Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[CH2:19]1[O:22][CH:20]1[CH3:21]>CO>[OH:22][CH:20]([CH3:21])[CH2:19][N:16]1[CH2:17][CH2:18][N:13]([C:2](=[O:1])[CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[CH:8]=[O:9])[CH2:14][CH2:15]1
Reactant: O=Cc1cccc(OCC(=O)N2CCNCC2)c1
Reactant: CC1CO1
Solvent: CO
Product: CC(O)CN1CCN(C(=O)COc2cccc(C=O)c2)CC1
Temperature: 70 °C
Yield: 50 %

Procedure:
3-(2-oxo-2-(piperazin-1-yl)ethoxy)benzaldehyde (50) (1 eq) was taken in MeOH to which propylene oxide (4 eq) was added and the reaction mixture was heated in a sealed tube at 70° C. for 16 h when LCMS showed completion of reaction. The reaction mixture was concentrated and purified by column chromatography using silica gel (100-200 mesh) to afford the pure product (50%) as a colorless oil. LCMS: 96.31% (M++1).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[CH3:17][C:18]([CH3:27])([CH2:23][CH2:24][CH2:25][CH3:26])[C:19](OC)=[O:20]>CCCCCC.O1CCCC1>[O:20]=[C:19]([C:18]([CH3:27])([CH3:17])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCC(C)(C)C(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 18.4 g. (0.116 moles) dimethyl methylphosphonate (Aldrich) in 200 ml. dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 67.3 ml. of 1.90 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 10.2 g. (58.1 mmoles) methyl 2,2-dimethylhexanoate is added dropwise at a rate that kept the reaction temperature less than -70°(20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 10 ml. acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml. water, the aqueous phase extracted with 100 ml. portions of chloroform (3×), the combined organic extracts are backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled (b.p. 80°-85° at 0.05 mm) to give dimethyl 2-oxo-3,3-dimethylheptylphosphonate.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[Cl:19][C:20]1[N:28]=[C:27]([Cl:29])[C:26]([F:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].CN([CH:34]=[O:35])C.Cl>C1COCC1>[Cl:19][C:20]1[C:21]2[C:22](=[O:24])[O:23][CH:34]([OH:35])[C:25]=2[C:26]([F:30])=[C:27]([Cl:29])[N:28]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C1OC(O)c2c(F)c(Cl)nc(Cl)c21
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
To a butyllithium-hexane solution (100 mL, 160 mmol) in THF (200 mL) was slowly added diisopropylamine (27.4 mL, 192 mmol) in THF (15 mL) at −78° C. The mixture was stirred at the same temperature for 15 min. A solution of 2,6-dichloro-5-fluoronicotinic acid (14.98 g, 71.4 mmol) in THF (15 mL) was added and the mixture was stirred for 2 h. Next, DMF (29.3 mL, 378 mmol) was added and the mixture was stirred for 1 h. Hydrochloric acid (1N, 400 mL) was added and the mixture was subsequently extracted with EtOAc (2×300 mL). The organic phase was basified with saturated aq NaHCO3 solution and the aqueous phase was separated. The aqueous phase was re-acidified with 1N HCl (300 mL) and extracted with EtOAc (2×300 mL). The organic phase was washed with H2O (200 mL) and brine (200 mL), dried over MgSO4, and evaporated. The residue was washed with Hexane/EtOAc (1/8) to give the title compound as a white solid (11.5 g, 67.7%). 1H NMR (500 MHz, DMSO-d6) δ ppm 6.85 (br s, 1H), 8.82 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:21](=[O:23])=[O:22].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:14][C:10]1([CH3:15])[O:9][CH:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:21]([OH:23])=[O:22])[CH2:13][CH2:12][O:11]1
Reactant: CC1(C)OCCC(c2cccc(Br)c2)O1
Reactant: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)OCCC(c2cccc(C(=O)O)c2)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A 1 g portion of 4-(3-bromophenyl)-2,2-dimethyl-1,3-dioxane was dissolved in 18 ml of THF solution and cooled to −78° C., and then 2.35 ml of hexane solution containing 1.57 M n-butyl lithium was added dropwise thereto spending 1 hour. After completion of the dropwise addition, this was further stirred for 30 minutes. After adding excess amount of carbon dioxide thereto at −78° C., the mixture was risen to room temperature. The reaction solution was mixed with ammonium chloride aqueous solution and extracted 10 times with chloroform-methanol (5:1), the organic layer was dried with sodium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 550 mg (63%) of 3-(2,2-dimethyl-1,3-dioxan-4-yl)benzoic acid (Reference Example 15-1). FA: 237
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:33])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and benzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](=[S:5])[S-:4].C[NH2+]C.C(=S)=S.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:21]([CH3:24])([O-:23])=[O:22]>C(O)C>[CH3:1][N:2]([CH3:6])[C:3](=[S:4])[S:5][CH:13]([CH2:24][N+:21]([O-:23])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: CCO
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccccc1

Procedure:
A solution of dimethylammonium dimethyldithiocarbamate (16.6 grams, 0.10 mole), carbon disulfide (7.6 grams, 0.10 mole), benzaldehyde (21.2 grams, 0.20 mole), and nitromethane (9.2 grams, 0.15 mole) in 95% ethanol (50 ml.) was allowed to stand at 23° C. for several days. The resulting precipitate was filtered off, washed with cold 95% ethanol, and dried in air. The solid product, which melted at 101° - 102° C., was recrystallized from 2-propanol to give α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 105° - 106° C. The structure was determined from infrared and nuclear magnetic resonance spectra and elemental analysis.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[S:3]([O:6][C:7]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]2=C)(=[O:5])=[O:4].[O:17]=[O+][O-].CSC.O>CO>[F:1][C:2]([F:16])([F:15])[S:3]([O:6][C:7]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]2=[O:17])(=[O:5])=[O:4]
Reactant: C=C1CC2CCC1(OS(=O)(=O)C(F)(F)F)C2
Reactant: O=[O+][O-]
Solvent: O
Solvent: CSC
Solvent: CO
Product: O=C1CC2CCC1(OS(=O)(=O)C(F)(F)F)C2
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of methylenebicyclo[2.2.1]heptan-1-yl trifluoromethanesulfonate (7.6 g, 0.03 mol) in methanol (100 mL) was cooled to −40° C. and an ozone stream was passed through the reaction mixture. When the color of the mixture turned to blue, the ozone was eliminated by passing a stream of argon through the solution for 10 min. Dimethyl sulfide (5 mL) was added to the mixture and the reaction mixture was allowed to warm to room temperature. The resulting mixture was poured into water and extracted with DCM (2×40 mL). The combined extracts were washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give the desired product (4.6 g, 18.1 mmol, yield: 60%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.73 (brs, 1H), 2.44-2.34 (m, 2H), 2.26-2.13 (m, 4H), 2.06-2.02 (m, 1H), 1.70-1.66 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([O:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][CH:3]=2)=[O:34])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc(C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
A 200 ml. four-necked flask equipped with a condenser tube and a thermometer was charged with 36 g of p-acetoxybenzoic acid and 71.4 g of thionyl chloride, and they were reacted at 50° C. for 4 hours. The excess of thionyl chloride was evaporated under reduced pressure to give p-acetoxybenzoyl chloride. Then, a 300 ml four-necked flask equipped with a condenser tube, a thermometer and a dropping funnel was charged with 45.7 g of benzyl p-hydroxybenzoate, 20.2 g of triethylamine and 100 ml of toluene. The temperature of the flask was raised to 30° C., and a solution of 39.7 g of p-acetoxybenzoyl chloride in 50 g of toluene was added dropwise over 1 hour, and the reaction was carried out at 50° C. for 30 minutes. After cooling, the reaction mixture was washed with three 50 ml portions of water, and the solvent was evaporated under reduced pressure. Recrystallization of the residue from methanol gave benzyl p-(p-acetoxybenzoyloxy)benzoate.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1>ClCCl>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][NH:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: NCC1OCCO1
Solvent: ClCCl
Product: c1ccc(NCC2OCCO2)cc1
Reaction time: 0.08 h
Yield: 28.6 %

Procedure:
A suspension of phenylboronic acid (0.5 g, 4.1 mmol), copper(II)-acetate-1-hydrate (0.041 g, 0.21 mmol) and molecular sieves (1.5 g, size 0.4 nm, powdered) in dichloromethane (12 ml) was stirred for 5 min. Then 2-(aminomethyl)-1,3-dioxolane (0.211 g, 2.05 mmol) was added and oxygen was bubbled through the mixture for 5 min. The vessel was closed and shaken overnight at room temperature. For workup ethyl acetate (50 ml) and 1 M sodium bicarbonate solution (30 ml) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (SiO2; eluent: heptane/ethyl acetate=90:10) to yield a light yellow oil (105 mg, 14%); MS (EI): 179.1 (M+.).
Reaction SMILES: [CH3:1][N:2]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C@@H:35]([OH:72])[C@@H:36]([OH:71])[C@@H:37]([NH:45][C:46](=[O:70])[C@H:47]([CH:67]([CH3:69])[CH3:68])[NH:48][C:49]([N:51]([CH2:53][C:54]1[N:55]=[C:56]([NH:59]C(OC(C)(C)C)=O)[S:57][CH:58]=1)[CH3:52])=[O:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:3][C:4]1[N:5]=[C:6]([NH:9]C(OC(C)(C)C)=O)[S:7][CH:8]=1.CO.C(N)(C)C>C(Cl)(Cl)Cl>[CH3:52][N:51]([C:49]([NH:48][C@H:47]([C:46]([NH:45][C@H:37]([C@@H:36]([OH:71])[C@@H:35]([OH:72])[C@@H:27]([NH:26][C:24](=[O:25])[C@H:20]([CH:21]([CH3:22])[CH3:23])[NH:19][C:17]([N:2]([CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)[CH3:1])=[O:18])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:70])[CH:67]([CH3:69])[CH3:68])=[O:50])[CH2:53][C:54]1[N:55]=[C:56]([NH2:59])[S:57][CH:58]=1
Reactant: CC(C)[C@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(C)C
Solvent: CC(C)N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)N(C)Cc1csc(N)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(N)n1)C(C)C

Procedure:
Using the procedure of Example 58B but replacing the resultant compound of Example 58A with the resultant compound of Example 93 provided, after silica gel chromatography using first 5% then 10% methanol in chloroform followed by 2% isopropylamine/10% methanol in chloroform, 53 mg (38%) of the desired compound (Rf 0.15, 10% methanol in chloroform) as a white solid, m.p. 130°-134° C. Mass spectrum: (M+1)+ =837.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH2:22][O:23][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of 1,4-di(tert-butoxycarbonyl)-2-(2-hydroxyethyl)piperazine (5.05 g) and p-toluenesulfonyl chloride (4.34 g) in methylene chloride (200 ml) was cooled to 0° C., followed by the dropwise addition of triethylamine (11 ml). The resulting mixture was stirred at 0° C. for 1 hour and at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure. After dilution with ethyl acetate, the residue was washed with 1N hydrochloric acid, water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane=1/4 to 1/1) using, as a carrier, silica gel, whereby the title compound (4.82 g) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:15])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>CC(C)=O>[C:16]([NH:24][C:25]([NH:15][C:4]1[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cnc(N2CCOCC2)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1cnc(N2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.1 %

Procedure:
To a stirred solution of 27.5 g (132 mmol) 5-methoxy-2-morpholin-4-yl-pyridin-4-ylamine in 400 ml acetone was added dropwise 19.5 ml (145 mmol) benzoyl isothiocyanate at room temperature. The reaction mixture then heated at reflux for 90 min before being cooled to room temperature and poured onto 400 ml hexane and stirred for 5 min. The resulting crystals were collected by filtration, washed with hexane and dried to afford 32.5 g (66%) 1-benzoyl-3-(5-methoxy-2-morpholin-4-yl-pyridin-4-yl)-thiourea as a brown crystalline solid. ES-MS m/e (%): 373 (M+H+, 100).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:32]([C:31]1[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][CH:30]=1)[OH:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(Cl)cc1)c1ccccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.44 M, 10.3 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (6.0 g, 22.8 mmol) in THF (228 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-chlorobenzaldehyde (2.67 g, 19.0 mmol) in THF (76 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for two hour and further more at 0° C. for one hour. Water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)] to obtain the title compound (4.76 g, 77%).
Reaction SMILES: [ClH:1].N[C:3]1[C:11]([S:12][CH3:13])=[CH:10][C:9]([CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].N([O-])=O.[Na+]>O.[Cu]Cl>[Cl:1][C:3]1[C:11]([S:12][CH3:13])=[CH:10][C:9]([CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CSc1cc(C)cc(C(=O)O)c1N
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CSc1cc(C)cc(C(=O)O)c1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
13 ml of concentrated hydrochloric acid were added to 6.00 g (30.4 mmol) of 2-amino-5-methyl-3-(methylthio)benzoic acid in 35 ml of water, and the mixture was heated at 60° C. for a few minutes. The solution was then cooled to a temperature of 0° C.-5° C., and a solution of 2.31 g (33.5 mmol) of sodium nitrite in 10 ml of water was slowly added dropwise at this temperature. The mixture was subsequently stirred at this temperature for another 1 h. This solution was added dropwise to a mixture, at RT, of 4.52 g (45.6 mmol) of copper(I) chloride, 35 ml of water and 27 ml of concentrated hydrochloric acid. The mixture was stirred at room temperature for 15 minutes and then slowly heated to reflux temperature. The contents were then heated under reflux for 15 minutes. For work-up, the reaction mixture was cooled and filtered, and the residue was washed with water. This gave 5.62 g of 2-chloro-5-methyl-3-(methylthio)benzoic acid as residue.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH3:7])=[O:6].[H-].[Na+].[Li]CCCC.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][C:32]2([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[O:33][C:3](=[O:2])[CH2:4][C:5](=[O:6])[CH2:7]2)=[CH:28][CH:29]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCC1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)(C2CCCC2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
Methylacetoacetate (1.63 mL, 15.1 mmol) was dissolved in dry THF (42 mL) and cooled to 0° C. NaH (60% in mineral oil, 0.604 g, 15.1 mmol) were carefully added and the reaction mixture was stirred for 20 min. A solution of BuLi in hexanes (1.6 M, 9.44 mL, 15.1 mmol) was added dropwise and the resulting mixture was stirred an additional 20 min. A solution of 3-(4-benzyloxyphenyl)-1-cyclopentylpropan-1-one (2.33 g, 7.55 mmol) from Step 5 above in THF (37 mL) was added dropwise. After stirring 1 h, the reaction mixture was quenched with saturated aq NH4Cl (100 mL) and extracted with Et2O (600 mL). The organic phase was dried over MgSO4 and evaporated. The residue was then stirred overnight in a mixture of 0.1 M NaOH (370 mL) and THF (37 mL). After the addition of an aq solution of 10% aq KHSO4 (50 mL) the resulting mixture was stirred 30 min and then extracted with Et2O (600 mL). The organic phase was washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (50% EtOAc in hexanes) to give the product (1.54 g, 52%) as a white foam. 1H NMR (CDCl3) δ 1.39-2.04 (m, 10H), 2.21-2.33 (m, 1H), 2.56-2.67 (m, 2H), 2.76 (s, 2H), 3.41 (s, 2H), 5.03 (s, 2H), 6.87-6.93 (m, 2H), 7.02-7.08 (m, 2H), 7.28-7.44 (m, 5H).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=1[F:18])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:19](OC(=O)C)(=O)C.C(OCC)(OCC)OCC.[NH2:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39]>CCO.C(Cl)Cl>[OH:39][CH2:38][C:37]([NH:36]/[CH:19]=[C:3](/[C:2](=[O:1])[C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=1[F:18])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:41])[CH3:40]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(N)CO
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)/C(=C\NC(C)(C)CO)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of commercially available ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propanoate (6) (15 g, 56.8 mmol), acetic anhydride (13.4 mL, 142 mmol) and triethyl orthoformate (14.1 mL, 18 mmol) was heated at 120° C. for 1.5 h. The mixture was concentrated in vacuo and dried under high vacuum for 5 hours. 10.1 g (31.5 mmol) of the crude product were dissolved in EtOH/DCM (30 mL) and cooled to 0° C. 2-Amino-2-methylpropan-1-ol (3.36 mL, 34.7 mmol) was added very slowly to this solution. After 30 minutes, the solvent was removed by evaporation and the product was freeze-dried to yield 7, as a yellow solid (11.9 g crude) that was used in the next step without further purification.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].CN([CH:11]=[C:12]([C:16](=O)[CH3:17])[C:13]([O-:15])=[O:14])C.[CH2:19](O)[CH3:20]>CCOCC>[C:2]([N:6]1[C:16]([CH3:17])=[C:12]([C:13]([O:15][CH2:19][CH3:20])=[O:14])[CH:11]=[N:7]1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CC(=O)C(=CN(C)C)C(=O)[O-]
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
In ethanol (10 mL) was placed the tert-butylhydrazine hydrochloride (1.35 g, 10.8 mmol) and ethyl 2-((dimethylaminomethylene)-3-oxobutanoate (2.00 g, 10.8 mmol). The mixture warmed to reflux and stirred for 2 hrs, cooled to RT and stirred overnight. The mixture was evaporated at reduced pressure to give an oil which was dissolved in ether (25 mL) and washed successively with water (25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL), dried (Na2SO4 and evaporated at reduced pressure to give an oil. The oil was purified by chromatography (Biotage S1-25 column, 10-40% ethyl acetate/Hex 750 mL) to give ethyl 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylate (1.48 g, 65% yield) as an oil. MS (ESI) m/z: 211.0 (M+H+).