.[NH2:15][C:16]1[C:17]([C:38](N(OC)C)=[O:39])=[N:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH:23]=2)=[CH:20][N:21]=1>O>[NH2:15][C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[C:28]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])=[N:18][C:17]=1[C:38]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:39]
Reactant: CON(C)C(=O)c1nc(-c2cccc(C(=O)NCc3ccccc3)c2)cnc1N
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc(-c2cccc(C(=O)NCc3ccccc3)c2)nc1C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4 %

Procedure:
3-Fluorophenylmagnesium bromide (1.5 mL of a 0.5 M solution in TBF, 0.75 mmol) was added dropwise to a THF (10 mL) solution of 3-amino-6-{3-[(benzylamino)carbonyl]phenyl}-N-methoxy-N-methylpyrazine-2-carboxamide (0.10 g, 0.25 mmol) at 0° C. under N2. The reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was diluted with water and extracted 3× with ethyl acetate. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. The crude product was separated by preparative HPLC and lyophilized to give a yellow solid (4 mg, 4% yield). 1H NMR (400 MHz, d6-DMSO): δ 9.10 (t, 1H), 9.05 (s, 1H), 8.42 (bs, 1H), 8.01 (m, 2H), 7.86-7.80 (m, 2H), 7.74 (d, 1H), 7.57-7.51 (m, 2H), 7.47-7.43 (m, 2H), 7.38-7.32 (m, 2H), 7.28-7.24 (m, 2H), 6.47-6.59 (m, 1H), 4.50 (d, 2H). MS (EI) for C25H19FN4O2: 427 (MH+).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1>CO.[Pd]>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1ccc(C2CCNCC2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (10 g) in methanol (200 mL) was added 10% palladium on charcoal (0.5 g) and the mixture was hydrogenated at 50 psi for 3 h. The catalyst was removed by filtration and solvent was evaporated to leave the product as a white powder, which was used in the next step without any purification.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[C:17]=1[Br:22]>CO.C(Cl)(Cl)Cl>[Br:22][C:17]1[C:18]([CH3:21])=[N:19][O:20][C:16]=1[NH:15][S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(-c2cccs2)s1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3cccs3)s2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2. Reaction of 2-chlorosulfonyl-5,2'-bithiophene (300 mg, 1.14 mmol) with 5-amino-4-bromo-3-methylisoxazole (183 mg, 1.03 mmol) yielded, after flash chromatography using 10% MeOH/CHCl3, 430 mg (94%) of a pale brown solid, m.p. 210° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:8])=[N+:4]([O-:17])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ncccc1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(Br)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A mixture of 3-bromo-2-methylpyridine (0.14 mL, 1.2 mmol) and m-chloroperbenzoic acid (420 mg, 1.8 mmol) in methylene chloride (4 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-10% methanol in dichloromethane) to afford the title compound as a white solid (140 mg, 61%), which was used in the next step without further purification.