Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([O:17]C)=[O:16])=[CH:7]1)[CH3:5]>C1COCC1>[CH2:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[CH:7]1)[CH3:5]
Reactant: CCn1cc(C(=O)OC)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCn1cc(C(=O)O)c2ccccc21
Temperature: 50 °C
Reaction time: 36 h
Yield: 90 %

Procedure:
In THF (9.0 ml) was dissolved the methyl 1-ethylindole-3-carboxylate obtained in the above-described (Step 1). To the resulting solution was added 0.25N NaOH (9.0 ml) at room temperature. After the reaction mixture was stirred at 50° C. for 36 hours, 1N NaOH (1.0 ml) was added thereto, followed by stirring at 70° C. for 9 hours. The reaction mixture was cooled to room temperature, and then neutralized with 1N HCl (4.5 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give 1-ethylindole-3-carboxylic acid (388.0 mg, 90%, yield of 2 steps) as a pale pink amorphous substance.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:12]I.[H-].[Na+]>>[CH3:12][N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CI
Reactant: C1=Cc2ccccc2NN=C1
Agent: [H-]
Agent: [Na+]
Product: CN1N=CC=Cc2ccccc21

Procedure:
The bromide 20 (Bogatskii A V, et al., (1977) Pharm Chem J (Engl Transl) 11:1520-1525; Vejdelek Z, Protiva M (1983) Collect Czech Chem Commun 48:1477-1482) was reacted with trimethylsilyacetylene in the presence of a palladium catalyst to provide trimethylsilyl analog 52. This product was methylated with methyl iodide/sodium hydride to give the N-methyl benzodiazepine 54 (XLi 351). This was subjected to fluoride-mediated desilylation to furnish 53 (XLi 350) from 53 and 55 (XLi 352) from 54.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:11](O)=[O:12])[O:9][CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.O.[BH4-].[Na+].Cl>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH2:11][OH:12])[O:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc(C(=O)O)c1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
4-Ethoxycarbonylfuran-2-carboxylic acid (0.47 g, 2.53 mmol) was dissolved in tetrahydrofuran (10 mL), triethylamine (0.53 mL, 3.80 mmol) and ethyl chloroformate (0.29 mL, 3.04 mmol) were added at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite, water (0.23 mL, 12.7 mmol) and sodium borohydride (0.19 g, 5.06 mmol) were added to the filtrate, and the mixture was stirred overnight. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50) to give the title compound (0.34 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[N+:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH2:28][CH2:27][CH2:26]2)([O-:22])=[O:21].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[N:14]1([C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([N:29]3[C:30]4[C:25](=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:32][CH:31]=4)[CH2:26][CH2:27][CH2:28]3)=[N:3][CH:4]=2)=[O:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCN2
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1cnc(N2CCCc3cc([N+](=O)[O-])ccc32)nc1C(F)(F)F)N1CCOCC1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
A mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (150 mg), 6-nitro-1,2,3,4-tetrahydroquinoline (136 mg), tris(dibenzylideneacetone)dipalladium(0) (14 mg), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg), sodium tert-butoxide (98 mg), and toluene (2 mL) was stirred at 110° C. for 30 minutes under radiation with microwave. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and the obtained residue was solidified from a mixed solvent of hexane and ethyl acetate to obtain 1-[5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)pyrimidin-2-yl]-6-nitro-1,2,3,4-tetrahydroquinoline (62 mg) as a yellow powder.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:12][NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:57][C:58]1[CH:62]=[CH:61][S:60][C:59]=1[C:63](O)=[O:64]>CN(C=O)C.O>[CH3:57][C:58]1[CH:62]=[CH:61][S:60][C:59]=1[C:63]([N:32]1[CH2:31][CH2:30][N:29]([C:11](=[O:10])[CH2:12][NH:13][C:14](=[O:28])[C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[CH2:34][CH2:33]1)=[O:64]
Reactant: Cc1ccsc1C(=O)O
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccsc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 74.8 %

Procedure:
DIPEA (85.5 mg, 0.114 mL, 0.66 mmol) was added to a stirred solution of N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide (60 mg, 0.176 mmol) in DMF (3 mL). HOBT (21.89 mg, 0.16 mmol) and EDCI.HCl (70.5 mg, 0.36 mmol) were then added at room temperature. After 2 minutes, 3-methyl-thiophene-2-carboxylic acid (20.9 mg, 0.15 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with cold water, and the resulting precipitate was filtered, washed with water then hexane and dried to afford 52 mg (76.5% yield) of N-{2-[4-(3-methyl-thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide as a pale brown solid. LCMS Purity: 98.86%, HPLC Purity: 98.50%. 1H NMR (CDCl3): δ 7.8 (d, 2H), 7.4 (m, 2H), 7.3 (d, 1H), 7.2 (s, 1H), 7.1 (t, 1H), 7.0 (m, 4H), 6.85 (d, 1H), 4.3 (dd, 2H), 3.7 (m, 6H), 3.5 (t, 2H), 2.2 (s, 3H).
Reaction SMILES: Cl[C:2](=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH3:12])[CH3:3].[CH2:13]([C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17])[CH3:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][C:2](=[N:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[CH2:13][CH3:14])[CH3:3])[CH3:12]
Reactant: CCc1ccccc1N=C(C)Cl
Reactant: CCc1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCc1ccccc1N=C(C)Nc1ccccc1CC
Reaction time: 1 h
Yield: 82.6 %

Procedure:
N-(1-chloroethylidene)-2-ethylbenzenamine (HS Imine I) (1.82 g, 10 mmol) was dissolved in 50 mL of toluene. 2-ethylaniline (1.24 mL, 10 mmol) was added dropwise at room temperature, resulting in a light pink solution, which was refluxed overnight. Toluene was removed under vacuum. Sodium hydroxide (100 mL of 0.10 M solution, 10 mmol) was added and the solution was stirred for 1 hour. The solid that deposited was extracted into 150 mL of diethylether. The ether layer was dried with MgSO4, filtered and taken to dryness, leaving 2.20 g of pink solid. The pink solid was dissolved in 60 mL of pentane and cooled to −30° C. A white crystalline solid was collected and dried (2.11 g, 79%). The 1H NMR spectrum is complex and is consistent with a mixture of E/Z isomers.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH:4]1[CH2:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5]1>[Rh].O1CCCC1>[CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5]1
Reactant: CC(C)(C)CC1C=C(C(=O)O)C1
Agent: [Rh]
Solvent: C1CCOC1
Product: CC(C)(C)CC1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 35 h
Yield: 106.4 %

Procedure:
3-(2,2-Dimethylpropyl)-1-cyclobutenecarboxylic acid (163 g) and tetrahydrofuran (1300 mL) were mixed. After an addition of 5 w/w % rhodium on activated carbon (8.2 g) to the mixture, the mixture was stirred at RT for 35 hr under hydrogen atmosphere (1 atm). The 5 w/w % rhodium on activated carbon was filtered off and the filtrate was concentrated in vacuo to give the title compound (175.56 g) as a crude product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([F:19])([CH:16]([OH:18])[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([F:19])([CH:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a −10° C. solution of 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (Example A14, 0.267 g, 1.00 mmol), triethylamine (0.4 g, 4 mmol) and dichloromethane (10 mL) is added methanesulfonyl chloride (0.229 g, 2.00 mmol). The mixture is stirred at room temperature for 2 hours and concentrated in vacuo. The residue is partitioned between ethyl acetate and water. The organic layer is dried over Na2SO4 and concentrated to afford the title compound (0.330 g). 1H NMR (200 MHz, CDCl3): δ 7.36 (s, 5H), 5.14 (s, 2H), 4.99–4.81 (m, 1H), 3.76–3.37 (m, 4H), 3.06 (s, 3H), 2.25–1.96 (m, 2H), 1.52–1.47 (m, 3H).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=3[C:17]3[C:25]4[C:20](=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=4)[N:19]([CH3:29])[CH:18]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:37]1[S:38][CH:39]=[CH:40][CH:41]=1)CCC>>[CH3:29][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:17]([C:16]2[C:15](=[O:30])[NH:14][C:13](=[O:31])[C:12]=2[C:6]2[C:5]3[C:9](=[CH:10][C:2]([C:37]4[S:38][CH:39]=[CH:40][CH:41]=4)=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)=[CH:18]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccc(I)cc21
Product: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccc(-c3cccs3)cc21
Yield: 37.3 %

Procedure:
3-(1-Methyl-6-nitro-1H-indol-3-yl)-4-(1-methyl-6-thiophen-2-yl-1H-indol-3yl)-pyrrole-2,5-dione (180 mg, 37%) was prepared from 3-(6-iodo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)pyrrole-2,5-dione (525 mg, 1 mmol) and 2-(tributylstannyl)thiophene (0.98 mL, 3.09 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH3:17])[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:16])[NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:20]([N:11]1[CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:17])[C:13]2([CH2:14][CH2:15]2)[C:12]1=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C)CNC(=O)C12CC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)C(=O)C12CC2
Reaction time: 0.67 h
Yield: 98 %

Procedure:
To a solution (65 mL) of 7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptan-4-one (3.12 g, 12.97 mmol) in dimethylformamide in an ice bath was gradually added sodium hydride (55%, dispersion in a mineral oil, 538 mg, 12.33 mmol) in 5 minutes, and the mixture was stirred at the same temperature for 40 minutes. Benzyl bromide (1.851 mL, 15.56 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted by adding ethyl acetate (300 mL), and the solution was washed with water (100 mL×2) and saturated aqueous solution of sodium chloride (100 mL). After drying the solution with anhydrous sodium sulfate and removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 9:1→4:1→2:1) to obtain 4.20 g (12.71 mmol, 98%) of the target compound as a colorless transparent gummy solid.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH:15]=[C:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:19]>CO>[CH3:17][C:16]([CH3:18])=[CH:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:19])[C:11]=2[N:12]=[CH:13]1
Reactant: CC(C)=Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: N
Solvent: CO
Product: CC(C)=Cn1cnc2c(N)nc3ccccc3c21

Procedure:
Similarly, the isomer 4-chloro-1-(2-methyl-1-propenyl)-1H-imidazo[4,5-c]quinoline was reacted with 19% ammonia in methanol to provide 1-(2-methyl-1-propenyl)-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 284°-289° C. after recrystallization from ethanol. Analysis: Calculated for C14H14N4 : %C, 70.6; %H, 5.9; %N, 23.5; Found: %C, 70.6; %H, 5.9; %N, 23.4.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[C:5]1([CH:11]([CH3:14])[CH:12]=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].C(O)(=O)C>CO>[CH3:3][C:2](=[CH:12][CH:11]([CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:1]=[O:4]
Reactant: CCC=O
Reactant: CC(C=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C=O)=CC(C)c1ccccc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
192 g of propionaldehyde are added dropwise to a solution of 402 g of 2-phenylpropan-1-al and 12 g of sodium hydroxide in 1 l of methanol in the course of 6 hours. Stirring is continued for one hour, after which the mixture is neutralized with glacial acetic acid (pH=6), stirred overnight and evaporated down, the residue is taken up with CH2Cl2 /H2O, and the solution is extracted with CH2Cl2. The organic phase is washed with water, dried over Na2SO4, evaporated down again and distilled to give 178 g of 2,4-dimethyl-4-phenylbut-2-en-1-al of boiling point 108°-120° C./0.5 mbar.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[C@@H:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1>C(OCC)(=O)C.[C].[Pd]>[C:20]([O:19][C:17]([C@H:4]1[CH2:3][C:2](=[O:1])[O:6][C@@H:5]1[C:7]([OH:9])=[O:8])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1CC(=O)O[C@@H]1C(=O)O
Reaction time: 3 h
Yield: 95.4 %

Procedure:
6.4 g of 2-benzyl 3-tert-butyl (2S,3S)-5-oxotetrahydrofuran-2,3-dicarboxylate was dissolved in 80 ml of ethyl acetate, and 640 mg of a 10% palladium-carbon catalyst was added thereto, followed by catalytic reduction for 3 hours at room temperature under hydrogen atmospheric pressure. The catalyst was filtered off, and the filtrate was evaporated to dryness under reduced pressure to obtain 4.39 g of the above-identified compound as white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH2:9]Cl)(=[O:4])[CH2:2][CH3:3].C1N2CN3CN(C2)CN1C3.C1N2S(=O)(=O)N3CN(C2)S(=O)(=[O:29])N1C3.ClCCCl>O>[C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:11])[CH:9]=[O:29])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OCC=C(C)CCl
Reactant: O=S1(=O)N2CN3CN1CN(C2)S3(=O)=O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: ClCCCl
Product: CCC(=O)OCC=C(C)C=O
Temperature: 35 °C
Reaction time: 4 h
Yield: 26.8 %

Procedure:
The crude 4-propionyloxy-2-methyl-1-chloro-2-butene (64.0 g, 0.362 mol) obtained in the above (i) was added to a solution of hexamethylenetetramine (50.9 g, 0.363 mol) in water (345 ml), and the mixture was stirred at 35° C. for 4 hours to prepare a tetramine salt. 1,2-Dichloroethane (200 ml) was added to the reaction mixture, and compounds insoluble in water were removed by extraction. 1,2-Dichloroethane (400 ml) was further added to the aqueous layer that had been washed, and the mixture was stirred at 60° C. for 4 hours to hydrolyze the tetramine salt. After completion of the reaction, the 1,2-dichloroethane layer was separated, and 1,2-dichloroethane (250 ml) was further added to the aqueous layer for extraction. The 1,2-dichloroethane layers were combined and dried over anhydrous sodium sulfate. The 1,2-dichloroethane was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane (=1:5)) to give 4-propionyloxy-2-methyl-2-buten-1-al (15.2 g, 0.0973 mol, Yield: 26.8% ).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[N:21]1([C:27]([N:13]2[CH2:14][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:4][CH:5]=3)[CH2:10][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: COC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2)C1
Reactant: O=C(Cl)N1CCOCC1
Product: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
According to General Method 3A, 9.25 g (32.2 mmol) of methyl 5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylate and 9.63 g (64.7 mmol) of morpholine-4-carbonyl chloride were reacted. This gave 16.3 g of crude product in 76% purity (LC-MS), which was converted without any further purifying operations.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:28][CH2:27][C:22]4(OCC[O:23]4)[CH2:21][CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]3[CH2:20][CH2:21][C:22](=[O:23])[CH2:27][CH2:28]3)(=[O:17])=[O:18])=[CH:14][CH:15]=2)=[O:7])=[CH:29][CH:30]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
4-chloro-N-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylsulfonyl)benzyl]benzamide 7c (2.7 g, 5.99 mmol) was suspended in 6 NHCl (40 ml) and THF added until a clear solution was obtained (about 40 ml). The reaction mixture was stirred at room temp overnight and THF was removed in vacuo. The resulting suspension was diluted with cold water (50 ml), aged for 1 h at room temp and filtered. The filter residue was dried under high vacuum for several hours to yield 2.0 g (82%) of ketone 4-chloro-N-{4-[(4-oxo-1-piperidinyl)sulfonyl]benzyl}benzamide 7d as colourless powder in >90% purity (LC-MS).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)=[O:2].[C:11](N1C=CN=C1)([N:13]1C=CN=[CH:14]1)=O.CNC>O1CCCC1>[CH3:11][N:13]([C:8]([C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)=[O:10])[CH3:14]
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(C=O)s1
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 5-formyl-2-thiophenecarboxylic acid (prepared according to Carpenter, A. J., et al., Tetrahedron 41:3808 (1985)) (2.75 g. 17.61 mmoles) in 75 ml of tetrahydrofuran was added 1,1'-carbonyldiimidazole (3.71 g, 22.88 mmoles), the solution stirred under dry argon for 21/2 hours and treated with excess gaseous dimethylamine. The solution was concentrated in vacuo to an oil which was dissolved in ethyl acetate (100 ml) and extracted with 1N hydrochloric acid (2×50 ml) followed by 5% sodium bicarbonate (2×50 ml). Each of the aqueous layers was backwashed with ethyl acetate (2×50 ml) and the combined organic layers were dried (magnesium sulfate). Concentration in vacuo furnished a pale yellow solid (2.42 g, 75%). EIMS (m/z): 183 (M+, 82%), 154 (M+ -CHO, 7%), 139 (M+ -(CH3)2N, base) and 111 (M+ -(CH3)2NCO, 59%; 1HNMR (CDCl3) delta, 9.91 (1H, s), 7.67 (1H, d, J=4.0Hz), 7.35 (1H, d, J=4.0Hz), 3.13 (6H, br s). This material was used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[O:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:38]1([CH2:41][N:42]2[C:50]3[N:49]=[C:48]([CH2:51][C:52]4[CH:57]=[CH:56][C:55]([NH:58][CH3:59])=[CH:54][CH:53]=4)[NH:47][C:46]=3[C:45](=[O:60])[N:44]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[F:68])[C:43]2=[O:69])[CH2:40][CH2:39]1>ClCCl>[CH:38]1([CH2:41][N:42]2[C:50]3[N:49]=[C:48]([CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N:58]([CH3:59])[C:7]([C:6]5[C:2]([CH3:1])=[N:3][O:4][C:5]=5[CH3:10])=[O:9])=[CH:56][CH:57]=4)[NH:47][C:46]=3[C:45](=[O:60])[N:44]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[F:68])[C:43]2=[O:69])[CH2:40][CH2:39]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1noc(C)c1C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1noc(C)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
A mixture of 3,5-dimethyl-isoxazole-4-carboxylic acid (8.1 mg, 0.057 mmol) in dichloromethane (1.5 mL) cooled to 0° C. was treated with triphenylphosphine (17 mg, 0.063 mmol), and N-chlorosuccinimide (10 mg, 0.074 mmol). This mixture was stirred at 0° C. for 15 min and at 25° C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (50 mg, 0.11 mmol). The reaction was then stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2:98 methanol/dichloromethane) afforded 3,5-dimethyl-isoxazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (7.4 mg, 23.2%) as an off-white solid: EI-HRMS m/e calcd for C30H29N6O4F (M+) 556.2234, found 556.2229.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11].Cl.[CH2:31]([NH2:33])[CH3:32].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:33][CH2:31][CH3:32])=[O:25])=[C:22]([F:29])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=[O:11]
Reactant: CCN
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2Cl)cc1F

Procedure:
In analogy to example 207, step 2, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluorobenzoic acid (example 216, step 4) was coupled with ethylamine hydrochloride using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=441.3 [M+H]+.