Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.CO[C:20]1[CH:21]=C([C@@H]2C[C@H]2CNC(=O)CCC)C=C[CH:25]=1.B(Br)(Br)Br>ClCCl>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1)[CH:20]=[CH2:25]
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(OC)c1
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CCOc1cccc([C@@H]2C[C@H]2CNC(=O)CCC)c1
Reaction time: 18 h
Yield: 75 %

Procedure:
(trans)-N-[[2-(3-Hydroxyphenyl)cyclopropyl]methyl]butanamide: To a stirred solution of (trans)-N-[[2-(3-methoxyphenyl)cyclopropyl]methyl]butanamide (3.50 g, 14.2 mmol) in dichloromethane (50 mL) at -78° C. was added BBr3 (28.4 mL, 1N in CH2Cl2, 28.4 mmol) dropwise. After addition was complete, the cooling bath was removed and stirring was continued for 18 h. The solution was poured over ice/H2O(100 mL) and extracted with 2.5 N NaOH. The basic extracts were combined, washed with dichloromethane, and acidified (conc. HCl). The acidic solution was extracted with dichloromethane, the organics were combined, washed with brine, dried (MgSO4), and concentrated to afford 2.49 g (75%) of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 0.72-0.84 (m, 5H), 1.09-1.15 (m, 1H), 1.42-1.54 (m, 2H), 1.63-1.69 (m, 1H), 2.02 (t, J=5.0 Hz, 2H), 2.99-3.11 (m, 2H), 6.39-6.50 (m, 3H), 6.98 (t, J=7.8 Hz, 1H), 7.91 (s, 1H), 9.19 (br s, 1H); IR (NaCl Film) 3300, 2964, 1642, 1585, 1542, 1466 cm-1 ; MS (isobutane-DCI) m/e 233; Analysis calc'd for C14H19NO2.0.1 H2O: C, 71.52; H, 8.23; N, 5.96; found: C, 71.53; H, 8.32; N, 5.92.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([OH:12])=[O:11].[CH3:17]O>>[CH3:17][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([OH:16])=[C:7]([Br:6])[CH:8]=1
Reactant: O=C(O)c1ccc(O)c(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
Sulfuric acid (conc., 10 ml) was added to a solution of 3-bromo-4-hydroxybenzoic acid (10.0 g, 46 mmol) in methanol (100 ml) and the mixture was stirred at room temperature for 72 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (250 ml). The mixture was washed with saturated aqueous sodium bicarbonate (2×250 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (8.83 g, 83%). 1H NMR (250 MHz, CDCl3) δ8.19 (1 H, d, J 2.0 Hz), 7.92 (1 H, dd, J 8.5, 2.0 Hz), 7.05 (1 H, d, J 8.5 Hz), 5.91 (1 H, s), and 3.90 (3 H, s).
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O>[CH:24]1([NH:30][C:22]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:21]=2)=[N:6][C:7]2[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3cc(NC4CCCCC4)c(F)cc3cc2c1=O

Procedure:
Ethyl 8-cyclohexylamino-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was prepared under the conditions of Example 4, but from 3 g of ethyl 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate and 2.2 cm3 of cyclohexylamine in 30 cm3 of dimethyl sulphoxide. After filtering 2 times with 15 cm3 of ethanol, 3.3 g of ethyl 8-cyclohexylamino-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow solid melting at about 220° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]1[C:5]=2[C:6](O)=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[N:9]1.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[S:3][C:4]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]1[C:5]=2[C:6]([Cl:22])=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[N:9]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc3nc(Cl)sc3c2c1O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc3nc(Cl)sc3c2c1Cl

Procedure:
A mixture of 3.09 g of ethyl 2-chloro-9-hydroxythiazolo[5,4-f]quinoline-8-carboxylate, 20 ml of phosphorus oxychloride and 0.2 g of phosphorus pentachloride was refluxed for 1 hour and the reaction mixture was treated in the same manner as described in Example 5 to give ethyl 2,9-dichlorothiazolo[5,4-f]quinoline8-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17]2[O:22][C:21](=[O:23])[C:20]([S:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:19]([OH:32])[CH:18]=2)[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][Si](C)(C)C(C)(C)C.Cl>C1COCC1>[OH:32][C:19]1[CH:18]=[C:17]([C:4]2[CH:3]=[C:2]([CH3:1])[C:7]([OH:8])=[C:6]([CH3:16])[CH:5]=2)[O:22][C:21](=[O:23])[C:20]=1[S:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc(C)c1O
Reaction time: 48 h

Procedure:
To a THF (10 mL) solution of 6-[3,5-dimethyl-4-[[dimethyl(1,1-dimethylethyl)silyl]oxy]phenyl]-4-hydroxy-3-[(phenylmethyl)thio]-2H-pyran-2-one at 0° C. is added 3 N HCl (9.0 mL). The reaction is stirred for 48 hrs. at room temperature. The reaction is quenched by pouring onto ethyl acetate and washed in succession with water, saturated sodium chloride; dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by flash column chromatography (SiO2 --230 to 400 mesh) using 50% ethyl acetate/hexanes. m.p. 174°-176° C.; 1H NMR (250 MHz, DMSO-d6) δ 2.21 (s, 6 H), 2.60 (m, 1 H), 3.96 (s, 2 H), 6.52 (s, 1 H), 7.23 (s, 5 H), 7.38 (s, 2 H), 9.06 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[CH2:4][CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=1.[C:17]1([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.C(OC(C)C)(C)C.N>ClCCl.CO.ClCCl>[CH3:1][N:2]([CH3:16])[C:3](=[O:15])[CH2:4][CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([N:27]2[CH2:28][CH2:29][N:24]([CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:25][CH2:26]2)=[CH:9][CH:8]=1
Reactant: CN(C)C(=O)CCC(=O)c1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: N
Solvent: CC(C)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)CCC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
The mixture of 33.48 g (0.15 Mol) of N,N-dimethyl-4-fluoro-γ-oxobenzenebutanoic acid amide, 29.6 g (0.168 Mol) of 1-(phenylmethyl)piperazine and 6 ml of DIEA was refluxed for 6 hours. Another 30 g (0.17 Mol) of (phenylmethyl)piperazine was added, and the mixture was refluxed for a further 7 hours. The mixture was taken up in a little dichloromethane, and purified by column chromatography on silica gel, using dichloromethane/methanol/conc. ammonia 99/1/0.5 for elution. The residue obtained from the appropriate fractions was stirred with diisopropylether, the formed crystals were then recrystallised from ethanol. 42.22 g (74% of theory) of colourless crystals were obtained, Rf=0.69 (eluant: dichloromethane/methanol/conc. ammonia 95/5/0.5 v/v/v).
Reaction SMILES: C([N:8]([CH:27]1[CH2:30][N:29]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:28]1)[CH2:9][CH:10]([OH:26])[CH2:11][O:12][C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:41]([O:40][C:37]1[CH:38]=[CH:39][C:34]([S:31]([N:29]2[CH2:28][CH:27]([NH:8][CH2:9][CH:10]([OH:26])[CH2:11][O:12][C:13]3[C:25]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[NH:18][C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH2:30]2)(=[O:33])=[O:32])=[CH:35][CH:36]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCOc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)CC(O)COc3cccc4[nH]c5ccccc5c34)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)N2CC(NCC(O)COc3cccc4[nH]c5ccccc5c34)C2)cc1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of 1-{Benzyl-[1-(4-butoxy-benzenesulfonyl)-azetidin-3-yl]-amino}-3-(9H-carbazol-4-yloxy)-propan-2-ol (0.18 g, 0.3 mmol) in methanol (6 ml) was added ammonium formate (0.29 g, 4.5 mmol), and 0.045 g of 10% Pd/C. The mixture was stirred at reflux for 18 h. After cooling to room temperature, it was filtered through Celite. The solvent was evaporated and the residue triturated with isopropyl ether to give 0.14 g of a white solid; m.p. 81-84° C.; MS (ES) m/z 524.0 (MH+); HRMS (ES) Calcd. for C28H34N3O5S (MH+): 524.2219, Found: 524.2252.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[O:19][CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[F:27][C:28]([F:33])([F:32])[C@@H:29]1[CH2:31][O:30]1>C(#N)C>[F:27][C:28]([F:33])([F:32])[C@@H:29]([OH:30])[CH2:31][N:16]1[CH2:17][CH2:18][O:19][CH:14]([C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=2)[CH2:15]1
Reactant: Fc1ccc(C2CNCCO2)cc1
Reactant: FC(F)(F)[C@@H]1CO1
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O[C@@H](CN1CCOC(c2ccc(F)cc2)C1)C(F)(F)F
Reaction time: 96 h
Yield: 72.3 %

Procedure:
To a solution of 2-(4-fluorophenyl)morpholine oxalate (50 mg, 184 μmol) and triethylamine (128 μL, 922 μmole) in 2.5 mL of acetonitrile was added (S)-2-(trifluoromethyl)oxirane (82.6 mg, 737 μmol) at room temperature. The mixture was stirred at this temperature for 4 days. The solution was purified by reverse phase column chromatography (30-100% acetonitrile in water). The desired fractions were pooled and lyophilized to give (2S)-1,1,1-trifluoro-3-(2-(4-fluorophenyl)morpholino)propan-2-ol (39 mg, 73%). Used as is in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH+:3]1[O-:11].OO.Cl.S(=O)(O)[O-].[Na+].[C:21](=O)([O-])O.[K+]>CC(C)=O.[Cu]Cl>[CH3:21][O:11][N:3]1[C:2]([CH3:12])([CH3:1])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]1([CH3:10])[CH3:9]
Reactant: CC1(C)CC(O)CC(C)(C)[NH+]1[O-]
Reactant: O=C([O-])O
Agent: Cl[Cu]
Agent: Cl
Agent: O=S([O-])O
Solvent: CC(C)=O
Product: CON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
17.8 g (100 mmol) of 2,2,6,6-tetramethyl-4-hydroxypiperidine-N-oxide was dissolved in 100 ml of acetone, and 34 g (300 mmol) of 30% hydrogen peroxide aqueous solution was added slowly for more than 10 minutes. With a cooling to 5° C., 0.49 g (5.0 mol %) of copper (I) chloride was added with keeping the temperature of the reaction mixture in a range of 5° C. to 55° C. After 15 minutes, 0.5 g of 35% hydrochloric acid was added, and the reaction mixture was stirred at room temperature for 2 hours. After 2 hours, 50 ml of 4 mol/L sodium bisulfite aqueous solution, and 100 ml of saturated potassium hydrogen carbonate aqueous solution were added, and an extraction was carried out using 300 mL of ethyl acetate. The organic layer was concentrated by a rotary evaporator to obtain 1-methyloxy-2,2,6,6-tetramethyl-4-hydroxypiperidine.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][NH:6][CH2:7]2)[CH2:3]1.Br[C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([Br:24])=[CH:18][CH:19]=3)[C:14](=[O:25])[C:13]=2[CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:24][C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[C:13](=[CH:12][C:11]([N:6]4[CH2:7][CH:8]5[CH:4]([CH2:3][N:2]([CH3:1])[CH2:9]5)[CH2:5]4)=[CH:23][CH:22]=3)[C:14](=[O:25])[C:15]=2[CH:16]=1
Reactant: CN1CC2CNCC2C1
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN1CC2CN(c3ccc4c(c3)C(=O)c3cc(Br)ccc3-4)CC2C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
A mixture of 3-methyl-3,7-diazabicyclo[3.3.0]octane (297 mg, 2.36 mmol; see Example 54C), 2,7-dibromofluoren-9-one (680 g, 2.01 mmol; Aldrich), tris(dibenzylideneacetone)dipalladium (0) (Pd2 dba3; 37 mg, 0.040 mmol; Alfa), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 63 mg, 0.10 mmol; Strem) and sodium tert-butoxide (270 mg, 2.81 mmol; Acros) in 10 mL toluene was warmed to 90° C. and stirred for 16 h. The reaction mixture was cooled to ambient temperature and filtered through Celite, rinsing with CH2Cl2. After concentrating the solution under reduced pressure, the residue was purified by flash chromatography (120 g silica gel, 1-20% gradient of NH4OH-MeOH (1:10) in CH2Cl2) to give the crude product. This material was purified further by flash chromatography (40 g Analogix NH2 column, 10-100% EtOAc in hexanes) to afford the title compound as a reddish solid (335 mg, 0.875 mmol; 44% yield): 1H NMR (300 MHz, CDCl3) δ ppm 7.64 (d, J=2 Hz, 1H), 7.49 (dd, J=8, 2 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 6.95 (d, J=2 Hz, 1H), 6.64 (dd, J=8, 2 Hz, 1H), 3.42-3.53 (m, 2H), 3.29 (dd, J=10, 3 Hz, 2H), 2.99-3.13 (m, 2H), 2.75-2.94 (m, 2H), 2.56 (dd, J=9, 3 Hz, 2H), 2.41 (s, 3H); MS (ESI): m/z 383 (M+1)+, 385 (M+3)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].O[NH:23][C:24](=[NH:32])[CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:32]=[C:24]([CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:23]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N=C(CN1CCOCC1)NO
Reactant: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN2CCOCC2)no1

Procedure:
Method as for preparations 2 and 3 combined using 2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (preparation 168) (1.00 g, 3.36 mmol) and N-hydroxy-2-(4-morpholinyl)ethanimidamide (J. Org. Chem.; 1958, 23, 1112) (534 mg, 3.36 mmol) as starting material.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.[OH-].[Na+]>CC(O)=O>[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15]1
Reactant: CNc1ccc(Cl)cc1-c1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CNc1ccc(Cl)cc1C1Cc2ccccc2N1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
Sodium cyanoborohydride (4.72 g) was added portionwise to a solution of 5.36 g 2-(2-methylamino-5-chlorophenyl)-1H-indole in 160 ml HOAc at 10° C. The mixture was stirred twenty hours at room temperature. It was then diluted and added to excess 50% NaOH in ice. The mixture was extracted with CH2Cl2, and the extracts were washed with saturated NaCl solution and dried (MgSO4). Concentration yielded 5.31 g solid. Purification by HPLC using CH2Cl2 /hexane (1:1) as eluent yielded 2.65 g solid, m.p. 106°-108° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:35])[C:19]([C:25]2[CH:34]=[CH:33][C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[CH:26]=2)=[CH:20][O:21][CH:22]([F:24])[F:23])=[CH:11][C:10]=1[O:36][CH3:37])C1C=CC=CC=1.Br.C(O)(=O)C>O>[F:23][CH:22]([F:24])[O:21][CH:20]=[C:19]([C:25]1[CH:34]=[CH:33][C:32]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH:26]=1)[C:18]([NH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:36][CH3:37])[CH:11]=1)=[O:35]
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1OCc1ccccc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
2.40 g (4.73 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-difluoromethoxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide, 1.20 g (7.09 mmol) of 48% hydrobromic acid and 30 ml of acetic acid were mixed and stirred at 80° C. for 2 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1) to give 1.81 g of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1371).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[Si:14]([O:13][CH2:12][CH2:11][CH2:10][O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: C#CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCCCOCCCO[Si](C)(C)C(C)(C)C
Reaction time: 0.67 h
Yield: 20.6 %

Procedure:
To a solution of 4-pentyn-1-ol (2.1 g, 26.1 mmol) in dry N,N-dimetylformamide (100 ml) was added sodium hydride (1.04 g, 60% in oil, 26.1 mmol) at room temperature. The mixture was stirred for 40 minutes, and 1-bromo-3-(t-butyldimethylsilyloxy) propane (4.4 g, 17.4 mmol) was added thereto. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, water was added thereto. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The organic solvent was removed under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=20:1) to give the title compound (920 mg, yield: 21%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.FC(F)(F)C(O)=O.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][CH:5]=[C:4]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]2)[N:3]=1
Reactant: COc1cc(C)c(F)cc1C(=O)c1ccc(Cl)nc1N
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(F)cc1C(=O)c1ccc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 43) and 1-methanesulfonyl-piperidin-4-ylamine (Step A, Example 6) using the procedure described in Step B. Example 6. HRMS, observed 437.1653, Calcd for (M+H)+: 437.1654.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]1[CH:7]=[CH:8][C:9]([O:12]C)=[CH:10][CH:11]=1)[CH3:3].[Na].C1(S)C=CC=CC=1.OP(O)(O)=O>O>[CH3:1][N:2]([CH2:4][CH:5]([C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3]
Reactant: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
Agent: O=P(O)(O)O
Agent: Sc1ccccc1
Agent: [Na]
Solvent: O
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Temperature: 160 °C

Procedure:
Venlafaxine (5.6 g) and benzenethiol sodium salt (6.9 g) are charged to PEG 400 (25 g). The reaction mixture is heated to 160° C. for 5 hours. Then the temperature is lowered and water is added (60 g). The pH is adjusted to 3.5 with H3PO4. The organic by-products are removed by extraction with heptanes (25 g). The pH of the aqueous layer is then adjusted to 9.5 with aqueous ammonia. The precipitate is collected by suction filtration, re-slurried in water (100 g), isolated by suction filtration and dried in vacuo.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH3:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:8]3[CH2:9][CH2:10][C:5]4[CH:4]=[CH:3][O:2][C:6]=4[CH2:7]3)=[O:24])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: COc1ccc(C(=O)c2ccc(C(=O)O)cc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)c2ccc(C(=O)N3CCc4ccoc4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.308 g (1.2 mmol) of 4-(4-methoxybenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times, The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane=3/1/1). The resulting purified product was washed with diethyl ether to yield the desired product.
Reaction SMILES: [Na].[CH:2]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Cl)([O-:10])=[O:9]>CO>[CH:2]1([S:7][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: SC1CCCC1
Agent: [Na]
Solvent: CO
Product: O=[N+]([O-])c1cccc(CSC2CCCC2)c1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A solution of sodium methoxyde (15.5 mL, 25 wt % in methanol) was diluted with methanol (85 mL) and treated with cyclopentanethiol (7.3 mL) at room temperature for 60 minutes, cooled to −15° C., treated with 3-nitrobenzylchloride (10.0 g) in 3 portions, kept for 2 hours at −15° C., then the temperature was increased to room temperature. The reaction mixture was concentrated in vacuo, treated with diethyl ether (350 mL), washed with water (2×150 mL) and brine (100 mL), dried with sodium sulfate and evaporated to dryness. The title compound (14.9 g) was thus obtained and used without further purification.
Reaction SMILES: N1([C:10]([CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[O:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)=[O:11])C2C=CC=CC=2N=N1.CCOCC.[Mg+2].[Br-].[Br-].[C:30]([S:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:32])[CH3:31].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]1([S:33][C:30](=[O:32])[CH2:31][C:10](=[O:11])[CH:12]2[CH2:13][C:14]([CH3:20])([CH3:21])[O:15][C:16]([CH3:18])([CH3:19])[CH2:17]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC1(C)CC(C(=O)n2nnc3ccccc32)CC(C)(C)O1
Reactant: CC(=O)Sc1ccccc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC1(C)CC(C(=O)CC(=O)Sc2ccccc2)CC(C)(C)O1
Reaction time: 8 h
Yield: 70 %

Procedure:
To a mixture of benzotriazol-1-yl-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-methanone (1.70 g, 5.62 mmol), magnesium bromide diethyl etherate (4.14 g, 16.06 mmol), and S-phenyl thioacetate (0.76 mL, 5.35 mmol) in 21 mL of DCM at RT was added dropwise DIEA (3.95 mL, 21.41 mmol). The mixture was stirred overnight and then diluted with 50 mL of DCM and washed with 1N HCl (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, concentrated, and the residue purified by flash chromatography on silica gel to give 1.2 g (70%) of a colorless oil. Mass spectrum (ESI, m/z): Calculated for C18H24O3S, 321.1 (M+H), found 321.1.