Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[CH:35]=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:35][C:34]2[CH:37]=[CH:38][C:39]([F:40])=[C:32]([Cl:31])[CH:33]=2)[CH3:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: CN(Cc1ccc(F)c(Cl)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1

Procedure:
As described for Example 75d, 2-[4-(1-benzyl-4-methylamino-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile was converted, using 3-chloro-4-fluorobenzaldehyde instead of 3,4-dichlorobenzaldehyde, to the title compound. MS m/e=546.3 [M+H]+.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[N:17]2[C:18]3[N:9]([C:10](=[O:20])[CH:11]=[N:12][C:13]=3[CH:14]=[CH:15][C:16]2=[O:19])[CH2:8]1)(=O)=O.N1C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1>CC#N>[O:20]=[C:10]1[CH:11]=[N:12][C:13]2=[C:18]3[N:9]1[CH2:8][C@@H:7]([CH2:6][N:27]1[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]1)[N:17]3[C:16](=[O:19])[CH:15]=[CH:14]2
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)OC[C@@H]1Cn2c(=O)cnc3ccc(=O)n1c32
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
A solution of [(1S)-3,8-dioxo-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylen-1-yl]methyl methanesulfonate (1.05 g, 3.53 mmol) in dry CH3CN (50 ml) at room temperature under argon was treated with pyridine (0.343 ml, 4.24 mmol), followed by 1,1-dimethylethyl 4-piperidinylcarbamate (0.884 g, 4.24 mmol). The mixture was heated at 70° C. for 1.5 h and then at 90° C. for 3 h. LCMS showed ˜25% of product. So 0.5 eq of pyridine and 0.5 eq of 1,1-dimethylethyl 4-piperidinylcarbamate were added and the reaction was heated at 90° C. overnight and then stirred at room temperature for 2 days. The reaction was complete. The solvent was evaporated and the residue partitioned between sat NaHCO3 and 20% MeOH/DCM (100 ml/100 ml). The layers were separated and the aqueous layer was extracted with 20% MeOH/DCM again (2×100 ml). The combined organic extracts were dried over MgSO4, filtered and evaporated to afford 1.7 g of crude which was purified by silica chromatography using a 0-5% MeOH/DCM gradient to afford the product as a yellow solid (0.57 g, 40.2%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:27]1[CH2:26][CH2:25][C:20]2[N:21]([CH3:24])[C:22]3[CH:23]=[C:15]([N:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:10][C:11]4=[O:29])[CH:16]=[CH:17][C:18]=3[C:19]=2[CH2:28]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Yield: 33.8 %

Procedure:
To a solution of 4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (0.2 g, 0.5 mmol) in CH2Cl2 (6 mL) was added triethylamine (0.20 mL, 1.4 mmol) followed by acetyl chloride (50 μL, 0.71 mmol). The reaction was stirred at room temperature until complete. After the solvent was removed under reduced pressure, the residue was purified by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) to give the title compound (72.2 mg, 36%) as a yellow solid and as a mixture of rotamers: mp 225-230° C.; 1H NMR (500 MHz, CDCl3) δ 7.53-7.36 (m, 6H), 7.32-7.30 (m, 2H), 7.06-7.00 (m, 1H), 6.09 (d, J=3.0 Hz, 1H), 6.07-6.04 (m, 1H), 5.06 (s, 2H), 4.82 (s, 1H), 4.67 (s, 1H), 4.03 (t, J=5.5 Hz, 1H), 3.84 (t, J=5.5 Hz, 1H), 3.64 (s, 3H), 2.90 (t, J=5.5 Hz, 1H), 2.84 (t, J=5.5 Hz, 1H), 2.24, 2.22 (2×s, 3H); ESI MS m/z 428 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=16.8 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12]C(=O)C)[C:9](=O)[CH3:10].[C:16](#[N:20])[CH2:17][C:18]#[N:19].[OH-].[K+].O>CO>[NH2:19][C:18]1[NH:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[C:9]([CH3:10])[C:17]=1[C:16]#[N:20]
Reactant: N#CCC#N
Reactant: CC(=O)NC(C(C)=O)c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(-c2ccccc2F)[nH]c(N)c1C#N
Yield: 22.4 %

Procedure:
1-(2-Fluorophenyl)-1-acetamido-2-propanone (3.13 g) and malononitrile (1.49 g) were dissolved in methanol (15 ml) and the solution was stirred under ice-cooling. Then, 55% aqueous solution of potassium hydroxide was added to the above solution to adjust to pH 10. The reaction mixture was then warmed and stirred at 55-60° C. for 0.5 hour. After cooling, the reaction mixture was poured into iced water and the resulting crystals were collected by filtration. This crude crystalline product was recrystallized from methanol-water and, further, from benzene to provide the title compound as colorless crystals (0.72 g). m.p. 117-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:24])[N:19]([CH3:23])[N:20]=[C:21](Cl)[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+].CO.O>CO>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:24])[N:19]([CH3:23])[N:20]=[C:21]([O:30][CH3:29])[C:16]=4[N:15]=[CH:14]3)=[CH:25][CH:26]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cn1nc(Cl)c2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nn(C)c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 70 %

Procedure:
In methanol (5 ml) was dissolved 1-[4-(4-chloro-benzoyl)benzyl]-4-chloro-6-methylimidazo[4,5-d]pyridazin-7(6H)-one (72 mg) followed by addition of 28% sodium methoxide/methanol (1.0 ml), and the mixture was refluxed for 5 hours. To this reaction mixture was added a large quantity of water and the resulting crystals were rinsed with water and dried under reduced pressure to provide 50 mg (yield 70%) of the title compound. 1H-NMR (CD3OD) δ: 3.7.1(3H,s), 4.00(3H,s), 5.85(2H,s), 7.50(2H,d,J=8.6Hz), 7.52(2H,d,J=8.8Hz), 7.74(2H,d,J=8.8Hz), 7.75(2H,d,J=8.6Hz), 8.42(1H,s).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:17]([SH:19])[CH3:18].C[O-].[Na+]>CO>[CH2:17]([S:19][C:2]1[C:3]([O:8][CH2:9][CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1)[CH3:18]
Reactant: CC(C)NCC(O)COc1nccnc1Cl
Reactant: CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSc1nccnc1OCC(O)CNC(C)C

Procedure:
Analogously to the description in Example 8, 7.5 g (0.03 mol) of 3-chloro-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine, 2.8 g (0.045 mol) of ethylmercaptan and 2.4 g (0.045 mol) of sodium methylate in 150 ml of methanol, when refluxed for 30 hours, give the crude base 3-ethylthio-2-(3'-isopropylamino-2'-hydroxy-propoxy)-pyrazine, and this is converted, with 1.74 g of fumaric acid, into the fumarate of melting point 158°-160° C. when crystallised from methanol-ether.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].C[O-].[Na+].[Cl:7][C:8]([Cl:24])([Cl:23])[CH:9](Cl)[CH:10]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>C(O)C>[Cl:7][C:8]([Cl:24])([Cl:23])[CH:9]([S:3][CH2:1][CH3:2])[CH:10]([N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CCS
Reactant: CC(C)(C)C(=O)C(C(Cl)C(Cl)(Cl)Cl)n1cncn1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCSC(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
3.1 g (0.05 mol) of ethylmercaptan were added dropwise to a solution of 3.4 g (0.05 mol) of sodium methylate in 50 ml of absolute ethanol. The mixture was subsequently stirred at room temperature for 1 hour. A solution of 16.7 g of 1,1,1,2-tetrachloro-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one (Example 3) in 200 ml of ethanol was then added dropwise to this mixture, and the resulting mixture was subsequently stirred at room temperature for 6 hours. The inorganic salt was then filtered off and the filtrate was concentrated. After triturating in hexane, the residue crystallized. 8.9 g (50% of theory) of 1,1,1-trichloro-2-ethylmercapto-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one of melting point 101°-105° C. were obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.C(N(CC)CC)C.[CH2:46]([O:48][C:49](Cl)=[O:50])[CH3:47]>O1CCCC1>[CH2:46]([O:48][C:49]([N:13]([CH2:12][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:50])[CH3:47]
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1OC)CC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.43 g, 0.85 mmole) and triethylamine (130 μl, 0.93 mmole) in 5 ml of anhydrous tetrahydrofuran, was added dropwise ethylchloroformate (89 μl, 0.93 mmole). The resulting mixture was stirred for about 16 hours at room temperature. The tetrahydrofuran was removed under reduced pressure.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])=[O:3].[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][S:2]([O:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[CH:7]=1)(=[O:3])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Oc1cnc2ccccc2c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-hydroxyquinol-3-yl methanesulphonate (0.48 g) and potassium carbonate (0.28 g) in dry dimethylformamide (20 ml) was stirred for 2 hours at ambient temperature. Methyl iodide (0.15 ml) was then added and the stirring at ambient temperature continued overnight. The solvent was removed under reduced pressure and the residue was triturated with water (10 ml). The resultant mixture was extracted extracts were evaporated to dryness. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (39:1) followed by crystallisation from industrial methylated spirit (10 ml) to give the novel compound ]-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 206°-208°.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C>>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:25]([O:26][CH3:27])[CH3:24])=[O:7]
Reactant: CNOC
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To a stirred solution of 3-(dimethylamino)benzoic acid (16.5 g, 100 mmol), cooled to 0° C. with a brine/ice bath, was added N,N-dimethylformamide (0.39 mL, 5 mmol) followed by oxalyl chloride (10.5 mL, 120 mmol). The resulting mixture was stirred 4 h at room temperature, until gas evolution stopped and a clear solution was obtained. The mixture was cooled to 0° C. with a brine/ice bath, N,O-Dimethylhydroxylamine (13.7 g, 140 mmol) was added at once, followed by dropwise addition of triethylamine (55.8 mL, 400 mmol) through a dropping funnel, while keeping the internal temperature under 20° C. The resulting suspension was stirred overnight at room temperature, then washed with brine. The aqueous layers were extracted with dichloromethane (2×50 mL), then the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford 3-(dimethylamino)-N-methoxy-N-methylbenzamide as an oil [15.5 g, yield 67%; HPLC/MS:m/z=209 (M+H); log P(HCOOH)=0.95].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:21][CH3:22])=[C:11]([C:13]([C:16]2[NH:17][CH2:18][CH2:19][N:20]=2)=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:25](CC)CC)C.N#CBr>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:13]2[C:16]3[N:20]([CH2:19][CH2:18][N:17]=3)[C:23]([NH2:25])=[N:12][C:11]=2[C:10]=1[O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(OCc2ccccc2)ccc(C2=NCCN2)c1N
Reactant: CCN(CC)CC
Agent: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Temperature: 0 °C

Procedure:
A mixture of 3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline (Step 6, 100 g, 336 mmol) and triethylamine (188 mL) in DCM (3 L) was cooled to 0° C. and treated with cyanogen bromide (78.4 g, 740 mmol). The reaction mixture was stirred and allowed to warm to room temperature gradually. After 16 h the reaction mixture was diluted with a solution of saturated sodium bicarbonate and extracted with DCM. The organic layer was washed three times with saturated bicarbonate solution followed by multiple washes with brine. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure to give a semi solid (130 g with triethylamine salt contamination): 1H NMR (DMSO-d6) δ: 7.30-7.48 (7H, m), 5.31 (2H, s), 4.32 (2H, m), 4.13 (2H, m), 3.81 (3H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[N:4]=1.C(OC(=O)C)(=O)C.[Br:18]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][S:2][C:3]1[C:8]([Br:18])=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1cc(C)[nH]c(=O)n1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSc1nc(=O)[nH]c(C)c1Br
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 35 %

Procedure:
4-Methylthio-6-methylpyrimid-2-one (see Wheeler, L. H. and MacFarland, F. D. J. Amer. Chem. Soc. 42 (1909) (43) (0.01 mol) was dissolved in acetic acid (30 ml) containing 2% acetic anhydride and N-bromo-succinimide (0.013 mol) added. The reaction mixture was kept at 55° C. for 40 min. Ice-cold water (150 ml) containing a little sodium bisulphite was added to the cold reaction mixture. The precipitate formed was recrystallised from water; yield 35%, m.p. 244° C. (Found: C, 30.34; H, 2.81. Calc. for C6H7BrN2OS: C, 30.65; H, 3.00).
Reaction SMILES: [C:1]([C:3](=[C:9]([OH:15])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].O(C)[Na].[Na].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C(O)C.C(#N)C>[C:1]([C:3](=[C:9]([O:15][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)C(C#N)=C(O)C(CC)CC
Agent: CO[Na]
Agent: [Na]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)C(C#N)=C(OC(=O)C(C)(C)C)C(CC)CC
Temperature: 20 °C

Procedure:
36 g (0.17 mol) of ethyl 2-cyano-3-hydroxy-4-ethyl-2-hexenoate were dissolved in ethanol, and 31 g (0.17 mol) of 30% strength NaOCH3 solution were added. The mixture was then concentrated to dryness, and the sodium enolate was released by adding toluene and reconcentration of alcohol residues. 39.7 g (0.17 mol) of the resulting sodium salt were initially charged in acetonitrile and, at 0° C. with warming to 20° C., mixed dropwise with 27.4 g (0.23 mol) of pivaloyl chloride. After 16 g of stirring at 25° C., the reaction mixture was concentrated and the residue was taken up in ethyl acetate and washed with 2% strength NaOH. The organic phase was dried and concentrated. Customary purification gave 41.5 g (83% of theory) of the title compound (b.p. 102° C./1 mbar).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].[C:13]1([Mg]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O1CCCC1>ClCCl>[OH:2][CH:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 4-formylbenzoate (2.83 g, 17.2 mmoles) at −78° C. in 60 mL of dichloromethane is added 10 mL a 2.0 M solution of phenylmagnesium chloride in tetrahydrofuran (20.0 mmoles) over 7 minutes. After stirring for an additional 20 minutes, the reaction was quenched with methanol then with saturated aqueous ammonium chloride. The aqueous layer was acidified with 1N hydrochloric acid and the phases were separated. The organic portion was washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate. Removal of the volatiles under reduced pressure and purification over silica gel afforded the title ester.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([C:7]([N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][N:21]3[CH2:20][CH2:19][N:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH3:10])[CH2:23][CH2:22]3)[CH2:26][CH2:27]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N1CCN(CC2CCNCC2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CC2CCN(C(=O)C3CCCCC3)CC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
Cyclohexanecarbonyl chloride (0.506 g, 3.5 mmol) was added to a solution of 1-(2-methoxyphenyl)-4-piperidin-4-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 1 and triethylamine (2 equivalents, 1 mL) in CH2Cl2 (30 mL) and the solution stirred under N2 at 0° C. for 16 hours. The mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3×25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (0.765 g, 55% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17].ClC1C=CC(NC(=O)N[C@H]2CC[C@H](OC3C=CC(C(O)=O)=CC=3)CC2)=CC=1C(F)(F)F>>[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:12]([NH:11][C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[O:13])=[CH:27][CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Agent: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)N[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)NC34CC5CC(CC(C5)C3)C4)cc2)ccn1
Yield: 60 %

Procedure:
Compound 2287 was prepared in 60% yield from adamantyl isocyanate and 4-(4-amino-phenoxy)-pyridine-2-carboxylic acid methylamide using the procedure detailed for compound 2221 in Example 4. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (q, J=5 Hz, 1H), 8.48 (d, J=6 Hz, 1H), 8.39 (s, 1H), 7.49-7.42 (m, 2H), 7.36 (d, J=2 Hz, 1H), 7.13-7.03 (m, 3H), 5.89 (s, 1H), 2.78 (d, J=5 Hz, 3H), 2.09-2.01 (m, 3H), 1.98-1.92 (m, 6H), 1.68-1.60 (m, 61).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 83.4 %

Procedure:
Treat 6-hydroxynaphthalene-2-carboxylic acid methyl ester (4.77 g, 23.6 μmmol) and benzyl bromide (3.3 mL, 28.3 mmol) in DMF (22 mL) with cesium carbonate (15.3 g, 47.2 mmol). Stir the mixture for 22 h at RT and concentrate. Dilute the concentrate with EtOAc (300 mL) and water (100 mL). Wash the organic layer with brine (3×100 mL), dry it over Na2SO4, and filter. Concentrate the filtrate. Purify the product using medium pressure silica gel chromatography (15:85 to 50:50 EtOAc:hex) to give the title compound as a white solid (5.75 g, 83%). MS (ES) m/e 293 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[C-:39]#[N:40].[K+]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([C:39]#[N:40])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: [C-]#N
Agent: [K+]
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(C#N)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting material: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and potassium cyanide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: C=CCN
Reactant: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)N1CC(Sc2ccc(Cl)cc2)C1
Reaction time: 3 h

Procedure:
A stirred solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was cooled in a water bath and treated with 2.2 g (0.02 mole) of 2-propenylamine. After stirring for 3 hr, the reaction mixture was diluted with 200 ml of water and the product separated as a yellow oil. The oil slowly solidified to yield a dull orange-red waxy material. After decanting the water and allowing the residue to air dry, the residue was triturated 5 times with boiling isopropyl ether and the decanted solutions upon cooling yielded 5 solid fractions, from white to pale beige color. The fractions were all consistent with the expected product by mass spectral analysis and TLC showed only a single product. All five fractions were combined to give 1.7 g (60.3%), m.p. 88°-89° C.