Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]3[N:27]([C:28]=2[CH:29]=O)[CH:26]=[CH:25][S:24]3)=[CH:17][CH:16]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.CCCCCC>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]3[N:27]([C:28]=2/[CH:29]=[CH:2]/[C:1]([C:4]2[CH:13]=[CH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=2)=[O:3])[CH:26]=[CH:25][S:24]3)=[CH:19][CH:20]=1
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: O=Cc1c(-c2ccc(F)cc2)nc2sccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(/C=C/c1c(-c2ccc(F)cc2)nc2sccn12)c1ccc2ccccc2c1
Temperature: 27 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
To a stirred solution of 2-acetyl napthalene (170 mg, 1.0 mmol) and a 6-(4-fluorophenyl) imidazo[2,1-b]thiazol-5-carbaldehyde (246 mg, 1.0 mmol) in ethanol (20 ml) 10% aqueous solution of NaOH was added (5 ml). The reaction mixture was stirred at room temperature 27° C. for 4 h and the reaction was monitored by TLC using ethyl acetate-hexane (3:7) as a solvent system. The solvent was evaporated under vacuum then the residue was dissolved in ethylacetate/water. The organic layer was washed with brine and evaporated. This was further purified by column chromatography using ethyl acetate:hexane (2:8) as a solvent system to obtain the pure product (12e) as yellow solid (298 mg, 75% yield). Mp: 216-218° C.
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH:5]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:3].C1CCN2C(=NCCC2)CC1.[CH2:41]([O:48][C:49]1[C:56]([F:57])=[CH:55][C:52]([CH:53]=O)=[CH:51][C:50]=1[F:58])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[CH2:41]([O:48][C:49]1[C:56]([F:57])=[CH:55][C:52](/[CH:53]=[C:5](\[O:4][CH2:2][CH3:3])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:51][C:50]=1[F:58])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C(=C/c1cc(F)c(OCc2ccccc2)c(F)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (1,2-diethoxy-2-oxoethyl)triphenylphosphonium chloride (679) (1.61 g, 3.76 mmol) in tetrahydrofuran (56 mL) was added DBU (0.67 ml, 4.51 mmol) and the reaction was stirred for 10 minutes at room temperature. 4-(benzyloxy)-3,5-difluorobenzaldehyde (1.40 g, 5.64 mmol) was added in one portion and the reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo, diethyl ether was added and the solids filtered. The filtrate was concentrated in vacuo and the residue oil was purified by flash column chromatography (0-30% EtOAc in hexanes) to provide (Z)-ethyl 3-(4-(benzyloxy)-3,5-difluorophenyl)-2-ethoxyacrylate (680).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)CCC>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([C:11]2[C:12]3[C:13]([C:34]4[S:35][CH:36]=[CH:37][CH:38]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[O:28])=[CH:26][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CC(C(=O)[O-])C1CCn2c1c(C(=O)c1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: O=C(O)CC1CCn2c1c(C(=O)c1ccc(Cl)cc1)c1c(-c3cccs3)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate and tributyl(thien-2-yl)stannane, the title compound was synthesized following the procedures described in Example 42 and Step 10 of Example 7.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 2 h

Procedure:
15 g (43.4 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate and 1.85 g (46.3 mmol) of sodium hydroxide are treated with 60 ml of ethanol and 10 ml of water, the mixture is then heated to boiling under reflux for 45 minutes, the ethanol is subsequently distilled off in vacuo, the mixture remaining is treated with 46.5 ml of 1N hydrochloric acid and left to stand in an ice-bath for 2 hours. The precipitated material is filtered off under suction, washed with water and dried up to constant weight. There is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid having a decomposition point of 265°.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC([O-])=O.[OH:13][C:14]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:15]=1[C:16](=[O:34])[N:17](COC(=O)C(C)(C)C)[CH:18]=[N:19]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:55]1[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]1.N>C(Cl)Cl>[CH3:25][O:24][C:23]1[C:14]([O:13][CH:55]2[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]2)=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][NH:17][C:16]2=[O:34]
Reactant: COc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1O
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)[O-]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2nc[nH]c(=O)c2c1OC1CCN(C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of di-(tert-butyl azodicarboxylate (1.75 g) in methylene chloride (3 ml) was added to a stirred mixture of 5-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.55 g), triphenylphosphine (1.99 g), 4-hydroxy-1-methylpiperidine (0.75 g) and methylene chloride (12 ml) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9:10:1 mixture of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was stirred in a saturated methanolic ammonia solution for 48 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The resultant solid was washed with diethyl ether and dried under vacuum to give 6-methoxy-5-(N-methylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one (0.92 g); NMR Spectrum: (DMSOd6) 1.7-1.9 (m, 4H), 1.95 (t, 2H), 2.15 (s, 3H), 2.7 (m, 2H), 3.85 (s, 3H), 4.08 (m, 1H), 7.4 (d, 1H), 7.6 (d, 1H), 7.85 (s, 1H), 11.8 (br s, 1H); Mass Spectrum: M+H+ 290.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH:5]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 64 %

Procedure:
As described for Example 12, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (97 mg, 64%) which was obtained as an off-white solid. MS: m/e=347.3 [M+H]+.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]1[CH:23]=[CH:22][C:14]2[S:15][C:16]([C:18](OC)=[O:19])=[CH:17][C:13]=2[CH:12]=1.C(OCC)(=O)C>C1COCC1.CCCCCC>[F:10][C:11]1[CH:23]=[CH:22][C:14]2[S:15][C:16]([CH2:18][OH:19])=[CH:17][C:13]=2[CH:12]=1
Reactant: COC(=O)c1cc2cc(F)ccc2s1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCc1cc2cc(F)ccc2s1
Temperature: -10 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
DIBAL-H (59.4 mL, 59.41 mmol) was added to a solution of methyl 5-fluorobenzo[b]thiophene-2-carboxylate (I-50a: 2.5 g, 11.882 mmol) in THF (75 mL) at −70° C. and the resulting reaction mass was stirred at −10° C. for 2 hours. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was quenched with methanol at −70° C. and concentrated under reduced pressure. The crude residue obtained was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (15% ethyl acetate in hexane) afforded 1.8 g of the product (83.33% yield).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[NH:19]1[CH:23]=[C:22]([C:24](O)=[O:25])[N:21]=[CH:20]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:24]([C:22]2[N:21]=[CH:20][NH:19][CH:23]=2)=[O:25])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(O)c1c[nH]cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2c[nH]cn2)CC1
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (400 mg), 1H-imidazole-4-carboxylic acid (191 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (326 mg), 1-hydroxy-1H-benzotriazole monohydrate (260 mg), triethylamine (0.697 mL), and N,N-dimethylformamide (5 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to purification by high performance liquid chromatography [Column: Gilson, Ltd. High throughput purification system, YMC Combiprep ODS-A, S-5 μm, 50 mm×20 mm; Gradient cycle: H2O (contains 0.1% CF3COOH)-acetonitrile (contains 0.1% CF3COOH), 90:10 (0 min)-90:10 (1 min)-10:90 (4.2 min)-10:90 (5.4 min)-90:10 (5.5 min)-90:10 (5.6 min); Flow rate: 25 mL/min; detection wavelength: UV 220 nm] to give the title compound (322 mg, 75%.) as a white solid.
Reaction SMILES: [CH:1]1([C:4]([Cl:6])=O)[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C@H:13]([NH:20][CH2:21][CH:22]1[CH2:24][CH2:23]1)[C@@H:14]2[CH3:19].C(N(CC)CC)C>CCOCC>[ClH:6].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C@H:13]([N:20]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH2:21][CH:22]1[CH2:24][CH2:23]1)[C@@H:14]2[CH3:19]
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc2c1CC[C@H](NCC1CC1)[C@@H]2C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cccc2c1CC[C@H](N(CC1CC1)CC1CC1)[C@@H]2C
Product: Cl

Procedure:
Cyclopropanecarboxylic acid chloride (0.49 g) in dry ether (10 ml) is added to a solution of cis-5-methoxy-1-methyl-2-(N-cyclopropylmethylamino)tetralin (400 mg) and triethylamine (0.49 g) in dry ether (80 ml). After 30 minutes at room temperature the reaction mixture is filtered and the ether is evaporated. The resulting crude amide is passed through an alumina column eluted with ether. The purified amide dissolved in dry THF (20 ml) is added to a suspension of lithium aluminum hydride (1.0 g) in dry THF (30 ml) under N2. After stirring under reflux for 3 hours, the reaction mixture is hydrolyzed, the precipitate is filtered off and the solvent is evaporated. The oily residue is chromatographed on an alumina column with ether-light petroleum (1:1). The hydrochloride is prepared and recrystallized from ethanol-ether to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].C([Li])CCC.CN([CH:16]=[O:17])C.[Cl-].[NH4+]>C1COCC1.C(O)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH:16]=[O:17])[S:5][C:6]=1[CH3:7]
Reactant: Cc1ncsc1C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1nc(C=O)sc1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, to a solution of 4,5-dimethylthiazole (0.62 g, 5.5 mmol) in anhydrous THF (40 mL) at −78° C., n-butyllithium (2.3 M in hexanes, 3.6 mL, 8.28 mmol) was slowly added and the reaction mixture was stirred at −78° C. for 1 h. Then a solution of anhydrous DMF (1.1 mL, 14.2 mmol) in anhydrous THF (10 mL) was added. The resulting mixture was stirred for 2.5 hours, allowing the temperature to raise to −60° C. Acetic acid (0.5 mL) and an aqueous solution of ammonium chloride were added, and warmed to room temperature. The resulting solution was extracted with diethyl ether and ethyl acetate. The combined organic phase were dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (silica gel, PE/EA, 1/0 to 7/3) to afford 4,5-dimethyl-1,3-thiazole-2-carbaldehyde, as a yellow oil which turns into a white solid after storage at −18° C. LCMS m/z (M+H) 142.1 found, 142.1 required.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH2:10][NH:22][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: O=CCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(C(CCNC2CC2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 3,3-bis(4-fluorophenyl)propanal (1.00 g, 4.06 mmol, see Method H for preparation) in MeOH (15 ml) was added cyclopropanamine (0.285 ml, 4.06 mmol). The reaction mixture was stirred for overnight at 25° C. Sodium borohydride (0.307 g, 8.12 mmol) was carefully added to the reaction mixture over 15 min. After stirring an additional 15 min volatiles were removed by concentration under reduced pressure. The leftover residue was solubilized with 60 mL of a 1:2 mixture of 10% NaOH and ethyl acetate. The organic phase was separated and the aqueous phase was extracted further with ethyl acetate (2×40 mL). Purification by chromatography on silica (eluted with 0->10% MeOH/CH2Cl2+0->1% NH4OH) gave N-(3,3-bis(4-fluorophenyl)propyl)cyclopropanamine 181. The product was dissolved in CH2Cl2 and made into the HCl salt by precipitation with etheral HCl and then concentration of volatiles.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C:21]([OH:25])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC(O)(c2ccccc2)C1
Reaction time: 0.5 h
Yield: 29.4 %

Procedure:
To a solution of 9 ml (9 mmol) phenylmagnesium bromide (1M solution in THF) in THF (13 ml) was added a solution of 1.5 g (6.00 mmol) 3-oxo-piperidine-1-carboxylic acid benzyl ester (commercial) in THF (5 ml) at room temperature over a period of 15 minutes. The mixture was stirred for 30 minutes and then quenched under ice bath cooling with a 20% ammonium chloride solution (4 ml). The organic layer was decanted and the residue was extracted once with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 50%) to provide 0.55 g (30%) of the title compound as a white solid. MS (m/e): 312.0 (M+H+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:47])([F:46])[C:24]([F:45])([F:44])[C:25]([F:43])([F:42])[O:26][C:27]([F:41])([C:32]([F:40])([F:39])[O:33][C:34]([F:38])=[C:35]([F:37])[F:36])[C:28]([F:31])([F:30])[F:29]>C1COCC1>[F:37][C:35]([F:36])([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:34]([F:38])[O:33][C:32]([F:39])([F:40])[C:27]([F:41])([O:26][C:25]([F:42])([F:43])[C:24]([F:44])([F:45])[C:23]([F:22])([F:46])[F:47])[C:28]([F:31])([F:30])[F:29]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc(C(=O)OC)c1

Procedure:
Anhydrous THF (12 liters) and dimethyl 5-hydroxy-isophthalate (2100 g) were combined under nitrogen in an oil jacketed 22 liter RB flask equipped with a condenser, mechanical stirrer, pressure equalizing addition funnel. To this stirred solution was added anhydrous potassium carbonate (345 g), followed by 1,1,1,2,2,3,3-heptafluoro-3-(1,1,1,2,3,3-hexafluoro-3-(1,2,2-trifluorovinyloxy)propan-2-yloxy)propane (4750 g). Ca. 2 liters of additional THF was used to wash all the reagents into the reaction vessel. The resulting mixture was refluxed for 12.0 hours.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:10]1(C)C=[CH:14][CH:13]=[CH:12][CH:11]=1.C[OH:18]>>[CH3:10][C:11]1[N:9]=[C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[S:8][C:12]=1[CH2:13][CH2:14][OH:18]
Reactant: CO
Reactant: NC(=S)c1cccnc1
Reactant: Cc1ccccc1
Product: Cc1nc(-c2cccnc2)sc1CCO
Temperature: 80 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
2-(4-Methyl-2-pyridin-3-yl-thiazole-5-yl)-ethanol was prepared according to the general procedure presented hereinabove, by adding 20 grams (0.145 moles) of thionicotinamide (purchased from Acros, Belgium) to 200 ml of dry toluene, followed by addition of 26 grams (0.145 moles) of ACP over a time period of 20 minutes. The reaction mixture heated for 24 hours at 80° C. and thereafter about 180 ml of toluene were removed by evaporation. 100 ml of water and 20 ml of HCl solution (32%) were added and reflux was continued for 1 hour at 90° C. The organic phase was then removed by washing with chloroform and the aqueous phase was turned basic (pH 8-9) using a 5 N solution of NaOH. The 2-(4-methyl-2-pyridin-3-yl-thiazole-5-yl)-ethanol was extracted with three portions of 100 ml of chloroform and the combined extracts were dried over sodium sulfate. The chloroform was thereafter removed and 5 the residue was purified by liquid chromatography, using a mixture of 9:1 ethyl acetate:methanol as eluent, to give 10 grams (31% yield) of the 2-(4-methyl-2-pyridin-3-yl-thiazole-5-yl)-ethanol product as a violet-brown powder.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][C:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([O:11][CH3:12])[C:7]([NH:9][NH2:10])=O.Cl.Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26](/[CH:36]=[CH:37]/[C:38](=[NH:42])OCC)[CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1.C(OCC)(=O)C.O>C(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2([O:11][CH3:12])[CH2:5][CH2:4][CH2:3][N:9]3[N:10]=[C:38](/[CH:37]=[CH:36]/[C:26]4[CH:27]=[CH:28][C:29]([N:30]5[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]5)=[C:24]([O:23][CH3:22])[CH:25]=4)[N:42]=[C:7]23)=[CH:14][CH:15]=1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Reactant: COC(CCCCl)(C(=O)NN)c1ccc(F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3(OC)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 75 °C
Reaction time: 24 h
Yield: 30.1 %

Procedure:
A solution of 5-chloro-2-(4-fluorophenyl)-2-methoxyvaleric acid hydrazide monohydrochloride (81 mg) and TEA (0.16 ml) in ethanol (1 ml) was added to a solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (94 mg) and TEA (0.16 ml) in ethanol (1 ml), and the reaction solution was stirred at 75° C. for 24 hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system) and again purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 36 mg of 8-(4-fluorophenyl)-8-methoxy-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine as a racemate. Then, the racemate was separated by CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the title optically active compound with a retention time of 15 minutes and negative optical rotation (14.2 mg, 100% ee) and the title optically active compound with a retention time of 18 minutes and positive optical rotation (14.3 mg, >99% ee).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].O[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].S(=O)(=O)(O)[OH:24]>>[CH3:7][O:6][C:4]([CH2:3][C:1]([NH:2][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:24])=[O:5]
Reactant: CCOC(=O)CC(C)(O)c1ccccc1
Reactant: O=S(=O)(O)O
Reactant: COC(=O)CC#N
Product: CCOC(=O)CC(C)(NC(=O)CC(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Concentrated sulphuric acid (80 ml) was added at 0°-5° C. to a stirred solution of methyl cyanoacetate (28 ml) and ethyl 3-hydroxy-3-phenylbutyrate (65 g) and the mixture stirred at ambient temperature for 18 hours. The mixture was added to crushed ice (250 g) and the acidic mixture extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (4×250 ml), dried over sodium sulphate and evaporated under reduced pressure to give ethyl 3-(methoxycarbonylacetamido)-3-phenylbutyrate (43.16 g), as a clear brown oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]=2[Cl:34])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:45])[CH2:43][CH3:44].O>ClCCl>[Si:17]([O:16][CH2:15][C:10]1[C:9]([Cl:34])=[C:8]([N:4]2[CH:5]=[CH:6][CH:7]=[C:3]2[CH2:2][NH:1][C:42](=[O:45])[CH2:43][CH3:44])[CH:13]=[CH:12][C:11]=1[Cl:14])([C:30]([CH3:31])([CH3:33])[CH3:32])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2CN)c1Cl)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCc1cccn1-c1ccc(Cl)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a mixture of 2-aminomethyl-1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]pyrrole (167 mg) and triethylamine (39.8 mg) in dichloromethane (2 ml) was added propionyl chloride (33.4 mg) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature and for 3 hours at ambient temperature. The mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-(propionamidomethyl)pyrrole (185 mg) as oil.