Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:13](=O)[CH:12](C(OC(C)(C)C)=O)[S:11][C:10]=2[C:22]=1[F:23])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.B.[Na]>C1(C)C=CC=CC=1.CO>[F:24][C:7]1[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:25])=[C:22]([F:23])[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH:8]=1
Reactant: CCOC(=O)Cc1c(F)cc2c(c1F)SC(C(=O)OC(C)(C)C)C2=O
Agent: B
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cc1c(F)cc2ccsc2c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
In 60 mL of toluene is dissolved 19.2 g of tert-butyl 6-(2-ethoxy-2-oxoethyl)-5,7-difluoro-3-oxo-2,3-dihydrobenzo[b]thiophene-2-carboxylate, to which is added 0.96 g of p-toluenesulfonic acid monohydrate. The mixture is heated under reflux for 2.5 hours. Water is added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is dissolved in 100 ml of methanol, 0.97 g of sodium boron hydride is added, and the mixture thus formed is stirred at ambient temperature for 30 minutes. Then, 5.88 g of p-toluenesulfonic acid monohydrate is added and the mixture thus formed is heated under reflux for one hour. The reaction mixture is concentrated under reduced pressure, water and ethyl acetate are added to the residue, and the organic layer is separated. The organic layer is washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: hexane:ethyl acetate=50:1 to 20:1) to obtain 1.98 g of ethyl 2-(5,7-difluorobenzo[b]thiophen-6-yl)acetate as an oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl.O>C1COCC1.C1(C)C=CC=CC=1>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Yield: 71.4 %

Procedure:
To a suspension of 6-nitro-2H-1,4-benzoxazin-3(4H)-one (J. Med. Chem. 1989, 32, 1627-1630) (1 g, 5.7 mmol) in dry THF (20 ml) at 0° C. under argon, was added NaH (0.16 g, 5.7 mmol, 80% dispersion in mineral oil). A solution of 2-dimethylaminoethyl chloride (2.3 g, 20.8 mmol) in dry toluene (15 ml) was added and the reaction mixture heated under reflux for 19 hr. After cooling, water was added dropwise until effervescence had ceased, then the mixture was separated and the aqueous further extracted with EtOAc. The organic layers were combined, dried (Na2SO4) and evaporated under reduced pressure to give a pale brown solid (1.08 g, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)=[CH:11][CH:12]=2)[CH:7]1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:2].Cl>C(Cl)Cl.CC(O)C>[ClH:34].[NH2:19][CH2:18][CH2:17][O:16][C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH2:15][CH:6]([NH:5][C:4](=[O:36])[O:3][CH2:1][CH3:2])[CH:7]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)NC1CCc2ccc(OCCNC(=O)OC(C)(C)C)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOC(=O)NC1CCc2ccc(OCCN)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 142.2 %

Procedure:
[7-(2-tert-Butoxycarbonylamino-ethoxy)-1-(3,4-dichloro-benzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-carbamic acid ethyl ester (9.27 g, 17.3 mmol) example 1 was dissolved in CH2Cl2 (200 ml) and HCl in iPrOH (6N) was added. The reaction was stirred at RT over night after which a solid precipitates. To the reaction mixture diethyl ether was added and the precipitating HCl salt was separated by filtration to give the final product as a solid (5.85 g, 12.3 mmol, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:28])[CH:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:30]\[OH:31])=[C:4]([F:28])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(CO)cc2)c2ccc(Cl)cc2F)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(CO)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-fluorophenyl)-3-(4-(hydroxymethyl)-phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid containing 15% of the corresponding Z isomer, MS (ESI+): m/z=415.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>CC#N>[CH3:15][N:4]1[C:3](=[O:16])[C:2]([NH:27][C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:21][CH2:22][O:17][CH2:18][CH2:19]3)=[CH:29][CH:28]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S1(=O)=O
Reaction time: 0.25 h
Yield: 42.6 %

Procedure:
4-Chloro-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (70 mg, 0.27 mmol) and 4-morpholinoaniline (97 mg, 0.54 mmol) in MeCN (2 ml) was heated in a microwave reactor at 140° C. for 15 mins, then at 140° C. for 15 mins. The mixture was purified by preparative HPLC (Kromasil-column C8, 0.1M NH4OAc/MeCN, gradient) to give the title compound (46 mg, 42%); 1H NMR (400 MHz, CDCl3): δ 7.10-7.23 (m, 6H), 6.58-6.63 (m, 2H), 6.49-6.55 (m, 2H), 3.77-3.83 (m, 4H), 3.27 (s, 3H), 2.96-3.01 (m, 4H); Mass Spectrum: M+H+ 400.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].O[CH:12]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:12]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)[CH3:2]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Reactant: CCOc1ccccc1O
Product: CCOc1ccccc1OC(CCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure A and Scheme AN using 2-ethoxyphenol and N-(3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 529.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:31])[C:15](=[O:30])[C:16]([CH3:29])=[C:17](OS(C4C=CC(C)=CC=4)(=O)=O)[C:12]=3[C:11](=[O:32])[N:10]([CH:33]3[CH2:35][CH2:34]3)[C:9]2=[O:36])=[CH:4][CH:3]=1.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)C.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:31])[C:15](=[O:30])[C:16]([CH3:29])=[C:17]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:12]=3[C:11](=[O:32])[N:10]([CH:33]3[CH2:35][CH2:34]3)[C:9]2=[O:36])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(Br)cc2)cc1
Reactant: Nc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1c(Nc2ccccc2)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(Br)cc3)c2n(C)c1=O
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 93 %

Procedure:
To toluene-4-sulfonic acid 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 39 (100 mg) obtained in Step 6 was added aniline 40 (0.64 ml), and the mixture was stirred at 150° C. for 2.5 hrs. After allowing to cool to room temperature, diethyl ether-hexane [1:1 (volume ratio), 30 ml] was added to the reaction mixture, and the crystals were collected by filtration. The obtained crystals were purified by column chromatography (chloroform:acetone=15:1) to give 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-phenylamino-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 41 (81 mg, yield 93%) as pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]=2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33]Cl)[CH3:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=3[C:11]=2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:30][CH2:29][N:31]([CH2:35][CH3:36])[CH2:32][CH3:33])=[CH:15][CH:14]=2)=[CH:25][CH:26]=1
Reactant: O=C(c1ccc(O)cc1)c1c(Cc2ccc(Cl)cc2)oc2ccccc12
Reactant: CCN(CC)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CC)CCOc1ccc(C(=O)c2c(Cc3ccc(Cl)cc3)oc3ccccc23)cc1

Procedure:
A solution of 2-(4-chlorobenzyl)-3-(4-hydroxybenzoyl)benzofuran (2.0 g., 5.5 mmol.) of 50 ml. of toluene is added to a slurry of 0.5 g. of a 57% sodium hydride dispersion (0.01 mol.) in 5 ml. of toluene. The reaction mixture is refluxed for 10 minutes, then 0.82 g. (5.5 mmol.) of 2-diethylaminoethyl chloride is added and the mixture is heated at 90° for four hours. The mixture is filtered and the filtrate concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:30]=[O:31])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[C:26]([F:29])([F:28])[F:27])[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[C:26]([F:28])([F:27])[F:29])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:30]([OH:31])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.35 mL, 1.05 mmol) was added to a stirred solution of 9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (400 mg, 0.966 mmol) in tetrahydrofuran (3.0 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol to give the title compound as a colorless crystal (411 mg, 0.925 mmol, 96%).
Reaction SMILES: [Mg].[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CCOCC>[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][CH2:14][CH:16]2[O:18][CH2:17]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: ClCC1CO1
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CCC2CO2)cc1
Temperature: 80 °C

Procedure:
A Grignard solution freshly prepared from 12.15 g (0.50 gram atom) magnesium chips and 91.7 g (0.50 mole) 4-tert.-butylbenzyl chloride in 550 ml dry ether is dripped with agitation into a precooled solution of 92.5 g (1.00 mole) epichlorohydrin in 165 ml dry ether, so that the temperature does not exceed -40° C. After addition is complete, the cooling bath is removed, the solution is allowed to stand for several hours at room temperature, and then hydrolyzed with ice water and dilute hydrochloric acid. The ether phase is separated, washed with water and dried over sodium sulfate. After the ether has been drawn off, the bath temperature is raised to 80° C. and the volatile components carefully removed at 0.1 mbar. The residue is taken up in 270 ml methanol and a freshly prepared solution of 6.90 g (0.30 g atom) sodium in 200 ml methanol added at room temperature. After three hours the sodium chloride precipitated is separated, the filtrate concentrated in vacuum, the residue taken up in ether and washed with water. After drying over sodium sulfate the solvent is removed and the oily residue distilled in vacuum. A colorless liquid with a boiling point of 79°-81° C./0.1 mbar is obtained.
Reaction SMILES: [NH:1]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([O:26]CC1C=CC=CC=1)=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1>CO.[Pd]>[NH:1]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
Boc-D-Tyr(Me)-L-Ile-L-Pro-OBzl (595 mg, 1.0 mmol) was dissolved in methanol (10 mL), Pd—C (200 mg) was added, and this mixture was stirred under hydrogen atmosphere for 3 hours. Pd—C was filtered off, and methanol was removed by evaporation to obtain the desired product as a foam. Yield: 380 mg (0.8 mmol, 80%).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:14])[CH:2]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].CC1C(C)=NC=CC=1>ClCCl>[C:22]([O:14][C:3]1[CH:2]=[CH:1][C:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:5][CH:4]=1)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC(=O)Cl
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: Cc1cccnc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 159.7 %

Procedure:
4,4'-Diphenol (0.1 g) and triethylamine (0.57 g) were dissolved in dichloromethane (20 ml). Nonanoyl chloride (1.0 g) and dimethylpyridine (0.2 g) were added thereto, and the mixture was stirred at room temperature for about 20 hours. The reaction mixture was poured into ice-water and subjected to extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and removed by evaporation to give a crude product. It was purified by silica gel column chromatography (developer: hexane/ethyl acetate=3/2) to give the titled compound (0.28 g).
Reaction SMILES: N1CCCCC1.[CH3:7][C:8]1([CH3:24])[O:12][CH:11]([CH2:13][O:14][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][O:9]1.[Cl:25][C:26]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O>CC(O)C>[Cl:25][C:26]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=[C:17]([C:16]([CH2:15][O:14][CH2:13][CH:11]1[CH2:10][O:9][C:8]([CH3:7])([CH3:24])[O:12]1)=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC(=O)COCC1COC(C)(C)O1
Reactant: O=Cc1cccc(Cl)c1Cl
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)COCC1COC(C)(C)O1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
Piperidine (1.0 g) was added dropwise over 5 minutes to a stirred, ice-cooled solution of ethyl 4-{(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy}acetoacetate (26.0 g) (see Preparation 5) and 2,3-dichlorobenzaldehyde (17.5 g) in 2-propanol (200 ml) and the mixture was stirred with ice-cooling for 2 hours and at room temperature for 14 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on silica (150 g) using toluene plus 0-40% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give essentially pure ethyl 2-(2,3-dichlorobenzylidene)-4-{(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy}acetoacetate (17.3 g) as an oil. A solution of this oil in 2-propanol (150 ml) was treated with methyl 3-aminocrotonate (5.0 g) and the mixture stirred at room temperature for 24 hours. The mixture was evaporated and the residue twice taken up in toluene and evaporated. The residue was purified by chromatography on SiO2 (110 g) using toluene plus 0-10% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated to give the title compound (2.75 g), m.p. 135°-137° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=2)[CH:7]=[CH:8][C:9]=1OS(C(F)(F)F)(=O)=O)([CH3:3])[CH3:2].[CH3:31][N:32](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([C:9]1[CH:8]=[CH:7][C:6]([C:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH:23]=2)=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2])#[N:32]
Reactant: CC(C)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC(C)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl 4-(3-isopropyl-4-{[(trifluoromethyl)sulfonyl]oxy}-phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.14 g), zinc cyanide (65 mg), and tetrakis(triphenylphosphine)palladium(0) (25.0 mg) in DMF (3.0 mL) was stirred at 100° C. under nitrogen for 4 h. The reaction was cooled down, diluted with water, extracted with diethyl ether. The combined extract was washed with water, brine, dried and concentrated. tert-Butyl 4-(4-cyano-3-isopropylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (85 mg) was isolated by Combiflash. The isolated product was dissolved in a minimum amount of ethyl acetate and 4 N HCl in dioxane (3.0 mL) was added and stirred for 1 h. Diethyl ether (10 mL) was added and the solid was filtered and washed with ether to give the product 2-isopropyl-4-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile hydrochloride (65 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:14]1CCC[CH2:15]1.C([Li])CCC.CN(C)C=O>O>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:15]=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1CCOC1
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a mixture of 3-bromobiphenyl (0.50 mL, 3.0 mmol) and tetrahydrofuran (8 mL) was added n-butyl lithium (2.6 mL, 1.5 M n-hexane solution, 3.9 mmol) under nitrogen atmosphere at −78° C., which was stirred for 20 minutes at that temperature. N,N-dimethylformamide (0.35 mL, 4.5 mmol) was added to the reaction mixture at the same temperature, and the temperature was gradually raised to 0° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (430 mg, 79%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:27])[CH3:26])=[O:5])C.[OH-].[Na+].O.Cl>C(#N)C>[CH3:25][S:22]([C:18]1[CH:17]=[C:16]([CH:11]2[CH2:10][C:9]([CH3:27])([CH3:26])[C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(S(C)(=O)=O)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(c2cccc(S(C)(=O)=O)c2)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A mixture of 2-(3-methanesulfonyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.3 g, 8.53 mmol), sodium hydroxide (3.41 g, 85.3 mmol), water (10 mL) in acetonitrile (30 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 mol/L aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-methanesulfonyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.76 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=360.3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15].[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C.CCOC(C)=O>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8](=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]1[CH2:32][CH2:33][CH:28]([C:24]2[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=2)[CH2:29][CH2:30]1
Reactant: O=C(CCCCCCCl)c1ccccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3F)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
A 50-mL round-bottom flask was charged with a solution of 7-chloro-1-oxo-1(2-fluorophenyl)heptane (2.42 g, 10.0 mmol), 2-methyl-N-[3-(4-piperidyl)phenyl]propanamide (2.46 g, 10.0 mmol), K2CO3 (2.76 g, 20.0 mmol) and NaI (2.25 g, 15.0 mmol) in DMF (25.0 mL). The mixture was stirred for 10 min at 25° C. and then heated at 100° C. for 12 h, cooled to 25° C. and diluted with EtOAc (100 mL). The reaction mixture was washed with water (4×50 mL) and the aqueous layer was extracted with EtOAc (100 mL). The organic layers were washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and the crude product was purified by chromatography (EtOAc:MeOH 97:3) to give the desired product (3.70 g, 82.0%).