Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1)(O)=[O:2].[CH3:39][O:40][CH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH2:50]>>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:7][CH:6]2[O:5][CH2:4][C:1](=[O:2])[NH:50][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][CH2:42][CH2:41][O:40][CH3:39])=[CH:17][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)O)cc1
Reactant: COCCCc1ccccc1N
Product: COCCCc1ccccc1NC(=O)COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Example 3a, 0.537 g of tert-butyl 3-carboxymethoxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 34b) and 0.207 g of 2-(3-methoxypropyl)phenylamine are reacted. The title compound is obtained as a yellow oil. Rf=0.19 (1:1 EtOAc-heptane); Rt=5.94.
Reaction SMILES: [CH:1]12[NH:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:7]2[CH:4]3[CH2:5][CH2:6][CH:1]2[CH:2]([NH:8][C:9]2[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]4)[CH2:3]3)=[CH:21][CH:20]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: c1cc2[nH]ncc2cc1NC1CC2CCC1N2
Product: Cc1ccc(CN2C3CCC2C(Nc2ccc4[nH]ncc4c2)C3)cc1

Procedure:
Reaction of Intermediate 24 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Yield: 61.5 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (390 mg, 0.98 mmol) and 10% palladium on activated carbon (50 mg) in methanol (200 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb pressure for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (240 mg, 61.4%) as a white solid: LC/MS m/e calcd for C22H26N2O3S [M+H]+ 399.53; observed 399.2. 1H NMR (400 MHz, CDCl3) δ ppm 11.86 (s, 1H), 7.92 (d, J=8.6 Hz, 3H), 7.55 (d, J=7.8 Hz, 1H), 7.28 (s, 3H), 6.49 (s, 1H), 4.37 (t, J=7.6 Hz, 1H), 3.97 (s, 3H), 3.07 (s, 3H), 2.13-2.29 (m, 2H), 1.79 (d, J=20.0 Hz, 2H), 1.65 (m, 2H), 1.45-1.56 (m, 2H), 1.14-1.25 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.Cl.[CH3:34][S:35](Cl)(=[O:37])=[O:36].CCN(C(C)C)C(C)C>CO>[F:1][C:2]1[C:3]([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:7][CH2:6]2)=[CH:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23]([NH:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)=[O:24]
Reactant: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)cn1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(S(C)(=O)=O)CC3)c2F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (1.3 g, 2.9 mmol, 1.0 equiv) in MeOH (10 mL) was added by syringe HCl (4.0 M in dioxane, 10 mL, 40 mmol, 13.8 equiv) After 30 minutes, the reaction mixture was concentrated in vacuo. The resulting solid was then suspended in THF (10 mL) and methanesulfonyl chloride (220 μL, 2.9 mmol, 1.0 equiv) and DIPEA (2.0 mL, 11.5 mmol, 4.0 equiv) were added by syringe. The reaction mixture was allowed to stir at room temperature for 0.5 h and then quenched by the addition of aq. satd. NaHCO3. The organic layer was separated, dried over sodium sulfate and purified by flash chromatography on silica gel (1%-10% MeOH/DCM) to provide 1-(2-fluoro-3-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)-3-(6-methylpyridin-3-yl)urea (930 mg, 76%). LCMS m/z (APCI)=422.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=2[O:5][C:4]=1/[N:17]=[CH:18]/[N:19](C)C)#[N:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[Cl:30])N>C(#N)C.C(O)(=O)C>[Cl:22][C:23]1[CH:24]=[C:25]([NH:2][C:1]2[C:3]3[C:11]4[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=4[O:5][C:4]=3[N:17]=[CH:18][N:19]=2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)N1CCc2c(oc(/N=C/N(C)C)c2C#N)C1
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)N1CCc2c(oc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Yield: 32.1 %

Procedure:
Ethyl 3-cyano-2-{[(1E)-(dimethylamino)methylidene]amino}-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate from Example 37A (1.00 g, 4.14 mmol) and 3,4-dichloroaniline (1.12 g, 6.89 mmol) were heated in a mixture of acetonitrile (20 mL) and acetic acid (2 mL) for 20 h under reflux. The mixture was then half-concentrated in vacuo and heated for further 20 h. Subsequently, it was diluted with water, basified with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated. The residue was triturated with methanol. The precipitate was collected by suction filtration to yield 542 mg (34%) of the title compound. A second batch of 50 mg (4%) was obtained from the mother liquor after purification by preparative HPLC.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:30][N:31]1[CH:35]=[C:34]([CH3:36])[C:33]([C:37](Cl)=[O:38])=[N:32]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:30][N:31]1[CH:35]=[C:34]([CH3:36])[C:33]([C:37]([NH:23][C:14]2[CH:15]=[C:16]([Sn:19]([CH3:20])([CH3:22])[CH3:21])[CH:17]=[C:18]3[C:13]=2[CH:12]=[N:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[O:38])=[N:32]1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: Cc1cn(C)nc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cn(C)nc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(Phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (250 mg) was dissolved in DCM (10 ml) and pyridine (0.051 ml) was added. 1,4-Dimethyl-1H-pyrazole-3-carbonyl chloride (100 mg) in DCM (5 ml) was added dropwise. The reaction was stirred at RT for 2 h. After this time saturated sodium bicarbonate aq (25 ml) was added and the reaction was stirred vigorously for 5 min before the DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DCM, and then applied to the top of a 20 g silica cartridge preconditioned with cyclohexane. The column was washed with 50% cyclohexane:ether (100 ml), before the compound was eluted with ether, then 5% methanol in ether. The product containing fractions were evaporated to dryness to afford the title compound, 310 mg.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36](=[O:41])[CH2:35]3)=[CH:28][CH:27]=1>>[OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11](/[CH:14]=[C:35]3\[C:36](=[O:41])[NH:37][C:38]4[C:34]\3=[CH:33][C:32]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[CH:40][CH:39]=4)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16]
Reactant: COc1ccc(-c2ccc3c(c2)CC(=O)N3)cc1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Product: COc1ccc(-c2ccc3c(c2)/C(=C/c2[nH]c4c(c2C)C(=O)N(C[C@@H](O)CN2CCOCC2)CC4)C(=O)N3)cc1
Yield: 87.2 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 5-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-2-[5-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 21 (53 mg, yield 87.2%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][CH:6]=1.[N+:8]([O-])([OH:10])=[O:9].S(=O)(=O)(O)O>>[Br:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][C:6]=1[N+:8]([O-:10])=[O:9]
Reactant: Brc1ccc(Br)s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)sc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
2,5-dibromothiophene (10.0 g, 0.0413 mol) was added in portions to nitric acid (38 mL) and concentrated sulfuric acid (75 mL) cooled at 0° C. with an ice bath. On complete addition, the reaction was removed from the cold bath and was stirred for 30 minutes before the reaction mixture was poured onto ice water (400 mL) and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), concentrated under vacuum and the residue purified by silica gel chromatography to afford the title product as solid (1.6 g, 13.7% yield).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:9]([O:15]C)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].B(Br)(Br)Br.[OH-].[Na+].O>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:9]([OH:15])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCc1cc(F)c(C(=O)OC)cc1OC
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCc1cc(F)c(C(=O)O)cc1O
Temperature: -70 °C
Yield: 97.7 %

Procedure:
Methyl 2-fluoro-5-methoxy-4-propylbenzoate (1.27 g, 5.63 mmol) was dissolved in CH2Cl2 (20 mL) and cooled to -70° C. Boron tribromide (1.64 mL, 16.9 mmol) was added and the temperature was slowly raised to 0° C. during 4.5 h. Methylene chloride (20 mL) and 2M NaOH (25 mL) were added and the mixture was stirred over-night at room temperature. Water (20 mL) was added, the phases separated and the aqueous phase was extracted with CH2Cl2 (20 mL) and acidified to pH 1 by concentrated HCl thus precipitating the acid. Ethyl acetate (50 mL) was added to the mixture and the phases separated. The aqueous phase was extracted by additional EtOAc (50 mL) and the combined organic phases were washed with brine (20 mL), dried (MgSO4) and evaporated yielding 2-fluoro-5-hydroxy-4-propylbenzoic acid (1.09 g) Mp: 134.5°-135.5° C. 1H NMR (DMSO-d6): d 12.88 (br, 1 H), 9.57 (br, 1 H), 7.23 (d, J=6.5 Hz, 1 H), 6.96 (d, J=11.6 Hz), 2.48 (t, J=7.5 Hz, 2 H), 1.53 (m, J=7.5 Hz, 2 H), 0.87 (t, J=7.4 HZ, 3 H). 13C NMR (DMSO-d6): δ 164.96 (d, J=3 Hz), 154.38 (d, J=248 Hz), 150.84 (d, J=2 Hz), 135.82 (d, J=7 Hz), 117.44 (d, J=24 Hz), 116.28 (d, J=11 Hz), 116.22, 31.38, 21.79, 13.65. MS (EI, 70 eV): m/z (rel.int) 198 (M+, 38).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[CH2:31]1.C([O-])([O-])=O.[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([NH:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[CH2:31]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: NC1CCCC(O)C1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(NC3CCCC(O)C3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Yield: 48.2 %

Procedure:
A suspension of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (100 mg, 0.204 mmol, obtained from Example 7, Step B), 3-aminocyclohexanol (70.5 mg, 0.612 mmol), Cu(I)I (7.77 mg, 0.0408 mmol), K2CO3 (141 mg, 1.02 mmol) and L-proline (9.39 mg, 0.082 mmol) was stirred in DMSO (5 mL) and heated to 100° C. for 12 hours. Water (5 mL) was added and the reaction mixture was extracted with CH2Cl2. The organic layer washed with water and brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (47 mg, 48.3% yield) as a brown oil. LRMS (APCI pos) m/e 694.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][CH2:4][CH2:3][C:2]1=[O:10].[H-].[Na+].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN(C=O)C>[C:18]([O:17][C:15]([CH2:14][N:1]1[C:2](=[O:10])[CH2:3][CH2:4][N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6](=[O:9])[CH2:7][CH2:8]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1CCNC(=O)CCN1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(=O)N(CC(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.3 g of perhydro-1,5-diazocin-2,6-dione are suspended in 30 ml of absolute DMF, and 732 mg of sodium hydride (80%) are then added. The mixture is stirred at RT for 15 min and then cooled to 0° C., and 3.76 ml of tert-butyl bromoacetate are then added. The mixture is stirred at 0° C. for 15 min and at RT for 30 min, and is then once again cooled to 0° C., and another 732 mg of sodium hydride (80%) are added. After 15 min, a further 3.76 ml of tert-butyl bromoacetate are added using a pipette, the ice bath is removed after 15 min and the mixture stirred at RT overnight. The mixture is then diluted with dichloromethane, water is added, and the phases are then separated and the organic phase is washed twice with water. The organic phase is dried over MgSO4 and concentrated, and the residue is dried under high vacuum and recrystallized from n-hexane. This gives 2.5 g of the title compound of m.p. 180° C. The mass spectrum shows the molecular peaks MH+ and MNH4+ at 371 and 388 Da.
Reaction SMILES: C(O[K])(C)(C)C.CN(C)C=O.[OH:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:23].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2c(O)cccc21
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2c(OCc3ccccc3)cccc21
Reaction time: 2 h

Procedure:
3.1 g of t-butoxypotassium was added under ice cooling and nitrogen replacement to a 50 mL dimethylformamide solution of 4.0 g of 5-hydroxytetralone, and the system was stirred for 15 minutes at the same temperature, after which 3.2 mL of benzyl bromide was added, and the system was stirred for 2 hours at the same temperature. After the reaction, water was added, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate, then subjected to reduced-pressure solvent distillation, and the residue was refined by silica gel column chromatography (20% ethyl acetate/hexane) to obtain 6.3 g of 5-benzyloxytetralone (compound 2-7 in Table 3-1) in the form of a colorless solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][C:4](=[N:6][OH:7])[NH2:5].CCN(CC)CC.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19]>C(#N)C>[NH2:5][C:4](=[N:6][O:7][CH:19]=[CH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])[CH2:3][C:2]([F:9])([F:8])[F:1]
Reactant: C#CC(=O)OCC
Reactant: NC(CC(F)(F)F)=NO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C=CON=C(N)CC(F)(F)F
Temperature: 80 °C

Procedure:
Into a flask containing 3,3,3-trifluoro-N′-hydroxypropanimidamide (21 mmol, 3 g) in ACN (50 ml), Et3N (21 mmol, 3.5 ml) was added at RT. The resulting mixture was heated at 80° C. and a solution of ethyl propiolate (25.1 mmol, 2.5 g) in ACN (20 ml) was added. The reaction mixture was heated at 80° C. for overnight. The solvent was evaporated and the crude was purified by flash-chromatography. Yield 3.8 g. 1H-NMR (400 MHz; DMSO-d6): δ 1.17 (t, 3H), 3.18 (q, 2H), 4.09 (q, 2H), 5.44 (d, 1H), 6.78 (bs, 2H), 7.70 (d, 1H). LC-MS: [M−1]=239.17.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C@@H:11]([CH3:29])[CH2:10]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:8]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:28])[C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C@@H:11]([CH3:29])[CH2:10]2)[C:6](=[O:7])[CH2:5][OH:4])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)COC(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CO)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
2-{(4-Chlorophenyl)[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-oxoethyl acetate (496 mg, 0.98 mmol, 1 eq.) was dissolved in methanol (12 ml). A solution of potassium carbonate (1.08 g, 7.84 mmol, 8 eq.) in water (5 ml) was added and reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated and the residue dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride/methanol: 98/2) to afford N-(4-chlorophenyl)-2-hydroxy-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (380 mg, 84%).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:27]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:27][O:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1OC
Yield: 89.9 %

Procedure:
Dissolve compound 8 (1.2 g, 3.4 mmol) in DMF (20 ml), add anhydrous K2CO3 (0.7 g, 5.1 mmol), MeI (0.96 g, 6.8 mmol), react at 60° C. for 2h. After completion of the reaction, cool the mixture, filter and evaporate the DMF from filtrate under reduced pressure, feed the redissolved residue solution to a silica gel column, evaporate the solvent in the eluent to obtain a colorless oil (1.12 g, 90%). 1H NMR (400 MHz, DMSO-d6): 1.62 (s, 3H), 1.71 (s, 3H), 3.23 (d, J=6.4 Hz, 2H), 3.68 (s, 3H), 3.86 (s, 3H), 3.90 (s, 3H), 5.10 (t, J=6.4 Hz, 1H), 6.98 (d, J=16.0 Hz, 1H), 7.18 (s, 1H), 7.28 (t, J=7.2 Hz, 1H), 7.30 (d, J=16.0 Hz, 1H), 7.38 (t, J=7.2 Hz, 2H), 7.53 (d, J=7.2 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:32][OH:33])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[CH2:32][O:33][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (s)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.
Reaction SMILES: [K].Cl[C:3]([O:5][CH2:6][C:7]([Cl:10])([Cl:9])[Cl:8])=[O:4].Cl.C[N:13]1[CH2:18][CH2:17][C@H:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[C@H:15]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:14]1>C1C=CC=CC=1>[C:30]1([C@H:15]2[C@@H:16]([O:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)[CH2:17][CH2:18][N:13]([C:3]([O:5][CH2:6][C:7]([Cl:10])([Cl:9])[Cl:8])=[O:4])[CH2:14]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN1CC[C@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: [K]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.46 g of anhydrous potassium carbohate and 0.5 ml of 2,2,2-trichloroethyl chloroformate are added under nitrogen to a solution of 1.11 g of the free base of cis-1-methyl-3-phenyl-4-(4-trifluoromethylphenoxy)piperidine of Example 22 in 10 ml of dry benzene. After 1 hour at room temperature the mixture is refluxed 18 hours. Another 0.045 ml of 2,2,2-trichloroethyl chloroformate is added, the mixture is again refluxed 18 hours, then cooled and partitioned between ether and water. The organic phase is washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to an oil. This material is dissolved in benzene and filtered through a column of silica gel, then is further purified by preparative chromatography on five 2 mm silica preparative plates, using 3:1 petroleum ether as solvent. A nearly colorless glass of cis-3-phenyl-1-(2,2,2-trichloroethoxycarbonyl)-4-(4-trifluoromethylphenoxy)piperidine is obtained.