Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22]OC.[CH3:25][O:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=[O:32].[O:37]1CCC[CH2:38]1>CCCCCC>[Cl:14][C:15]1[C:16]([O:21][CH3:22])=[C:17]([CH:31]([C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[O:28][CH2:27][O:26][CH3:25])[OH:32])[CH:18]=[CH:19][C:20]=1[O:37][CH3:38]
Reactant: COCOc1ccccc1Cl
Reactant: C1CCOC1
Reactant: COCOc1ccccc1C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COCOc1ccccc1C(O)c1ccc(OC)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1.6M solution of n-butyl lithium in hexane (140 ml) was placed in a 1 l flask and cooled in an ice bath. To this was added with stirring 34 ml of tetramethylethylenediamine and, after a 10 min reaction period, 34.5 g of 1-chloro-2-methoxymethoxybenzene (dropwise over a 30 min period). A pale orange suspension formed and this was stirred for 4 hours continuing the ice bath cooling. A solution of 34.5 g of 2-methoxymethoxybenzaldehyde in 30 ml of tetrahydrofuran was added with stirring and cooling. The reaction was exothermic. When the addition was complete, the mixture was allowed to warm to room temperature and was then quenched carefully with water. The resulting mixture was poured into a mixture of 1 l of ethyl acetate and 500 ml of aqueous ammonium chloride. The phases were separated and the organic phase was extracted twice with water and once with brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a viscous, pale orange oil. This was purified by filtration chromatography, eluting with mixtures of hexane and dichloromethane starting with pure hexane and ending with pure dichloromethane, to obtain 52.2 g (77 percent of theory) of the title compound as a pale yellow oil. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[CH2:36](O)[CH2:37][CH2:38][OH:39]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[O:39]1[C:32]2([CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:35][CH2:36][CH2:37][CH2:38]1
Reactant: OCCCO
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCCO3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g), propane-1,3-diol (0.12 g), p-toluenesulfonic acid monohydrate (0.01 g) and toluene (15 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.56 g, 100%).
Reaction SMILES: C([O:3][C:4](=[O:25])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)C>[OH-].[Na+]>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:25])=[O:3])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)/C=C/C=C(c1cccc(OC)c1)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(C(=C/C=C/C(=O)O)c2cccc(OC)c2)c1
Yield: 87.6 %

Procedure:
A mixture of (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid ethyl ester (19.8 g) methanol (200 mL) and 2N sodium hydroxide solution (40 mL) was heated at reflux for 30 minutes. After most of the methanol was distilled off in vacuo, the solution was diluted with water (300 ml), acidified with 2N hydrochloric acid (50 mL) and the resulting solid filtered. The dried material (17.8 g) was crystallized from dichloromethane-hexane to afford 15.9 g of (E)-5,5-bis (3-methoxyphenyl)-2,4-pentadienoic acid, mp 179°-180.5° C.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:33][CH:32]=[CH:31][C:18]=3[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:33][CH:32]=[CH:31][C:18]=3[NH:19][N:20]=2)[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(N3CCN(Cc4ccccc4)CC3)c3sccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(CN2CCN(c3n[nH]c4ccsc34)CC2)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of KOH(s) (56.09 g, 2.66 mol) in methly alcohol (1.33 L) is added 3-(4-benzyl-piperazin-1-yl)-1-(toluene-4-sulfonyl)-1H-thieno[3,2-c]pyrazole (241 g, 0.532 mol). The mixture is heated at reflux for 1.25 hours, cooled to room temperature and evaporated. The is residue is taked up in EtOAc (1 L) washed with water (2 L), dried (MgSO4) filtered and evaporated. The residue was recrystallized from EtOAc/Heptane yielding 129 g (81%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:18]=[C:17]([F:19])[C:10]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:9]([F:20])[CH:8]=1.[O:21]=[C:22]1[CH2:25][CH:24]([C:26]([OH:28])=O)[CH2:23]1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[F:20][C:9]1[CH:8]=[C:7]([C:22]2([OH:21])[CH2:23][CH:24]([C:26]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])[CH2:25]2)[CH:18]=[C:17]([F:19])[C:10]=1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: Fc1cc(Br)cc(F)c1CN1CCCC1
Reactant: C1CCNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(C1CC(O)(c2cc(F)c(CN3CCCC3)c(F)c2)C1)N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
A 2.5 M solution of n-BuLi in hexanes (4.34 ml, 10.9 mmol) was added over 15 min to a solution of intermediate 18, 1-(4-bromo-2,6-difluoro-benzyl)-pyrrolidine (3.0 g, 10.9 mmol) in absolute THF (20 ml) under a flow of nitrogen at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Then a −78° C. chilled solution of 3-oxocyclobutanecarboxylic acid (0.62 g, 5.43 mmol) in absolute THF (6 ml) was added drop wise at −78° C. The mixture was warmed to RT slowly and left stirring for 18 hrs. Pyrrolidine (0.674 ml, 8.15 mmol) and T3P (3.8 ml, 5.97 mmol, 50% solution in EtOAc) were added and stirred for 30 min and the reaction was then quenched with 1N NaOH (25 ml) and extracted with CH2Cl2 (3×100 ml) to recover 2.8 g of crude product. This was purified by flash column chromatography using a 120 g ISCO™ column and 5% and 8% MeOH/CH2Cl2 with 0.2% NH4OH to obtain the title compound (520 mg, 26% yield). Rf=0.75 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C20H26F2N2O2, 364.2, found, 365.4 (M+H) APCI; 1H-NMR (CDCl3) δ 7.03 (ddd, J=8.7, 3.7, 2.5 Hz, 2H), 3.76 (s, 2H), 3.51 (t, J=6.8 Hz, 2H), 3.47-3.40 (m, 4H), 3.13-3.06 (m, 1H), 2.80-2.73 (m, 2H), 2.60-2.50 (m, 5H), 2.00-1.90 (m, 2H), 1.90-1.83 (m, 2H), 1.76-1.72 (m, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])[CH2:3][CH2:2]1.S(Cl)([Cl:26])=O>C(Cl)Cl.CN(C=O)C>[Cl:26][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[C:7]([C:4]2[CH2:3][CH2:2][O:1][CH2:6][CH:5]=2)[CH:12]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCOCC2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2=CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.3 %

Procedure:
To a solution of 66.46G (39.3 mg, 0.13 mmol) in dry DCM (1.0 mL) and dry DMF (0.010 mL) was added thionyl chloride (0.020 mL, 0.27 mmol) at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was concentrated and then purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 66.46H (39.5 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.39 (3H, m), 7.02 (1H, t, J=8.8 Hz), 6.85 (2H, m), 5.57 (1H, s), 4.64 (2H, s), 4.13 (2H, q, J=2.7 Hz), 3.80 (3H, s), 3.70 (2H, t, J=5.3 Hz), 2.14 (2H, dd, J=4.5, 2.5 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:26][CH2:27][O:28][CH2:29][C:30]1[O:31][CH:32]=[CH:33][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CC(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:16]2[N:17]([CH2:26][CH2:27][O:28][CH2:29][C:30]3[O:31][CH:32]=[CH:33][CH:34]=3)[C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: OCCOCc1ccco1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2CCOCc2ccco2)CC1
Reaction time: 21 h

Procedure:
Combine ethyl 2-fur-2-ylmethoxyaceate (1.2 g, 6.5 mmol) and tetrahydrofuran (10 mL). Cool in an ice-bath. Add dropwise a solution of lithium aluminum hydride (8.0 mL, 1.0 M in THF, 8.0 mmol). After 2 hours, add water (0.3 mL), add 15% sodium hydroxide solution (0.3 mL), and add water (0.9 mL). Stir vigorously. After 15 minutes, filter the reaction mixture and dry the filtrate over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2% ethyl acetate/dichloromethane to give fur-2-ylmethyl 2-hydroxyethyl ether: Rf =0.22 (silica gel, 5% acetone/dichloromethane) Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.71 g, 5.2 mmol), fur-2-ylmethyl 2-hydroxyethyl ether (0.74 g, 5.2 mmol), and triphenylphosphine (1.67 g, 6.4 mmol) in tetrahydrofuran (20 mL). Add diethyl azodicarboxylate (1.0 mL, 6.35 mmol). After 21 hours, evaporate the reaction mixture in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% acetone/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(2-fur-2-ylmethoxy-ethyl)-1H-benzimidazole-2-carbonyl)piperidine: Rf =0.30 (silica gel, 5% acetone/dichloromethane).
Reaction SMILES: ClC(Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[C:13]([O:16][CH2:17][CH2:18][N:19]([CH2:21]C1C=CC=CC=1)C)(=[O:15])[CH3:14].[CH2:28]([Cl:30])Cl>>[C:13]([O:16][CH2:17][CH2:18][N:19]([C:28]([Cl:30])=[O:4])[CH3:21])(=[O:15])[CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: ClCCl
Reactant: CC(=O)OCCN(C)Cc1ccccc1
Product: CC(=O)OCCN(C)C(=O)Cl
Temperature: 25 °C
Yield: 92 %

Procedure:
To a 1000 mL dry round bottom flask were added triphosgene (24.2 g, 81.5 mmol) and anhydrous CH2Cl2 (500 mL). The mixture was stirred in a dry ice-acetone bath, then a solution of 2-(benzyl(methyl)amino)ethyl acetate (50.7 g, 244.6 mmol) in 150 mL of anhydrous CH2Cl2 was added slowly. After the addition, the resulting mixture was cooled in an ice-water bath, then warmed slowly to room temperature, followed being stirred at room temperature overnight. After removal of the volatile materials, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 2-(chlorocarbonyl(methyl)amino)ethyl acetate (40.2 g) as a yellow oil. Yield: 92%. 1H NMR (CDCl3, 300 MHz, mixture of two isomers): isomer 1: δ=4.27 (t, J=5.7 Hz, 2H), 3.76 (t, J=5.7 Hz, 2H), 3.10 (s, 3H), 2.09 (s, 3H); isomer 2: δ=4.26 (t, J=5.1 Hz, 2H), 3.66 (t, J=5.1 Hz, 2H), 3.20 (s, 3H), 2.07 (s, 3H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): δ=170.5, 149.9, 149.0, 61.2, 61.1, 51.4, 50.0, 39.4, 37.4, 20.7.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=1)=[O:7].[CH2:28]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([C:32]1[CH:33]=[CH:34][C:35]([NH:36][CH2:2][C:3]2[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=2)[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:37][CH:38]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)Cc1ccc(N)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc(CCl)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(CNc3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 100 °C
Yield: 42.2 %

Procedure:
A mixture of ethyl 4-[3-[3-(chloromethyl)benzoyl]indol-1-yl]butyrate (42.1 mg), 4-isobutylaniline (18.0 mg) and potassium carbonate (30.3 mg) in N,N-dimethylformamide (5 ml) was heated at 50° C. for 20 hours and at 100° C. for 2.5 hours. The mixture was worked up in an usual manner and purified by this layer silica gel chromatography eluting with a mixture of chloroform, hexane and ethyl acetate (6:2:1) to give ethyl 4-[3-[3-[(4-isobutylphenyl)aminomethyl]benzoyl]indol-1-yl]butyrate (23 mg) as an oil.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([NH:7][S:8]([C:11]1[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1)(=[O:10])=[O:9])=[O:6])[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl>[CH3:3][CH:2]([NH:4][C:5]([NH:7][S:8]([C:11]1[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[N:13][C:14]([S:17]([CH3:18])=[O:32])=[N:15][CH:16]=1)(=[O:10])=[O:9])=[O:6])[CH3:1]
Reactant: CSc1ncc(S(=O)(=O)NC(=O)NC(C)C)c(Nc2cccc(C)c2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cccc(Nc2nc(S(C)=O)ncc2S(=O)(=O)NC(=O)NC(C)C)c1
Yield: 80.8 %

Procedure:
N-[[(1-Methylethyl)amino]carbonyl]-4-[(3-methylphenyl)amino]-2-(methylthio)-5-pyrimidinesulfonamide (4.46 g, 11.29 mmol) was suspended in methylene chloride (250 mL) and m-chloroperoxybenzoic acid (2.44 g, 11.29 mml) was added as a solid. The mixture was then stirred until it became homogeneous. The methylene chloride was removed under reduced pressure and the residue was triturated with hot tert-butyl methyl ether (100 mL). The beige solid was filtered, washed with tert-butyl methyl ether and dried in a vacuum oven at 65° C. for three hours to yield 3.75 g (9.12 mmol, 81%) of pure product as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16](F)=[CH:15][C:14]=1[CH3:21]>>[ClH:12].[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)=[CH:15][C:14]=1[CH3:21]
Reactant: Cc1cc(F)cc(C)c1Cl
Reactant: CN1Cc2occc2C(O)C1
Product: Cc1cc(OC2CN(C)Cc3occc32)cc(C)c1Cl
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-chloro-1-fluoro-3,5-dimethylbenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][N:14]2[C:13](=[O:16])[CH:12]=[C:11]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)[CH2:29][CH2:28]1
Reactant: ClCC1CC1
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1
Product: COc1ccc(-c2cc(=O)n(CC3CC3)nc2-c2ccc(OC)c(F)c2)cc1
Yield: 93 %

Procedure:
Using 6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained in a yield of 93.0%.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][N:3]=1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: Cc1ncc(CO)cn1
Reactant: O=S(Cl)Cl
Product: Cc1ncc(CCl)cn1

Procedure:
A solution of (2-methylpyrimidin-5-yl)methanol (95 mg, 0.77 mmol) in thionyl chloride (1 mL) was stirred at room temperature for 1 h. The mixture was concentrated to dryness and used without purification. LCMS MH+ 143.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][C:25]([NH:24][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])([CH3:29])[CH3:28]
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC(C)(C)CO)nc1
Yield: 84 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (81.6 mg, 0.26 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (84 mg, 84%), which was obtained as a white solid. MS: m/e=383.2 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=1.[ClH:15].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][NH2:28].C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][NH:28][C:12]([C:9]1[CH:8]=[C:7]([CH2:6][Cl:15])[O:11][N:10]=1)=[O:14]
Reactant: O=C(O)c1cc(CO)on1
Reactant: Cl
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(CCl)on1
Temperature: 80 °C
Reaction time: 72 h
Yield: 16.3 %

Procedure:
Thionyl chloride (0.5 mL; 7.26 mmol) was added to a mixture of 5-(hydroxymethyl)isoxazole-3-carboxylic acid (0.207 g; 7.26 mmol) and stirred at 80° C. for 72 h. The solution was concentrated under reduced pressure and the crude material was dissolved in dichloromethane (5 mL) and added to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.370 g; 1.60 mmol) and triethylamine (0.524 mL; 3.62 mmol) in dichloromethane (5 mL). The resulting solution was stirred at room temperature for 20 min, concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to afford N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(chloromethyl)isoxazole-3-carboxamide 0.088 g (22%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].CO[C:11](=[O:26])[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:15](Cl)=[N:14][CH:13]=1.[NH2:27][CH2:28][C@@:29]([CH3:34])([CH:31]1[CH2:33][CH2:32]1)[OH:30]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[C:15]([CH2:2][CH2:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[N:14][CH:13]=[C:12]([CH:17]=2)[C:11]([NH:27][CH2:28][C@@:29]([CH:31]2[CH2:33][CH2:32]2)([OH:30])[CH3:34])=[O:26])=[CH:23][CH:22]=1
Reactant: C#Cc1ccccn1
Reactant: C[C@](O)(CN)C1CC1
Reactant: COC(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Product: C[C@](O)(CNC(=O)c1cnc(CCc2ccccn2)c(-c2ccc(Cl)cc2)c1)C1CC1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 140, using 2-ethynyl-pyridine (CAN 1945-84-2), 6-chloro-5-(4-chloro-phenyl)-nicotinic acid methyl ester, and (R)-α-(aminomethyl)-α-methyl-cyclopropanemethanol as starting materials, LC at 215 nm; Rt 3.16: 88%, m/z (ES+): 436.4 (M+H).
Reaction SMILES: IC1C=CC([C@H]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]3[CH2:18][CH2:19][CH2:20][N:10]3C2)=CC=1.[Br:21][C:22]1[CH:32]=[CH:31][C:25]([CH:26]([OH:30])[C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1.C1(C2CCCN2)C=CC=CC=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>>[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH:26]([OH:30])[C:27]([O:29][N:10]2[CH2:20][CH2:19][CH2:18][CH:11]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:28])=[CH:31][CH:32]=1
Reactant: Ic1ccc([C@@H]2CN3CCC[C@@H]3c3ccccc32)cc1
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc(C2CCCN2)cc1
Product: O=C(ON1CCCC1c1ccccc1)C(O)c1ccc(Br)cc1

Procedure:
Trans-1,2,3,5,6,10b-hexahydro-6-(4'-iodophenyl)pyrrolo[2,1-a]isoquinoline (trans-6), was synthesized by a four step reaction sequence outlined in FIG. 1A. 4-Bromomandelic acid (1) was coupled with 2-phenylpyrrolidine (2) in the presence of BOP reagent to yield 2-phenylpyrrolidino 4-bromophenyl-α-hydroxyacetate (3). Upon treatment with PPA, the amide 3 was cyclized to the lactam (4) which was reduced with aluminum hydride to provide a pair of diastereomers (5) with a trans-to-cis ratio of 2. The desired trans-6-(4'-bromophenol)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]-isoquinoline (trans 5) was separated by flash chromatography. Trans-5 was treated with butyllithium followed by iodination to afford trans-1,2,3,5,6,10b-hexahydro-6-(4'-iodophenyl) pyrrolo [2,1-a]isoquinoline (trans-6). Enantiomeric enriched (+)-(6S, 10bR)-1,2,3,5,6,10b-hexahydro-6-(4'-iodophenyl)pyrrolo[2,1-a]isoquinoline was obtained by the same reaction sequence starting with (+)-2(R)-phenylpyrrolidine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].O.[CH3:13]O>S(=O)(=O)(O)O>[CH3:13][C:4]1[C:3]([F:11])=[C:2]([Br:1])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(=O)O)ccc(Br)c1F
Temperature: 25 °C

Procedure:
4-Bromo-3-fluorobenzoic acid (WAKO, 1.0 g) was dissolved in methanol (10 mL), followed by addition of concentrated sulfuric acid (10 drops). The mixture was refluxed for three hours. After cooling to room temperature, water was added and the extraction was carried out with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the target compound (618 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@H:13]([OH:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>O1CCCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][CH2:22][CH:21]=[CH2:20])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C=CCBr
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (5.00 g) in tetrahydrofuran (20 ml) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.16 g). After 30 minutes, allyl bromide (3.35 ml) was added and the mixture refluxed for 16 hours. The reaction was quenched by careful addition of saturated NH4Cl solution at 0° C. and diluted with diethyl ether. The organics were dried (brine, MgSO4) and concentrated under reduced pressure to afford the title compound as a crude oil.