Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1.O1CCOCCOCCOCCOCCOCC1>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:33]=[CH:32][C:24]([O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=3)=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: COC(=O)C(C)Oc1ccc(CCl)cc1
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(COc2ccc(-n3nc(C)n(C(F)F)c3=O)c(F)c2)cc1
Yield: 93.3 %

Procedure:
By the method of Example 1, Step I, 0.50 g (0.0019 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (Example 1, Step E) and 0.87 g (0.0038 mole) of methyl 2-(4-chloromethylphenoxy)propionate were reacted in the presence of 0.2 g of 1,4,7,10,13,16-hexaoxacyclooctadecane in 25 mL of N,N-dimethylformamide, yielding 0.80 g of methyl 2-[4-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]phenoxy]propionate as a colorless oil that solidified upon standing, m.p. 83°-85° C. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH =8.0 Hz); 2.44 (s, 3H); 3.76 (s, 3H); 4.78 (q, 1H, JHH =8.0 Hz); 4.90 (s, 2H); 6.78-7.38 (m, 8H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH3:29])[CH:25]=[C:24]4[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH3:29])[CH:25]=[C:24]4[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1cn(CC)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCn1cc(CCC(=O)O)c2cccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
Sodium hydroxide (66 mg) was added to a solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-ethyl-1H-indol-3-yl]propanoate (D120) (79 mg) in THF (5 mL), isopropanol (4 mL) and water (2 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-ethyl-1H-indol-3-yl]propanoic acid (E26) (42 mg). δH (DMSO-d6, 400 MHz): 1.04 (3H, t), 1.37 (6H, d), 2.62 (2H, t), 2.98 (2H, t), 4.14 (2H, q), 4.89 (1H, m), 7.18 (1H, t), 7.27 (1H, s), 7.45 (2H, t), 7.81 (1H, dd), 8.13 (1H, dd), 8.20 (1H, d), 12.07 (1H, s); MS (ES): C24H24ClN3O4 requires 453; found 454.2 (M+H+).
Reaction SMILES: Cl.N[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([C:14]2[N:15]=[N:16][N:17]([CH3:19])[N:18]=2)[CH:4]=1.[N:20]([O-])=O.[Na+].[S:24](=[O:26])=[O:25]>O.C(O)(=O)C.C(O)=O>[CH3:19][N:17]1[N:16]=[N:15][C:14]([C:5]2[CH:4]=[C:3]([S:24]([NH2:20])(=[O:26])=[O:25])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:6]=2)=[N:18]1
Reactant: O=S=O
Reactant: Cn1nnc(-c2cc(N)n(-c3ccccc3)n2)n1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: O=CO
Product: Cn1nnc(-c2cc(S(N)(=O)=O)n(-c3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3.1 mL of 12N hydrochloric acid, 12.5 mL of acetic acid, 3.7 mL of formic acid and 4.5 g of 5-amino-1-phenyl-3-(2-methyl-2H-tetrazol-5-yl)-1H-pyrazole was added dropwise 1.4 g of sodium nitrite in 2.5 mL of water at -8° to -6° C. The mixture was stirred for 15 minutes and then added to 20 mL of acetic acid containing 3.7 mL (liquid) of sulfur dioxide and 0.75 g of cupric chloride dihydrate. After stirring for thirty minutes and allowing to warm to room temperature, the mixture was poured into an ice and water mixture and the precipitate removed by filtration. After washing with water the solid was dissolved in tetrahydrofuran, cooled to -78° C., and ammonia (liquified, 1.0 mL) was added dropwise. The mixture was allowed to stand overnight at ambient temperature and filtered to yield a brown solid. This solid showed peaks at 3300 and 3200 cm-1, consistent for NH2, and 1370, 1185 and 1170 cm-1, consistent for SO2.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[N:4]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:5]([CH3:22])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:11]=1[O:12][CH2:13][C:14](O)=[O:15].C[N:33]1CCO[CH2:35][CH2:34]1.ClC(OCC(C)C)=O.C(N)C>CC(N(C)C)=O>[Br:1][C:2]1[C:3](=[O:31])[N:4]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:5]([CH3:22])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:11]=1[O:12][CH2:13][C:14]([NH:33][CH2:34][CH3:35])=[O:15]
Reactant: Cc1cc(OCc2ccc(F)cc2OCC(=O)O)c(Br)c(=O)n1-c1c(F)cccc1F
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: CC(=O)N(C)C
Product: CCNC(=O)COc1cc(F)ccc1COc1cc(C)n(-c2c(F)cccc2F)c(=O)c1Br
Yield: 50.8 %

Procedure:
To a cooled (−10° C.) solution of [2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]acetic acid (from Step 4) (0.15 g, 0.30 mmol) in DMA (2.0 mL) was added 4-methylmorpholine (0.04 mL, 0.36 mmol) and isobutyl chloroformate (0.05 mL, 0.36 mmol). Ethylamine (0.04 mL, 0.45 mmol) was added after 20 minutes. DMF removed by distillation after 1 h. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (30 mL) and extracted in DCM (3×25 mL). The organic extracts were dried over Na2SO4, filtered, concentrated, and dried in vacuo to give a white solid (0.080 g, 51%). 1H NMR (CD3OD/400 MHz) δ7.60 (m, 1H), 7.53 (t, 1H, J=8.0 Hz), 7.23 (t, 2H, J=8.4 Hz), 6.82 (m, 2H), 6.71 (s, 1H), 5.42 (s, 2H), 4.61 (s, 2H), 3.31 (q, 2H, J=6.4 Hz), 2.10 (s, 3H), 1.09 (t, 3H, J=7.2 Hz). ESHRMS m/z 525.0616 and 527.0568 (M+H calculated for C23H21BrF3N2O4 requires 525.0631 and 527.0614).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[CH3:12].[CH2:14]([Si:16]([CH2:20][CH3:21])([CH2:18][CH3:19])Cl)[CH3:15]>C(N(CC)CC)C>[CH2:1]([O:13][Si:16]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[CH3:12]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C/C=C/C=C/CCCCCCCO
Solvent: CCN(CC)CC
Product: C/C=C/C=C/CCCCCCCO[Si](CC)(CC)CC
Reaction time: 15 h

Procedure:
A mixture of trans,trans-8,10-dodecadien-1-ol (1.82 g), triethylamine (3.5 ml) and triethyl-chlorosilane (1.85 ml) is held at 25° C. for 15 hours. After dilution of the mixture with hexane (100 ml), it is thoroughly washed with ice-water (3×50 ml), dried (CaSO4), concentrated by evaporation and distilled. The title compound is obtained in the boiling range of 107° to 112° C. (nD20 =1.4697).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.[F:23][CH:24]([F:44])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][C:28]=1[O:42][CH3:43].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.CCOC(C)=O>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:30]4[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH:24]([F:44])[F:23])=[C:28]([O:42][CH3:43])[CH:29]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC(F)F
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1OCC(F)F
Temperature: 105 °C

Procedure:
In a 50 mL 3-neck flask with a magnetic stir bar and condenser was placed (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-on (125 mg, 0.34 mmol), 2-(4-(2,2-difluoroethoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (135 mg, 0.43 mmol) and Pd(PPh3)4 (40 mg, 0.027 mmol). Evacuated and filled with nitrogen 3×. Added 2.5 mL DME and 2N sodium carbonate (0.51 ml, 1.03 mmol) via syringe and heated in a 105° C. oil bath for 2 hrs at which time LC-MS indicated a complete reaction. Let cool, added EtOAc and water, separated, washed with brine, dried over Na2SO4, filtered and concentrated. Purified by chromatography: ISCO 50 g C18 reverse phase 0-30% water/acetonitrile/0.1% TFA. Partially concentrated under reduced pressure added EtOAc and sat.aq.bicarb, separated, washed with brine, dried over Na2SO4, filtered and concentrated to give a white solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[CH:26]=[CH:25][NH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:14][CH2:13]1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:10][N:11]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[CH:26]=[CH:25][NH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:14][CH2:13]1)[C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CNC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccccc1)C1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIPEA (642 μl, 3.67 mmol) was added to a mixture of N-methyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D13 (177 mg), benzoic acid (93 mg, 0.765 mmol), HATU (349 mg, 0.918 mmol), aza-HOBt (62.5 mg, 0.459 mmol) in N,N-Dimethylformamide (DMF) (2551 μl). The mixture was stirred at room temperature during 2 h. Then the solvents were evaporated. The crude was finally purified via MDAP using a high pH method. Because of the NMR the solid was purified again using the High pH MDAP method. Fractions of each MDAP were combined and evaporated together to give a white solid of E30 in 51 mg. LCMS [M+H]+336.19@0.62 min (2 min run)
Reaction SMILES: [CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([CH3:23])=[C:16]([C:20](Cl)=[O:21])[N:17]([CH3:19])[N:18]=3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1.[NH3:36]>>[CH:1]1([C:4]2[C:5]([CH2:6][O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14]4[C:15]([CH3:23])=[C:16]([C:20]([NH2:36])=[O:21])[N:17]([CH3:19])[N:18]=4)=[CH:10][C:9]=3[CH3:24])=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nn(C)c(C(=O)Cl)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reactant: N
Product: Cc1cc(-c2nn(C)c(C(N)=O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O

Procedure:
At room temperature, to 28%-Ammonia solution 50 ml was added 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carbonyl chloride (described in Reference Preparation example 117) 1.3 g. The mixture was stirred for twelve hours and concentrated under reduced pressure and added 10%-hydrochloric acid solution 10 ml. The precipitates were filtrated and were washed with water and were dried under reduced pressure to give 1-{3-cyclopropyl-2-[2-methyl-4-(5-aminocarbonyl-1,4-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 49”) 0.8 g.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([CH2:15][C:16]#[C:17][Si](C)(C)C)=[C:13]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:12]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CCOCC.O>[C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([CH:15]=[C:16]=[CH2:17])=[C:13]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:12]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nnc(-c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2CC#C[Si](C)(C)C)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=C=Cc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(3-(trimethylsilyl)prop-2-ynyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole (300 mg, 0.46 mmol) in tetrahydrofuran (5 ml) at 0° C. was added tetrabutylammonium fluoride (0.7 ml, 1.0 M in tetrahydrofuran, 0.7 mmol). After reaction mixture was warmed up to room temperature, it was stirred for 10 minutes. After the resulting solution was diluted with ether (20 ml), water was added (10 ml). Organic layer was separated with ethyl acetate (20 ml twice). After evaporation, crude residue was purified with silica gel column (hexane/ethyl acetate=7/1 to hexane/ethyl acetate 5/1). The less polar compound 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(propa-1,2-dienyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole was obtained as light yellow solid (87 mg, 34% yield). And relatively more polar compound 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(prop-2-ynyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole was produced as yellow solid (140 mg, 54% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.C(N(C(C)C)CC)(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=[C:25]([Cl:28])[C:26]=1[OH:27]>O1CCCC1>[Cl:28][C:25]1[CH:24]=[C:23]([S:29]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)(=[O:31])=[O:30])[CH:22]=[C:21]([Cl:20])[C:26]=1[OH:27]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(O)c(Cl)c1
Reactant: c1cc2c(cn1)NCCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(c1cc(Cl)c(O)c(Cl)c1)N1CCOc2ccncc21
Reaction time: 0.17 h
Yield: 3.4 %

Procedure:
To a 5 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (30 mg, 0.220 mmol) was dissolved in tetrahydrofuran (3 ml). Diisopropylethylamine (0.153 ml, 0.878 mmol) was added and then stirred at 0□ for 10 minutes, and then 3,5-dichloro-4-hydroxy-benzenesulfonyl chloride (69 mg, 0.264 mmol) was added thereto and then stirred at 0□ for 1 hour. The reaction mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:ethyl acetate=1:2. The fractions containing the product were collected and evaporated to obtain the target compound 21 as pale-yellow solid (2.7 mg, 3.4%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17]>>[Br-:14].[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[CH2:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: c1ccc(Cc2ccccn2)cc1
Product: O=C(C[n+]1ccccc1Cc1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
Prepared by reacting 2-benzylpyridine with 2-bromo-1-phenyl-1-ethanone according to known procedures:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[C:11]1(=[O:16])[NH:15][CH2:14][CH2:13][CH2:12]1>>[C:5]1([O:4][C:2]([N:15]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCCN1
Reactant: O=C(Cl)Oc1ccccc1
Product: O=C1CCCN1C(=O)Oc1ccccc1

Procedure:
The title compound was prepared by customary methods from phenyl chloroformate and γ-butyrolactam (2-pyrrolidone).
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.Cl.Cl.[CH3:15][S:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.[CH3:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[CH:35]([NH:37][C:38]1[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH2:48])[CH:44]=3)[N:39]=1)[CH2:34][CH2:33]2>>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[CH:35]([NH:37][C:38]1[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH:48][C:1]([NH:25][CH:22]4[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][S:16][CH3:15])[CH2:24][CH2:23]4)=[O:2])[CH:44]=3)[N:39]=1)[CH2:34][CH2:33]2
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CSCCN1CCC(N)CC1
Agent: Cl
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(CCSC)CC4)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(2-methylsulfanyl-ethyl)-piperidin-4-ylamine dihydrochloride and rac-N2-(7-methoxy-indan-1-yl)-quinoline-2,6-diamine (Example 172); MS: m/e=506.8 (M+H+).
Reaction SMILES: [F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5]([O:7][CH2:15][CH3:16])=[O:6]
Reactant: CCO
Reactant: CC1(C(=O)O)CC1(F)Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(C)CC1(F)Cl
Yield: 79 %

Procedure:
44 ml of ethanol are added at room temperature and with stirring to 43 g (0.28 mol) of 2-fluoro-2-chloro-1-methyl-cyclopropanecarboxylic acid. After the addition of sulphuric acid, the reaction mixture is refluxed for 16 hours. Excess ethanol is subsequently distilled off and the residue is dried and distilled under reduced pressure. In this manner, 40 g (79% of theory) of ethyl 2-fluoro-2-chloro-1-methyl-cyclopropane-carboxylate are obtained in the form of a liquid of boiling point 62-63° C./ 17 mbzr.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.[BrH:10]>>[Br:10][CH2:2][C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1
Reactant: O=c1ccc(CO)c[nH]1
Reactant: Br
Product: O=c1ccc(CBr)c[nH]1
Temperature: 100 °C

Procedure:
To 5-hydroxymethyl-2-pyridone-(114.9 mg, 0.9 mmol) was added 3.0 ml of 48% hydrobromic acid. The mixture was heated at 100° C. for 20 minutes. The excess hydrobromic acid was then evaporated in vacuo to give the corresponding 5-bromomethyl-2-pyridone. This compound was used without purification. HRMS: m/e, M+ found; 186.9626, 7.4% Calc. for C6H6BrNO: 186.9633, −3.9 ppm.
Reaction SMILES: [CH2:1]([C:3]([CH2:10][OH:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].C(C(CCCC)C=O)C.C=O>>[CH2:6]([C:3]([CH2:1][CH3:2])([CH2:4][OH:5])[CH2:10][OH:11])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(C=O)(CC)CO
Agent: C=O
Agent: CCCCC(C=O)CC
Product: CCCCC(CC)(CO)CO

Procedure:
This invention pertains to an improved process for the preparation of 2-ethyl-2-(hydroxymethyl)hexanal by the condensation of 2-ethylhexanal and formaldehyde in the presence of a trialkylamine catalyst. More specifically, this invention pertains to a continuous process for the manufacture of 2-ethyl-2-(hydroxymethyl)hexanal wherein 2-ethylhexanal, formaldehyde and a tertiary amine are continuously fed to a reaction zone, crude product comprising an aqueous phase and an organic phase containing 2-ethyl-2-(hydroxymethyl)hexanal and 2-ethylhexanal is continuously removed from the reaction zone. This invention also concerns the azeotropic distillation of the organic phase of the crude product whereby unreacted 2-ethylhexanal is recovered. Finally, this invention provides for the catalytic hydrogenation of the refined, organic phase of the crude product to produce 2-butyl-2-ethyl-1,3-propanediol.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12](O)=[O:13])[CH2:4][CH2:3]1.P(Cl)(Cl)[Cl:17].Cl>>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([C:12]([Cl:17])=[O:13])[CH2:4][CH2:3]1
Reactant: ClP(Cl)Cl
Reactant: CC1(C)CCC(C(=O)O)c2ccccc21
Agent: Cl
Product: CC1(C)CCC(C(=O)Cl)c2ccccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 195.8 %

Procedure:
102 g of 1,1-dimethyl-tetralin-4-carboxylic acid are treated while stirring with 27.4 g of phosphorus trichloride and the mixture is stirred at 50° C. for 3 hours. This treatment is carried out while excluding moisture and conducting away the resulting hydrochloric acid gas. The upper phase is separated after 12 hours and distilled over a short Vigreux column. There are obtained 87 g of 1,1-dimethyl-tetralin-4-carboxylic acid chloride of boiling point 89° C./0.2 mmHg; nD20 =1.5418-20; yield 78%.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[C:7]1=[O:28].[CH3:29]I>C1COCC1.N>[CH3:29][O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:14][CH2:13]2)[C:7]1=[O:28]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCCN(CCO)C2=O)CC1
Reactant: CI
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil; 71 mg) was added under ice-cooling to a solution of benzyl 4-[3-(2-hydroxyethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]piperidin-1-carboxylate (0.59 g) obtained in Example 39a) in THF (30 mL), and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.11 mL) was added to the reaction mixture, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with an aqueous saturated ammonia solution to separate the organic layer. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (0.60 g, quantitative) as a white powder.
Reaction SMILES: C([O:4][C:5]1[C:6]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:7][C:8]([OH:14])=[C:9]([C:11]([CH3:13])=[O:12])[CH:10]=1)(=O)C.Cl(O)(=O)(=O)=O.[CH:25](OC(C)C)(C)C>C([O-])([O-])OCC>[OH:4][C:5]1[C:6]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:7][C:8]2[O:14][CH:25]=[CH:13][C:11](=[O:12])[C:9]=2[CH:10]=1
Reactant: CC(=O)Oc1cc(C(C)=O)c(O)cc1NS(C)(=O)=O
Reactant: CC(C)OC(C)C
Agent: CCOC([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CS(=O)(=O)Nc1cc2occc(=O)c2cc1O
Reaction time: 1.5 h
Yield: 59 %

Procedure:
2.0 g of methyl 5-acetoxy-2-hydroxy-4-methylsulfonylaminophenyl ketone was suspended in 14 ml of ethyl orthoformate. Thereto was dropwise added 2.0 g of 70% (w/w) perchloric acid in 10 minutes with ice-cooling. The mixture was stirred for 1.5 hours at 20°-25° C. The reaction mixture was mixed with 20 ml of diisopropyl ether. The resulting crystal was collected by filtration and mixed with 20 ml of water. The mixture was refluxed for 5 minutes and then cooled. 50 ml of ethyl acetate was added thereto. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 14 ml of a 1N aqueous sodium hydroxide solution. The mixture was stirred for 30 minutes at 20°-25° C. The reaction mixture was adjusted to pH 2 with 6N hydrochloric acid. The resulting crystal was collected by filtration and recrystallized from a mixed solvent of N,N-dimethylformamide and water to obtain 1.0 g (yield: 59%) of 6-hydroxy-7-methylsulfonylamino-4H-1-benzopyran-4-one having a melting point of >250° C.