Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:17]([CH3:28])[CH2:16]1)(=[O:14])=[O:13].[C:29](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.CCOC(C)=O>O1CCOCC1.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>[CH3:28][C@H:17]1[CH2:16][N:15]([S:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[CH3:29])(=[O:14])=[O:13])[CH2:20][CH2:19][N:18]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2Br)CCN1C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 100 °C
Yield: 90.6 %

Procedure:
A solution of 1,1-dimethylethyl (2S)-4-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-2-methyl-1-piperazinecarboxylate (may be prepared as described in Description 23) (1.00 g, 2.05 mmol), potassium carbonate (0.737 g, 5.34 mmol) in 1,4-dioxane (43 ml) were stirred for 5 min then trimethylboroxin (0.743 ml, 5.34 mmol) and Pd(Ph3P)4 (0.403 g, 0.349 mmol) were added and the reaction mixture heated at 100° C. overnight. EtOAc (100 ml) was added, then the mixture was washed with aqueous sodium bicarbonate (100 ml), water (100 ml) and concentrated under vacuum. Flash chromatography (silica; linear gradient (0-20%) EtOAc in isohexane) gave 1,1-dimethylethyl (2S)-2-methyl-4-{[2-methyl-4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (0.785 g). This material was re-dissolved in DCM (10 ml) and 1,4-dioxane (3 ml), then HCl in dioxane (5 eq) was added and the mixture stirred at room temperature for 4 h. Aqueous sodium bicarbonate (20 ml) and EtOAc (20 ml) were added and the organic phase washed with aqueous sodium bicarbonate (2×10 ml), brine (10 ml) and dried using a hydrophobic frit. The solvent was removed under vacuum. The residue was re-dissolved in DCM (10 ml) and 1,4-dioxane (3 ml), then 4M HCl in 1,4-dioxane (6.97 mL, 27.9 mmol) added. The mixture was stirred at room temperature for 4 h. The solvent was evaporated under vacuum to give the title compound (0.615 g) as the hydrochloride salt.
Reaction SMILES: C([O:3][P:4]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]3[CH:28]=[C:29]([Cl:44])[C:30]([C:32]4[CH:37]=[CH:36][C:35]([CH:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:34][CH:33]=4)=[CH:31][C:18]=3[N:17]=2)[CH:12]=[CH:11][C:10]=1[CH3:45])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>ClCCl.C[Si](C)(C)N[Si](C)(C)C>[CH2:21]([N:20]1[C:19]2[CH:28]=[C:29]([Cl:44])[C:30]([C:32]3[CH:33]=[CH:34][C:35]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:36][CH:37]=3)=[CH:31][C:18]=2[N:17]=[C:16]1[O:15][C:13]1[CH:12]=[CH:11][C:10]([CH3:45])=[C:9]([P:4](=[O:3])([OH:8])[OH:5])[CH:14]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOP(=O)(OCC)c1cc(Oc2nc3cc(-c4ccc(C5CCCCC5)cc4)c(Cl)cc3n2Cc2ccccc2)ccc1C
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: Cc1ccc(Oc2nc3cc(-c4ccc(C5CCCCC5)cc4)c(Cl)cc3n2Cc2ccccc2)cc1P(=O)(O)O
Temperature: 25 °C

Procedure:
To a solution of {5-[1-Benzyl-6-chloro-5-(4-cyclohexyl-phenyl)-1H-benzoimidazol-2-yloxy]-2-methyl-phenyl}-phosphonic acid diethyl ester (3.2 g, 5.0 mmol) in dichloromethane (15 ml) and hexamethyldisilazane (15 ml) was added bromotrimethylsilane (7.7 ml, 50 mmol). After stirring over night at rt the volatiles were removed from the mixture on a rotary evaporator. The residue was dissolved in methanol (15 ml) and treated with sonication in a water bath. The resulting suspension was filtered to yield a white solid. This solid was dried under vacuum at 40° C. for 15 hours to yield the title compound. The filtrate was evaporated to dryness, treated with hexanes (15 ml) and subjected to sonication in a water bath. The beige solid thus obtained upon filtration was dried under vacuum at 40° C. for 15 hours to yield additional title compound in sufficient purity.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17](=[O:24])[CH2:18][C:19](OCC)=[O:20])[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:31]O.Cl>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([C@H:11]2[CH2:16][C@@H:15]([C:17]3[O:24][NH:31][C:19](=[O:20])[CH:18]=3)[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(c2cccc(C(C)(C)C)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cccc(C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 23.9 %

Procedure:
Methyl 2-(3-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (3.14 g, 8.06 mmol) was dissolved in MeOH (50 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.322 g, 8.06 mmol) dissolved in water (5.00 mL) was added during 5 min and the colourless mixture continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.494 mL, 8.06 mmol) was added during 8 min. The resulting solution was stirred at −55° C. for 6 h 30 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (60 mL, 360.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a brown oil. The crude was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 40-85% Acetonitrile in H2O/MeCN/HOAc 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-tert-butylphenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (690 mg, 24%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.29 (s, 9H), 1.81-1.88 (m, 1H), 2.14-2.21 (m, 1H), 2.22-2.31 (m, 1H), 2.35-2.42 (m, 1H), 3.03-3.10 (m, 1H), 3.37-3.44 (m, 1H), 3.66 (s, 3H), 4.16-4.22 (m, 1H), 5.12-5.16 (m, 1H), 5.48 (s, 1H), 6.97-7.01 (m, 1H), 7.17 (s, 1H), 7.21-7.25 (m, 2H). MS m/z 359 (M+H)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][N:35]3[CH2:39][CH:38]=[CH:37][CH2:36]3)[CH2:24][CH:23]2[OH:40])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][N:35]3[CH2:36][CH:37]=[CH:38][CH2:39]3)[CH2:24][C:23]2=[O:40])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccccc3NN3CC=CC3)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3NN3CC=CC3)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-[N-(2,5-dihydropyrrol-1-yl)amino]phenyl]piperidin-3-ol (0.7 g) obtained in Step 1 in 6 ml of dimethylsulfoxide (DMSO), was added 0.8 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.75 g) was added slowly to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 0.6 g of the titled compound as white color.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:4][CH:3]=1>C(O)C>[CH:4]1[C:5]([C@H:8]([NH2:9])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: NC(C(=O)O)c1ccc(O)cc1
Solvent: CCO
Product: N[C@H](C(=O)O)c1ccc(O)cc1
Reaction time: 2 h

Procedure:
A mixture of DL-2-(4-hydroxyphenyl)glycine (10 g.), d-3-bromo-2-oxo-10-bornanesulfonic acid (20 g.) and hot 99% ethanol (100 ml.) was filtered, and the filtrate was concentrated under reduced pressure to a total weight of 40 g. Chloroform (265 g.) was added to the solution, and the solution was seeded with the authentic specimen of d-3-bromo-2-oxo-10-bornanesulfonic acid salt of L-2-(4-hydroxyphenyl)glycine and allowed to stand for 2 hours at room temperature. The precipitating crystals were collected by filtration, washed with a mixture of ethanol and chloroform (5 : 1) and dried for 12 hours at room temperature under reduced pressure to give the solvate (16.1 g.) of d-3-bromo-2-oxo-10-bronanesulfonic acid salt of L-2-(4-hydroxyphenyl)glycine with chloroform. Recrystallization from a mixture of ethanol (20 g.) and chloroform (250 g.) in a similar manner to the above gave the pure solvate (15.1 g.), m.p. 190° to 197° C. The differential thermal analysis of this solvate gave the endothermic peak at 155° to 156° C.
Reaction SMILES: O[CH:2](O)[C:3]([C:5]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=1[NH2:27].C([O-])(O)=O.[Na+]>CCO>[Cl:19][C:20]1[C:21]2[C:22](=[N:26][C:3]([C:5]3[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][N:6]=3)=[CH:2][N:27]=2)[N:23]=[CH:24][CH:25]=1
Reactant: Nc1nccc(Cl)c1N
Reactant: NC(=O)c1cnc(C(=O)C(O)O)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cnc(-c2cnc3c(Cl)ccnc3n2)c(C(F)(F)F)c1

Procedure:
Dissolve 6-(2,2-dihydroxyacetyl)-5-(trifluoromethyl)nicotinamide (8.0 g) in 100.0 mL of EtOH and then add 4-chloro-2,3-diaminopyridine (800 mg) followed by addition of NaHCO3 (3.6 g). Stir the reaction at room temperature for 18 hours under N2 atmosphere. Concentrate the reaction mixture under vacuum, and purify by column chromatography to afford the title product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)(C)C>>[CH3:21][N:22]([CH3:24])[CH:23]=[C:11]1[C:10](=[O:15])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCCCC1c1ccc(Cl)c(Cl)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCCC(c2ccc(Cl)c(Cl)c2)C1=O

Procedure:
2-(3,4-Dichloro-phenyl)-cyclohexanone (101 mg, 0.42 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (119 mg) as a red oil which was used directly in the next step. MS ISP (m/e): 298.0 [(M+H)+].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:14]4[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)[N:12]=3)[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)N1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCNCC3)c(F)cc2c1=O
Yield: 86.7 %

Procedure:
A solution of 10.2 g (25 mmole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(ethoxycarbonyl)-1-piperazinyl]-1,8-naphthyridine-3-carboxylic acid, 100 ml of 10% aqueous sodium hydroxide and 40 ml of ethanol was refluxed for three hours. The solution was concentrated to 125 ml and acidified to pH 7.3 with glacial acetic acid. The resulting precipitate was removed by filtration, washed with 50% aqueous ethanol, ether and dried in vacuo to give 7.2 g of the title compound, mp 274°-276°.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[CH2:14])[N:10]=[C:9]([Cl:18])[N:8]=1)(=O)=O.[F:19][C:20]1([F:26])[CH2:23][CH:22]([CH2:24]O)[CH2:21]1.[OH-].[Na+]>C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:18][C:9]1[N:8]=[C:7]([CH2:6][O:5][CH2:24][CH:22]2[CH2:23][C:20]([F:26])([F:19])[CH2:21]2)[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[CH2:14])[N:10]=1
Reactant: C=C(OCC)c1cc(COS(C)(=O)=O)nc(Cl)n1
Reactant: OCC1CC(F)(F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: C=C(OCC)c1cc(COCC2CC(F)(F)C2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.2 %

Procedure:
To a solution of (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methyl methanesulfonate (0.5 g, 1.71 mmol) in benzene (8 mL) were added (3,3-difluorocyclobutyl)methanol (0.313 g, 2.56 mmol), sodium hydroxide (aq, 5 M, 0.512 mL, 2.56 mmol) and tetrabutylammonium hydrogen sulfate (0.058 g, 0.17 mmol). The mixture was stirred vigorously at rt for 72 h. The mixture was extracted with diethylether. The organic phase was washed with 50% brine, dried over magnesium sulfate and the solvent was evaporated to give 484 mg crude product. 123 mg material from a different batch synthesized using the same method was added. The residue was purified by column chromatography on silica eluting with a gradient of EtOAc in heptane to give the title compound as a gum (0.110 g, 20%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6C(=O)C(NC(OC(C)(C)C)=O)C6C=CC=CC=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:65][O:66][C:67]([NH:69][C:70]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)([CH3:74])[C:71]([OH:73])=O)=[O:68]>>[CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:71](=[O:73])[C:70]([NH:69][C:67]([O:66][CH3:65])=[O:68])([C:75]6[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=6)[CH3:74])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C)(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(C)(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 20 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(2-{5-[6-(4-{2-[1-(2-tert-Butoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using 2-Methoxycarbonylamino-2-phenyl-propionic acid (0.068 g, 0.308 mmol) to provide [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-propionyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.035 g, 20%) as a white solid. LCMS-ESI+: calc'd for C48H52N8O6: 836.40 (M+); Found: 837.92 (M+H+).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:17]([NH2:23])(=[O:22])[CH2:18][C:19]([CH3:21])=[O:20].Cl.N1C2C(=CC=CC=2)C=CC=1>CNC>[C:19]([C:18]1[C:17](=[O:22])[NH:23][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH2:9]2)(=[O:20])[CH3:21]
Reactant: CC(=O)CC(N)=O
Reactant: CC(=O)C1CC(c2ccncc2)CCC1=O
Agent: CNC
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: CC(=O)c1c2c(c(C)[nH]c1=O)CC(c1ccncc1)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.8 %

Procedure:
In 40 ml of 50% aqueous solution of dimethylamine was dissolved 20 g of the 2-acetyl-4-(4-pyridyl)-cyclohexanone obtained by the above method (b) under ice cooling, and 30 g of acetoacetamide was added thereto. After stirring at room temperature for 2 days, the reaction mixture was neutralized with 6N hydrochloric acid under ice cooling. After allowed to stand for 1 hour under ice cooling, the resulting mixture was filtered to afford 12 g of crude crystals containing 3-4% of the above-said quinoline compound (IV) which was impurities. The crude crystals were recrystallized with 300 ml of methanol to afford 8 g of purified 4-acetyl-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone. The physical property values were as follows.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH:9]([C:11]1[C:12]([O:25][CH2:26][C:27]#[C:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=2)=[CH:13][C:14]2[C:15]([CH3:24])([CH3:23])[CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[C:19]=2[CH:20]=1)=O>CO>[OH:3][N:2]=[CH:9][C:11]1[C:12]([O:25][CH2:26][C:27]#[C:28][C:29]2[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=2)=[CH:13][C:14]2[C:15]([CH3:24])([CH3:23])[CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[C:19]=2[CH:20]=1
Reactant: CCOC(=O)c1ccc(C#CCOc2cc3c(cc2C=O)C(C)(C)CCC3(C)C)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1ccc(C#CCOc2cc3c(cc2C=NO)C(C)(C)CCC3(C)C)cc1
Temperature: 50 °C
Reaction time: 11 h
Yield: 62.5 %

Procedure:
0.2 g of hydroxylamine hydrochloride and 0.26 g of sodium acetate were added to 15 ml of a solution of 0.51 g of ethyl 4-[3-(3-formyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoxy)-1-propynyl]benzoate in methanol at room temperature. The obtained mixture was stirred at 50° C. for 11 hours and distilled to remove the methanol, followed by the addition thereto of 20 ml of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel chromatography (developer: 30% diethyl ether/n-hexane) to give 0.33 g of the title compound as a pale-yellow oil. 1H-NMR (400 MHz, CDCl3) δ(ppm); 1.28(s, 6H), 1.30(s, 6H), 1.36(t, J=7.2 Hz, 3H), 1.68(brs, 4H), 4.36(q, J=7.2 Hz, 2H), 4.94(s, 2H), 7.04(s, 1H), 7.47(d, J=8.4 Hz, 2H), 7.68(s, 1H), 7.98(d, J=8.4 Hz, 2H), 8.50(s, 1H)
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][N:15]2[C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=3)=[CH:19][N:20]=[C:14]2[N:13]=1)([O:4][Si](CC)(CC)CC)[CH3:3]>CCO.Cl>[F:29][C:27]([F:28])([F:30])[C:23]1[N:22]=[C:21]([C:18]2[N:15]3[CH:16]=[CH:17][C:12]([C:2]([OH:4])([CH3:3])[CH3:1])=[N:13][C:14]3=[N:20][CH:19]=2)[CH:26]=[CH:25][N:24]=1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(C(F)(F)F)n3)cnc2n1
Agent: Cl
Solvent: CCO
Product: CC(C)(O)c1ccn2c(-c3ccnc(C(F)(F)F)n3)cnc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
7-(1-Methyl-1-triethylsilanyloxyethyl)-3-(2-trifluoromethylpyrimidin-4-yl)imidazo[1,2-α]pyrimidine (136 mg, 0.31 mmol) in EtOH (5 ml) was treated with conc. HCl (5 drops) and the mixture stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure and then NaHCO3 solution (20 ml) added. The organics were extracted with CH2Cl2 (3×20 ml) and concentrated under reduced pressure while dry loading onto MgSO4. The residue was purified by column chromatography on silica using 5% MeOH/CH2Cl2 as the eluent to afford 2-[3-(2-trifluoromethylpyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol (60 mg, 60%): 1H NMR (400 MHz, d6-DMSO) δ 9.97 (1H, d, J 7.4), 9.00 (1H, d, J 5.6), 8.97 (1H, s), 8.35 (1H, d, J 5.6), 7.73 (1H, d, J 7.4), 1.53 (6H, s); m/z (ES+) 324 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13](O)(=[O:16])[C:14]#[CH:15]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:8]=[C:9]1[C:10]([O:12][C:13](=[O:16])[C:14]1=[CH:15]2)=[O:11]
Reactant: O=C(O)C#Cc1ccc(Cl)cc1
Reactant: C#CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc3cc(Cl)ccc3cc21
Yield: 54.1 %

Procedure:
p-Chlorophenylpropiolic acid (3.3 g) and propiolic acid (7.6 g) in acetic anhydride (80 ml) were refluxed for 12 hr. The solution was concentrated (to 40 ml) and the precipitate which formed on cooling was recrystallised from acetone to give 6-chloro-2,3-naphthalenedicarboxylic anhydride (2.3 g) m.p. 220°.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Br:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][C:29]2[S:30][C:31]([CH3:35])=[C:32]([CH3:34])[CH:33]=2)=[CH:26][CH:25]=1>CN(C)C=O>[Br:23][C:24]1[CH:37]=[CH:36][C:27]([CH2:28][C:29]2[S:30][C:31]([CH3:35])=[C:32]([CH3:34])[C:33]=2[C:9]([C:8]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]=2)=[O:11])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Reactant: Cc1cc(Cc2ccc(Br)cc2)sc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2c(Cc3ccc(Br)cc3)sc(C)c2C)cc1C1CCCC1
Yield: 52.7 %

Procedure:
The tide compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (3.50 g, 15.9 mmol, RN-59216-82-9), oxalyl chloride (1.52 mL, 17.5 mmol), N,N-dimethylformamide (2 drops) tin(I) chloride (2.04 mL, 17.5 mmol) and 2-(4-bromobenzyl)-4,5-dimethylthiophene (4.46 g, 15.9 mmol). Purification on silica gel eluting 5% EtOAc/pet. ether gave 4.05 g (53%) of the title compound as yellow oil. (DMSO-d6) δ1.43-1.47 (m, 2 H), 1.61-1.75 (m, 4 H), 1.81 (s, 3 H), 1.91-1.99 (m, 2 H), 2.28 (s, 3 H), 3.24 (quintet, 1 H), 3.84 (s,2 H), 3.88 (s, 3 H), 7.02 (d, 2 H), 7.06 (d, 1 H), 7.40 (d, 2 H), 7.52 (dd, 1 H), 7.57 (1 H).
Reaction SMILES: ClC1C=CC(O[CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=CC=1.Cl.N[C@@H](CCN1CC([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)C1)CO>>[F:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[CH:42][CH:43]=1
Reactant: N[C@H](CO)CCN1CC(Cc2ccc(F)cc2)C1
Reactant: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)s1
Agent: Cl
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Cc3ccc(F)cc3)C2)s1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea in Example 99 except using (S)-2-amino-4-[3-(4-fluoro-benzyl)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.