Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].Br[CH:17]=[CH:18][CH2:19][CH2:20][CH3:21].Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH2:21]([C:3]12[CH2:12][CH2:11][CH2:10][C:5]3[C:4]1=[C:9]([CH:8]=[CH:7][CH:6]=3)[NH:1][C:2]2=[O:13])[CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: CCCC=CBr
Reactant: O=C1Nc2cccc3c2C1CCC3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCCCC12CCCc3cccc(c31)NC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2a,3,4,5-Tetrahydro-1H-benz[cd]indol-2-one (4.0 g, 23 mmol) was dissolved in anhydrous N,N-dimethylformamide (100 ml), and the solution was mixed with sodium hydride (760 mg, 190 mmol) and stirred at 0° C. for 1 hour. The reaction solution was mixed with 1-bromopentene (3.8 ml, 25 mmol) and stirred at −40° C. for 2 hours. Ethyl acetate, water and hydrochloric acid (1 N) were added to the reaction solution. The reaction product was extracted with ethyl acetate, washed with saturated brine and then dried with anhydrous sodium sulfate, and the material obtained by evaporating the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 2.7 g (11 mmol, 49% in yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][CH:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: COCCCCCCSC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCCCCSC1CCNCC1
Yield: 205.8 %

Procedure:
To a solution of 4-(6-methoxyhexylthio)-N-t-butoxycarbonylpiperidine (3.32 g) in dichloromethane (40 ml) were added triethylsilane (8.0 ml) and trifluoroacetic acid (15.4 ml) with stirring in an ice bath. The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (400 ml) eluting with a mixture of dichloromethane and methanol (4:1 v/v). The fractions containing the object compound were collected and evaporated under reduced pressure to give 4-(6-methoxyhexylthio)piperidine (4.77 g). This compound was immediately used as the starting compound for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:16]C)C(C#N)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Br.[OH-].[Na+].CCCCCC.[C:27]([O:30]CC)(=[O:29])[CH3:28]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:16])[C:28]([C:27]([OH:30])=[O:29])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(F)c2)cnc1C#N
Reactant: CCOC(C)=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(O)c1ncc(-c2cccc(F)c2)cc1O
Reaction time: 3 h

Procedure:
To a 50 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser is charged 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine, 9, (0.912 g, 4 mmol) and a 48% aqueous solution of HBr (10 mL). While being stirred, the reaction solution is heated to reflux for 20 hours. The reaction can be determined to be complete due to the disappearance of 5-(3-fluorophenyl)-3-methoxy-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction is then cooled to 0° C. to 5° C. with stirring and the pH is adjusted to approximately 2 by the slow addition of 50% aqueous NaOH. Stirring is then continued at 0° C. to 5° C. for 3 hours. The resulting solid is collected by filtration and washed with water, then hexane. The resulting cake is dried in vacuo at 40° C. to afford the desired product.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[CH:17][C:18]=3F)[N:13]=[CH:12][N:11]=2)=[C:7]2[O:22][CH2:23][O:24][C:6]2=[CH:5][CH:4]=1.CCC([O-])(C)C.[Na+].CN1CCCC1=O.[OH:39][CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O>[Cl:2][C:3]1[C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[CH:17][C:18]=3[O:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:13]=[CH:12][N:11]=2)=[C:7]2[O:22][CH2:23][O:24][C:6]2=[CH:5][CH:4]=1
Reactant: Fc1cc(F)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Reactant: OC1CCOCC1
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1cc(OC2CCOCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 60 °C

Procedure:
4-(6-Chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline hydrochloride salt (80 g) was added portionwise to a stirred mixture of sodium tert-pentoxide (90.2 g) and N-methylpyrrolidin-2-one (500 ml) under an atmosphere of nitrogen gas. 4-Hydroxytetrahydropyran (23.5 ml) and N-methylpyrrolidin-2-one (35 ml) were added and the resultant mixture was heated to 60° C. for 3 hours. Water (764 ml) was added to the heated reaction mixture during 3 hours and the mixture was stirred and heated to 60° C. for a further 3 hours. The warm reaction mixture was filtered and the isolated solid was washed with water (2×230 ml) and dried in vacuo to constant weight. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (68.6 g, 95% HPLC purity using Method A, retention time 4.6 minutes); m.p. 209-212° C.; NMR Spectrum: (DMSOd6) 1.9-2.0 (m, 2H), 2.1-2.2 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.95 (m, 2H), 5.05 (m, 1H), 6.1 (s, 2H), 6.95 (d, 1H), 7.05 (d, 1H), 7.1 (d, 1H), 7.3 (d, 1H), 8.4 (s, 1H), 9.3 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]2)[CH2:9][CH3:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].S(Cl)(Cl)=O.[CH3:24]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2([C:14]([O:16][CH3:24])=[O:15])[CH2:12][CH2:13]2)[CH2:9][CH3:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CO
Reactant: CCC(c1ccc(Cl)c([N+](=O)[O-])c1)C1(C(=O)O)CC1
Solvent: O=S(Cl)Cl
Product: CCC(c1ccc(Cl)c([N+](=O)[O-])c1)C1(C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
262 mg (about 0.93 mmol) of 1-[1-(4-chloro-3-nitrophenyl)propyl]cyclopropanecarboxylic acid were dissolved in 5 ml of methanol, the mixture was cooled to 0° C. and 0.14 ml (1.85 mmol) of thionyl chloride was added dropwise. The reaction solution was then slowly warmed to room temperature and stirred at this temperature overnight. The reaction mixture was then concentrated to dryness and the residue was taken up in 10 ml of dichloromethane. The solution was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. This gave 224 mg of the target compound (81% of theory).
Reaction SMILES: C(OC([N:6]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]2=[N:21][C:22]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)=[CH:23][C:24](=[O:25])[N:9]2[CH2:8][CH2:7]1)=O)C.[BrH:32]>C(O)(=O)C>[BrH:32].[CH2:14]([NH:13][CH:11]1[C:10]2=[N:21][C:22]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)=[CH:23][C:24](=[O:25])[N:9]2[CH2:8][CH2:7][NH:6][CH2:12]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc(-c2ccncn2)nc2n1CCNCC2NCc1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 92.1 %

Procedure:
To a solution of 0.090 g (0.21 mmol) of 9-benzylamino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester dissolved in 3.00 mL of glacial acetic acid was added 0.75 mL (4.28 mmol) of hydrobromic acid (33 wt % solution in glacial acetic acid). The resulting mixture was stirred at 80° C. for 16 hours, cooled and evaporated to dryness. Toluene was added to the residue and evaporated. Ethanol was added to the residue and evaporated. The crude was triturated with diethyl ether and dichloromethane and filtered to afford 0.083 g (76%) of the product as a powder.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.C1(C)CCC(C(C)C)C(OCCOCCO)C1>>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:10])[CH3:11])[CH:6]([OH:8])[CH2:7]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: CC1CCC(C(C)C)C(OCCOCCO)C1
Product: CC1CCC(C(C)C)C(O)C1

Procedure:
Mixtures of l-menthol and 2-(2-l-menthyloxyethyl) ethanol obtained in Example 1 at 7:3 and 9:1 (ratio by mass) were prepared. 1,000 ml of aqueous solutions containing each obtained mixture in a concentration of 20 ppm were prepared and subjected to the oral evaluation. For comparison, a 20 ppm aqueous solution of l-menthol alone was also subjected to the oral evaluation.
Reaction SMILES: [OH:1][CH:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1>[C].[Pd].CO>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH:2]([P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])[OH:1])=[CH:8][CH:7]=1
Reactant: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(OCC)C(O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a mixed solution of diethyl α-hydroxy-4-nitrobenzylphosphonate (1.42 g) and methanol (30 mL) was added 10% palladium-carbon (0.14 g) and the mixture was stirred at room temperature under an atmospheric hydrogen pressure for 3 hrs. Palladium-carbon was removed from the reaction mixture by filtration and the filtrate was concentrated to give diethyl 4-amino-α-hydroxybenzylphosphonate as a solid (1.02 g, yield 80%).
Reaction SMILES: [C:1]([C:4]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH2:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].C(C(C1C=CC=CC=1)(CCCC(OCC1C=CC=CC=1)CCCCC)CCCCCCC(OCC)=O)(=O)C>>[C:1]([C:4]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH2:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(C)=CCCC(CCCCCCC(=O)OCC)(C(C)=O)c1ccccc1
Agent: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(C)=O)c1ccccc1)OCc1ccccc1
Product: CCCCCC(C)=CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1

Procedure:
By following the hydrolytic procedure of Example 3, Step E, but substituting ethyl 8-acetyl-8-phenyl-12-methyl-11-heptadecenoate for the ethyl 8-acetyl-8-phenyl-12-benzyloxyheptadecanoate therein employed, there is obtained 8-acetyl-8-phenyl-12-methyl-11-heptadecenoic acid.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: Nc1ccc(S(=O)(=O)c2ncccn2)cc1
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1ccc(S(=O)(=O)c2ncccn2)cc1)C(O)(C(F)F)C(F)F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 moles) in dimethyl acetamide (10 ml) at -10° C. was added thionyl chloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution was stirred at -10° C. for approximately 30 mins. 4-(2-pyrimidylsulfonyl)aniline (0.59 g, 2.5 mmoles) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and sodium bicarbonate solution was added to give a pH of 7-7.5. A dark colored precipitate was formed that was filtered, washed with water and dried. The crude material was preabsorbed onto silica gel and chromatographed on silica gel eluting with 70-80% ethyl/acetate/hexane. Evaporation of product-containing fractions and crystallization from methylene chloride/methanol/hexane gave the title compound (0.33 g, 34%) as a white solid; mp 209°-210° C. 1H-NMR (300 MHz, d6 -DMSO):6.46(t, J=54.06 Hz, 2H, HCF2), 7.78 (t, J=4.8 Hz, 1H, ArH), 7.95-7.98(m, 3H, ArH, OH), 8.02-8.06(m, 2H, ArH), 9.01 (d, J=5.01 Hz, 2H, ArH), 10.58 (s, 1H, NH). MS(CI):394(M+1, 100%).
Reaction SMILES: CC(C)CS[S:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH:11][C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:22](Br)[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(P(CCCC)CCCC)CCC.O>CN(C)C=O>[C:14]1([CH2:13][C:12]([NH:11][C@H:7]2[C@@H:6]([S:5][CH2:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])[NH:9][C:8]2=[O:10])=[O:20])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)CSS[C@H]1NC(=O)[C@H]1NC(=O)Cc1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N[C@@H]1SCC(=O)c1ccccc1
Yield: 80.7 %

Procedure:
(3R,4R)-4(2'-Methyl-n-propyldithio)-3-phenylacetamidoazetidin-2-one (0.5 g., 0.0015 mole), phenacyl bromide (1.0 g., 0.005 mole), and tributyl phosphine (0.8 ml., 0.0032 mole) were stirred in N,N-dimethylformamide (10 ml.) for 0.25 hours. The reaction mixture was poured into water (100 ml.) and extracted with ethyl acetate (3×100 ml.). The combined organic phases were washed with water (2×100 mls.) and evaporated to a yellow oil which was chromatographed on silica gel eluting with 33% ethyl acetate in benzene to yield (3R,4R)-3-phenylacetamido-4-phenacylthioazetidin-2-one (0.429 g., 78%). The constants were as described previously for compound B in Example 3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([Cl:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]=[C:39]=[O:40])[CH:33]=1>C1COCC1>[Cl:23][C:5]1[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:7][C:2]([NH:1][C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[CH:33]=2)=[O:40])=[C:3]([F:24])[CH:4]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC)cc21
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A 0° C. solution of Example A5 (200 mg 0.58 mmol) and pyridine (68 mg, 0.87 mmol) in THF (20 mL) was treated with 1-fluoro-3-isocyanato-benzene (80 mg, 0.58 mmol), warmed to RT and stirred for 3 h. The mixture was concentrated in vacuo and purified by preparative HPLC to give 1-[4-chloro-5-(1-ethyl-7-methylamino-2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-2-fluoro-phenyl]-3-(3-fluoro-phenyl)-urea (193 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.34 (s, 1H), 8.78 (s, 1H), 8.51 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 7.87-7.49 (br. s, 1H), 7.59 (d, J=10.8 Hz, 1H), 7.48 (d, J=11.6 Hz, 1H), 7.33 (m, 1H), 7.08 (m, 1H), 6.83 (m, 1H), 6.44 (s, 1H), 4.18 (m, 2H), 2.94 (s, 3H), 1.24 (t, J=6.8 Hz, 3H); MS (ESI): m/z 484.1 [M+H]+.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]([O:14]CC)=O)=[O:8])C.O>CO.C1(C)C=CC=CC=1>[CH3:2][O:4][C:5]([CH:6]1[C:12](=[O:14])[CH2:11][CH2:10][NH:9][C:7]1=[O:8])=[O:17]
Reactant: CCOC(=O)CCNC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)CCNC1=O
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of β-alanine ethylester hydrochloride (13.8 g, 90 mmol) in dichloromethane (90 mL) and triethylamine (TEA, 13.8 mL, 99 mmol) was stirred at room temperature for 1 hour. More TEA (13.8 mL, 99 mmol) was added, the solution was cooled to 0° C. under stirring and ethylmalonylchloride (12.6 mL, 99 mmol) was added dropwise. After 1 hour at 0° C., the reaction mixture was stirred 1 hour at room temperature. A 15% aqueous solution of K2CO3 (90 mL) was added and the layers were separated. The organic phase was washed with 10% HCl (90 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was chromatographed on flash silica gel (450 g, eluant: ethyl acetate/n-hexane 2:1) to give N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester as a yellow oil (15 g, 64.9 mmol, 72% yield). Sodium metal (610 mg, 26.6 mmol) was dissolved in dry MeOH (25 mL) at room temperature under stirring and inert atmosphere. After complete dissolution the mixture was stirred 10′ longer, then N-(2-ethoxycarbonyl-ethyl)-malonamic acid ethyl ester (6.15 g, 26.6 mmol) in dry toluene (150 mL) was added dropwise. After addition, the reaction mixture was stirred at 90° C. for 6 hours, cooled to room temperature, water (30 mL) was added and the layers were separated. The organic phase was washed with water (2×10 mL), the combined aqueous phases were acidified with 37% HCl and extracted thoroughly with a mixture of DCM/MeOH (5:1). After drying over Na2SO4 and concentration, 3-methoxycarbonylpiperidin-2,4-dione as a pink solid was obtained (4 g, 88% yield). 3-Methoxycarbonylpiperidin-2,4-dione (4 g, 23.4 mmol) was dissolved in acetonitrile containing 1% of water (250 mL) and refluxed for 4 hours. The reaction mixture was concentrated to give the title compound, as a yellow solid (2.4 g, 90% yield).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:44])[NH:29][CH:30]([CH:33]([C:35]1[O:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1)[OH:34])[CH2:31][CH3:32])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([O:27][C:28](=[O:44])[NH:29][CH:30]([C:33]([C:35]1[O:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1)=[O:34])[CH2:31][CH3:32])([CH3:24])([CH3:25])[CH3:26]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)c1nc2ccccc2o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(NC(=O)OC(C)(C)C)C(=O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
Dess-Martin Periodinane (15 wt % in DCM, 8.8 g, 3.1 mmol) was added to a solution of [1-(Benzooxazol-2-yl-hydroxy-methyl)-propyl]-carbamic acid tert-butyl ester (475 mg, 1.55 mmol) in dry methylene chloride (15 ml) and stirred at room temperature for 4 hrs. The reaction was quenched with a solution of Na2S2O3 in aqueous NaHCO3. The organic layer was separated and the aqueous extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of heptane and methylene chloride gave the title compound as a off-white powder (0.38 g).
Reaction SMILES: [Cl:1][C:2]1([C:5]([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([CH2:14][CH2:15][C:16](O)=[O:17])=O)=[CH:10][CH:9]=2)=[O:6])[CH2:4][CH2:3]1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1([C:5]([NH:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]3[CH2:14][CH2:15][C:16](=[O:17])[NH:22][N:23]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)C2(Cl)CC2)cc1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(NC(=O)C3(Cl)CC3)cc2)=NN1
Yield: 92.1 %

Procedure:
2.75 g (9.3 millimoles) of 3-[p-(1-chlorocyclopropylcarbonylamino)-benzoyl]-propionic acid, 0.47 g (9.4 millimoles) of hydrazine hydrate and 20 ml of ethanol are refluxed for 6 hours. The product is filtered off at 10° C., washed with ethanol and dried under reduced pressure at 50° C., giving 2.5 g (92% of theory) of 6-[p-(1-chlorocyclopropylcarbonylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone as colorless crystals (identical with the compound from Example 7).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[C:6]([F:13])=[CH:5][C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:16]1=[O:27].Cl[C:29]1[N:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([N:24]2[CH2:23][CH2:22][CH:21]([N:17]3[CH2:18][CH2:19][CH2:20][C@H:15]([NH:14][C:4]4[CH:5]=[C:6]([F:13])[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:8][C:3]=4[F:2])[C:16]3=[O:27])[CH2:26][CH2:25]2)=[N:34][CH:33]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(N2CCC(N3CCC[C@H](Nc4cc(F)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 68.5 %

Procedure:
(S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride (Example 45, Steps A-E; 0.4 g, 0.944 mmol), 1-(6-chloropyridin-3-yl)ethanone (0.220 g, 1.42 mmol) and DIEA (0.523 mL, 2.83 mmol) were dissolved in DMF (5 mL) and heated at 100° C. overnight. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes) to afford (S)-1′-(5-acetylpyridin-2-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (0.328 g, 0.647 mmol, 68.6% yield) as yellow solid.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:10][N:9]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8]1)(=O)=O.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([O-:33])=[O:32].[Na+].[I-].[Na+]>CN(C)C=O>[C:18]1([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]2[CH2:8][CH:7]([CH2:6][S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[F:24])(=[O:33])=[O:32])[CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S([O-])c1ccccc1F
Reactant: CS(=O)(=O)OCC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(CC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1F
Yield: 36.5 %

Procedure:
[1-(Diphenylmethyl)azetidin-3-yl]methyl methanesulfonate [Example 1, step 1] (3.15 g, 9.50 mmol), sodium 2-fluorobenzenesulfinate (2.65 g, 14.3 mmol) and sodium iodide (2.18 g, 14.5 mmol) were reacted in dimethylformamide (50 mL) by the procedure of Example I Step 3a to afford the title compound (1.37 g, 36%); 1H NMR (500 MHz, CDCl3) δ 2.80–2.88 (3H, m), 3.33 (2H, t, J=7.0 Hz), 3.57 (2H, d, J=6.9 Hz), 4.28 (1H, s), 7.16 (2H, t, J=7.3 Hz), 7.20–7.26 (5H, m), 7.29–7.35 (5H, m), 7.61–7.65 (1H, m), 7.86–7.90 (1H, m); 19F NMR (471 MHz, CDCl3) δ −108.9; m/z (ES+) 396 ([M+H]+, 100%).