Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:16][CH2:17][C:18]2([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:12](OC)=[O:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:7]=2)[CH:3]=1.[BH4-].[Li+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:16][CH2:17][C:18]2([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:12][OH:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:43])[CH3:44])[N:7]=2)[CH:3]=1
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (850 mg, 1.28 mmol) in tetrahydrofuran (7.4 mL) and methanol (0.37 mL) at 0° C. was added lithium borohydride (55.9 mg, 2.57 mmol). The ice bath was removed and stirring continued for 30 min. The reaction was diluted with diethyl ether and quenched by addition of saturated ammonium chloride. The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→50% ethyl acetate/n-hexane) gave 794 mg (98%) as a foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.33 (dd, J=8.6, 5.2 Hz, 2H), 7.05 (dd, J=8.6, 8.5 Hz, 2H), 6.75 (s, 1H), 5.65 (d, J=10.7 Hz, 1H), 5.62 (d, J=10.7 Hz, 1H), 4.95 (dd, J=7.0, 3.4 Hz, 1H), 3.55-3.85 (m, 6H), 3.52 (d, J=8.9 Hz, 1H), 3.41 (d, J=8.9 Hz, 1H), 3.06 (m, 2H), 2.10-2.35 (m, 3H), 1.88 (m, 2H), 1.43 (s, 9H), 0.90 (t, J=8.2 Hz, 2H), −0.06 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=246 Hz), 155.0, 145.7, 138.6, 130.2, 128.8 (d, J=7.7 Hz), 128.1, 124.2, 122.8, 122.5, 118.5, 115.4 (d, J=21 Hz), 81.9, 79.5, 79.1, 78.6, 67.7, 66.2, 41.5, 40.0, 32.3, 32.2, 28.6, 17.9, −1.4. Mass spec.: 634.38 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH:5]=[C:4]([CH3:8])[O:3]1.[CH:18]#[N:19]>N1C=CC=CC=1>[CH3:8][C:4]1([C:18]#[N:19])[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:3]1
Reactant: C#N
Reactant: CC1=CCCC(C)(COCc2ccccc2)O1
Solvent: c1ccncc1
Product: CC1(C#N)CCCC(C)(COCc2ccccc2)O1
Reaction time: 16 h

Procedure:
A mixture of 15.0 g 3,4-dihydro-2,6-dimethyl-2-[(phenylmethoxy)methyl]-2H-pyran, 1.75 g liquid hydrogen cyanide, and 0.1 g pyridine sealed in a 30 ml glass bomb was kept at 150° C. for 16 hours. The resulting dark brown solution was distilled (Kugelrohr) to give 15.7 g colorless product, bp 112°-118° C. (0.01 torr), as an isomeric mixture, ca 4:6, cis:trans, based on NMR spectrum in CDCl3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:5]=[C:6]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:27]I>>[F:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:27])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CI
Reactant: OC1(c2cc(F)cc(OCc3ccc4ccccc4c3)c2)CCOCC1
Product: COC1(c2cc(F)cc(OCc3ccc4ccccc4c3)c2)CCOCC1
Yield: 98 %

Procedure:
Using the procedure described in Example 3, 4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-hydroxytetrahydropyran was reacted with methyl iodide to give 4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-methoxytetrahydropyran in 98% yield, m.p. 109°-111° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:35])[CH2:33]Br)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:26]1[CH2:30][CH2:29][C@@H:28]([NH:31][C:32](=[O:35])[CH2:33][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc(O)ccc1C=O
Reactant: O=C(CBr)N[C@@H]1CCN(Cc2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)N[C@@H]2CCN(Cc3ccccc3)C2)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.6 %

Procedure:
(R)-(−)-1-Benzyl-3-aminopyrrolidine (5 g, 28 mmol) was dissolved in dichloromethane (10 ml). To this solution, a solution of bromoacetyl chloride (4.55 g, 28 mmol) in dichloromethane (5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 6.8 g (72%) of (3R)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step. 4-Hydroxy-2-methoxybenzaldehyde (2.05 g , 13 mmol) was dissolved in DMF (7 ml) and potassium carbonate (6.2 g, 45 mmol) was added followed by a suspension of the above (3R)-N-(1-Benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 9 mmol) in DMF (16 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were washed with saturated sodium chloride (3×15 ml), dried (MgSO4) and concentrated in vacuo. The residue was crystallized from diethyl ether to afford 2.11 g (64%) (R)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide as a solid. M.p.: 98-101° C.
Reaction SMILES: [CH2:1]([N:3]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:29][Si](CC)(CC)CC)([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])[CH2:16][CH2:15]1)[S:4]([C:7]1[N:8]=[C:9]([CH3:13])[N:10]([CH3:12])[CH:11]=1)(=[O:6])=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([N:3]([C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]([OH:29])([C:25]([F:28])([F:26])[F:27])[C:21]([F:23])([F:24])[F:22])[CH2:18][CH2:19]1)[S:4]([C:7]1[N:8]=[C:9]([CH3:13])[N:10]([CH3:12])[CH:11]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCN([C@H]1CC[C@H](C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)CC1)S(=O)(=O)c1cn(C)c(C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN([C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1)S(=O)(=O)c1cn(C)c(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 130 mg (0.23 mmol) of trans 1,2-dimethyl-1H-imidazole-4-sulfonic acid ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide in 2 mL of THF was treated with an excess of TBAF and stirred for 2 hrs at RT. Distribution between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases, evaporation of the solvent and column chromatography on silica gel with EtOAc/heptane 1:1 gave 42 mg (25%) of trans 1,2-dimethyl-1H-imidazole-4-sulfonic acid ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-amide as a yellow viscous oil, MS: 452 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:32]1([S:42]([NH2:45])(=[O:44])=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:45][S:42]([C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:35]=[CH:34][CH:33]=3)(=[O:43])=[O:44])=[O:31])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cccc2ccccc12
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccc3ccccc23)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 1-naphtylsulfonamide (Arnswald, M.; Neumann, W. P. Chem. Ber., 1991, 124, 1997; Khorgami, M. H. Synthesis, 1972, 574).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:16]3[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C.C1COCC1>[C:17]1([C:23]#[C:24][C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[N:16]4[C@@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]4)[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccc([C@@H]2CC[C@@H]3CCCCN32)cc1
Reactant: C#Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C(#Cc1ccc([C@@H]2CC[C@@H]3CCCCN32)cc1)c1ccccc1
Temperature: 25 °C
Yield: 42 %

Procedure:
A 27.7 g (0.099 mole sample of trans-3-(4-bromophenyl)octahydroindolizine was dissolved in a mixture of 55 mL of triethylamine and 225 mL of dry THF under an atmosphere of argon and 12.1 g (0.12 mole) of phenylacetylene was added. Then 2.3 g (2 mmol) of tetrakistriphenylphosphine palladium (O) and 0.75 g 3.9 mmol) of cuprous iodide were added to the reaction mixture and the reaction refluxed overnight. An additional 1.2 g (1 mmol) of tetrakistriphenylphosphine palladium (O) and 0.38 g (1.9 mmol) of cuprous iodide were added to the reaction mixture and the mixture allowed to reflux overnight. The reaction was allowed to cool to room temperature, the mixture was filtered, and the THF evaporated in vacuo to a brown oil. The oil was partially dissolved in EtOAc and the insoluble material was filtered off. The EtOAc was evaporated in vacuo to an oil. The oil was flash chromatographed using 99% hexane, 1% EtOAc as the eluant. The major product bearing fractions were pooled, and the solvent evaporated in vacuo to give 12.5 g (42% yield) of the title compound as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][N:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH2:26])=[O:27])=[CH:21][N:20]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(Oc3ccc(C(N)=O)cn3)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(Oc2cccc3c2CNCC3)nc1
Reaction time: 12 h
Yield: 57.4 %

Procedure:
Combine 8-(5-Carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (249.6 mg, 1.01 mmol), CH2Cl2 (25 ml), and TFA (10 ml) at room temperature under nitrogen atmosphere. After the reaction stirs for 12 hours then concentrate under reduced pressure. Solubilize the mixture in MeOH and add to a 2 g SCX Column (pre-treated with 5% AcOH-MeOH), wash several times with MeOH, and elute the product with 1N NH3 MeOH to afford 156.1 mg, 0.58 mmol (57% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[F:17][C:18]1([F:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[F:17][C:18]1([F:24])[CH2:23][CH2:22][N:21]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: FC1(F)CCNCC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(F)(F)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4,4-difluoropiperidine hydrochloride (9.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (3.2 mg). Calcd for C16H16F2N2O2: 306.1180, found 306.1179.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[C:17]([C:21]([O:23]CC)=[O:22])=[N:18][N:19]([CH3:20])[C:10]=4[C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+:27]>C(O)C>[CH:1]1([NH:6][C:7]2[N:16]=[CH:15][C:14]3[CH2:13][CH2:12][C:11]4[C:17]([C:21]([O-:23])=[O:22])=[N:18][N:19]([CH3:20])[C:10]=4[C:9]=3[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1.[K+:27]
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(NC3CCCC3)nc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(=O)[O-])c2c1-c1nc(NC3CCCC3)ncc1CC2
Yield: 82 %

Procedure:
Ethyl 8-(cyclopentylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (230 mg, 0.67 mmol) was suspended in anhydrous ethanol (5 mL) and treated with a 1.5 M solution of potassium hydroxide in ethanol (1.33 mL, 3 eq.) at reflux temperature for 1.5 hours. After cooling in ice bath, the resulting precipitate was collected by filtration to give the title compound (193 mg, 82% yield) as a crystalline solid.
Reaction SMILES: O[NH:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[NH:4].CO>[Ni].C(O)(=O)C>[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[NH:2])[NH2:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C(=N)N)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
Into a 2-L round-bottom flask purged and maintained with an inert atmosphere of argon, was placed tert-butyl 4-(N-hydroxycarbamimidoyl)piperidine-1-carboxylate (46.5 g, 181.56 mmol, 1.00 equiv, 95%), methanol (1500 mL), acetic acid (20 mL), and Raney-Ni (13 g). The reaction system was bubbled for 5 times with hydrogen. The resulting mixture was stirred for 3 h at 50° C. in an oil bath. The solids were filtered out. The resulting solution was concentrated under vacuum to afford 40 g of tert-butyl 4-carbamimidoylpiperidine-1-carboxylate as yellow green crude oil, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 278.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br)[CH2:2]2.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:10](=[O:19])[O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CN2CCC1CC2
Yield: 86.8 %

Procedure:
Using general procedure E, quinuclidin-3-yl2-bromophenylcarbamate (130 mg, 0.400 mmol), phenylboronic acid (96 mg, 0.8 mmol) and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (112 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 8.07 (br s, 1H), 7.55-7.33 (m, 6H), 7.25-7.21 (dd, J=7.6 & 1.6 Hz, 1H), 7.43 (td, J=8.0, 1.2 Hz, 1H), 6.65 (br s, 1H), 4.78 (m, 1H), 3.24 (m, 1H), 2.90-2.68 (m, 5H), 2.04 (m, 1H), 1.80-1.62 (m, 2H), 1.61-1.50 (m, 1H), 1.41-1.30 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 151.2, 135.9, 132.5, 129.5, 128.0, 127.0, 126.9, 126.2, 125.7, 121.4, 117.9, 69.9, 53.1, 45.1, 44.3, 23.1, 22.3, 17.2 ppm. Purity: 100% LCMS (214 nm & 254 nm); retention time 1.47 min; (M+1) 323.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:16]([CH2:29][CH3:30])[CH2:17][CH2:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([CH:24]([OH:26])[CH3:25])=[CH:22][CH:21]=1)[CH3:15]>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:26][CH:24]([CH3:25])[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:16]([CH2:29][CH3:30])[CH2:14][CH3:15])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CCN(CC)CCOc1ccc(C(C)O)cc1
Product: CCN(CC)CCOc1ccc(C(C)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 37.2 %

Procedure:
By using 1.0 g of 2-t-butyl-4,5-dichloro-3(2H)-pyridazinone and 1.1 g of 4-(2-diethylaminoethoxy)-α-methylbenzyl alcohol and similarly to the procedures in Preparation Example 1, a crude product was obtained. The crude product was then purified through column chromatography (eluting with chloroform/methanol=200/5) to obtain 710 mg of the aimed product as an oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH:22]1[CH2:24][O:23]1>C(C(C)=O)C>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:21][CH:22]2[O:23][CH2:24]2)=[C:7]([CH3:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)c(O)cc1C
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)Oc1cc(C)c(OCC2CO2)cc1C

Procedure:
Using 3.25 g of 4-acetoxy-2,5-dimethylphenol, 2.49 g of anhydrous potassium carbonate, 2.8 ml of chloromethyloxirane and 50 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 2.97 g of 1-(4-acetoxy-2,5-dimethylphenoxy)-2,3-epoxypropane as yellow oil. Using the epoxy compound thus obtained, 2.66 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup were carried out as in Examples 1-A and 4. After hydrolysis, workup and then conversion to hydrochloride with 2N HCl, recrystallization from methanol-acetone gave 0.80 g of white crystals, m.p. 214-215° C. (decomp.).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:24]S(OC)(=O)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][N:17]([CH2:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]1)[C:18](=[O:23])[C:19]([F:20])([F:21])[F:22]
Reactant: COS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(F)(F)F
Reaction time: 0.67 h

Procedure:
Under nitrogen, 0.21 g (5.25 mM) of 60% sodium hydride-liquid paraffin was added to a solution of 1.51 g (4.87 mM) of N-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)trifluoroacetamide in N,N-dimethylformamide (10 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 40 minutes. To this reaction mixture was added 0.5 ml (5.90 mM) of methyl methanesulfonate and the mixture was stirred at room temperature for 112 hours. The mixture was further stirred at 100° C. for 2.5 hours, at the end of which time the reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate. The reaction mixture was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The crude product thus obtained was purified by column chromatography (ethyl acetate-hexane 40%) to provide the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([Br:14])[C:11](Cl)=[N:10][CH:9]=1.[CH2:17]([OH:20])[CH2:18][OH:19]>>[C:4]([O:3][CH2:4][CH2:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([Br:14])[C:11]([O:19][CH2:18][CH2:17][O:20][C:7](=[O:6])[CH3:8])=[N:10][CH:9]=1)(=[O:3])[CH3:5]
Reactant: O=C(OCCO)c1cnc(Cl)c(Br)c1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Product: CC(=O)OCCOC(=O)c1cnc(OCCOC(C)=O)c(Br)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.29 g, 60% purity in mineral oil) was dissolved in ethylene glycol (25 ml) and the raw material of step 1 was added. This mixture was stirred at 60° C. for 1 h. Volatiles were evaporated at 95° C., 1 mbar. The remainder was suspended in pyridine (25 ml), acetic anhydride (25 g) was added slowly during 30 minutes with stirring and stirring continued for 1 h. The mixture was partitioned between ethyl acetate and water, the organic phase was washed with 2N HCl and saturated sodium bicarbonate solution, dried over sodium chloride and evaporated to dryness in vacuo. The remainder was titurated in diethyl ether, cooled in an ice bath and filtered to yield 2.5 g of the title compound.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1S.[CH3:9][S:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>>[CH2:9]([S:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ccccc1N
Reactant: Nc1ccccc1S
Product: Nc1ccccc1SCc1ccccc1

Procedure:
2-(amino)thiophenol and 2-(methylthio)aniline were purchased from Aldrich Chemical Company.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[C:12]([Cl:21])[CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:21][C:12]1[CH:11]=[C:10]([NH:9][C:4](=[O:5])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1])[CH:20]=[CH:19][C:13]=1[C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CN(C)C(=O)c1ccc(N)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(NC(=O)C(C)(C)CCl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloro-2,2-dimethylpropionyl chloride (1.86 g) was added dropwise over 5 minutes to 4-amino-2-chloro-N,N-dimethylbenzamide (2.00 g) suspended in dry methylene chloride (40 ml) and dry triethylamine (1.21 g) with stirring, keeping the temperature below 10° C. After stirring for 1 hour and warming to room temperature, methylene chloride (40 ml) was added and the solution washed with 2M hydrochloric acid, saturated aqueous sodium bicarbonate and then saturated brine. The solution was then dried and evaporated to yield a sticky yellow solid which was recrystallised from ethyl acetate/chloroform to give 2-chloro-4-(3'-chloro-2',2'-dimethylpropionamido)-N,N-dimethylbenzamide, as a white crystalline solid (2.349 g) m.p. 179°-181° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>C(Cl)Cl>[C:21](=[O:22])([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1])[O:23][CH3:24]
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccccc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
2-(Trifluoromethoxy)phenol (6.0 g, 32.7 mmol) was dissolved in methylene chloride and triethylamine (9.1 mL, 65.4 mmol). The mixture was cooled to 0° C. and methyl chloroformate (2.8 mL, 36.0 mmol) was added dropwise. The mixture was stirred for 2 h at room temperature then quenched with saturated NH4Cl. The reaction was diluted with water and the aqueous layer extracted with dichloromethane (2×30 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to provide methyl 2-(trifluoromethoxy)phenyl carbonate (7.1 g, 92% yield). 1H NMR (400.0 MHz, DMSO-d6) δ7.36-7.26 (m, 4H), 3.93 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[C:4]([CH3:11])[CH:3]=1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+].S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[C:14]([CH2:10][C:8](=[O:9])[C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([CH3:11])[CH:5]=1)(=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: COC(=O)c1ccccc1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Cc1cc(C)cc(C(=O)CC(=O)c2ccccc2)c1
Temperature: 135 °C
Reaction time: 6 h
Yield: 27 %

Procedure:
3,5-dimethylacetophenone (37.1 grams; 0.75 mol), methylbenzoate (156 grams; 1.0 mol) and xylene (308.6 grams) were placed into a four-necked round bottom one liter flask equipped as in Example 1. Sodium methoxide (16.4 grams; 0.30 mol) was added to the stirred reaction mixture under a blanket of nitrogen and the mixture was heated to 135° C. As the temperature of the mixture reached 100° C., solution began coming over. The temperature was held at about 135° C. for 6 hours after which time it was cooled to room temperature. Sulfuric acid (375 ml of 10% solution) was added slowly over a 30 minute period with stirring. The xylene layer was separated and washed with water, then with sodium carbonate solution (100 ml of 10% solution) and again with water (100 ml). Xylene was stripped off at 175° C. resulting in the desired product, benzoyl 3,5-dimethylbenzoylmethane (51 grams; 63 weight percent yield) having a melting point of 48°-53° C..