Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:17][O:16][C:10]1[CH:15]=[CH:14][C:13]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:12][CH:11]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: COc1ccc(C(=O)c2ccccc2)cc1
Yield: 47 %

Procedure:
370 mg of benzoylchloride were reacted with 12 ml anisole to give the benzoylated product 4-methoxybenzophenone in 47% yield. The catalyst used is a HS—AlF3 metal fluoride on a Al2O3 support prepared according to the present invention, which is used in an amount of 300 mg. The reaction is carried out in a discontinuous batch process at 60° C. under reflux with stirring.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13](=[O:22])[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][CH2:10]O.S(Cl)([Cl:25])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13](=[O:22])[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][CH2:10][Cl:25]
Reactant: O=S(Cl)Cl
Reactant: O=C(NC(CCO)c1ccccc1Br)c1c(F)cccc1F
Solvent: c1ccccc1
Product: O=C(NC(CCCl)c1ccccc1Br)c1c(F)cccc1F
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of 12.9 g of N-[1-(2-bromophenyl)-3-hydroxypropyl]-2,6-difluorobenzamide in 80 ml of benzene under refluxing, was added dropwise 5.0 g of thionyl chloride for 10 minutes and stirring continued for an additional 30 minutes. Aftercooling, the precipitated solid was filtered, washed several times with n-hexane and dried to afford 13.0 g of N-[1-(2-bromophenyl)-3-chloropropyl]-2,6-difluorobenzamide. m.p. 183°-185° C.
Reaction SMILES: OS(O)(=O)=O.[OH:6]O.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([O:26][C:27]1[CH:34]=[CH:33][C:30](C=O)=[CH:29][CH:28]=1)=[C:21]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[CH:20]=[CH:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(Cl)Cl>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:6])=[CH:33][CH:34]=1)=[C:21]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[CH:20]=[CH:19]2)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(Oc2c(-c3ccc(F)cc3)ccc3cc(OCc4ccccc4)ccc23)cc1
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Oc2c(-c3ccc(F)cc3)ccc3cc(OCc4ccccc4)ccc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
Add 18M H2SO4 (1 mL, 16.8 mmol) dropwise into a solution of H2O2 (1 mL, 9.7 mmol) and 4-[6-benzyloxy-2-(4-fluoro-phenyl)-naphthalen-1-yloxy]-benzaldehyde at 0° C. and stir at room temperature for 12 hours. Add H2O (20 mL) and CH2Cl2 (100 mL). Separate layers and extract the aqueous layer with CH2Cl2 (2×50 mL). Combine the organic layers, dry with magnesium sulfate and concentrate in vacuo to obtain 1.88 g (73%) of the title compound: mass spectrum (ion spray) m/z=435.1 (M−H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: Cc1c2n(c3c(-c4ccc(N(C)C)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (31 mg, 37%), MS (ISP) m/z=338.5 [(M+H)+], mp 256° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-dimethylamino-phenylboronic acid (53.6 mg, 0.325 mmol).
Reaction SMILES: COCC1NC(C2C=C(C=CC=2C)C(OC)=O)=CN=1.[F:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1I.[Br:32][CH2:33][C:34](C1C=C(C=CC=1C)C(OC)=O)=[O:35]>>[Br:32][CH2:33][C:34]([C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:21]=1[F:20])[C:25]([O:27][CH3:28])=[O:26])=[O:35]
Reactant: COC(=O)c1ccc(F)c(I)c1
Reactant: COC(=O)c1ccc(C)c(C(=O)CBr)c1
Agent: COCc1ncc(-c2cc(C(=O)OC)ccc2C)[nH]1
Product: COC(=O)c1ccc(F)c(C(=O)CBr)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 27.3, except methyl 4-fluoro-3-iodobenzoate (compound 132.1) was used in place of methyl 3-(2-bromoacetyl)-4-methylbenzoate (compound 27.2).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl[C:29]1[N:34]=[C:33]([S:35][C:36]#[N:37])[C:32]([N+:38]([O-:40])=[O:39])=[CH:31][N:30]=1.O>O1CCCC1>[CH:1]1([N:4]([C:29]2[N:34]=[C:33]([S:35][C:36]#[N:37])[C:32]([N+:38]([O-:40])=[O:39])=[CH:31][N:30]=2)[C:5]2[CH:6]=[C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH:8]=[CH:9][CH:10]=2)[CH2:2][CH2:3]1
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC2CC2)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(N(c2ncc([N+](=O)[O-])c(SC#N)n2)C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [3-(cyclopropylamino)phenyl]carbamate (5.51 g, 15.4 mmol) in tetrahydrofuran (100 mL) were added N-ethyl-N-isopropylpropane-2-amine (8.06 mL, 46.2 mmol) and 2-chloro-5-nitropyrimidin-4-yl thiocyanate (6.66 g, 30.7 mmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water (100 mL), and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with saturated brine (30 mL), and filtered through a silica gel pad. The obtained filtrate was concentrated under reduced pressure to give tert-butyl {3-[cyclopropyl(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate as a brown amorphous solid. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [CH:1]1([N:7]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[CH:9][C:8]2=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[Br:20][C:9]1[C:8](=[O:19])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2ccc(=O)n(C3CCCCC3)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc2cc(Br)c(=O)n(C3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
8-Cyclohexyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (4 g, 14.5 mmol) was dissolved in dimethyl formamide (100 mL) and to this solution was added N-bromosuccinimide (3.9 g, 21.8 mmol) and benzoylperoxide (0.53 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 3 days then diluted with ethyl acetate and washed with water then twice with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 6-bromo-8-cyclohexyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one a cream colored solid (8 g). This crude intermediate was redissolved in CH2Cl2 and treated with 2-benzenesulfonyl-3-phenyl-oxaziridine (3.78 g, 14.5 mmol). The resulting solution was stirred at room temperature overnight then concentrated under reduced pressure and chromotographed on silica gel eluting with ethyl acetate. 6-Bromo-8-cyclohexyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one was obtained as a colorless solid (3.72 g, 67%). 1H NMR: δ(400 MHz, CDCl3) 8.90 (s, 1H), 8.13 (s, 1H), 5.41 (br s, 1H), 2.96 (s, 3H), 2.58-1.70 (m, 2H), 1.87 (br d, J=13 Hz, 2H), 1.31-1.47 (m, 2H), 1.28 (t, J=3 Hz, 2H).
Reaction SMILES: [CH:1]1([CH:4]([N:11]([CH2:15][CH2:16][CH3:17])[C:12]([NH2:14])=[S:13])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH:26]([CH3:37])[C:27]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[Cl:36])=O>C(O)C>[Cl:36][C:30]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:29]=1[C:27]1[N:14]=[C:12]([N:11]([CH:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH3:17])[S:13][C:26]=1[CH3:37]
Reactant: CCCN(C(N)=S)C(c1ccccc1)C1CC1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccccc1)C1CC1
Temperature: 75 °C
Yield: 79 %

Procedure:
To 1.35 g of N-(α-cyclopropylbenzyl)-N-propylthiourea (Compound 75) in 35 ml of ethanol, add 546 mg of triethylamine, then slowly 1.52 g of 2-bromo-1-(2,4-dichlorophenyl)-1-propanone (Compound 15). After 3 hours of heating at 75° C., remove the precipitate formed by filtration. The ethanolic solution is evaporated to dryness. Take up the residue in ethyl ether and wash with water until bromide ions have disappeared. Dry the organic phase over anhydrous sodium sulphate and then evaporate to dryness. Purify the residue on a silica column, using a mixture of cyclohexane and ethyl acetate (10:1 V/V) as eluent, to obtain the expected product. Recrystallise in acetonitrile (white crystals).
Reaction SMILES: [C:1]([C@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:20]C([N-]C(C)C)C.C1COCC1.CCCCCCC.IC.[NH4+].[Cl-]>C1COCC1>[C:1]([C@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[C@H:7]([CH3:20])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: CN1C(=O)CN(C(=O)OC(C)(C)C)[C@H]1C(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CI
Product: C[C@H]1C(=O)N(C)[C@H](C(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (S)-tert-butyl 2-(tert-butyl)-3-methyl-4-oxoimidazolidine-1-carboxylate (0.5 g, 1.95 mmol; available from Aldrich#337595) in dry THF (15 ml) cooled to −78° C., LDA 2M in THF/heptane (0.97 ml, 1.95 mmol) was added and the reaction mixture stirred at this temperature for 40 min before adding iodomethane (0.146 ml, 2.34 mmol). The reaction was allowed to warm to RT and stirred for 18 hrs. The reaction mixture was cooled again at −78° C. then LDA 2M in THF/hepatane (0.3 ml) and iodomethane (0.04 ml, 0.6 mmol) were added in sequence. The mixture was allowed to reach RT and further stirred for 5 hrs. The resulting solution was treated with NH4Cl sat sol (5 ml) and extracted with Et2O. The organic phases were collected and washed with NaCl sat sol, dried over Na2SO4 and evaporated in vacuo to afford a residue which was purified by Biotage SNAP-Si column (25 g) eluting with cHex/Et2O 60/40. Collected fractions after solvent evaporation afforded the title compound (D43) (430 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=[C:16]1CNCCN1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[H-].[Na+].CI.[Cl-].[Na+]>CN(C)C=O>[CH3:16][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]1=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: O=C1CNCCN1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8 g of 4-t-butoxycarbonyl-2-oxopiperazine (previously prepared from 2-oxopiperazine and di-t-butyl dicarbonate) were dissolved in 80 ml of dimethylformamide. 1.92 g of sodium hydride (55%, in paraffin) were added to this solution, and the mixture was stirred at room temperature for one hour. A solution of 6.8 g of methyl iodide in 20 ml of dimethylformamide was then added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography through silica gel, eluted with ethyl acetate, to give 3.0 g of 1-methyl-2-oxo-4-t-butoxycarbonylpiperazine in the form of colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=1.C([Li])CCC.[CH3:19][S:20]SC>C(OCC)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:20][CH3:19])[CH:4]=1
Reactant: COc1ccnc(-c2cccs2)c1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccnc(-c2sccc2SC)c1
Temperature: 25 °C

Procedure:
The product of step (b) above (5 g) dissolved in dry diethyl ether (100 ml) was cooled to -50° and treated with butyl lithium in hexane (2.2M, 13 ml) dropwise during 0.5 hour. The mixture was warmed to -10° for 10 minutes, then cooled to -30°. Dimethyl disulphide (3.5 ml) was then added dropwise. The mixture was maintained at -30° for 0.5 hour then warmed up to room temperature during several hours. Aqueous work-up and ethyl acetate extraction gave the sub-title compound as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]Br)=[N:13][NH:12][C:11]=1[NH2:20].NC1NN=C(CCCCO)C=1[C:32]1SC2C=CC=C[C:35]=2[N:36]=1.CNC.C1COCC1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:36]([CH3:35])[CH3:32])=[N:13][NH:12][C:11]=1[NH2:20]
Reactant: Nc1[nH]nc(CCCCBr)c1-c1nc2ccccc2s1
Reactant: Nc1[nH]nc(CCCCO)c1-c1nc2ccccc2s1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)CCCCc1n[nH]c(N)c1-c1nc2ccccc2s1

Procedure:
The title compound (41 mg) was prepared using 185 mg (0.39 mmol) of 4-benzothiazol-2-yl-5-(4-bromobutyl)-2H-pyrazol-3-ylamine, which was derived from 4-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-butan-1-ol, and 5 mL of a 2 M solution of dimethylamine in THF (10 mmol). MS (m/z, ES+): 316.4 (M+1, 100%).
Reaction SMILES: C(NCC(C)C)C(C)C.[OH:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][O:17][C:13]=2[C:12]=1[CH2:24][CH2:25][CH3:26].S(Cl)([Cl:30])(=O)=O.O1C2C=CC=CC=2C=N1.S(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)C>[Cl:30][C:23]1[C:11]([OH:10])=[C:12]([CH2:24][CH2:25][CH3:26])[C:13]2[O:17][N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[C:14]=2[CH:22]=1
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)CNCC(C)C
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCc1c(O)c(Cl)cc2c(C(F)(F)F)noc12
Reaction time: 8 h

Procedure:
Diisobutylamine (0.8 ml, 0.10 eq) and 6-hydroxy-7-propyl-3-trifluoromethylbenzisoxazole (11 gm, 1.0 eq) were dissolved in toluene (275 ml) at room temperature. Slow addition of sulfuryl chloride (4.20 ml, 1.15 eq) results in a suspension which was stirred overnight. Additional diisobutylamine (total 1.6 ml, 0.4 eq) was added in four equal portions over 24 hr until no further starting benzisoxazole was detected by analytical TLC. The reaction mixture was poured into saturated sodium bisulfite (500 ml) and ethyl ether (700 ml). The phases were separated. The ether phase was washed with brine and dried over Na2SO4. The solvent was evaporated in vac to give an orange solid which was purified by chromatography on silica gel eluting with acetone:hexane (2:98) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:24]1([CH2:34][C:35](Cl)=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.O>C(Cl)Cl>[C:24]1([CH2:34][C:35]([N:12]2[CH2:11][CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[CH2:14][CH2:13]2)=[O:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1cccc2ccccc12
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cccc2ccccc12)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
To a solution of 7.5 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and 4.6 ml of triethylamine in 40 ml of methylene chloride, 6.75 g of 1-naphthylacetyl chloride in 30 ml of methylene chloride area added dropwise at 0° C. The mixture is stirred at 0° C. for 2 hours and water is added. The organic phase is separated, washed with water many times and concentrated under reduce pressure to give 11 g of crude product. Crystallization from 95% ethanol yields 8 g of 1-(1-napthylacetyl)4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine; m.p. 137°-140° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][N:6]=1)=[O:4].O.[OH-].[Li+]>CO.O>[F:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ncc(F)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(F)cnc1C(=O)O
Reaction time: 16 h
Yield: 86.9 %

Procedure:
To a solution of 5-fluoro-3-methyl-pyridine-2-carboxylic acid methyl ester (1.28 g) in MeOH (6 ml) was added at 22° C. a solution of lithium hydroxide mono hydrate (636 mg) in water (3 ml) and stiring was continued for 16 h. The mixture was diluted with water, the MeOH was evaporated at reduced pressure and the pH was adjusted to 1 using 1 N aqueous HCl. The aqueous layer was extracted with AcOEt, the organic layer was dried, evaporated and the residue was crystallized from AcOEt/n-heptane to give the title compound (1.02 g) as a pale yellow solid. MS: m/z=153.7 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].Br[CH2:15][C:16]([C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=O>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([C:6]2[O:7][CH:15]=[C:16]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Product: CCOC(=O)c1ccc(-c2coc(-c3cccc(C(F)(F)F)c3)n2)cc1
Yield: 22 %

Procedure:
In the same manner as in Example 1, 3-trifluoromethylbenzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-[2-(3-trifluoromethylphenyl)-4-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 22%. Pale yellow prisms. Melting Point: 132 to 133° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([CH3:19])([CH3:18])[CH2:7][CH2:6][C:5]2([CH3:21])[CH3:20].[Li]CCCC.[C:27](=[O:29])=[O:28]>O1CCCC1>[CH:12](/[C:11]1[C:2]([C:27]([OH:29])=[O:28])=[CH:3][C:4]2[C:5]([CH3:20])([CH3:21])[CH2:6][CH2:7][C:8]([CH3:19])([CH3:18])[C:9]=2[CH:10]=1)=[CH:13]/[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C=O
Reactant: CCCC/C=C\c1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC/C=C\c1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C
Temperature: 25 °C

Procedure:
3.72 g of (Z)-6-bromo-7-hex-1-enyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (75% pure) were placed in 25 ml of abs. tetrahydrofuran and treated at -75° with 8.25 ml of 1.55M n-BuLi (hexane) (1.2 eq.). After 1/2h., a CO2 stream was conducted vigorously through the solution for 30 min., with the temperature rising to -60° in spite of constant cooling. The mixture was left to warm to room temperature, poured on to ice/HCl solution, extracted with diethyl ether, washed with H2O, dried over Na2SO4 and the solvent was removed in a vacuum. Two-fold flash chromatography on SiO2 (hexane/ethyl acetate=85/15, then 9/1) yielded 1.06 g of (Z)-3-hex-1-enyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.N#N.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C1COCC1.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnc(Cl)n1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a mixture of Pd(PPh3)2Cl2 (0.9 g) and PPh3 (0.7 g) in THF (200 mL) and Et3N (300 mL) was added 2,4-dichloropyrimidine (40 g, 0.27 mol) under a stream of N2. After bubbling N2 into the solution for 15 min, CuI (0.5 g) was added, followed by (trimethylsilyl)acetylene (29 g, 0.29 mol). The mixture was heated at reflux for 4.5 h. The mixture was cooled to rt and filtered, washing with EtOAc. The filtrated was concentrated and the residue was diluted with hexanes (500 mL) and loaded directly onto a short pad of SiO2. The product was eluted with 10% EtOAc/hexanes to provide a light orange solid (49.3 g), which was used without further purification. TLC: Rf=0.42. mp 51-54° C. IR: 3125 (w), 2961 (w), 1557 (s), 1523 (s). 1H NMR: 8.58 (d, J=5.0 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 0.28 (s, 9H). 13C NMR: 162.23, 160.16, 153.41, 122.52, 104.23, 100.75, 0.01. Anal. Calcd for C9H11ClN2Si: C, 51.29; H, 5.26; N, 13.29. Found: C, 51.45; H, 5.16; N, 13.33.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:13]=2[C:14]([OH:16])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:30])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:13]=2[C:14]([Cl:30])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)c(C(=O)O)c(-c3ccco3)nn12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(C(=O)Cl)c(-c3ccco3)nn12
Reaction time: 0.5 h
Yield: 105.3 %

Procedure:
To a solution of 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid (358 mg) and N,N-dimethylformamide (1.39 mg) in dichloromethane (3 mL) was added oxalyl chloride (157 mg) at room temperature. After stirring for 30 minutes, the volatile was removed in vacuo, and the residue was azeotroped with toluene three times to afford 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carbonyl chloride as an yellow gum (396 mg, 106%).
Reaction SMILES: [C:1]([OH:12])(=O)[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10].COC(=O)CC(OS(C)(=O)=O)CCC[Cl:21].COC(=O)CC(O)CCCCl>>[C:1]([Cl:21])(=[O:12])[CH:2]=[CH:3][CH2:4][CH2:5][CH:6]=[CH:7][CH:8]=[CH:9][CH3:10]
Reactant: COC(=O)CC(CCCCl)OS(C)(=O)=O
Reactant: CC=CC=CCCC=CC(=O)O
Agent: COC(=O)CC(O)CCCCl
Product: CC=CC=CCCC=CC(=O)Cl

Procedure:
GC/MS (m/e); 184 (M+, 6%), 149 (7), 121 (3), 105 (2), 93 (3), 81 (100), 68 (14), 53 (15), 41 (14)