Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([NH:20][O:21]C2CCCCO2)=[O:19])[CH:13]=[CH:14][CH:15]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([NH:20][OH:21])=[O:19])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(C=Cc1cccc(-c2nc3ccccc3[nH]2)c1)NOC1CCCCO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: O=C(C=Cc1cccc(-c2nc3ccccc3[nH]2)c1)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the appropriate 3-[3-(1H-benzoimidazol-2-yl)-phenyl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (11, 0.25 mmol) in MeOH (2 mL) was added CSA (0.28 mmol). The reaction was stirred for 2 hr at ambient temperature and, without further work-up, purified by preparative LCMS to yield the desired 3-[3-(1H-benzoimidazol-2-yl)-phenyl]-N-hydroxy-acrylamide (12).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]1[CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[CH3:12][CH:3]1[C:2]([CH3:13])([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[OH:11]
Reactant: CC1C(=O)c2ccccc2C1(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1C(O)c2ccccc2C1(C)C
Yield: 98.7 %

Procedure:
3,3,2-Trimethyl-1-indanone (9.03 g, 50 mmol) as prepared above was dissolved in THF (40 ml) and added to the suspension of LiAlH4 (3.80 g, 100 mmol, 2 equiv.) in THF (10 ml). The mixture was heated to reflux for 2 h, then cooled to 5° C. and hydrolysed via addition of 2N aq. HCl-solution. The crude product obtained after extraction with MTBE, washing with sat. aq. NaHCO3 solution and brine, drying over MgSO4 and concentrating in a rotary evaporator was distilled at 0.1 mbar/72-73° C. to yield 8.70 g (95%) of product as a colourless viscous oil. The compound was obtained as a mixture of diastereomers 87:13, the major isomer being the 1,2-trans compound upon NMR-analysis.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=O)[C:13]([N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:14])[CH3:2].C1(C)C=CC=CC=1.O.[OH-].[Li+].Cl>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:14])[N:15]([CH3:24])[N:16]=[C:17]([CH3:23])[C:18]=1[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To a 25 mL volume three-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34)-(1)-39) (1.95 g), toluene (4.85 ml), and methanol (1.05 ml) were added under a nitrogen atmosphere, then added lithium hydroxide monohydrate (169 mg) at 0° C. After the mixture was stirred at 0° C. for 4 hours, 10 w/w % of hydrochloric acid was added to adjust to pH to less than 1, and extracted with toluene 3 times. The organic layers were combined and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane:ethyl acetate=3:1) to give 1.077 g of 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-39).
Reaction SMILES: [OH-].[K+].[O:3]1[C@H:5]([C:6]([O:8]CC)=[O:7])[C@H:4]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]>CCO>[CH2:14]([O:13][C:11]([C@H:4]1[O:3][C@@H:5]1[C:6]([OH:8])=[O:7])=[O:12])[CH3:15]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
An ethanolic solution of KOH (4.2 g, 64 mmol, in EtOH [50 ml]) was added dropwise to the 3a (9.7 g, 63 mmol) in EtOH (20 ml) at 0° C. for 30 min, and then the reaction was continued at r.t. for 8 h. The resulting viscous solution was diluted with ice water (150 ml), extracted with EA (2×200 ml). The aqueous layer was acidified with 1N HCl to pH˜4, and extracted with EA (3×150 ml). Combined organic extracts washed with brine (2×50 ml), dried over Na2SO4, and concentrated to afford the pure epoxide monoester 4 as colorless oil (8.9 g, 86.9%). 1H NMR (CDCl3, 400 MHz): δ 7.57 (br, 1H); 4.35-4.24 (m, 2H); 3.73 (s, 1H); 3.72 (s, 1H); 1.36-1.32 (t, 3H). 13C NMR (CDCl3, 100 MHz): 171.61, 166.40, 62.45, 52.20, 51.45, 13.89.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35])[CH2:17][CH2:18]1)=[N:7]2
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C(=O)OCC(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure N using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and isobutyl chloroformate to give isobutyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazine-1-carboxylate. 1H NMR (DMSO-d6) δ ppm 0.86-0.92 (m, 6H), 1.86-1.91 (m, 1H), 2.09 (br s, 3H), 3.05 (t, J=4.4 Hz, 4H), 3.28-3.32 (m, 4H), 3.57 (br s, 4H), 3.69 (t, J=4.4 Hz, 4H), 3.83 (d, J=6.4 Hz, 2H), 6.50 (s, 1H), 7.13-7.19 (m, 1H), 7.28-7.32 (m, 1H), 7.517 (s, 1H), 7.78 (d, J=2 Hz, 1H), 8.36 (s, 1H). Mass Spectrum (ESI) m/e=541.4 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]=2[NH2:30])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[C:38]1([CH2:51][O:52][C:53](Cl)=[O:54])[C:50]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]=2[NH:30][C:53]([O:52][CH2:51][C:38]2[C:50]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:54])=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)COc1ccc(COc2cccc(C(=O)c3ccccc3)c2N)cc1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)COc1ccc(COc2cccc(C(=O)c3ccccc3)c2NC(=O)OCc2cccc3c2Cc2ccccc2-3)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
4-(2-Amino-3-benzoylphenoxymethyl)-phenoxyacetic acid allyl ester (9.03 g, 20.8 mmol) and freshly distilled pyridine (1.97 g, 25.0 mmol, 1.2 equiv) were dissolved in 100 mL of CH2Cl2. The resulting yellow solution was cooled to 0° C., and fluorenylmethoxycarbonyl chloride (4.83 g, 21.8 mmol, 1.05 equiv) was added. The resulting solution was stirred at 0° C. for 15 min and then at ambient temperature for 1 h. The solution was diluted with CH2Cl2 (150 mL), extracted twice with 1 N aqueous sodium bisulfate (100 mL), once with dilute aqueous sodium chloride (100 mL), and then concentrated to give a yellow foam. Silica gel chromatography with CH2Cl2 afforded 8.68 g (65% yield) of purified material as a white solid that was homogeneous by 1H NMR. The carboxylic acid (3-[3-Benzoyl-2-fluorenylmethoxycarbonylaminobenzoyloxymethyl]-phenoxyacetic acid) was full characterized after removal of the allyl ester.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[S:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:11])=[O:10].Br[C:24]1[CH:25]=[CH:26][C:27]2[CH:38]=[CH:37][C:31]3=[N:32][CH:33]=[C:34]([Cl:36])[CH:35]=[C:30]3[C:29](=[O:39])[C:28]=2[CH:40]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:36][C:34]1[CH:35]=[C:30]2[C:29](=[O:39])[C:28]3[CH:40]=[C:24]([CH:12]([S:9]([N:8]([CH3:7])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:11])[C:13]([O:15][CH3:16])=[O:14])[CH:25]=[CH:26][C:27]=3[CH:38]=[CH:37][C:31]2=[N:32][CH:33]=1
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Reactant: COC(=O)CS(=O)(=O)N(C)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: COC(=O)C(c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1)S(=O)(=O)N(C)c1ccccc1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
Sodium tert-butoxide (8.99 g, 94 mmol) was added in one portion to a 250 mL flask containing methyl {[methyl(phenyl)amino]sulfonyl}acetate (7.59 g, 31.2 mmol) and dioxane (125 ml) at room temperature. After 15 min., 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (10.00 g, 31.2 mmol) was added followed by palladium(II) acetate (0.350 g, 1.560 mmol) and tri-t-butylphosphonium tetrafluoroborate (1.358 g, 4.68 mmol). The resulting suspension was degassed by sparging with nitrogen for 30 min. Then, the mixture was heated to 90° C. in a pre-warmed bath and left to stir for 1 h. Then, the reaction mixture was cooled to room temperature, acidified with 1N HCl (100 mL), basified with saturated aqueous sodium hydrogen carbonate (400 mL) and extracted with dichloromethane (3×250 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/Hexanes gradient) to afford the title compound as a yellow foam. 1H NMR (600 MHz, DMSO-D6) δ 8.99 (d, 1H); 8.46 (d, 1H); 8.42 (d, 1H); 8.03 (dd, 1H); 7.81 (d, 1H); 7.44 (d, 1H); 7.33 (d, 1H); 7.22 (m, 2H); 7.17 (m, 2H); 7.11 (m, 1H); 6.10 (s, 1H); 3.71 (s, 3H); 3.20 (s, 3H). LRMS (APCI) calculated for C24H20ClN2O5S [M+H]+, 483.1; found 483.0.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])[CH:2]=[CH2:3].[BH4-].[Na+].Cl>CO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCOc1ccc(CO)cc1[N+](=O)[O-]

Procedure:
The solution of 2.4 g of 4-allyloxy-3-nitrobenzaldehyde in 30 ml of methanol is cooled to 0° C. with stirring and subsequently admixed with 0.48 g of sodium borohydride in portions over 5 minutes. The reaction mixture is stirred further at 0° C. over 30 minutes, then poured onto cooled 2N HCl (100 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed with water (100 ml), 1M sodium hydrogencarbonate solution (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.12 (1:1 EtOAc-heptane); Rt=3.37.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22]C)[C:14]([C:24]3[CH:28]=[CH:27]NN=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C([C:45](OC)=[O:46])=C(O)C(Br)=CC=2)(=O)=O)C=CC=CC=1.O1C=CC(B(O)O)=C1>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:22])[C:14]([C:24]3[CH:28]=[CH:27][O:46][CH:45]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2cc[nH]n2)c1OC
Agent: OB(O)c1ccoc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 45, starting from methyl 6-(benzenesulphonylmethyl)-3-bromo-2-hydroxybenzoate (Intermediate 115) and furan-3-yl boronic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[C:5]([O:7][CH3:8])=[O:6].COC1C=CC=C(OC)[C:26]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(B2OC(C)(C)C(C)(C)O2)=CCC1>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:28][C:27]1([CH3:26])[C:32]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:5]([O:7][CH3:8])=[O:6])=[CH:31][CH2:30][CH2:29]1
Reactant: COC(=O)c1ccc(OC2CCCCO2)c(Br)c1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CCC=C1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC2CCCCO2)c(C2=CCCC2(C)C)c1
Temperature: 75 °C
Reaction time: 21 h
Yield: 80 %

Procedure:
A stirred mixture of 66.6F (10.1 g, 31.9 mmol), grounded S-Phos (2.62 g, 6.39 mmol), palladium acetate (0.72 g, 3.2 mmol), and potassium phosphate, tribasic (17.0 g, 80.2 mmol) in DMF (70 mL) and water (3.5 mL) was purged three times with argon and placed under vacuum three times. Before heating, 2-(5,5-dimethylcyclopent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (66.6C) (8.50 g, 38.3 mmol) was added via syringe. The resulting mixture was then heated to 75° C. After 21 hours (black solution), the reaction was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The organic layers were combined and washed twice with brine. After drying over anhydrous sodium sulfate and filtering, the organic solvent was removed under reduced pressure. The residue was purified on silica gel (0-20% EtOAc in hexanes) to yield 66.6G as a colorless oil that solidified (yield 80%). 1H NMR (400 MHz) (CDCl3) δ ppm 7.91 (1H, dd, J=8.6, 2.3 Hz), 7.74 (1H, d, J=2.3 Hz), 7.15 (1H, d, J=8.6 Hz), 5.55 (1H, t, J=2.3 Hz), 5.49 (1H, t, J=2.9 Hz), 3.88 (3H, s), 3.82 (1H, td, J=11.1, 2.9 Hz), 3.64 (1H, m), 2.43 (2H, td, J=7.0, 2.3 Hz), 1.92 (5H, m), 1.69 (1H, m), 1.61 (2H, m), 1.09 (6H, d, J=13.7 Hz).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40]>>[OH:40][CH2:39][CH:38]([NH:37][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:29][CH:30]=1)[CH2:41][OH:42]
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: NC(CO)CO
Product: O=C(NC(CO)CO)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 84 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol, 1.0M in DMF) were combined (reaction time 3 days at room temperature) to give 48 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 572 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[OH:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.I[CH:24]([CH3:26])[CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[O:14][CH:24]([CH3:26])[CH3:25])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(O)c(F)c(F)cc2c1=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(C)C)c(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A solution of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxoquinoline-3-carboxylate (1.10 g, 3.56 mmol), 2-Iodopropane (0.534 mL, 5.34 mmol) and K2CO3 (738 mg, 5.34 mmol) in DMF (10 mL) was stirred at room temperature for 1 h and at 70° C. for 3 h. After cooled to room temperature, the reaction mixture was poured into ice-water and the resulting precipitate was collected by filtration, washed with water and dried to yield ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-4-oxoquinoline-3-carboxylate (611 mg, 49%) as a colorless solid.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH3:47])[CH2:6][O:7][CH:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:9]1.[C:48]([O:52][CH3:53])(=[O:51])[CH:49]=[CH2:50]>C(O)C>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]2[CH2:12][CH2:11][N:10]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH2:9][CH:8]2[O:7][CH2:6][C:5]2[CH:44]=[CH:45][C:46]([CH3:47])=[C:3]([O:2][CH2:50][CH2:49][C:48]([O:52][CH3:53])=[O:51])[CH:4]=2)=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc(C)c(O)c2)cc1
Reactant: C=CC(=O)OC
Agent: [Na]
Solvent: CCO
Product: COC(=O)CCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of 5.1 mg of sodium in 0.5 ml of ethanol is admixed with 0.626 g of benzyl 3-(3-hydroxy-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 15 ml of methyl acrylate and stirred at room temperature over 18 hours. The reaction mixture is concentrated by evaporation, and the residue is admixed with 25 ml of 0.5M HCl (cold) and extracted with tert-butyl methyl ether (2×25 ml). The organic phases are washed with brine (25 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.42 (1:1 EtOAc-heptane); Rt=6.00.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[CH3:43][C:42]([CH3:45])([CH3:44])[C:41]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1)=[O:46]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(=O)C(C)(C)C)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 73.4 %

Procedure:
A solution of 45 mg (0.1 mmol) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, 12 mg (0.12 mmol) of triethylamine and 12 mg (0.1 mmol) of pivaloyl chloride in 5 ml of methylene chloride was stirred at room temperature for 15 hours. For the working-up, the reaction solution was diluted with 10 ml of methylene chloride, then washed with 5 ml of water, dried over sodium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica gel using a 4:1 mixture of hexane, and ethyl acetate as the eluent. There were obtained 39 mg (73% of theory) of tert-butyl (3RS,4RS)-4-[4-(2,2-dimethyl-propionyloxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 549 (M+NH4)+.
Reaction SMILES: C(Cl)Cl.[C:4]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12](=[O:29])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27]C)[CH:16]=2)[CH:5]=1.B(Br)(Br)Br>C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[C:4]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12](=[O:29])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([OH:27])[CH:16]=2)[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)NCc2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(/C=C/C(=O)NCc3cccc(-c4ccccc4)c3)cc2O)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.1 %

Procedure:
To a methylene chloride solution (3 mL) of (E)-N-biphenyl-3-ylmethyl-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid amide (100 mg) obtained in Example 121, boron tribromide (1M pentane solution, 1.18 mL) was added dropwise at −78° C. and the reaction solution was agitated at room temperature for 6 hours. The reaction solution was diluted with a saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was partitioned. The organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent:chloroform-methanol system), and 16.5 mg of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH2:18][NH:19]2)=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:19]1[C:20]2[C:15](=[CH:14][CH:13]=[C:12]([C:11]([F:10])([F:22])[F:23])[CH:21]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: FC(F)(F)c1ccc2c(c1)NCCC2
Reactant: BrCc1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1ccc2c(c1)N(Cc1cccc(Br)c1)CCC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
Under a nitrogen atmosphere, a solution of bromo-3-bromomethyl-benzene (3.47 g, 13.p mmol) and 7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (2.93 g, 14.6 mmol) in ethanol (15 mL, 1 M) was treated with sodium acetate (5.69 g, 69.3 mmol) and heated to 80° C. After stirring 2 h, the solution was cooled to room temperature, diluted with water, extracted with ethyl acetate and washed with saturated aq sodium chloride. The organic layer was dried over MgSO4, filtered and concentrated. Purification by column chromatography (10% ethyl acetate in heptane) provided 1-(3-bromo-benzyl)-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline 4.21 g (82%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(N(CC)CC)C>[CH3:7][C:4]1[C:3]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([S:17]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[C:2]([NH2:1])[NH:6][N:5]=1
Reactant: CN1CCNCC1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CCN(CC)CC
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)N3CCN(C)CC3)cc2s1
Yield: 19.6 %

Procedure:
the title compound (30 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (128 mg, 0.39 mmol), 4-methylpiperazine (39 mg, 0.43 mmol) and triethylamine (0.1 mL). MS (m/z, ES+): 393.1 (M+1,100%). Yield=20%.