Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[OH:12])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:21](Br)[CH3:22]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[O:12][CH2:21][CH2:22][NH:11][C:7]=2[CH:8]=[CH:9][CH:10]=1)=[O:13])[CH3:2]
Reactant: CCOC(=O)c1cccc(N)c1O
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1OCCN2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a solution of ethyl ester 3.6 g (20 mmol) of step 2 in dimethylformamide 30 mL was added K2CO3 5.5 g (40 mmol), followed by stirring at room temperature for 10 min. Dibromoethane 1.9 mL (22 mmol) was added dropwise to the reaction mixture which was then stirred for 3 hours under reflux. The reaction mixture was cooled to room temperature, concentrated in a vacuum, diluted with ethylacetate, and washed with a saturated sodium bicarbonate solution and a saturated NaCl solution. The resulting residue was dried over magnesium sulfate and concentrated in a vacuum to afford 3.7 g of the title compound (yield 89%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>CC(C)=O>[I:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1
Reactant: Oc1ccccc1I
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Ic1ccccc1OCc1ccncc1
Yield: 53 %

Procedure:
4-Picolyl chloride hydrochloride (4.00 g, 24.4 mmol) was dissolved in acetone (55 mL), potassium carbonate (10.1 g, 73.2 mmol) and o-iodophenol (6.97 g, 31.7 mmol) were added, and the mixture was heated under reflux for 24 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained crystals, and the mixture was suction-filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (4.02 g, 53%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(I)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2cccnc2)c1
Yield: 66 %

Procedure:
By carrying out the operation analogously to example 3, starting from 3-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation I, and 3-pyridineboronic acid, the expected product is obtained in the form of a light brown powder with a yield of 66%.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.Cl.[CH2:9]([C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:10].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[N:6]=[C:5]([N:14]2[CH2:15][CH2:16][C:11]([CH2:9][CH3:10])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:13]2)[S:4][N:3]=1
Reactant: CCOC(=O)C1(CC)CCNCC1
Reactant: Clc1nsc(Cl)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CC)CCN(c2nc(Cl)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
3,5-dichloro-1,2,4-thiadiazole (135 mg, 0.87 mmol) was added to a solution of ethyl 4-ethylpiperidine-4-carboxylate hydrochloride (190 mg, 0.87 mmol) and Triethylamine (264 mg, 2.61 mmol) in THF (9 mL) and stirred at rt for 1 h, giving a suspension, which was filtered, and the filtrate concentrated in vacuo to give ethyl 1-(3-chloro-1,2,4-thiadiazol-5-yl)-4-ethylpiperidine-4-carboxylate as a yellow oil (260 mg, 98%). ESI-MI m/z 304.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5](=[O:12])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10].C1(C)C=CC(S([N:23]=[N+:24]=[N-])(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[N+:23]=[N-:24])[C:5](=[O:12])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: COC(=O)CC(=O)CCC=C(C)C
Solvent: CCN(CC)CC
Product: COC(=O)C(=[N+]=[N-])C(=O)CCC=C(C)C
Yield: 89.3 %

Procedure:
In accordance with the process of Example 1, 3-oxo-7-methyl-6-octenoic acid methyl ester (0.54 g; 2.93 m mol), triethylamine (0.30 g; 2.93 m mol) and p-toluenesulfonyl azide (0.61 g; 2.93 m mol) were used as starting materials to obtain 0.55 g of 2-diazo-3-oxo-7-methyl-6-octenoic acid methyl ester as yellow oily product.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[C:19]([NH2:21])=[O:20])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].N1C=CC=CC=1>O1CCCC1>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[C:19]([NH2:21])=[O:20])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(C(N)=O)c(N)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C(=O)OC(C)(C)C)ccc1C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 157.2 %

Procedure:
Acetyl chloride (50 uL, 0.32 mmol) was added to a solution of 1,1-dimethylethyl 3-amino-4-(aminocarbonyl)benzoate (126 mg, 0.53 mmol) and pyridine (52 uL, 0.64 mmol) in tetrahydrofuran (3 mL) at 0° C., and the resulting mixture was stirred at 0° C. for one hour. The mixture was quenched with ice-water (10 mL) and extracted ethyl acetate (3×10 mL). The combined extract was washed with 15 mL, each of 5% aqueous citric acid, saturated aqueous sodium bicarbonate, and brine solutions then dried over sodium sulfate, filtered and concentrated to give the 1,1-dimethylethyl 3-(acetylamino)-4-(aminocarbonyl)benzoate (140 mg, 94% yield). MS (EI) for C14H18N2O4: 279 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH2:29]Br)=[O:19])=[CH:4][CH:3]=1.Cl.[CH3:33][NH:34][CH3:35]>C(Cl)Cl.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[C:21]=2[CH2:29][N:34]([CH3:35])[CH3:33])=[O:19])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc2ccccc2c1CBr
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)Cc1c(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 43 %

Procedure:
To a suspension of N-(4-chlorophenyl)-2-[((3-(bromomethyl)benzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide (0.075 g, 0.14 mmol) in methylene chloride (1.5 mL) in a pressure vessel was added dimethylamine hydrochloride (0.035 g, 0.43 mmol), followed by Bio-Rad AG1-X8 anion exchange resin (0.55 g, 0.7 mmol equivalents, OH− form). The vessel was sealed and the mixture was stirred at ambient temperature for 3.5 hours. The vessel was opened and the reaction mixture diluted with methylene chloride (25 mL) and acetonitrile (25 mL), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel, followed by crystallization from acetonitrile afforded 0.030 g (43% yield) of N-(4-chlorophenyl)-2-[((3-(dimethylamino)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide, as a crystalline solid; NMR (DMSO-d6/TFA) 13.2 (s, 1), 10.7 (s, 1), 7.3-8.1 (m, 11), 3.9 (s, 2), 2.1 (s, 6) ppm.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=1.[OH-].[Li+]>O.C1COCC1>[C:12]([O:11][C:9]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:18])=[O:2])=[CH:17][CH:16]=1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A solution of 4.2 g (16.78 mmol) of tert-butyl 4-(2-methoxy-2-oxoethyl)benzoate in 50 ml of water and 50 ml of THF is mixed with 0.8 g (33.6 mmol) of lithium hydroxide and stirred at room temperature for 1 hour. The phases are separated and the aqueous phase is adjusted to pH 3 with 2 M hydrochloric acid. It is extracted with ethyl acetate. The organic phase is then washed with sodium chloride solution, dried over sodium sulphate and evaporated. 3.6 g (15.2 mmol, 87% yield) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH3:28])[NH:5][CH:6]=[C:7]([C:21]#[N:22])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=1[Cl:20])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:23]([C:8]([NH:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=3[Cl:20])=[C:7]([C:21]#[N:22])[CH:6]=[N:5]2)=[CH:24][C:25]=1[O:26][CH2:27][CH3:28]
Reactant: CCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1Br
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
A suspension of 3-bromo-4-ethoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (630 mg, 1.29 mmol) in 35 mL of acetonitrile was heated to reflux and phosphorous oxychloride (0.80 mL) was added dropwise, via syringe. The reaction mixture was heated at reflux overnight, then cooled to room temperature. The solids were collected by filtration, washed with saturated aqueous sodium bicarbonate. The solids were stirred with saturated aqueous sodium bicarbonate for 1 hour and then collected by filtration, washed with saturated aqueous sodium bicarbonate and water. The solid was recrystallized from methanol and dried in vacuo to provide 225 mg of 7-bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-3-quinolinecarbonitrile as a yellow solid, mp >250° C. 1H NMR (400 MHz, DMSO-d6) δ 1.47 (t, J=7 Hz, 3H), 3.87 (s, 3H), 4.32 (q, J=7 Hz, 2H), 7.45 (s, 1H), 7.82 (s, 1H), 8.16(s, 1H), 8.27 (s, 1H), 8.76 (s, 1H), 10.73 (s, 1H); MS (ES) m/z 466.1, 468.0, 470.1 (M+H)+
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(#N)C>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:1][CH:2]=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=CO)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Product: CCOC(=O)C(=COS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
19.2 g (0.1 mol) of ethyl α-hydroxymethylene-phenylacetate are dissolved in 100 ml of acetonitrile, and first 11.2 g (0.1 mol) of potassium tert.-butylate are added, after which 19 g (0.1 mol) of p-toluenesulphonyl chloride are added in portions at 20° to 25° C. The mixture is stirred for 4 hours at room temperature and left to stand overnight. The precipitated salt is filtered off under suction, and the filtrate is evaporated down in vacuo. The residue is dissolved in toluene, and the solution is washed with water, dried over sodium sulphate and evaporated down in vacuo. 23 g (73% of theory) of ethyl α-(4-methyl-phenylsulphonyloxymethylene)-phenylacetate are obtained. The oil is dissolved in 150 ml of ethanol, and then 7.7 g (0.07 mol) of 2-hydrazino-pyrimidine are added. The mixture is stirred for 10 hours at room temperature, and then 13.5 g of concentrated sodium hydroxide solution are added dropwise in the course of 4 hours. After stirring has been continued for a further 5 hours at room temperature, dilute hydrochloric acid is added dropwise until the neutral point is reached, and the mixture is diluted with 750 ml of water. The oily product which separates out is taken up in a small amount of ether, 3.6 g (22% of theory) of 1-pyrimid-2-yl-4-phenylpyrazolin-5-one being precipitated. Melting point 159° to 160° C. (from ethanol).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][N:18]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH3:31])[CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccccc1B(O)O
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCc2ncnc(Nc3ccc(C(F)(F)F)cc3)c2C1
Reaction time: 6 h
Yield: 4.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added o-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (6.0 mg, 5%).
Reaction SMILES: C([C:3]1[C:4]([C:9]([OH:11])=O)=[C:5]([NH2:8])[S:6][CH:7]=1)C.C([O-])=O.[NH4+].[CH:16]([NH2:18])=O>>[N:8]1[C:5]2[S:6][CH:7]=[CH:3][C:4]=2[C:9]([OH:11])=[N:18][CH:16]=1
Reactant: NC=O
Reactant: CCc1csc(N)c1C(=O)O
Agent: O=C[O-]
Agent: [NH4+]
Product: Oc1ncnc2sccc12

Procedure:
Ethyl 2-amino-3-carboxythiophene 2 is refluxed with ammonium formate and formamide to give the cyclized intermediate 3 which is then treated with thionyl chloride to afford the chloro derivative 4. Boc-protected aminopiperidine 5 is reductively alkylated with a variety of arylaldehydes 6 to provide the corresponding intermediates 7. Deprotection of 7 with trifluoroacetic acid treatment yields the free amine intermediate 8. Reflux of a mixture of the key intermediates 4 and 8 in i-propanol or acetonitrile in the presence of triethylamine yields the final compound 1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1>CCOCC.CC(C)=O>[NH:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(CCl)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: N#Cc1ccc(Cc2ncc[nH]2)cc1
Reaction time: 26 h

Procedure:
To 48.0 L of acetone under nitrogen is added 4.326 Kg of potassium carbonate, 0.26 Kg of potassium iodide, 3.2 Kg of imidazole and 4.745 Kg of alpha-chloro-4-tolunitrile. The mixture is stirred at 45° under nitrogen for 26 hours. The reaction is cooled, filtered and the solvent is evaporated at reduced pressure. The residue is redissolved in 40 L of methylene chloride, washed with 40 L of water and twice with 10 L of water. The organic phase is dried over magnesium sulfate and evaporated to yield the crude product which is stirred with 6.4 L of ether for 2 hours. The solid is filtered, washed with 9 L of ether and dried at 40° and 20 mm Hg for 17 hours to yield 4-(1-imidazolylmethyl)-benzonitrile, the compound of Example 1.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)/[C:20](=[N:24]/[OH:25])/[CH2:19][CH2:18]2)=[CH2:14].[C:26]1([C:32]2[O:36][N:35]=[C:34]([C:37](OC)=[O:38])[C:33]=2[C:41]([F:44])([F:43])[F:42])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:26]1([C:32]2[O:36][N:35]=[C:34]([C:37]3([OH:38])[O:25][N:24]=[C:20]4[C:21]5[C:17]([CH2:18][CH:19]34)=[CH:16][C:15]([CH:13]=[CH2:14])=[CH:23][CH:22]=5)[C:33]=2[C:41]([F:43])([F:44])[F:42])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C=Cc1ccc2c(c1)CC/C2=N\O
Reactant: COC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)CC1C2=NOC1(O)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of diisopropylamine (0.441 mL, 3.10 mmol) in anhydrous THF (2 mL) was added n-BuLi (1.239 mL, 3.10 mmol) (2.5M solution in hexanes) dropwise at 0° C. under nitrogen. The pale yellow solution was then stirred at the same temperature for 20 min. before a solution of (E)-5-vinyl-2,3-dihydro-1H-inden-1-one oxime (Preparation 87B, 0.249 g, 1.438 mmol) in anhydrous THF (1 mL) was added dropwise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 h and then a solution of methyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (Intermediate 1-5, 0.3 g, 1.106 mmol) in anhydrous THF (1 mL) was added dropwise at 0° C. The mixture was stirred at 0° C. for 70 min before being quenched with saturated aqueous ammonium chloride solution (3 mL) and water (3 mL). The mixture was extracted with EtOAc (2×30 mL). The EtOAc extracts were washed with brine (20 mL), dried over sodium sulfate and concentrated to yield a brown foamy solid. Flash chromatography purification (12 g silica gel column, 10→50% ethyl acetate in n-heptane) afforded 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-6-vinyl-3a,4-dihydro-3H-indeno[1,2-c]isoxazol-3-ol as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH2:11]([C:18]1[C:23]([Cl:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=1[Cl:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[C:15]2[CH:16]=[CH:17][C:12]([CH2:11][C:18]3[C:19]([Cl:28])=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][C:23]=3[Cl:24])=[CH:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(C(=O)Cl)cn1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cc2ccccc2)c(Cl)c1
Product: Cc1ccc(C(=O)c2ccc(Cc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2)cn1
Yield: 14.8 %

Procedure:
The title compound was prepared as pale yellow crystals at yield of 14.8%, in a similar manner as in Reference Eample 1, by the reaction of 6-methylnicotinoylchloride and 4-benzyl-3,5-dichloronitrobenzene.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[C@@H:14]2[CH2:16][C:15]2([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=CC=1)([O-])=O.[CH3:34][C@@H:35]([NH2:45])[CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>O1CCCC1>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([C:15]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH2:16][C@@H:14]2/[CH:13]=[CH:12]/[C:11]([NH:45][C@@H:35]([CH3:34])[CH2:36][CH2:37][CH2:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:10])[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(C2(c3cccc(OC)c3)C[C@H]2/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: C[C@@H](N)CCCc1cccnc1
Solvent: C1CCOC1
Product: COc1cccc(C2(c3cccc(OC)c3)C[C@@H]2/C=C/C(=O)N[C@@H](C)CCCc2cccnc2)c1
Yield: 60.3 %

Procedure:
As in example 141, (S)-(E)-3-[2,2-bis(3-methoxyphenyl)cyclopropyl]-2-propenoic acid 4-nitrophenyl ester (2.2 g) was reacted with (R)-alpha-methyl-3-pyridinebutanamine (0.81 g) in tetrahydrofuran (15 mL) at ambient temperature overnight. The crude product, isolated in the usual manner, was purified by HPLC (ethyl acetate) and then crystallized from ethyl acetate-hexane to give 1.4 g of (S,R*)-(E)-3-[2,2-bis(3-methoxyphenyl)-cyclopropyl]-N-[1-methyl-4-(3-pyridinyl)butyl]-2-propenamide, mp 104°-106° C.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:15](=[O:16])[N:6]2[C@@H:7]([C:12]([O-:14])=[O:13])[C:8]([CH3:11])([CH3:10])[S:9][C@H:5]12)=[O:2].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19]>CN(C)C=O>[CH:1]([NH:3][C@@H:4]1[C:15](=[O:16])[N:6]2[C@@H:7]([C:12]([O:14][CH2:25][C:24]3[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=3)=[O:13])[C:8]([CH3:11])([CH3:10])[S:9][C@H:5]12)=[O:2]
Reactant: CC1(C)S[C@@H]2[C@H](NC=O)C(=O)N2[C@H]1C(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)S[C@@H]2[C@H](NC=O)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
A mixture of sodium (3S,5R,6R)-6-formamido-2,2-dimethylpenam-3-carboxylate (15.0109 g., 56.4 mmole) and p-nitrobenzyl bromide (12.16805 g., 56.3 mmole) in N,N-dimethylformamide (250 ml.) was stirred for 4 hours at +20 to +25°, after which time all the solid had dissolved. The solvent was removed by evaporation and the residual paste was suspended in ethyl acetate (100 ml.) and washed with brine. The aqueous layer was washed with ethyl acetate (150 ml.) and the combined organic layers washed with water (5 × 250 ml.), passed through phase-separating paper and evaporated to a pale-yellow foam. Chromatography on kieselgel G (600 g.) in benzene-ethyl acetate (1:1) gave p-nitrobenzyl (3S,5R,6R)-6-formamido-2,2-dimethylpenam-3-carboxylate which crystallised from ether-ethyl acetate (3:1) as a white solid (8.73 g., 23 mmole, 41%); m.p. 129° to 132°; [α]D + 190°; λmax. 262 (ε 10,170); νmax. 3420 (NH), 2880 (HCO), 1788 (azetidin-2-one), 1750 (CO2R), 1695 and 1505 (CONH), 1528 and 1346 (Ar-NO2), 841 cm.-1 (para-disubstituted aromatic ring); τ 1.73, 2.43 (2H, AB-q, J 8.5 Hz, p-nitrophenyl), 1.75 (1H, s, HCO), 3.37 (1H, d, J 9 Hz, NH), 4.21 (1H, dd, J 9 and 4.5 Hz, C6 -H), 4.42 (1H, d, J 4.5 Hz, C5 -H), 4.68 (2H, s, NO2C6H4CH2), 5.46 (1H, s, C3 -H), 8.36 (3H, s) and 8.54 (3H, s) (C[CH3 ]2). (Found : C, 50.5; H, 4.6; N, 11.1; S, 8.5. C16H17N3O6S (379.4) requires C, 50.7; H, 4.6; N, 11.1; S, 8.4%).
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1>CN(C=O)C.CCOC(C)=O>[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([N:6]2[CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4][CH2:5]2)[N:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC1(F)CCN(c2cncc(Cl)n2)CC1
Temperature: 100 °C
Yield: 85 %

Procedure:
A mixture of 4,4-difluoropiperidine hydrochloride (598 mg, 3.79 mmol), Cs2CO3 (2471 mg, 7.58 mmol) and 2,6-dichloropyrazine (538 mg, 3.61 mmol) in DMF (5 mL) was heated in a microwave at 100° C. for 35 min. The mixture was diluted with EtOAc (50 mL) and washed with 2×5 mL of H2O. The organic layer was dried, filtered and concentrated. The residue was purified on a silica gel column (eluting with 25-35% EtOAc in Hex) to give 2-chloro-6-(4,4-difluoropiperidin-1-yl)pyrazine (717 mg, 85%) as a brown amorphous solid. MS (ESI, pos. ion) m/z 234.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 7.89 (s, 1H), 3.75 (t, J=5.7 Hz, 4H), 2.06 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27]OS(C)(=O)=O)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([CH2:27][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:13])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reactant: COc1ccc2ccc(=O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(=O)n(CC3CN(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 100 °C
Yield: 44 %

Procedure:
A suspension of 7-methoxy-2(1H)-quinolinone (405 mg; commercial) in DMF (10 mL) was treated with NaH (111 mg; 50% dispersion in oil). The mixture was stirred at rt for 30 min before the addition of a solution of 3-[[(methylsulfonyl)oxy]methyl]-1-azetidinecarboxylic acid tert-butyl ester (674 mg; prepared according to WO 02/066470) in DMF (2 mL). The mixture was heated at 100° C. overnight. The reaction mixture was partitioned between EA and water. The org. phase was dried over MgSO4, concentrated under reduced pressure and purified by CC (Hept/EA 2:1 to 0:1). The second eluting compound was isolated as a colourless foam (350 mg, 44% yield).