Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:22])[S:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])=[N:6][CH:7]=1.[BH4-].[K+]>C(#N)C.O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:22])[S:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[OH:14])=[N:6][CH:7]=1
Reactant: O=C(CCSC(=S)Nc1ccc(Cl)cn1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: OC(CCSC(=S)Nc1ccc(Cl)cn1)c1ccc(F)cc1
Temperature: 2 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
The procedure of Example 1 is followed, but a suspension of 3-(4-fluorophenyl)-3-oxopropyl 5-chloropyrid-2-yldithiocarbamate (25.0 g) in acetonitrile (225 cc) and a solution of potassium borohydride (5.6 g) in distilled water (56 cc) are used as the starting materials at a maximum of 25° C. The reaction is allowed to proceed for 1 hour at between 20° and 25° C. The residual oil thus obtained (20.2 g) is dissolved in a mixture (100 cc) of chloroform (80 cc) and ethyl acetate (20 cc) and the solution is chromatographed on a column of diameter 4 cm, containing silica (0.063-0.2 mm, 450 g). Elution is carried out first with a mixture of chloroform (800 cc) and ethyl acetate (200 cc), this eluate being discarded, and then with a mixture (2,500 cc) of chloroform (2,000 cc) and ethyl acetate (500 cc), this eluate being evaporated under reduced pressure (20 mm Hg) at 50° C. The resulting product (16.5 g) is recrystallised from boiling isopropyl ether (80 cc). After filtering the boiling solution and then cooling for 2 hours at 2° C., the crystals which have appeared are filtered off, washed 4 times with ice-cooled isopropyl ether (20 cc in total), and dried under reduced pressure (0.1 mm Hg) at 45° C. 3-(4-Fluorophenyl)-3-hydroxypropyl 5-chloropyrid-2-yldithiocarbamate (12.1 g), which melts at 86° C., is thus obtained.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[C:7]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Fc1ncccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccnc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
Into a 1-neck round-bottom flask was added 2-fluoro-3-iodopyridine (1.0 g, 0.0045 mol), trimethylsilylacetylene (0.95 mL, 6.7 mmol), bis(triphenylphosphine)palladium(II) chloride (0.2 g, 0.2 mmol), copper(I) iodide (0.07 g, 0.4 mmol), and triethylamine (0.94 mL, 6.7 mmol) in N,N-dimethylformamide (20 mL). The reaction was stirred at 25° C. for 16 hours. The reaction was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated under vacuum. The product was purified by column chromatography on silica gel (10% ethyl acetate 90% hexanes) to give 0.747 g of the desired product. 1H NMR (400 MHz, CDCl3): δ 7.86-7.89 (m, 1H), 7.55-7.61 (m, 1H), 6.86-6.90 (m, 1H). MS [M+H]=194.0
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:10](I)[C:3]=12.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.CN(C=O)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:10]([C:22]3[CH:23]=[C:24]4[C:19]([CH2:18][CH2:17][N:16]4[CH3:15])=[CH:20][CH:21]=3)[C:3]=12
Reactant: CN1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC(C)n1cc(I)c2c(Br)ccnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2ccc3c(c2)N(C)CC3)c2c(Br)ccnc21
Temperature: 55 °C
Yield: 68.2 %

Procedure:
To a stirred suspension of 4-bromo-3-iodo-1-isopropyl-1H-pyrrolo[2,3-b]pyridine (D10) (2.5 g, 6.85 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (2.130 g, 8.22 mmol) in ACN (15 mL), DMF (15.00 mL) and DCM (7.50 mL) was added 2M sodium carbonate aq. solution (34.2 mL, 68.5 mmol). Bis(triphenylphosphine)palladium(II) chloride (0.577 g, 0.822 mmol) was then added to the solution and the resulting mixture was heated at 55° C. for ca. 1 hour. Temperature was raised to 65° C. and heated for another 1 hour. The reaction was allowed to cool to RT and diluted with DCM (70 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organics were dried and concentrated down. The residue obtained was purified on silica using 0-10% ethyl acetate/cyclohexane to afford the title compound (1.73 g). LCMS (A): m/z (M+H)+ 370/372, C19H20BrN3 requires 369/371 (acidic).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C1OCCOCCOCCOCCOCCOC1.[H-].[K+].Br[CH2:33][C:34]1[CH:49]=[CH:48][C:37]([C:38]([N:40]([CH3:47])[CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:39])=[CH:36][CH:35]=1>C(#N)C>[CH:41]1([N:40]([CH3:47])[C:38](=[O:39])[C:37]2[CH:48]=[CH:49][C:34]([CH2:33][N:8]3[CH:7]=[N:6][C:5]4[C:9]3=[N:10][C:2]([Cl:1])=[N:3][C:4]=4[Cl:11])=[CH:35][CH:36]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: CN(C(=O)c1ccc(CBr)cc1)C1CCCCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [K+]
Solvent: CC#N
Product: CN(C(=O)c1ccc(Cn2cnc3c(Cl)nc(Cl)nc32)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
To a stirred solution of 2,6-dichloropurine (500 mg, 2.64 minol) in acetonitrile (40 mL)at -10° C. was added 18-crown-6 (48 mg, 0.18 mmol) and potassium hydride (106 mg after ether wash of 35% dispersion in mineral oil, 2.64 mmol). The reaction was allowed to warm to room temperature and stirred for an additional 30 min. 4-Bromomethyl-N-methyl-N-cyclohexyl benzamide (900 mg, 2.90 mmol) was added in small amounts over 10 min and the mixture stirred under argon at 25° C. After 18 hr, the reaction was quenched by adding drops of acetic acid and the solvent removed under reduced pressure at <45° C. The residue was dissolved in ethyl acetate and washed with aqueous potassium carbonate, water and brine. The solvent was removed and the crude mixture (1.28 g) chromatographed (silica gel, CH2Cl2 /MeOH 100/7) to give pure 6A (278 mg, 25%). m.p. 134°-136° C. Anal calcd. for C20H21N5OCl2.0.25 H2O:C, 56.80; H, 5.08; N, 16.56; Cl, 16.80. Found: C, 57.00; H, 5.09; N, 16.20; Cl, 16.59.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CCCCCC.[CH2:23]([N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.CCOCC.O>[CH2:23]([N:30]1[CH2:35][CH2:34][C:33]2([C:2]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=3[C:4](=[O:5])[O:6]2)[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1cc(F)ccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC2(CCN(Cc3ccccc3)CC2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.3 %

Procedure:
To a stirred solution of 2-bromo-5-fluorobenzoic acid (5.0 g, 21.9 mmol) at −70° C. in tetrahydrofuran (30 ml) was added dropwise a 1.6M n-butyllithium solution in hexane (44 ml, 70.1 mmol) over a period of 1 hour. After 3 hours, a solution of 1-benzyl-4-piperidone (8.5 g, 43.8 mmol) in tetrahydrofuran (20 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was poured into a stirred mixture of water (150 ml) and ether (150 ml). The aqueous layer was extracted with ether (2×40 ml), acidified with HCl 5 N (20 ml) to pH 2 and boiled for 1 hour. The mixture was cooled to 0° C., basified (pH 10) with NaOH 5 N and rapidly extracted with dichloromethane (3×80 ml). The combined extracts were washed with water (80 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was chromatographed on silica gel (eluent: heptane/ethylacetate 1:1) to yield 2.27 g (33%) of 1′-benzyl-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one as light yellow solid. MS m/e: 312 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([N:20]3[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]3)[CH:28]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccnc(N3CCN(C)CC3)c2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.0 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.61 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.0 mmol) in toluene (4.0 mL) at 100° C. for 22 h to give 4-chloro-5,7-difluoro-3-methyl-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)quinoline as a light yellow solid. Mass Spectrum (ESI) m/e=389.1 (M+1).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8][CH2:9][CH3:10])=[CH2:7])CCC.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([CH:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH3:28])[N:21]=1.[F-].[K+]>CN(C)C=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:20]1[N:25]=[C:24]([C:6]([O:8][CH2:9][CH3:10])=[CH2:7])[CH:23]=[C:22]([CH:27]([O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH3:28])[N:21]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(OCC(F)(F)F)c1cc(Cl)nc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(C(C)OCC(F)(F)F)nc(Cl)n1
Temperature: 80 °C

Procedure:
Tributyl(1-ethoxyvinyl)stannane (0.466 mL, 1.38 mmol) was added to a degased solution of 2,4-dichloro-6-(1-(2,2,2-trifluoroethoxy)ethyl)pyrimidine (0.379 g, 1.38 mmol) and bis(triphenylphosphine)palladium chloride (0.019 g, 0.03 mmol) in dimethylformamide (8 mL) under nitrogen. The mixture was heated at 80° C. for 1.5 h, then cooled and poured into solution of potassium fluoride (2 g) in water (40 mL). The mixture was extracted with MTBE (2×50 mL), the organic phase was washed with water (30 mL), dried over sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica eluting with dichloromethane to yield the title product, 350 mg (82%).
Reaction SMILES: CC1(C)OC(CO[C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)CO1.[OH:22][CH2:23]C1C=CC(C#N)=CC=1>C(N(CC)CC)C>[OH:16][NH:15][C:13](=[NH:14])[C:12]1[CH:11]=[CH:10][C:9]([CH2:23][OH:22])=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(CO)cc1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(CO)cc1

Procedure:
The title compound is prepared in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine (step b) starting from 4-hydroxymethyl-benzonitrile and using triethylamine as base; LC-MS: tR=0.21 min, [M+1]+=167.04.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[N+](C1C=CC([N:43]([CH:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)[C:44](=O)[O-:45])=CC=1)([O-])=O>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:44]([NH:43][CH:47]3[CH2:51][CH2:50][CH2:49][CH2:48]3)=[O:45])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: O=C([O-])N(c1ccc([N+](=O)[O-])cc1)C1CCCC1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.9 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in acetonitrile (50 mL). After stirring for 20 min, 4-nitrophenyl-N-cyclopentylcarbamate (0.44 g, 1.85 mmol) was added. The mixture was stirred at room temperature for 17 hours. The mixture was filtered to afford N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclopentylamino)carboxamide (0.2 g, 27%) as a white solid: mp 151–153° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86–7.68 (m, 3H), 6.31 (t, 1H), 6.17 (d, J=6.9 Hz, 1H), 5.18–5.11 (dd, J=4.6 and 12.3 Hz, 1H), 4.62 (d, J=5.4 Hz, 2H), 3.83 (q, J=6.4 Hz, 2H), 2.96–2.85 (m, 1H), 2.64–2.50 (m, 2H), 2.07–2.04 (m, 1H), 1.70–1.29 (m, 8H); 13C NMR (DMSO-d6) δ 172.77, 169.83, 167.59, 167.04, 157.63, 141.12, 134.64, 133.43, 131.52, 128.99, 121.64, 51.09, 48.83, 38.70, 32.91, 30.94, 23.16, 21.99; Anal. Calcd. For C20H22N4O5: C, 60.29; H, 5.57; N, 14.06. Found: C, 60.09; H, 5.66; N, 14.15.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:4][N+:3]=1[O-].[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OCc1ccc(C)[n+]([O-])c1
Product: CC(=O)OCc1ccc(COC(C)=O)nc1

Procedure:
2-Methyl-5-acetoxymethylpyridine-N-oxide (0.05 mole) is refluxed in 50 ml. of acetic anhydride for two hours and then evaporated to dryness. The residue is fractionally distilled under high vacuum to obtain 2,5-di(acetoxymethyl)pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.C(O)(C)C>[Fe].O>[NH2:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: [Fe]
Solvent: CC(C)O
Solvent: O
Product: Nc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
2,3-Dichloro-5-nitropyridine (3.9 g) and iron powder (3.0 g) were added to isopropyl alcohol (40 ml) and water (8 ml) and the mixture refluxed for 4 hours. The mixture was then cooled to room temperature and filtered (celite). The filtrate was evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (80:20) to (50:50)] to give 5-amino-2,3-dichloropyridine (1.71 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][C:5]([N:16]2[C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][F:25])[N:18]=[N:17]2)=[C:4]([F:26])[CH:3]=1.Br[CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]([N:16]2[C:20](=[O:21])[N:19]([CH2:22][CH2:23][CH2:24][F:25])[N:18]=[N:17]2)=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:28]([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:13][CH:14]=1
Reactant: O=c1n(CCCF)nnn1-c1cc(Oc2ccc(O)cc2)c(Cl)cc1F
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc(-n3nnn(CCCF)c3=O)c(F)cc2Cl)cc1
Yield: 39.8 %

Procedure:
A stirred mixture of 1.0 g (0.0026 mole) of 1-[4-chloro-2-fluoro-5-(4-hydroxyphenoxy)phenyl]-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one, 1.5 g (0.0083 mole) of ethyl 2-bromopropionate, and 0.64 g (0.0046 mole) of potassium carbonate in 50 ml of acetone was heated at reflux for approximately 18 hours. The mixture was cooled and the solvent was removed by evaporation under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride to yield 0.5 g of ethyl 2-[4-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-1,4-dihydro-5-oxotetrazol-1-yl]phenoxy]phenoxy]propionate as an oil, compound 8 of Table 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([CH2:27][CH3:28])([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=3)[CH2:17][CH3:18])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:21]([CH3:26])[CH:20]=3)([CH2:27][CH3:28])[CH2:17][CH3:18])=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2ccc(C(CC)(CC)c3ccc(O)c(C)c3)cc2c1C
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1oc2ccc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc2c1C
Yield: 94 %

Procedure:
5-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-benzofuran-2-carboxylic acid ethyl ester (4.04 g, 10.6 mmol) and 1-bromopinacolone (2.66 g, 14.9 mmol) and K2CO3 (2.91 g, 21.2 mmol) are reacted analogous to Example 1E to give the title compound as a pale yellow oil (4.77 g, 94%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][N:12]1[C:18]2=[C:19]3[C:24](=[N:25][C:26]4=[CH:27][CH:28]=[CH:29][C:16](=[C:17]24)[O:15][CH:14]([CH3:30])[C:13]1=O)[CH2:23][CH2:22][CH2:21][CH2:20]3.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:11][N:12]1[C:18]2=[C:19]3[C:24](=[N:25][C:26]4=[CH:27][CH:28]=[CH:29][C:16](=[C:17]24)[O:15][CH:14]([CH3:30])[CH2:13]1)[CH2:23][CH2:22][CH2:21][CH2:20]3
Reactant: CC1Oc2cccc3nc4c(c(c23)N(C)C1=O)CCCC4
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CN(C)c2c3c(nc4cccc(c24)O1)CCCC3
Yield: 58.6 %

Procedure:
To a solution of lithium aluminum hydride in tetrahydrofuran (1M, 14.0 ml) and dry tetrahydrofuran (30 ml) was added aluminum chloride (1.86 g) in portions, with stirring. The reaction mixture was stirred for five mins and 1,3-dimethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (3.95 g) was added. After stirring for 30 min, ethyl acetate (200 ml) and 10% sodium hydroxide solution (200 ml) were added, and the organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. Recrystallization of the residue from diethyl ether/pentane gave 2.2 g (59%) of product, mp 125°-126.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1(C)C=CC=CC=1>[CH2:33]([O:32][C:30]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:31])[CH3:34]
Reactant: CCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: CCOC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)c1ccc(OC(=O)OCC)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
4.89 g (18.50 mmol) of 2-hydroxy-5-octanoylbenzoic acid and 9 ml (70.30 mmol) of N,N-dimethylaniline are dissolved in 30 ml of toluene. The medium is cooled to 0° C., and 1.77 ml (18.50 mmol) of ethyl chloroformate are then added dropwise. After stirring for 2 hours at room temperature, the mixture is washed with aqueous 0.5N hydrochloric acid solution and then with water. The organic phase is dried over magnesium sulfate, filtered and concentrated. 5.59 g of 2-ethoxycarbonyloxy-5-octanoylbenzoic acid are obtained in the form of a white solid in a yield of 89%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[C:17]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[CH:34]([CH3:35])[S:33][C:32](=[O:36])[NH:31][N:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:18].C(N(CC)CC)C>ClCCl>[CH2:8]([N:7]([CH2:6][CH2:5][O:4][C:2]([N:31]1[N:30]=[C:29]([C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[N:19]([C:17](=[O:18])[C:16]2[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:20][CH2:21][CH2:22]3)[CH:34]([CH3:35])[S:33][C:32]1=[O:36])=[O:3])[CH2:10][CH3:11])[CH3:9]
Reactant: CCN(CC)CCOC(=O)Cl
Reactant: COc1ccc(C(=O)N2CCCc3cc(C4=NNC(=O)SC4C)ccc32)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)CCCN3C(=O)c2ccc(OC)c(OC)c2)C(C)SC1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
6 g of 2-(N,N-diethylamino)ethyl chloroformate dissolved in 50 ml of dichloromethane are added dropwise with stirring to a solution of 10 g of 3,6-dihydro-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-2H-1,3,4-thiadiazin-2-one ("A") and 9.8 ml of triethylamine in 100 ml of dichloromethane, and the mixture is subsequently stirred at 20° C. for one hour. The solvent is removed, and the mixture is worked up in the conventional manner to give 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; hydrochloride.
Reaction SMILES: [H-].I[CH3:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:16]2[O:17][C:18]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][OH:29])=[CH:23][C:19]=3[C:20]=2[S:21][CH3:22])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH3:15]>C1COCC1>[CH3:3][O:29][CH2:28][CH2:27][C:24]1[CH:25]=[CH:26][C:18]2[O:17][C:16]([C:8]3[CH:9]=[CH:10][C:11]([O:12][CH2:13][O:14][CH3:15])=[C:6]([O:5][CH3:4])[CH:7]=3)=[C:20]([S:21][CH3:22])[C:19]=2[CH:23]=1
Reactant: CI
Reactant: COCOc1ccc(-c2oc3ccc(CCO)cc3c2SC)cc1OC
Agent: [H-]
Solvent: C1CCOC1
Product: COCCc1ccc2oc(-c3ccc(OCOC)c(OC)c3)c(SC)c2c1
Temperature: 25 °C

Procedure:
642 mg of hydride substance (16.1 mM) and 2.26 g of iodomethane (15.9 mM) were added to the solution containing 595 mg of 2-[2-(3-methoxymethoxy-phenyl)-3-methylsulfanyl-benzofuran-5-yl]-ethanol (13a; 1.59 mM) dissolved in 40 ml of THF. The reaction mixture was performed to reflux distillation for 16 hours and cooled to room temperature. The reaction mixture was extracted with 50 ml of water and ethylacetate to divide into water layer and organic solvent layer. The organic solvent layer was dried with magnesium sulfuric acid, filtrated and the filtrate was concentrated with vaccuo.