Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:6][C@H:5]([O:7][CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10].[C:18]1([CH2:31][O:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[C:30]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>ClCCl>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C@:2]1([NH:1][C:36]([NH:35][C:33](=[O:34])[O:32][CH2:31][CH:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:30][C:29]=3[C:28]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[S:37])[CH2:6][C@H:5]([O:7][CH3:8])[CH2:4][C@H:3]1[CH2:9][OH:10]
Reactant: CO[C@@H]1C[C@@H](CO)[C@](N)(c2ccccc2F)C1
Reactant: O=C(N=C=S)OCc1cccc2c1Cc1ccccc1-2
Solvent: ClCCl
Product: CO[C@@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2F)C1
Yield: 62.5 %

Procedure:
A solution of [(1R*,2S*,4R*)-2-amino-2-(2-fluorophenyl)-4-methoxycyclopentyl]methanol (250 mg) and fluorenylmethyloxycarbonyl isothiocyanate (351 mg) in dichloromethane (20 mL) was stirred at room temperature for three days. The reaction solution was purified by silica gel column chromatography to obtain the title compound (340 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][C:15]=1I>>[Br:9][C:10]1[CH:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][C:15]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(S)cc1
Reactant: FC(F)(F)c1ccc(I)c(Br)c1
Product: Cc1ccc(Sc2ccc(C(F)(F)F)cc2Br)cc1

Procedure:
Prepared from 4-methyl-benzenethiol and 3-bromo-4-iodo-benzotrifluoride.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:13]2=[CH:14][N:15]=[CH:16][CH:17]=[C:12]2[C:11]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:9]>C(O)(=O)C.[Pt]>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8]([C:10]1[N:19]([CH3:20])[C:18](=[O:21])[C:13]2[CH2:14][NH:15][CH2:16][CH2:17][C:12]=2[C:11]=1[C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2ccncc2c(=O)n1C
Agent: [Pt]
Solvent: CC(=O)O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1c(-c2ccc(F)cc2)c2c(c(=O)n1C)CNCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.5 %

Procedure:
To a solution of the compound (270 mg) obtained in Example 8 in acetic acid (15 ml) was added 5% Pt-C (270 mg), and the mixture was stirred for 6 hours at room temperature under hydrogen atmosphere. The catalyst was filtered off, and the filtrate was washed with ethyl acetate. The filtrate and the washing were combined, then the solvent was distilled off. To the residue was added ethyl acetate, and the mixture was washed with an aqueous solution of sodium hydrogencarbonate and water, which was then dried. The solvent was distilled off to leave the above-titled compound as colorless crystals (170 mg). m.p.178°-180° C. (recrystallized from ethyl acetate-ethyl ether)
Reaction SMILES: COC([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:12]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:13]=3[S:14][CH:15]=2)[CH2:7][CH2:6]1)=O.[BrH:24]>>[BrH:24].[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:12]2[C:11]([CH:8]3[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]3)=[CH:15][S:14][C:13]=2[CH:16]=1
Reactant: COC(=O)N1CCC(c2csc3cc(C(F)(F)F)ccc23)CC1
Agent: Br
Product: FC(F)(F)c1ccc2c(C3CCNCC3)csc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
A mixture of 4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester (3.1 g, 9.0 mmol) in HBr (45 mL, 30% in acetic acid) was stirred at room temperature for 20 hours wher the volatiles were removed in vacuo. The residue was washed with EtOAc and the product was collected by filtration yielding 3.09 g (94%) of the desired product as a white solid.
Reaction SMILES: [CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[C:9]([Cl:18])[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1)[CH3:2].[CH2:19]([N:21]1[C:25](O)=[CH:24][CH:23]=[N:22]1)[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.C1(NC(NC2CCCCC2)=O)CCCCC1>C(O)(CC)(C)C.CCCCCC.C(OCC)(=O)C>[CH2:1]([S:3][CH:4]1[C:13]2[C:8](=[C:9]([Cl:18])[CH:10]=[C:11]([C:15]([O:17][C:25]3[N:21]([CH2:19][CH3:20])[N:22]=[CH:23][CH:24]=3)=[O:16])[C:12]=2[CH3:14])[S:7][CH2:6][CH2:5]1)[CH3:2]
Reactant: CCSC1CCSc2c(Cl)cc(C(=O)O)c(C)c21
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCC(C)(C)O
Solvent: CCCCCC
Product: CCSC1CCSc2c(Cl)cc(C(=O)Oc3ccnn3CC)c(C)c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 106.9 %

Procedure:
1.0 Gram (3.3 mmol) of 4-ethylthio-5-methyl-6-carboxy-8-chlorothiochroman was dissolved in 5 ml of t-amyl alcohol, and 0.45 g (4.0 mmol, 1.2 eq.) of 1-ethyl-5-hydroxypyrazole and 0.83 g (4.0 mmol, 1.2 eq.) of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 2.5 hours. After the completion of the reaction, ethyl acetate and hexane were added, and liberated N,N'-dicyclohexylurea was filtered off. The filtrate was concentrated and purified by column chromatography (silica gel/hexane+ethyl acetate=5:1) to give 1.4 g (yield 100%) of 4-ethylthio-5-methyl-6-(1-ethylpyrazol-5-yl)oxycarbonyl-8-chlorothiochroman.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3([CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[C:7](=O)[C:6]=2[CH:21]=1.C[Si](C)(C)[N:24]=[C:25]=[N:26][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3([CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[C:7](=[N:26][C:25]#[N:24])[C:6]=2[CH:21]=1
Reactant: O=C1c2cc(Br)ccc2OC12CCc1ccccc1CC2
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1c2cc(Br)ccc2OC12CCc1ccccc1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5′-bromo-5,6,8,9-tetrahydro-3′H-spiro[benzo[7]annulene-7,2′-benzofuran]-3′-one (0.1660 g, 0.48 mmol) in CH2Cl2 (5 mL) was added TiCl4 (1.0 M in CH2Cl2, 1.0 mL, 1.0 mmol) dropwise at room temperature. The reaction mixture was turned into orange precipitates in a few minutes. After 1 h, 1,3-bis(trimethylsilyl)carbodiimide (0.30 mL, 1.32 mmol) was added via a syringe. The precipitates were disappeared and the reaction mixture was turned into a red solution. The mixture was stirred at room temperature for 15 h and then quenched with ice, extracted with CH2Cl2, dried over Na2SO4. After the solvent was removed under reduced pressure, the crude product was directly used in the next step without further purification. LC-MS tR=2.27 min in 3 min chromatography, m/z 367, 369 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([C:23]#[N:24])=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[OH-:25].[Na+]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([C:23]([NH2:24])=[O:25])=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Temperature: 0 °C

Procedure:
3-(2-Ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (1.4 g, 4.19 mmol) was stirred in concentrated sulfuric acid (10 mL) overnight at ambient temperature. Ice (100 g) was added and the solution was neutralized using 4M NaOH. Ice was added as necessary to maintain the temperature below 20° C. The product was extracted into ethyl acetate, washed with brine, dried over MgSO4, filtered and concentrated to afford 3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (1.5 g, 4.2 mmol).
Reaction SMILES: C([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:33])([F:32])[CH:26]([F:31])[C:27]([F:30])([F:29])[F:28])[CH:6]=1)(=O)C.S(=O)(=O)(O)O>C(O)C.O>[NH2:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:20])([F:21])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:32])([F:33])[CH:26]([F:31])[C:27]([F:28])([F:29])[F:30])[CH:6]=1
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)cc2N)cc1SCC(F)(F)F
Temperature: 25 °C
Yield: 81.7 %

Procedure:
1.2 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole was dissolved in 50 mL of ethanol, and an aqueous solution comprising 0.5 g of concentrated sulfuric acid in 2.0 mL of water was added, followed by reflux with heating for 6 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.9 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][N:7]=1)(=O)C.[ClH:16]>>[ClH:16].[OH:4][CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: CC(=O)OCc1nccc2c1CCCC2
Agent: Cl
Product: OCc1nccc2c1CCCC2

Procedure:
A solution of l-acetoxymethyl-5,6,7,8-tetrahydro-isoquinoline (0.44 g) in 6N hydrochloric acid (10 ml) aqueous solution was heated for 4 hours at ca. 100° C. After cooling, the mixture was concentrated in vacuo to give 1-hydroxymethyl-5,6,7,8-tetrahydroisoquinoline hydrochloride (0.42 g) as a brown solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:27])[CH2:19][CH2:18][CH2:17][CH:16]2[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:27][C:15]1([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][NH:5][C:1](=[O:3])[CH3:2])=[CH:10][CH:11]=2)[CH2:19][CH2:18][CH2:17][CH:16]1[NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:23])=[O:22]
Reactant: CC(=O)Cl
Reactant: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(OCCN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCOc1ccc(C2(O)CCCC2NS(=O)(=O)C(C)C)cc1
Temperature: 0 °C

Procedure:
In a 100 mL 3 neck flask fitted with a stirrer and thermometer, acetyl chloride (63 mg, 1.2 eq) is added dropwise to {2-[4-(2-aminoethoxy)phenyl]-2-hydroxycyclopentyl}[(methylethyl)sulfonyl]amine (230 mg, 0.67 mmol) and triethylamine (102 mg, 1.5 eq) in CH2Cl2 (40 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction is allowed to warm to room temperature and stirred for 2 hours. The reaction is then diluted with CH2Cl2 (50 mL) and the organic layer is washed two times with H2O, dried over Na2SO4, filtered, and concentrated under reduced vacuum to yield the product. This material is purified via silica gel chromatography employing the Chromatotron® and using 2000 micron rotor while eluting with a suitable eluent, such as hexanes/ethyl acetate to provide the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH3:23])=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:22]([C:14]1[S:13][C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=1)[CH3:23]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1cc(CC)sc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(CC)sc1Nc1ccccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
o-Fluoronitrobenzene (b 56.4 g, 0.4 mol) and ethyl 2-amino-5-ethylthiophene-3-carboxylate (100 g, 0.5 mol) were dissolved in dry dimethylsulphoxide (320 ml). The stirred solution, under nitrogen, was heated in an oil bath. When the internal temperature reached 60° C., potassium carbonate (55 g, 0.4 mol) was added and the mixture stirred at 100° C. until GLC indicated that all the o-fluoronitrobenzene had been consumed (6.5 hours). The mixture was then poured onto ice-water, acidified with concentrated hydrochloric acid and extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO4) and the solvent evaporated to give a red semi-solid which was recrystallised from ethanol to give the title product as a solid (m.p. 66°-68° C.).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[CH2:20])[C:14]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10])[CH:4]=[CH2:5]>CO.O>[CH2:3]([O:6][C:7]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[CH2:20])[C:14]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:8]=1[C:9]([OH:11])=[O:10])[CH:4]=[CH2:5]
Reactant: C=CCOc1cc(OCC=C)c(C(C)C)cc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1cc(OCC=C)c(C(C)C)cc1C(=O)O
Temperature: 25 °C
Yield: 97.6 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 0.5 ml) was added to a mixture of methyl 2,4-bis-allyloxy-5-isopropylbenzoate (450 mg, 1.55 mmol) in methanol (6 ml) and water (2 ml) and the mixture was stirred and held at reflux for 3 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford 2,4-bis-allyloxy-5-isopropylbenzoic acid (418 mg, 98%) as an off-white solid. 1H NMR (DMSO-d6) 12.16 (1H, br s), 7.58 (1H, s), 6.66 (1H, s), 6.07 (2H, m), 5.51 (1H, dm), 5.44 (1H, dm), 5.28 (2H, m), 4.68 (2H, m), 4.64 (2H, m), 3.17 (1H, m), 1.15 (6H, d). MS: [M+Na]+ 299.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:5]1[O:1][CH2:2][CH2:3][CH:4]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1=COCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a stirred solution of 0.35 ml (7.13 mmol) 2,3-dihydrofuran in 10 ml dry THF under argon at −78° C. was added 4.7 ml (7.2 mmol) tert-butyllithium solution (1.5M in pentane) and stirring continued for 5 minutes at −78° C. and 15 minutes at 0° C. The reaction mixture was then recooled to −78° C. and 1.92 ml (7.13 mmol) tributyltin chloride added dropwise and stirring continued for 16 hours at room temperature. The reaction mixture was partitioned between ether and water. The organic phase was then washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 2.37 g (93%) tributyl-(4,5-dihydro-furan-2-yl)-stannane as a yellow liquid which was used in the next step without further purification. EI-MS m/e (%): cluster at 303 ([M—C4H9]+, 100).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN=[N+]=[N-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 97 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(azidomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (723 mg) in THF (7.5 mL) were added triphenylphosphine (567 mg) and water (1.5 mL), and the mixture was stirred at room temperature for 36 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/methanol) to give the title compound (656 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[F:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].Cl>ClCCCl>[F:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18]([C:12]1[CH:11]=[CH:10][C:9]([O:13][CH3:14])=[CH:8][C:7]=1[OH:6])=[O:19]
Reactant: COc1cccc(OC)c1
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccc(F)cc2F)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
Aluminum chloride (2.03 g, 15.2 mmol) was added in portions to a solution of 1,3-dimethoxybenzene (1.86 mL, 15.2 mmol) and 2,4-difluorobenzoyl chloride (1.86 mL, 15.2 mmol) in 1,2-dichloroethane at 0° C. The mixture was allowed to warm to rt over 3 h then heated at reflux for 6 h. The resultant mixture was allowed to cool to rt, then poured into a mixture of ice (˜100 g) and concentrated hydrochloric acid (˜20 mL). The organic layer was separated. The aqueous solution was stirred at ambient temperature overnight, and extracted with dichloromethane. The organic layers were washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvents were evaporated in vacuo to give crude product. A portion of the product was purified by flash chromatography on silica gel, using a gradient of 1%-10% EtOAc/heptane as the eluent to give the title compound 3i (1.8 g). MS: m/z 264.9 (MH+). 1H NMR (CDCl3): δ 3.90 (s, 3H), 6.42 (d of d, 1H, J=9.0 and 2.5 Hz), 6.50 (d, 1H, J=2.5 Hz), 6.91-7.04 (m, 2H), 7.27-7.29 (m, 1H), 7.44-7.50 (m, 1H) and 12.44 (s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH3:24])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]1.CC1C=CC=CC=1N.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:55][CH2:56][C:57]([N:59]1[CH2:64][CH2:63][CH:62]([O:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:75])([F:74])[F:73])[CH:67]=2)[CH2:61][CH2:60]1)=[O:58]>CN(C=O)C.CO.CCCCCC.O>[O:58]=[C:57]([N:59]1[CH2:60][CH2:61][CH:62]([O:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:75])([F:73])[F:74])[CH:67]=2)[CH2:63][CH2:64]1)[CH2:56][NH:55][C:21]([C:19]1[N:18]=[N:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:24])[CH:20]=1)=[O:23]
Reactant: Cc1ccccc1-n1cc(C(=O)O)nn1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-n1cc(C(=O)NCC(=O)N2CCC(Oc3cccc(C(F)(F)F)c3)CC2)nn1
Reaction time: 0.03 h
Yield: 86.17 %

Procedure:
DIPEA (171 mg, 1.32 mmol) was added to a stirred solution of 1-o-tolyl-1H-[1,2,3]triazole-4-carboxylic acid (60 mg, 0.29 mmol) (prepared by the method used for the synthesis of Intermediate 64, starting from 2-methylaniline) in DMF (5 mL) followed by HOBt (44 mg, 0.32 mmol) and EDCI (141 mg, 0.73 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (110 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Cold water was then added and the solid was collected. The solid obtained was purified by recrystallisation from a solvent system (3:7:0.2), EtOAc:hexane:MeOH to afford 124 mg (86.17% Yield) 1-o-tolyl-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 488, 98.68%. 1H NMR (300 MHz, DMSO-d6): δ 9.0 (s, 1H), 8.5 (t, 1H), 7.6-7.48 (m, 4H), 7.48 (m, 1H), 7.36 (t, 3H), 4.9 (m, 1H), 4.3 (d, 2H), 4.0 (s, 1H), 3.8 (s, 1H), 3.6 (m, 2H), 2.2 (s, 3H), 2.1 (t, 2H), 1.7 (s, 1H), 1.6 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[C:4]([O:18][CH3:19])[CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:10]([C:5]1[C:4]([O:18][CH3:19])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[O:8][CH3:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc(Br)cc(OC)c1C(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Br)cc(OC)c1Cc1ccccc1
Temperature: 80 °C
Yield: 98 %

Procedure:
(4-bromo-2,6-dimethoxyphenyl)(phenyl)methanone (87 mg, 0.271 mmol) was solubilized and stirred into a mixture of trifluoroacetic acid (250 μL, 12 eq) and triethylsilane (260 μL, 6 eq) heated at 80° C. for 15 h. After cooling to r.t., 20 mL of DCM were added to the reaction mixture. The organic layer was washed with a saturated NaHCO3 solution (2×20 mL), with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography (cyclohexane/AcOEt 95:5) to afford the reduced compound in 98% yield (81.4 mg) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.28-7.21 (m, 4H), 7.20-7.12 (m, 1H), 6.73 (s, 2H), 3.98 (s, 2H), 3.81 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 158.77 (2C), 141.23 (C), 128.57 (2CH), 128.14 (2CH), 125.63 (CH), 120.45 (C), 116.86 (C), 107.71 (2CH), 56.04 (2OCH3), 28.58 (CH2); MS (ESI) m/z: 307.4, 309.0 [M+H, 79Br, 81Br]+; 324.1, 326.1 [M+NH4, 79Br, 81Br]+.
Reaction SMILES: C1(C)C=CC=CC=1.FC(F)(F)C(O)=O.[C:15]([C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([CH:29](N(C)C)[C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=2)[C:20]=1[OH:41])([CH3:18])([CH3:17])[CH3:16]>O>[C:15]([C:19]1[C:20](=[O:41])[C:21](=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=2)[CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: Cc1ccc(C(c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)N(C)C)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C=C2C=C(C(C)(C)C)C=C(C(C)(C)C)C2=O)cc1C
Temperature: 110 °C
Yield: 81.7 %

Procedure:
60 ml of dry toluene and 2.9 g (25.5 mmol) of trifluoroacetic acid are added, under argon, to 6.24 g (17 mmol) of 2,4-di-tert-butyl-6-[dimethylamino-(3,4-dimethyl-phenyl)-methyl]-phenol(compound (201). Table 2), prepared according to Example 1a. The reaction mixture is then maintained at 110° C. for 6 hours. After colling to room temperature, the mixture is poured into 50 ml of water and extracted three times using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Crystallisation of the residue from isopropanol yields 4.48 g (82%) of a mixture of 2,4-di-tert-butyl-6-(3,4-dimethyl-benzylidene)-cyclohexa-2,4-dienone (compound (301), Table 3) and the corresponding dimer (compound (401), Table 4), m.p. 214-217°C.