Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)[CH3:2].[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:12]([C:11]#[N:15])[C:13]#[N:14])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CBr)cc1
Reactant: N#CCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc(CC(C#N)C#N)cc1
Yield: 35.4 %

Procedure:
A mixed solution of 4-ethylbenzyl bromide (10.0 g), malononitrile (6.64 g), potassium carbonate (6.94 g) and tetra-n-butylammonium bromide (648 mg) in toluene (100 ml) was agitated at room temperature for 17 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate twice. The extract was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to give 2-(4-ethylphenylmethyl)malononitrile (3.28 g) as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Sc1ccccc1
Reactant: O=C1CCc2cc(OCCCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(6-bromohexoxy)-3,4-dihydro-carbostyril (m.p. 107.5°-108° C.) and thiophenol.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[NH:10][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: OCc1ccc(Cl)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: OCc1ccc(Nc2nccs2)nc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A suspension of (6-chloropyridin-3-yl)methanol (11.23 g, 78.22 mmol), 2-aminothiazole (9.40 g, 93.86 mmol, 1.2 eq), sodium carbonate (11.6 g, 109.5 mol, 1.4 eq) and XANTPHOS (0.543 g, 0.939 mmol, 0.012 eq) in THF (60 mL, bubbled with argon for 5 minutes) was bubbled again with argon for 5 additional minutes. Tris(dibenzylideneacetone)dipalladium (0) (0.269 g, 0.293 mmol, 0.004 eq) was then added to the suspension which was heated at 120° C. for 4 days. The mixture was cooled down to RT and filtered. The resulting solid was washed with toluene and tetrahydrofuran and suspended in water. This suspension was stirred for ˜0.5 hour and then filtered. The resulting solid was dried overnight under vacuum to give the title material (15.072 g, 93%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 4.44 (2H, d, J=5.6 Hz), 5.16 (1H, t, J=5.6 Hz), 6.98 (1H, d, J=3.7 Hz), 7.04 (1H, d, J=8.5 Hz), 7.37 (1H, d, J=3.6 Hz), 7.66 (1H, dd, J=8.5 and 2.2 Hz), 8.21 (1H, br d, J=1.5 Hz), 11.22 (1H, s). LC/MS (M+H)+: 208. HPLC ret. time (Condition A): 0.375 min.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([NH:23][OH:24])[CH3:22])[C:16]=1[Cl:25].C([O-])(=O)C.[Na+].O1CCOCC1>O>[CH3:5][O:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([N:23]([C:1](=[O:3])[CH3:2])[OH:24])[CH3:22])[C:16]=1[Cl:25]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccccc1Nc1cccc(C(C)NO)c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccccc1Nc1cccc(C(C)N(O)C(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
Acetyl chloride (0.49 g, 6.2 mmol) is added dropwise to a mixture of 2[[2-chloro-3-[1-(N-hydroxyamino)ethyl]phenyl]amino]benzoic acid methyl ester (2.0 g, 6.2 mmol) and sodium acetate (0.77 g, 9.4 mmol) in 2:1 dioxane:water with ice bath cooling. The reaction mixture is stirred at room temperature overnight. It is then diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer is washed with water (200 mL) and brine (100 mL), and is dried over magnesium sulfate. Evaporation of the ethyl acetate gives the crude product which is purified by flash chromatography (silica, 50% ethyl acetate/hexane). Recrystallization gives 2-[[3-[1-(acetylhydroxyamino)ethyl]-2-chlorophenyl]amino]benzoic acid methyl ester (0.34 g, 15%). mp=171-172° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH2:10][O:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:15][CH3:16].C([Li])CCC.[B:22](OC)([O:25]C)[O:23]C.[Cl-].[NH4+]>O1CCCC1>[CH:12]([O:11][CH2:10][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([B:22]([OH:25])[OH:23])=[C:3]([O:15][CH3:16])[CH:4]=1)([CH3:14])[CH3:13]
Reactant: COB(OC)OC
Reactant: COc1cc(COC(C)C)cc(OC)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(COC(C)C)cc(OC)c1B(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a tetrahydrofuran (20 ml) solution of 2-bromo-5-(isopropoxymethyl)-1,3-dimethoxybenzene (1.85 g, 6.40 mmol) was added dropwise 2.77M n-butyllithium (2.77 ml, 7.68 mmol) at −78° C., and the mixture was stirred for one hour. To the mixture was added trimethyl borate (0.86 ml, 7.68 mmol), and the mixture was warmed to room temperature. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added while cooling on ice, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate: 3/1 then 1/1) to obtain the title compound (571 mg, 2.25 mmol).
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([Li])(CC)C.C1CCCCC1>C1COCC1>[C:3]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[CH:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=C(Br)Br
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
Tert-butyl (2R)-2-(2,2-dibromovinyl)pyrrolidine-1-carboxylate (Intermediate XXXVIII, 8.1 g, 22.8 mmol) was dissolved in dry THF (200 mL) and cooled to −78° C. Then added sec-butyllithium 1.4M in cyclohexane (32.6 mL, 45.6 mmol) over 30 minutes and continued mixing an additional 30 minutes before quenching with 20% ammonium chloride solution (200 mL). The mixture was warmed to rt and diluted with ethyl ether (200 mL). The organic phase was separated, washed with brine, dried in vacuo and purified on a silica gel column using a 100% to 99:1 gradient of methylene chloride to methanol as mobile phase to yield pure tert-buty (2R)-2-ethynylpyrrolidine-1-carboxylate. LC-MS m/z (minus t-butyl+1)=220. 1H NMR (CD3OD, 400 Mhz) 4.44 ppm (s, 1H), 3.44-3.37 (m, 1H), 3.34-3.25 (m, 1H), 2.61 (s, 1H), 2.08-1.85 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH2:5][N:6]([CH3:11])[CH2:7][CH2:8][C:9]=2[N:10]=1.[BrH:12].N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:12][C:2]1[S:3][C:4]2[CH2:5][N:6]([CH3:11])[CH2:7][CH2:8][C:9]=2[N:10]=1
Reactant: Br
Reactant: CN1CCc2nc(N)sc2C1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCc2nc(Br)sc2C1
Temperature: 30 °C
Reaction time: 1.5 h

Procedure:
2-Amino-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (600.0 g) was suspended in water (6.0 L), and 48% hydrobromic acid (4.2 L) was added dropwise thereto at 5 to 15° C. A solution of sodium nitrite (367.2 g) in water (1.8 L) was added dropwise thereto at 0 to 5° C. over 1.5 hours, and the reaction mixture was heated to 30° C., followed by stirring for 24 hours. The resultant mixture was made strongly basic (pH 12.5) with 5N aqueous sodium hydroxide (6.0 L). The aqueous layer was extracted with toluene twice (12.0 L, 6.0 L), and the toluene layers were combined. The combined toluene layer was dried over sodium sulfate anhydrate (1202.0 g), and after any insoluble material was filtered off, the mother liquor was concentrated at 40° C. under reduced pressure, to thereby give 557.6 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(CO)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of tert-butyl 3-bromo-5-(hydroxymethyl)benzoate (0.8 g, 2.79 mmol) in dichloromethane (14 mL) at 0° C. was added Dess-Martin reagent (1.54 g, 3.62 mmol). The mixture was warmed to ambient temperature. After 1 h, saturated NaHCO3 and saturated Na2SO3 were added the mixture was extracted with dichloromethane (3×) The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→80% hexanes/ethyl acetate) gave the title compound (440 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C=C(OC)C=CC=3COC2=O)CC1>>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1/[CH:16]=[CH:15]/[CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C/C=C/c2cc(F)ccc2F)CC1
Agent: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C/C=C/c2cc(F)ccc2F)CC1

Procedure:
tert-Butyl{1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]piperidin-4-yl}carbamate (Intermediate 123, 299 mg, 0.85 mmol) was reacted as described for Intermediate 106. The crude trifluoro acetate of the title compound was obtained as an oil, 430 mg (quantitative), and used without further purification for the next step
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.CS(O[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: COC(=O)c1nc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Br)ccc1OCC1CCN(C(=O)OC(C)C)CC1
Yield: 81.9 %

Procedure:
Methyl 6-bromo-3-{[(1-{[(1-methylethyl)oxy]carbonyl}-4-piperidinyl)methyl]oxy}-2-pyridinecarboxylate (0.945 g, 86% pure) was prepared as a colorless oil from methyl 6-bromo-3-hydroxy-2-pyridinecarboxylate (0.70 g, 2.78 mmol), 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 131, Step 4, 1.23 g, 4.16 mmol) and K2CO3 (0.78 g, 5.55 mmol) in DMF (30 mL) in a manner similar to Example 131, Step 5. The crude product was purified by flash chromatography on an ISCO silica gel column using 0 to 45% EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 7.53 (d, 1H, J=8.5 Hz), 7.21 (d, 1H, J=8.8 Hz), 4.91 (septet, 1H, J=6.2 Hz), 4.30-4.10 (m, 2H), 3.93 (s, 3H), 3.86 (d, 2H, J=6.3 Hz), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.75 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 415/417 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[C:23]([F:28])[CH:22]=2)=[N:16]1.[CH3:29][C:30]([CH3:34])([CH3:33])[C:31]#[CH:32].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:32]#[C:31][C:30]([CH3:34])([CH3:33])[CH3:29])=[C:23]([F:28])[CH:22]=2)=[N:16]1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)c(F)c3)[nH]c2=O)c1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC(C)(C)C)c(F)c3)[nH]c2=O)c1
Yield: 12.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-3-(3-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide (0.080 g, 0.155 mmol), 3,3-dimethylbut-1-yne (0.019 g, 0.233 mmol), TBAF (0.121 g, 0.466 mmol), bis(triphenylphosphine)palladium(II)chloride (0.004 g, 0.006 mmol) and DMSO (3.0 mL) to afford 0.009 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.02 (d, J=6.9 Hz, 6H), 1.31 (s, 9H), 2.39-2.42 (m, 1H), 4.29 (d, J=5.7 Hz, 2H), 7.35 (d, J=7.5 Hz, 1H), 7.43 (s, 1H), 7.57-7.67 (m, 4H), 8.37 (m, 1H), 13.0 (br s, 1H); MS (m/z): 469.31 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[CH:19]=[CH:18][C:17]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:22][CH:21]=2)=[N:4][CH:3]=1
Reactant: Brc1cccnc1Br
Reactant: CCCCCCCCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc(-c2ccc(Br)cn2)cc1
Temperature: 100 °C
Yield: 95 %

Procedure:
To a 1000 mL round bottom flask equipped with a stirbar was added dibromopyridine 7C (22.506 g), boronic acid 7B (22.356 g), tetrakis(triphenylphosphine)palladium(0) (3.294 g), saturated sodium carbonate solution (238 mL), and toluene (190 mL). A reflux condenser was attached and the reaction was heated at 100° C. for 24 hours. The cooled reaction mixture was extracted with 1:1 hexane:ethyl acetate, and the combined organic layers were washed with brine and dried over magnesium sulfate and the solvent was removed in vacuo. The solid product was dissolved in dichloromethane, placed on silica gel, and silica gel filtered. The elution solvents were hexane, which removed a higher Rf side product, and 2.5% E/H, resulting in 31.251 g of solid. The product was recrystallized from acetonitrile to give 30.125 g of a white solid.
Reaction SMILES: [CH2:1]1[O:20][CH:4]([CH:5]2[CH2:14][CH2:13][C:12]3[C:7](=[C:8]([O:17][CH3:18])[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=3)[C:6]2=[O:19])[O:3][CH2:2]1.OC=C1CCC2C(=C(OC)C=C(OC)C=2)C1=O.[BH4-].[Na+]>CC(O)C>[CH2:2]1[O:3][CH:4]([CH:5]2[CH2:14][CH2:13][C:12]3[C:7](=[C:8]([O:17][CH3:18])[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=3)[CH:6]2[OH:19])[O:20][CH2:1]1
Reactant: COc1cc2c(c(OC)c1)C(=O)C(C1OCCO1)CC2
Agent: COc1cc2c(c(OC)c1)C(=O)C(=CO)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: COc1cc2c(c(OC)c1)C(O)C(C1OCCO1)CC2

Procedure:
A mixture of crude 1,2,3,4-tetrahydro-6,8-dimethoxy-1-oxo-2-naphthaldehyde ethylene acetal obtained from 5.73 g. of 2-hydroxymethylene-6,8-dimethoxy-1-tetralone, and 0.91 g. of sodium borohydride in 25 ml. of 2-propanol was stirred two hours at room temperature. The mixture was cooled and treated with 80 ml. of saturated aqueous ammonium chloride and extracted with ether. The ethereal extracts were washed with saturated aqueous solutions of sodium bicarbonate and sodium chloride, dried over anhydrous magnesium sulfate and evaporated to dryness to give 1,2,3,4-tetrahydro-1-hydroxy-6,8-dimethoxy-2-naphthaldehyde ethylene acetal which was converted directly to 3,4-dihydro-6,8-dimethoxy-2-naphthaldehyde as described hereinabove in Example 154.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]>C(O)(C)C.S(=O)(=O)(O)O>[OH:4][C:3]1[C:5]([CH:2]([CH3:8])[CH3:1])=[CH:6][C:7]([CH:5]([CH3:6])[CH3:3])=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: O=C(O)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)c1cc(C(=O)O)c(O)c(C(C)C)c1
Yield: 40 %

Procedure:
Salicylic acid (0.67 m) was alkylated with 1.33 m isopropanol using 3.3 m concentrated sulphuric acid as catalyst at 70°C for six hours, to give 2-hydroxy-3,5-diisopropyl benzoic acid (m.p. 113°-116°C) in 40% yield. This was esterified to form the methyl ester and converted into its hydrazide using hydrate in aqueous ethanol. The hydrazide had a melting point of 111°-113°C and the following elemental analysis by weight:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=CC=CC=1CN1CCNCC1.[C:16](=[O:19])([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]1[O:2][CH2:3][CH2:15][O:19][CH2:16][CH2:1][O:2][CH2:3][CH2:15][O:19][CH2:16][CH2:1][O:2][CH2:3][CH2:15][O:19][CH2:16]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1CN1CCNCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: C1COCCOCCOCCOCCOCCO1

Procedure:
3.0 g of intermediate compound 8a were reacted in 70 ml of DMF with 2.9 g of N-(2-methoxybenzyl)piperazine analogously to Example 8b in the presence of 5.7 g of potassium carbonate and a spatula tipful of 18-crown-6, 1.3 g (27%) of the product being obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)C(O)=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1.C(O)(C)(C)C.Cl>C1(C)C=CC=CC=1.C(OCC)C.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[O:35])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=C(C(=O)O)c2ccc(C)cc2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: CSc1ccc(CC(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 1000 mL four-necked round-bottomed flask equipped with mechanical stirrer, reflux condenser, nitrogen inlet, constant pressure addition funnel and thermometer was charged with 3-(4-methylthiophenyl-2-(4-methylphenyl)propenoic acid from Step 1 (25 g, 87.91 mmol), triethylamine (12.9 mL, 92.31 mmol) and toluene (200 mL). The addition funnel was charged with diphenylphosphoryl azide (19 mL, 87.91 mmol) dissolved in toluene (100 mL), and the reaction vessel was cooled to 0° C. Over approximately ten minutes, the diphenylphosphoryl azide solution was added to the reaction flask, keeping the reaction temperature ≥10° C. After holding the reaction temperature at 0° C. for 30 minutes, water (100 mL) was added, and the biphasic solution was transferred to a separatory funnel and extracted with toluene (2×200 mL). The combined organic solution was dried over anhydrous MgSO4 and filtered. Over approximately thirty minutes, the solution was carefully warmed to reflux and held for one hour. Upon removing the heat source, tert-butanol (9 mL, 96.7 mmol) was added, and reflux was continued for an additional thirty minutes. Concentrated HCl (8 mL, 96.8 mmol) was added with extreme caution, producing copious evolution of gas. After continuing reflux for a final twenty minutes, the reaction was cooled to room temperature, and held for 16 hours. The solvent volume was reduced in vacuo, until crystals appeared. Diethyl ether (300 mL) was added, and the suspension was cooled to 0° C., held for 30 minutes, filtered and washed with diethyl ether to provide, after air-drying, pure 2-(4-methylthiophenyl)-1-(4-methylphenyl) ethanone (11.3 g, 50%): mp 120°-121° C. 1H NMR (CDCl3) 300MHz 7.89 (d, J=8.26 Hz, 2H), 7.23-7.15(m, 6H), 4.21(s, 2H), 2.45(s, 3H), 2.40(s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].[F:13][C:14]1([F:32])[CH2:19][CH2:18][C:17]([CH2:30][NH2:31])([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[C:1]([C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:31][CH2:30][C:17]1([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)[CH2:18][CH2:19][C:14]([F:13])([F:32])[CH2:15][CH2:16]1)=[O:8])#[N:2]
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: Cc1c(C#N)cccc1C(=O)O
Product: Cc1c(C#N)cccc1C(=O)NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1

Procedure:
From 3-cyano-2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=438.2, tR (minutes, Method D)=0.75
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: N#Cc1ccc(Br)nc1
Product: N#Cc1ccc(-c2ccc(O)cc2)nc1
Yield: 23 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 4-hydroxybenzene boronic acid and 2-bromo-5-cyanopyridine to afford the title compound as a white solid (250 mg, 23%)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:17][CH3:18])(=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].C1(C)C=CC=CC=1.N1CCCCC1>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:11]([C:10]([O:17][CH3:18])=[O:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(O)cc1)C(=O)OC
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (280.9 g), dimethyl malonate (289.2 mL) and toluene (1.12 mL) were successively added acetic acid (13.2 mL) and piperidine (11.4 mL). After dehydration under refluxing at internal temperature of 70° C.-75° C. for about 4 hr, the mixture was cooled to internal temperature of not more than 10° C. and stirred further for 1 hr. The precipitated crystals were collected by filtration and washed with toluene (350 mL) to give the title compound (compound [8]; 523.7 g, yield 96.4%).,