Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[N:7]([C@H:8]2[C@@H:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:16]3[CH:15]=[C:14]([O:26][CH2:27][CH2:28][NH:29][S:30]([C:33]4[N:34]=[CH:35][N:36]([CH3:38])[CH:37]=4)(=[O:32])=[O:31])[CH:13]=[CH:12][C:11]=3[CH2:10][CH2:9]2)[C:6](=O)[CH:5]2[CH:3]1[CH2:4]2.CO>O1CCCC1.ClCCl>[CH:5]12[CH2:4][CH:3]1[CH2:2][N:7]([C@H:8]1[C@@H:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:16]3[CH:15]=[C:14]([O:26][CH2:27][CH2:28][NH:29][S:30]([C:33]4[N:34]=[CH:35][N:36]([CH3:38])[CH:37]=4)(=[O:32])=[O:31])[CH:13]=[CH:12][C:11]=3[CH2:10][CH2:9]1)[CH2:6]2
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)[C@H](Cc2ccccc2F)[C@H](N2C(=O)C4CC4C2=O)CC3)c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)[C@H](Cc2ccccc2F)[C@H](N2CC4CC4C2)CC3)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
cis-N-(2-{[7-(2,4-Dioxo-3-azabicyclo[3.1.0]hex-3-yl)-8-(2-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide (38 mg, 0.069 mmol) was dissolved in tetrahydrofuran (2 mL) and borane tetrahydrofuran complex was added (1 N, 0.4 mL, 0.4 mmol). The reaction mixture was heated to 50° C. for 3.5 h. After cooling to room temperature methanol (0.2 mL) was added dropwise and stirring was continued for 30 min. The reaction mixture was diluted with dichloromethane, washed with saturated sodium chloride solution and dried (magnesium sulfate). The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (silica, dichloromethane/methanol). Yield: 4 mg (7.6 μmol, 11%, colorless oil).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(O)(=O)/C=C/C1C=CC(O)C=C1.C(N(CC)CC)C.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>CN(C=O)C.ClCCl>[C:10]([NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)(=[O:12])/[CH:9]=[CH:8]/[CH:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH2:6]1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: O=C(O)/C=C/C1C=CC(O)C=C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/C1C=CC(O)=CC1)NCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of 3-(4-hydroxyphenyl)propionic acid or p-dihydrocoumaric acid (1 g; 6.02 mmol) and of triethylamine (1.5 eq; 9.03 mmol) in DMF (10 mL) is cooled to 4° C. using an ice bath. An amine, tyramine (1 eq; 6.02 mmol) is added to the medium, followed by addition of a solution of BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1 eq; 6.02 mmol) in dichloromethane (10 mL); the mixture is stirred for about thirty minutes in the ice bath and then for 20 hours at room temperature. Stirring is then stopped and the dichloromethane is evaporated off under vacuum. 100 mL of water are added to the remaining solution and the mixture obtained is extracted with ethyl acetate (3×75 mL). The organic phase is successively washed with 100 mL of 1N HCl solution, 100 mL of water and 100 mL of 1M sodium bicarbonate (NaHCO3) solution. It is then dried over sodium sulfate and evaporated to dryness. The product is obtained in the form of a white precipitate after purification by chromatography on a column of silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].[CH:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:31]3[CH:32]=[CH:33][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:29][CH:30]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
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: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(-c3ccc(C(C)C)cc3)c1)C(C)(C)C2
Yield: 53.5 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (680 mg, 1.67 mmol), 4-isopropylphenylboronic acid (320 mg, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (193 mg, 0.17 mmol) in dioxane (5.0 mL) was added 2 M sodium carbonate solution in water (1.7 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 110° C. The mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 6-chloro-2-(4′-isopropyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (400 mg, 53.4%) as a white solid: LC/MS m/e calcd for C28H30ClNO2 (M+H)+: 449.01, observed: 448.1.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=[C:13]([C:29]([F:32])([F:31])[F:30])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[N:41]=[C:42]=[O:43].C(N(CC)CC)C.O>ClCCl>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[NH:41][C:42]([NH:10][C:8]1[N:7]([C:11]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=[C:13]([C:29]([F:30])([F:32])[F:31])[N:12]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1)=[O:43]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CC(C)(C)c1cc(N)n(-c2nc(C(F)(F)F)nc(-c3ccccc3)c2-c2ccccc2)n1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)Nc2c(Cl)cccc2Cl)n(-c2nc(C(F)(F)F)nc(-c3ccccc3)c2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 3-t-butyl-1-[5,6-diphenyl-2-(trifluoromethyl)pyrimidin-4-yl]-1H-pyrazol-5-amine (0.23 mmol) in dichloromethane (3 ml) was treated with 2,6-dichlorophenyl isocyanate (0.056 g, 0.3 mmol) in the presence of triethylamine (0.05 ml), and the reaction was mixture was stirred at room temperature, overnight. Subsequently water (15 ml) was added to above and it was extracted with ethyl acetate (25 ml). The organic layer was evaporated and the crude material purified by column chromatography; elution with 1.5% of ethyl acetate in hexane yielded the title compound. 1H-NMR (CDCl3) δ: 0.86 (s, 9H), 6.58 (s, 1H), 7.02-7.05 (m, 3H), 7.14 (d, 2H), 7.24-7.33 (m, 8H), 8.43-8.44 (br, 1H, D2O exchangeable), 10.52 (br, 1H, D2O exchangeable). MS m/z: 625 (M+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([OH:18])=[CH:5][C:6]([O:14][CH:15]([CH3:17])[CH3:16])=[C:7]2[OH:13]>C(OCC)C.O.C(O)(C)C>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([O:14][CH:15]([CH3:16])[CH3:17])[C:7]2=[O:13]
Reactant: CC(C)Oc1cc(O)c2c(F)cc(F)cc2c1O
Solvent: CCOCC
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC1=CC(=O)c2c(F)cc(F)cc2C1=O
Reaction time: 0.75 h
Yield: 80.6 %

Procedure:
A solution of 0.55 g (2.1 mM) of 5,7-difluoro-1,4-dihydroxy-2-isopropoxy-naphthalene in 20 mL of diethyl ether was added over 0.05 hours to a stirred, room temperature solution of4.05 g (25 mM) of ferric chloride in 46 mL of water and 12 mL of isopropanol. The mixture was stirred for 0.75 hours and then extracted with ethyl acetate. The organic extracts were dried with sodium sulfate, filtered and concentrated to give 0.44 g of tan solid which was recrystalized from 3 mL of warm acetic acid and a few drops of water. After cooling to room temperature, the solid was filtered off, washed withacetonitrile and then water before vacuum drying at room temperature to give 0.057 g of yellow solid. mp 172.0°-173.2°; 1H NMR(CDCl): δ=7.68 (dd, 1H), 7.15 (m, 1H), 6.09 (s, 1H), 4.55 (m, 1H), 1.45(d, 6H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH3:3].Cl[C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:10][C:9]1[C:4]([CH:2]([CH3:1])[CH3:3])=[CH:5][C:6]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:7][C:8]=1[CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
Propofol 5 (1.78 g, 10.0 mmol) and methyl 4-chloro-4-oxobutyrate (4.5 g, 25 mmol) were dissolved in methylene chloride (350 mL), the reaction mixture was cooled to −78° C. and titanium (IV) chloride (5.7 g, 30 mmol) was added drop-wise. The reaction mixture was stirred for 2 h at −78° C., allowed to warm up to room temperature and stirred overnight. The reaction mixture was then poured into water (300 mL), the organic phase was washed sequentially with saturated sodium bicarbonate solution, water and brine, and the solution dried over anhydrous magnesium sulfate. The product was purified by column chromatography on silica gel using hexane and hexane-ethyl acetate (4:1) step-gradient as an eluent to produce pure 6 (1.14 g, 39%) as a slightly yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.75 (s, 2H), 5.84 (s, 1H), 3.72 (s, 3H), 3.32 (t, J=6.8 Hz, 2H), 3.20 (septet, J=6.9 Hz, 2H), 2.76 (t, J=6.8 Hz, 2H), 1.28 (d, J=6.9 Hz, 12H). 13C NMR (100.61 MHz, CDCl3): δ 196.81, 173.35, 154.40, 133.27, 129.05, 123.97, 51.41, 32.59, 27.82, 26.79, 22.18. HRMS (m/z): [M+H]+ calcd. for C17H24O5 293.1747. found 293.1759.
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[CH3:32][C:2]([O:1][C:34](=[O:36])[CH3:35])([CH3:33])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:28])[F:30])[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CC(=O)OC(C)(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 19, making variations only as required to use 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (3-hydroxy-3-methylbutyl)amide in place of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl)amide to react with acetic anhydride, the title compound was obtained as a white powder (80% yield). 1H NMR (500 MHz, CDCl3) δ 8.05, 8.01, 7.75, 7.65, 7.57, 7.37, 6.99, 4.06, 3.88, 3.81-3.67, 3.58, 3.36, 2.06, 2.01, 1.52. MS (ES+) m/z 508 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:23][CH2:24][CH:25]=[C:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]=2[CH2:30][O:29][C:28]2[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][CH2:23][CH2:24][CH:25]=[C:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[N:36][C:31]=3[CH2:30][O:29][C:28]3[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]2=3)=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: NCCNc1ccc(Cl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCNCCNc1ccc(Cl)cc1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of N-(4-chloro-phenyl)-ethane-1,2-diamine (0.68 g, 3.96 mmol) in isopropanol (8.0 mL) was added 2,6-lutidine (0.31 mL, 2.64 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and then treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.15 g, 0.4 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/20% methanol) to yield the title compound. 1H-NMR (DMSO) δ: 1.40 (6H, s), 2.20–2.40 (2H, m), 2.70–2.90(3H, m), 3.10–3.30 (3H,m), 5.20 (2H, br, s), 5.80 (1H, m), 6.15 (1H, t), 6.60–6.70 (1H, m), 7.10–7.30 (4H, m) 7.50 (2H, m), 7.80 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 464 (M+1), UV retention time: 1.40 min.
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:18][CH:17]([N:19]2[CH2:24][CH2:23][N:22]3[C:25](=[O:29])[CH2:26][CH2:27]C[CH:21]3[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8].N1CC(N2CCN(C(=O)CC)CC2)C1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[ClH:1].[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:18][CH:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:29])[CH2:26][CH3:27])[CH2:23][CH2:24]2)[CH2:16]1)[CH3:10])=[O:8]
Reactant: CN(C[C@@H](CCN1CC(N2CCN3C(=O)CCCC3C2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCC(=O)N1CCN(C2CNC2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCC(=O)N1CCN(C2CN(CC[C@H](CN(C)C(=O)c3cc(Br)cc(C(F)(F)F)c3)c3ccc(F)cc3)C2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.7 %

Procedure:
3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 165 mg, 0.4 mmol) and 1-azetidin-3-yl-4-propionylpiperazine (see Method 7; 80 mg, 0.41 mmol) were dissolved in methylene chloride (10 mL) together with a small amount of dry methanol (0.2 mL). Sodium triacetoxyborohydride (157 mg, 0.74 mmol) was added together with DIPEA (143 mg, 1.11 mmol). The reaction mixture was stirred at RT for 2.5 h and then diluted with methylene chloride. The solution was washed twice with aqueous NaHCO3 and then with brine. The organic phase was separated by means of a phase separator column and then the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol-methylene chloride 5:95). The oily product was dissolved in 2M hydrochloric acid and the solvent was then removed by freeze-drying. There was obtained 120 mg (48%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3): 1.2-3.8 (cm, 28H), 6.8-7.8 (cm, 7H); LCMS: m/z 628 (M+1)+.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])=O.[NH4+:21].[ClH:22]>O>[ClH:22].[CH3:16][CH:15]([NH2:21])[C:12]1[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)c1ccc(CCc2ccccc2)cc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C[O-]
Solvent: O
Product: CC(N)c1ccc(CCc2ccccc2)cc1
Yield: 73 %

Procedure:
A mixture of 87.5 g (0.39 mole) of 4'-phenethylacetophenone, M.P. 67°-70° C., prepared according to R. E. Lutz et al., J. Org. Chem. 12, 617 (1947), and 98.5 g (1.56 mole) of ammonium formate is slowly heated to 150° C. with stirring. After the initial foaming has subsided the temperature of the heating bath is raised to 185°-190° C. for a period of 4 hours. Upon cooling, the mixture is treated with several portions of water. To the residue is added 75 ml of concentrated HCl. The mixture is refluxed for 2 hours and is allowed to cool. The resulting solid is collected, washed with several portions of benzene and is recrystallized from isopropanol containing about 5% of water to yield 74.0 g (73% yield) of the desired product, M.P. 212°-214° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].O.[BH4-].[Na+].Cl>C(O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([CH2:14][OH:15])=[CH:16][CH:17]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=Cc1ccc(-c2cc(F)c(F)c(F)c2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1ccc(-c2cc(F)c(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
Then, 14.77 g of 4-(3,4,5-trifluorophenyl)benzaldehyde and 15 mL of water were dissolved in 70 mL of ethanol, the resultant solution was cooled with ice, and 0.75 g of sodium tetrahydroborate was slowly added. After stirring at room temperature for 2 hours, 10% hydrochloric acid was added until the system became acidic, followed by stirring for 1 hour. Then, toluene was added to the mixture to separate an organic layer, and an aqueous layer was subjected to extraction with toluene. The toluene extract was combined with the organic layer and washed with saturated brine. The organic layer mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane to yield 12.64 g of 4-(3,4,5-trifluorophenyl)benzyl alcohol.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:29])[CH3:28]>O>[CH2:27]([O:29][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2)[CH3:28]
Reactant: CCO
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Temperature: 25 °C

Procedure:
A mixture of 0.29 g of 2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine, 0.15 g of potassium carbonate and 6 ml of ethanol was refluxed with heating for 8 hours. The reaction mixture was cooled down to room temperature. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 2-(3-ethoxypyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as the present compound 11).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:29]([O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[NH2:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.C(Cl)Cl.O1CCCC1>[CH2:29]([O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:42])[CH3:43])[NH:39][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
To a solution of N-tert-butoxycarbonylalanine (0.06 mole) and N-methylmorpholine (0.06 mole) in dry tetrahydrofuran (100 ml) at -20° to -25° is added isobutyl chloroformate (0.06 mole) with stirring. After 10-15 minutes, a solution of leucine benzyl ester (0.06 mole) and N-methylmorpholine (6.8 ml) in methylene chloride-tetrahydrofuran (1:1, 100 ml) is added over a period of 1/2 hour. The mixture is allowed to warm to room temperature and stirred at room temperature overnight. The resulting mixture is concentrated in vacuo and the residue extracted between chloroform and dilute hydrochloric acid. The chloroform layer is separated, washed with water, dried over sodium sulfate and concentrated to give the crude N-tert-butoxycarbonylalanylleucine benzyl ester to be used as in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[OH-:11].[Na+].O=O>O>[OH:11][C:6]1([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3](=[O:10])[C:2]([CH3:1])=[CH:7]1.[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10]
Reactant: [OH-]
Agent: Cc1cc(C)c(O)c(C)c1
Agent: O=O
Agent: [Na+]
Solvent: O
Product: CC1=CC(C)(O)C=C(C)C1=O
Reaction time: 2 h

Procedure:
45 Parts of 2,4,6-trimethylphenol, 10 parts of sodium hydroxide, and 150 parts of water were fed to a stainless steel autoclave equipped with a gas-introducing pipe, temperature recorder and stirrer, and 100 Kg/cm2G oxygen pressure was applied. The reaction was conducted at 30°C. for 120 minutes, during which the pressure was reduced to 83 Kg/cm2G. The reaction product was recovered and extracted 2 times with 150 g of benzene with shaking. Analyses of benzene parts and water parts yielded 31.130 parts of 4-hydroxy-2,4,6-trimethyl-2,5-cyclohexadiene-1-one and 3.866 parts of unreacted 2,4,6-trimethylphenol from the benzene parts. 0.705 Parts of 4-hydroxy-2,4,6-trimethyl-2,5-cyclohexadiene-1-one and 0.090 parts of unreacted 2,4,6-trimethylphenol were also yielded from the water parts. Analyses of the results proved 91.2 % of conversion and 69.4 % of selectivity. Expelling the benzene out of said benzene solution and concentrating the benzene, 34 parts of oily product was obtained. The oily product was analyzed to be composed of 92.2 % of 4-hydroxy-2,4,6-trimethyl-2,5-cyclohexadiene-1-one and 9.6 % of 2,4,6-trimethylphenol.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(Cl)cc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.13 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-chlorobenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23](C2N=NN(CCOC3CCCCO3)C=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].[N:40]([C:43]1C=CC(C)=[C:47]([C:49](C2C=CC(NC3C=CC(F)=CC=3)=CC=2Cl)=[O:50])[CH:48]=1)=[N+:41]=[N-:42].C(O)CC#C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:40]2[CH:43]=[C:48]([CH2:47][CH2:49][OH:50])[N:42]=[N:41]2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Agent: C#CCCO
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 433 (1.10 mmol) and 3-butyne-1-ol (1.10 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 50:50 to 100:0 as the eluent to afford the title compound as foam.