Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5](=[O:21])[N:6]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH:7]=1)#[N:2].[ClH:22].O1CCOCC1>C(OCC)(=O)C>[ClH:22].[O:21]=[C:5]1[NH:4][C:3]([C:1]#[N:2])=[CH:7][N:6]1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)[nH]c2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1cn(C2CCNCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-(4-cyano-2-oxo-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (45 mg, 0.154 mmol) was dissolved in ethyl acetate (5.0 mL). 4M Hydrogen chloride in 1,4-dioxane (10 mL, 40 mmol) was added to the mixture. Reaction was stirred at room temperature for 18 hours. Liquids were decanted off. Remaining solids were dissolved in methanol and then transferred to a smaller flask. Material was concentrated by roto-vap. Residue was treated with dichloromethane and then concentrated to dryness. Title compound was obtained as yellow solid in quantitative yield. MS (M+H)+=193.0.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[N:4]=1.[CH3:20][CH:21]([CH3:23])[O-:22].[Li+].[Li].[CH3:26]C(O)C>>[F:19][C:18]1[C:13]([N:5]2[CH:6]=[C:7]([C:8]([O:10][CH:11]([CH3:26])[CH3:12])=[O:9])[C:3]([CH2:2][O:22][CH:21]([CH3:23])[CH3:20])=[N:4]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)O
Reactant: CC(C)[O-]
Reactant: CCOC(=O)c1cn(-c2ncccc2F)nc1CBr
Agent: [Li+]
Agent: [Li]
Product: CC(C)OCc1nn(-c2ncccc2F)cc1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-(bromomethyl)-1-(3-fluoro-2-pyridyl)pyrazole-4-carboxylate (1.5 g, 4.57 mmol), in propan-2-ol (23 mL), lithium isopropoxide (3.02 g) is added and the mixture is stirred overnight at room temperature. After that time more lithium isoproxide (4.5 g) is added in three portions of 1.5 g each every 16 hours. After the last addition, the reaction mixture is finally stirred at 40° C. for 16 hours. Solvent is evaporated and the residue dissolved in ethyl acetate and washed with brine. Organic layer is decanted and dried over sodium sulfate. Solvent is evaporated and the residue is purified by normal phase Isco chromatography using as eluent dichloromethane and methanol to give 317 mg of isopropyl 1-(3-fluoro-2-pyridyl)-3-(isopropoxymethyl)pyrazole-4-carboxylate. MS (m/z): 322 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[CH2:13](O)[CH2:14][OH:15].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1([C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[O:15][CH2:14][CH2:13][O:3]1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(OCC)OCC
Solvent: ClCCl
Product: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Temperature: 25 °C

Procedure:
P-Nitroacetophenone (1.65 g, 10 mmol), ethylene glycol (5 ml, 89 mmol), triethyl orthoformate (2.96 g, 20 mmol), and p-toluenesulfonic acid (0.086 g, 0.5 mmol) were combined in methylene chloride (4 ml). The solution was heated with an oil bath (50°-70° C., 6 hrs), cooled to room temperature, and poured into excess 10% sodium hydroxide solution. The phases were separated and the aqueous phase was extracted twice with methylene chloride. The combined organic phase was washed three times with water and dried with anhydrous sodium sulphate. Evaporation of the solvent left a light yellow product (1.78 g) with mp. 69°-71° C., (lit. 73°-75° C., see J. Pharm. Sci. 57, 784 (1968)).
Reaction SMILES: O.C([O-])=O.[Na+].C(O)(=O)C.C([O:17][C:18]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][C:19]=1[C:20]([NH:22][C:23]1[CH:32]=[C:31]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])=[O:21])C1C=CC=CC=1>[C].[Pd].O1CCOCC1>[O:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:31]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([NH:22][C:20](=[O:21])[C:19]2[CH:38]=[C:39]([N:42]3[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]3)[CH:40]=[CH:41][C:18]=2[OH:17])[CH:32]=1
Reactant: COC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2ccco2)cc1NC(=O)c1cc(N2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
Water (0.20 mL), sodium formate (0.045 g), acetic acid (0.043 mL) and 10% palladium-carbon (8 mg) were added to a dioxane (1 mL) solution of methyl 2-(2-(benzyloxy)-5-(piperidin-1-yl)benzamido)-4-(furan-2-yl)benzoate (0.085 g), followed by stirring at room temperature for 3 hours and 30 minutes and then at 60° C. for 50 minutes. To the reaction mixture, 10% palladium-carbon (8 mg) was added, followed by stirring at 70° C. for 50 minutes. After cooling the reaction mixture to room temperature, the insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.048 g of methyl 4-(furan-2-yl)-2-(2-hydroxy-5-(piperidin-1-yl)benzamido)benzoate.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[S:9](Cl)([OH:12])(=O)=[O:10].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][S:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:10]
Reactant: c1ccccc1
Reactant: O=S(=O)(O)Cl
Reactant: OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(OCC(F)(F)F)c1ccccc1
Reaction time: 0.17 h

Procedure:
4.4 Moles of a 30% aqueous solution of sodium hydroxide were dissolved in 4 moles of 2,2,2-trifluoroethanol with cooling to maintain the temperature of the reaction mixture between 50° and 55° C. The solution was added at once with stirring at the same temperature to a mixture of 4.2 moles of benzene sulphochloride and 1 liter of water, which had also been brought at 50°-55° C. After 10 min of stirring the oil layer was decanted and washed with 1 liter of water. The oil was filtered through paper to remove water drops.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][C:23](F)=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1>CN(C=O)C.O>[CH3:17][O:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][C:23]([NH:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)CCN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NCCS(C)(=O)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83 %

Procedure:
To a solution of 2-methanesulfonylethylamine (1.3 g, 10.56 mmol) and DIPEA (3.5 mL, 31.69 mmol) in DMF (15 mL) was added 4-fluoro-3-nitro-benzoic acid methyl ester (1.2 g, 15.84 mmol) in portions. The reaction mixture was allowed to stir for 15 h at room temperature. It was then diluted with water and extracted with EtOAc. The organic layers were washed with water, brine and concentrated to give 4-(2-methanesulfonyl-ethylamino)-3-nitro-benzoic acid methyl ester (83%). 1H NMR (300 MHz, CDCl3) δ 8.9 (d, 1H), 8.6 (t, 1H), 8.2 (d, 1H), 6.9 (d, 1H), 4.0 (q, 2H), 3.9 (s, 3H), 3.4 (t, 2H), 3.0 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16]([OH:19])(=O)[CH3:17].O.C([BH3-])#N.[Na+].[CH2:25]1[CH2:29]OC[CH2:26]1>>[O:19]1[CH:29]=[CH:25][CH:26]=[C:16]1[CH2:17][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)O
Reactant: C1CCOC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccco3)CC2)cc1
Temperature: 25 °C
Yield: 54 %

Procedure:
To a solution of 1-(4-nitrophenyl)-piperazine (0.6 g, 2.89 mmol) in THF (10 mL) was added fufaraldehyde (0.41 g, 4.31 mmol), acetic acid (3 mL) and water (1.5 mL) and the mixture stirred at r.t. for half an hour. Sodium cyanoborohydride (0.27 g, 4.31 mmol) was added and the reaction heated at reflux for four hours. The reaction was cooled and the solvent evaporated. The resulting residue was diluted with water and extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate and brine solution, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography over silica gel (60-120 mesh) using 5% methanol/chloroform as eluent afforded 1-furan-2-ylmethyl-4-(4-nitrophenyl)-piperazine (0.45 g, 54%) as a yellow solid.
Reaction SMILES: [C-]#N.[Na+].BrC[C:6]1[CH:21]=[CH:20][C:9]2[C:10](=[O:19])[C:11]3[CH:18]=[CH:17]C=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1.[CH3:22][C:23]([CH3:27])(O)[C:24]#[N:25]>CCOCC>[CH:15]1[C:12]2[CH:13]=[CH:14][C:8]3[CH:7]=[CH:6][CH:21]=[CH:20][C:9]=3[C:10](=[O:19])[C:11]=2[CH:18]=[CH:17][C:22]=1[CH:23]([CH3:27])[C:24]#[N:25]
Reactant: CC(C)(O)C#N
Reactant: O=c1c2ccccc2ccc2cc(CBr)ccc12
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Product: CC(C#N)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
12.0 Gm. of sodium cyanide and 6.0 gm. of 2-bromomethyl-5H-dibenzo[a,d]cyclohepten-5-one are stirred at 100°C. for 40 minutes in 150 ml. of acetone cyanohydrin. The mixture is cooled and poured into ether. The ethereal layer is washed with water, dried and evaporated. The residue is chromatographed on 350 gm. of silica gel, eluting with hexane/ethyl acetate (3:2) to obtain 8.8 gm., 78%, of 5H-dibenzo[a,d]cyclohepten-5-on-2-yl acetonitrile which is recrystallized from ethyl acetate/hexane, m.p. 119°-121°C. Use of 2-(α-bromoethyl)-5H-dibenzo[a,d]cyclohepten-5-one gives a similar yield of 2-(5H-dibenzo[a,d] cyclohepten-5-on-2-yl)propionitrile, m.p. 108°-109°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:21])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:21])[CH2:13][CH2:14]2)[S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)(=[O:32])=[O:31])=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1N1CCC(Nc2ccc(F)cc2)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)N(c2ccc(F)cc2)C2CCN(C3CCCCC3=O)CC2)cc1

Procedure:
The title compound, MS (ISP): m/e=539.4 (M+H+), was prepared as for example 99, steps (A) to (F). Step (B) was performed using 4-fluoro-aniline, and yielded (+/−)-trans-2-[4-(4-fluoro-phenylamino)-piperidin-1-yl]-cyclohexanol, which was oxidized to (+/−)-2-[4-(4-fluoro-phenylamino)-piperidin-1-yl]-cyclohexanone in step (C). This was then reacted with 4-methoxy-benzensulfonyl chloride in step (D), yielding (+/−)-N-(4-fluoro-phenyl)-4-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide. The final step (F) was performed with bromobenzene.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].O>C(O)C.O1CCCC1>[F:25][C:2]([F:1])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnn(Cc2ccc(-c3cccc(C(F)(F)F)c3)s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(Cc2ccc(-c3cccc(C(F)(F)F)c3)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a mixed solution of the compound (260 mg, 0.65 mmol) obtained in Example 39c in ethanol/tetrahydrofuran (v/v=1/1, 6 mL) was added 2N aqueous sodium hydroxide solution (1.3 mL, 2.6 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (160 mg, 69%) as colorless crystals.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][C:17]=2[F:27])[N:8]=1)=O.Cl.[F:30][C:31]([F:42])([F:41])[O:32][C:33]1[CH:34]=[C:35]([NH:39][NH2:40])[CH:36]=[CH:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(O)C>[F:27][C:17]1[CH:18]=[C:19]([N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)[CH:20]=[CH:21][C:16]=1[N:9]1[CH:10]=[C:11]([O:14][CH3:15])[C:12](=[O:13])[C:7]([C:5]2[N:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([O:32][C:31]([F:41])([F:42])[F:30])[CH:34]=3)[N:40]=[CH:3][CH:4]=2)=[N:8]1
Reactant: NNc1cccc(OC(F)(F)F)c1
Reactant: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(C(=O)C=CN(C)C)c1=O
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(-c2ccc(-n3cccn3)cc2F)nc(-c2ccnn2-c2cccc(OC(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.9 %

Procedure:
To a suspension of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one (200 mg) in ethanol (2.0 mL) was added dropwise a solution of [3-(trifluoromethoxy)phenyl]hydrazine hydrochloride (139 mg) and TFA (0.2 mL) in ethanol (2.0 mL), and the mixture was so stirred at room temperature for 24 hr. To the reaction mixture was added an ethanol solution (0.3 ml) of [3-(trifluoromethoxy)phenyl]hydrazine hydrochloride (16.7 mg), and the mixture was stirred at room temperature for 24 hr. The precipitated solid was collected by filtration. The mother liquor was concentrated, and the precipitated solid was collected by filtration. The solid was combined with the previously obtained solid, and recrystallized from acetone/water to give the title compound (96.1 mg).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.CC(C)C(O)=O.[CH3:14][N:15]([CH3:18])[CH:16]=O>>[CH3:14][N:15]([CH3:18])[CH:16]=[N:7][C:5]1[S:6][C:2]([CH3:1])=[CH:3][N:4]=1
Reactant: CN(C)C=O
Reactant: Cc1cnc(N)s1
Solvent: CC(C)C(=O)O
Product: Cc1cnc(N=CN(C)C)s1

Procedure:
prepared by reaction of 5-methyl-thiazol-2-ylamine with N,N-dimethylformamide dimethyl acetate. LC-MS: tR=0.52 min; [M+H]+=170.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([CH2:12][NH:13][C:14](=O)[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[OH:16])[CH2:8][CH2:7]2.B.CSC>O1CCCC1.CO>[ClH:23].[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([CH2:12][NH:13][CH2:14][CH:15]([OH:16])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:8][CH2:7]2
Reactant: O=C(NCC1CCc2cccc(O)c2C1)C(O)c1cccc(Cl)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: Cl
Product: Oc1cccc2c1CC(CNCC(O)c1cccc(Cl)c1)CC2

Procedure:
A solution of the product of step (i) above (1.6 g, 0.0046 mol) in anhydrous tetrahydrofuran (30 ml) is heated to the reflux temperature under nitrogen atmosphere and a mixture of a 10M solution of borane-methyl sulfide (1.4 ml, 0.0014 mol) and anhydrous tetrahydrofuran (10 ml) is slowly dripped in. The obtained solution is refluxed for 4 hours and then diluted with methanol (10 ml). The solvent is evaporated off under vacuum and the obtained residue is dissolved in ethyl ether. The organic solution is made acidic by the addition of HCl saturated isopropanol and the product of the title is obtained therefrom by filtration (0.9 g) M.p. 175°-178° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: OB(O)c1ccccc1F
Product: Nc1ccc(-c2ccccc2F)nc1
Yield: 31 %

Procedure:
Obtained (0.210 g, yield 31%) following the procedure described in Intermediate 39, starting with 6-chloropyridin-3-amine (3.50 mmol, 0.45 g), 2-fluorophenylboronic acid (6.94 mmol, 0.97 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[NH:20][CH2:21][CH2:22][N:23]=2)=[CH:14][CH:13]=1.CC(C)([O-])C.[K+].CC(C)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[N:23]3[CH2:22][CH2:21][NH:20][C:19]=23)=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Clc1ccc(CC2=NCCN2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=c1c2cccnc2c(-c2ccc(Cl)cc2)c2n1CCN2
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Add a solution of 2-chloro-3-pyridinylcarbonyl chloride (4.4 g) in tetrahydrofuran (55 ml) to a stirred, cooled mixture of 2-(4-chlorophenyl)methylimidazoline (4.9 g), potassium tert.-butoxide (2.8 g) and tetrahydrofuran (200 ml). Use a bath of ice and acetone for cooling. Keep the reaction mixture in the bath for 15 minutes, and then allow it to warm to 20° C. over another 15 minutes. To the warmed mixture, add a second portion (2.8 g) of potassium tert.-butoxide; allow the reaction mixture to stir at 20° C. overnight. Evaporate solvent, partition the residue between chloroform and water, and dry the chloroform solution Use sodium sulfate as a drying agent. Filter the dried solution, evaporate the solvent, and crystallize the residue from acetonitrile to obtain 10-(4-chlorophenyl)-2,3-dihydro-imidazo[1,2-g]-[1,6]naphthyridin-5(1H)-one, mp 260°-262° C.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].Br[CH2:8][C@@H:9]1[O:28][CH2:27][C@:12]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[N:13]=[C:14]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:15][C@H:16]([CH3:17])[C@@H:11]2[CH2:10]1>O1CCCC1>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[C@:12]12[CH2:27][O:28][C@@H:9]([CH2:8][O:4][CH:2]([CH3:3])[CH3:1])[CH2:10][C@H:11]1[C@@H:16]([CH3:17])[S:15][C:14]([NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N:13]2
Reactant: CC(C)O
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CBr)C[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
2-Propanol (139 μL, 1.82 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 29 mg, 0.73 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred for 30 minutes. A solution of N-[(4R,4aR,6R,8aS)-6-(bromomethyl)-8a-(2,4-difluorophenyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C26) (90 mg, 0.18 mmol) in tetrahydrofuran (0.5 mL) was added, and the reaction mixture was heated at 55° C. for 6 hours. After cooling to room temperature, it was partitioned between saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (25 mL). The aqueous layer was extracted with ethyl acetate (2×25 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 70% ethyl acetate in heptane) provided the product as a white solid. Yield: 39.2 mg, 82.4 μmol, 46%. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=7 Hz, 2H), 7.51-7.57 (m, 1H), 7.39-7.49 (m, 3H), 7.01-7.11 (m, 2H), 4.14 (br d, J=12 Hz, 1H), 3.89 (d, J=11.9 Hz, 1H), 3.78-3.85 (m, 1H), 3.67 (septet, J=6.0 Hz, 1H), 3.48-3.58 (m, 2H), 3.19-3.28 (br m, 1H), 2.96-3.04 (m, 1H), 1.75-1.82 (m, 1H), 1.51-1.64 (m, 1H), 1.25 (d, J=7.0 Hz, 3H), 1.14 (d, J=6.0 Hz, 3H), 1.14 (d, J=6.0 Hz, 3H).
Reaction SMILES: [K].[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]=1[OH:16])([CH3:5])([CH3:4])[CH3:3].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>C(O)(C)(C)C>[C:12]([C:8]1[CH:9]=[C:10]([CH2:19][CH2:18][C:17]([O:21][CH3:22])=[O:20])[CH:11]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[C:7]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: C=CC(=O)OC
Agent: [K]
Solvent: CC(C)(C)O
Product: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 50 °C

Procedure:
To 500 parts by volume of dry t-butyl alcohol in a flask fitted with mechanical stirrer, inert gas inlet, thermometer, condenser and dropping funnel are added 2.1 parts of potassium metal. After the ensuing reaction is complete, there are added 37.3 parts of 2,6-di-t-butylphenol, followed rapidly by 17.7 parts of methyl acrylate. The stirred reaction mixture is heated to 50° C. for 18 hours and allowed to cool. The solvent is removed under reduced pressure and the residual mass neutralized by addition of dilute hydrochloric acid. This mixture is then extracted with two portions of 200 parts by volume each of ethyl ether. The combined ethereal extracts are washed with two portions of 100 parts by volume each of water and then dried over anhydrous sodium sulfate. The ether layer is removed by filtration and concentrated on a steam bath. The residual oily mass is then vacuum distilled. The fraction collected at 125°-130 °C./0.1 mm Hg crystallizes upon standing to yield methyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate, M.P. 63.0°-64.5° C. Rerystallization from hexane yields a white solid, M.P. 66°-66.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH2:13][CH3:14])([O-:12])=[O:11].N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:13](/[N+:10]([O-:12])=[O:11])\[CH3:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: C/C(=C\c1ccc(Cl)cc1)[N+](=O)[O-]
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of 4-chlorobenzaldehyde (28.57 g, 203 mmol), nitroethane (44.0 mL, 610 mmol) and piperidine (4.01 mL, 40.6 mmol) in toluene (200 mL) was stirred at reflux (Dean-Stark) for 6 h and the mixture was stored at room temperature overnight. The solvent was removed under reduced pressure and the product was recrystallised from absolute EtOH. The crystals were filtered off, washed with a small amount of absolute EtOH and dried to give 23.25 g of the desired product. The mother liquor was concentrated, heated, cooled. Another batch of crystals was filtered off, washed with a small amount of absolute EtOH and dried in vacuo, to afford 3.95 g of the desired product. Total yield: 27.20 g (68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([CH2:26][CH2:27][NH2:28])=[CH:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([CH2:26][CH2:27][NH:28][C:11]([C:8]2[CH:7]=[C:6]([CH2:5][C:4]3[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=3)[O:10][N:9]=2)=[O:13])=[CH:18]1
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Reactant: NCCc1coc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1coc2ccccc12)c1cc(Cc2cccc(F)c2)on1
Yield: 8.5 %

Procedure:
A solution of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g, 0.257 mmol), 2-(benzofuran-3-yl)ethanamine (0.042 g; 0.260 mmol), HATU (0.108 g; 0.285 mmol) and N,N-diisopropylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC (method 2) to yield 0.008 g (9%) of the title compound as a white solid.