Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH2:4]([N:7]1[C:13]2[CH:14]=[CH:15][C:16](Br)=[CH:17][C:12]=2[CH:11]=[C:10]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH3:36])[CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:24][CH:23]=2)=[O:20])[CH2:9][CH2:8]1)[CH:5]=[CH2:6].B([O-])([O-])O[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH2:4]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[CH:41][CH:40]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH3:36])[CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:24][CH:23]=2)=[O:20])[CH2:9][CH2:8]1)[CH:5]=[CH2:6]
Reactant: C=CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C=CCN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 14.4 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 1-allyl-7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (262 mg), 4-butoxyethoxyphenyl borate (169 mg) and potassium carbonate (196 mg), and the suspension was stirred under argon atmosphere for 30 minutes. Then, to the mixture was added tetrakistriphenylphosphinepalladium (45 mg), and the mixture was heated under argon atmosphere at 100° C. for 6 hours. After allowing to cool, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:16), which was recrystallized from hexane-ethyl acetate to give 1-allyl-7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 50) (46 mg) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN(C=O)C.O>[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:4]=1[Cl:16])(=[O:20])[CH3:19]
Reactant: CC(=O)OCCCCBr
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 80 °C
Reaction time: 20 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 25 grams (0.093 mole) of 2,6-dichloro-4-phenylmethoxyphenol (known compound), 19.5 grams (0.10 mole) of 4-bromobutyl acetate and 19.4 grams (0.14 mole) of potassium carbonate in 400 mL of DMF was stirred at ambient temperature for two hours, then it was heated to 80° C. where it was maintained during a 20 hour period. After this time the reaction mixture was allowed to cool to ambient temperature where it stirred during an additional 20 hour period. The reaction mixture was then stirred with 400 mL of water, saturated with sodium chloride and extracted with four 150 mL portions of diethyl ether. The combined extracts were washed with two 150 mL portions of water, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The crude residue was purified with column chromatography on silica gel using 1:1 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 33.1 grams of compound the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10]>CC(C)=O>[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([N:3]=[C:2]=[S:1])=[O:10]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1cccc(F)c1
Temperature: 40 °C
Reaction time: 6 h
Yield: 37.8 %

Procedure:
Potassium thiocyanate (11.03 g, 114 mmol) was suspended in acetone (63.1 mL) and heated to 40° C. under nitrogen atmosphere. To this was added 3-fluorobenzoyl chloride (11.35 mL, 95 mmol), and the resulting mixture was stirred at 50° C. for 6 hours. The heterogeneous mixture was filtered, and the solid was further washed with acetone. The filtrate was concentrated and purified by silica gel chromatography (10% EtOAc/Hexanes as the eluent) to afford 3-fluorobenzoyl isothiocyanate (6.5 g, 37.9% yield) as a light orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([OH:18])=[CH:9][CH:8]=2)=[O:4].[C:29]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([O:18][C:36]1[CH:37]=[CH:38][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=1)=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(O)cc12
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(C)(C)C)cc3)cc12

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 5-hydroxy-1-(4-isopropoxyphenyl)indole-2,3-dicarboxylic acid dimethyl ester (250 mg, 0.65 mmol, see step (a) Example 19) and 4-tert-butylphenylboronic acid (175 mg, 0.98 mmol). Yield 240 mg (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:12]1[CH2:16][CH2:15][CH2:14]C1)[CH2:6][CH2:5]2.C(N)(=[O:20])C=C>C(O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3[CH2:14][CH2:15][C:16](=[O:20])[NH:12][C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C=CC(N)=O
Reactant: Clc1ccc2c(c1)CCC(N1CCCC1)=C2
Solvent: CCO
Product: O=C1CCC2=C(CCc3cc(Cl)ccc32)N1

Procedure:
701 g (3 mol) of 1-(6-chloro-3,4-dihydro-2-naphthyl)pyrrolidine and 640 g (19 mol) of acrylamide in 7 ml of ethanol were boiled under reflux for 3 days with the addition of 70 g of Amberlite IR200. The separated solid was filtered off. Extractive crystallization with dioxan gave 8-chloro-1,4,5,6-tetrahydrobenzo[f]-quinolin-3(2H)-one of melting point 228°-230° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:18]=[C:19]([NH2:22])[S:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.[O:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH:24]1[C:33](O)=[O:34].N1(O)C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:18]=[C:19]([NH:22][C:33]([CH:24]3[CH2:25][CH2:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:23]3)=[O:34])[S:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: Cn1nnnc1C(=NOCc1csc(N)n1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cn1nnnc1C(=NOCc1csc(NC(=O)C2CCc3ccccc3O2)n1)c1ccccc1
Yield: 44 %

Procedure:
To a stirred solution of 4-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-amine (200 mg, 0.63 mmol) in dimethylformamide (1.5 mL) were added chromane-2-carboxylic acid (124 mg, 0.70 mmol) and 1H-benzotriazol-1-ol (94 mg, 0.70 mmol). The reaction mixture was poured at room temperature on a cartridge filled with 1.44 g of silica linked with N,N′-dicyclohexylcarbodiimide (loading: 1.05 mmol/g). After one night at room temperature, the cartridge was eluted with 1 mL of dimethylformamide. The filtrated solution was then poured on a cartridge filled with 1.5 g of basic alumina. After 2 hours of reaction a room temperature, the cartridge was rinsed twice with 10 mL of ethyl acetate. The combined filtrated solutions were evaporated in vacuo to yield a yellow oil. Purification on silica gel afforded of N-{4-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}chromane-2-carboxamide as a colorless oil [150 mg, yield 44%; HPLC/MS: nm/z=476 (M+H); log P(HCOOH)=3.78].
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]([O:20]C)=[O:19])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]([OH:20])=[O:19])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ncnc2c1CCN(Cc1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ncnc2c1CCN(Cc1ccccc1)C2
Temperature: 85 °C
Yield: 91.1 %

Procedure:
Methyl 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxylate (0.2 g, 0.705 mmol) was dissolved in MeOH (10 mL). 10% NaOH solution (1.5 mL) was added. The solution was heated at 85° C. for 1 h. Solvent was removed under reduced pressure. The aqueous. layer was acidified to ca. pH 4. The aqueous layer was then extracted with DCM (2×50 mL) to remove organic impurities. The acidic aqueous layer was dried on the lyophilizer. The resulting solids were washed with MEOH (10 mL) and filtrate concentrated to give 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxylic acid (0.173 g, 0.642 mmol, 91%) as a brown oil. The resulting product was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:32])[NH:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH3:33][S:34]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:32])[NH:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)NC3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)cs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 3-hydroxy-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (360 mg, 0.780 mmol) (obtained as described in Reference Example 51(6)) in methylene chloride (18 ml) were added methanesulfonyl chloride (181 μl, 2.34 mmol) and triethylamine (328 μl, 2.34 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (98:2) as the eluant to afford 3-methanesulfonyloxy-1-{4-[1-(p-nitrobenzyloxycarbonyl)-piperidin-4-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (390 mg, yield 93%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:8]([N:25]([CH3:27])[CH3:26])([CH2:23][CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([Si:30]([O:35][CH3:36])([O:33][CH3:34])[O:31][CH3:32])=[CH2:29]>C1(C)C=CC=CC=1>[CH2:1]([C:8]([N:25]([CH3:27])[CH3:26])([CH2:23][CH3:24])[C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:13][C:12]=1[CH2:29][CH2:28][Si:30]([O:35][CH3:36])([O:33][CH3:34])[O:31][CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Si](OC)(OC)OC
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Solvent: Cc1ccccc1
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1CC[Si](OC)(OC)OC)N(C)C
Yield: 67 %

Procedure:
14.6 g (40 mmol) of 2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-1-butanone, 750 mg (0.8 mmol) of RuH2 (CO) (PPh3)3 and 13.4 ml (88 mmol) of vinyltrimethoxysilane were dissolved in 50 ml of toluene and degased using N2. After heating with stirring at reflux for 41 hours, the solvent was distilled off and the product was chromatographed (silica gel, CH2Cl2 /ethyl acetate). 13.8 g (67%) of dark red oil were obtained which were purified by boiling in heptane with active charcoal followed by filtration to give a yellow, viscous oil. 1H-NMR (CDCl3): 0.61 ppm (3H, t, Bu-H4, 3JH,H =7.2 Hz); 1.2 ppm (2H, mc, Et-H2); 1.88 ppm (2H, mc, Bu-H3); 2.37 ppm (6H, s, N(CH3)2); 2.71 ppm (2H, mc, Et-H1); 3.16 ppm (2H, mc, CH2 -Ph); 3.25 ppm (4H, mc, morpholine-N--CH2); 3.63 ppm (9H, s, Si(OCH3)3); 3.85 ppm (4H), mc, morpholine-O-CH2); 6.61 ppm (1H, dd, Ph-H5, 3JH5,H6, =8.6 Hz, 4 JH3, H6 =2.6 Hz); 6.75 ppm (1H, d, Ph-H3); 7.14-7.29 ppm (5H, m, Ph'-H); 8.44 ppm (1H, d, Ph-H6).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[S:25]1[C:29]([C:30]([OH:32])=O)=[CH:28][C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]1=2.[Si:37]([O:44][CH2:45][CH2:46][C:47]1[C:48]([F:65])=[C:49]([CH:62]=[CH:63][CH:64]=1)[CH2:50][N:51]1[CH2:61][CH2:60][C:54]2([O:59][CH2:58][CH2:57][NH:56][CH2:55]2)[CH2:53][CH2:52]1)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].C(N(CC)CC)C>CN(C=O)C>[S:25]1[C:29]([C:30]([N:56]2[CH2:55][C:54]3([CH2:53][CH2:52][N:51]([CH2:50][C:49]4[CH:62]=[CH:63][CH:64]=[C:47]([CH2:46][CH2:45][O:44][Si:37]([C:40]([CH3:42])([CH3:41])[CH3:43])([CH3:38])[CH3:39])[C:48]=4[F:65])[CH2:61][CH2:60]3)[O:59][CH2:58][CH2:57]2)=[O:32])=[CH:28][C:27]2[CH:33]=[CH:34][CH:35]=[CH:36][C:26]1=2
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: O=C(O)c1cc2ccccc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2cc4ccccc4s2)CCO3)c1F
Reaction time: 1 h

Procedure:
2-(3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.378 g) was added to a stirred solution of benzo[b]thiophene-2-carboxylic acid (0.186 g), 9-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecane (example 78, step d) (0.40 g), and triethylamine (0.383 g) in DMF (4 mL). After 1 h, the reaction mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water and once with brine, dried over magnesium sulphate, filtered and evaporated in vacuo. Purification by silica gel chromatography eluting with 7:1:0.5, isohexane:ethyl acetate:triethylamine gave the subtitled compound as a gum. Yield 0.38 g.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[O:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>[Zn]>[CH:12]1([C:13](=[O:9])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:11]1
Reactant: CCOC(=O)CBr
Reactant: C1CCOC1
Agent: Cl
Agent: [Zn]
Product: CCOC(=O)CC(=O)C1CC1

Procedure:
To a solution of 2-oxazolydone (20.8 g) in tetrahydrofuran (750 ml) was added n-butyllithium (1.56 M hexane solution, 153 ml) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of cyclopropanecarbonyl chloride (25 g) in tetrahydrofuran (50 ml) at −78° C. over 30 minutes. The mixture was stirred for 14 hours while gradually raising the temperature to room temperature. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give white crystals (26 g). A mixture of the obtained white crystals (10 g), ethyl bromoacetate (21.5 ml) and zinc powder (25.3 g) in tetrahydrofuran (300 ml) was ultrasonicated for 2 hours and heated under reflux for 2 hours. To the reaction mixture was added 10% hydrochloric acid and the insoluble material was filtered off through Celite. The filtrate was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give ethyl 3-cyclopropyl-3-oxopropionate (5.7 g) as a yellow oil. Subsequently, the title compound was prepared from 2-chlorobenzaldehyde, 3-aminopyrazole and ethyl 3-cyclopropyl-3-oxopropionate in the same manner as in Example 275.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[C:32]([Si:34]([CH3:37])([CH3:36])[CH3:35])#[CH:33]>C(N(CC)CC)C.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.[Cu]I>[CH3:21][C:5]1[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[N:7][C:2]([C:33]#[C:32][Si:34]([CH3:37])([CH3:36])[CH3:35])=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C#C[Si](C)(C)C)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 125 °C
Reaction time: 96 h
Yield: 67.8 %

Procedure:
0.90 g (1.99 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3), 0.042 g (0.06 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.021 g (0.11 mmol) of copper(I) iodide were suspended in 2.0 ml of triethylamine. After addition of 2.14 ml=1.50 g (15.0 mmol) of ethinyltrimethylsilane, the reaction vessel was sealed, heated up to 125° C. and stirring continued for four days. The reaction mixture was then poured into crashed ice and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.693 g (68%) of the title compound as dark brown oil. MS: 514.4 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[CH:20]=[CH:21][C:22]([OH:24])=O)[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:22](=[O:24])[CH:21]=[CH:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]1[CH:5]=[C:6]([C:14]([F:15])([F:17])[F:16])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C=CC(=O)O)Cc1ccc(Cl)cc1
Reactant: COc1ccccc1CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)C=CC(Cc1ccc(Cl)cc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
This is the compound of Example 1. It can be prepared also by the following synthesis method: a mixture of 0.493 g of 4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-pent-2-enoic acid, 0.137 g of 2-methoxy-benzylamine, 0.21 g of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 0.134 g of 4-dimethylaminopyridine and 10 ml of methylene chloride is stirred at room temperature under argon for 16 hours and then concentrated by evaporation. The residue is chromatographed (silica gel, hexane/ethyl acetate 1:1). In this way the title compound is obtained in the form of a colourless amorphous solid. 1H-NMR, 200 MHz, CDCl3, delta (ppm): 7.3-7.0(m, 4H), 6.95-6.7(m, 5H), 6.0(s,1H), 5.77(d, 1H), 5.0(b, 1H), 4.5(d, 2H), 3.85(s, 3H), 2.9-2.6(m, 5H), 1.3(bs, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:20])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](Cl)(=[O:23])[CH3:22].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:20][C:21](=[O:23])[CH3:22])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(C)c2)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(-c2cccc(C)c2)c(-c2ccnc(C)c2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
To a solution of [4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.8 mmol) and 4-dimethylaminopyridine (0.061 g, 0.50 mmol) in N,N-dimethylacetamide (15 mL) was added acetyl chloride (0.19 mL, 2.7 mmol), and the mixture was stirred for 14 hours at 80° C. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the deposited solid was filtrated. The resulted solid was washed with water, then, dried. The crude crystal was recrystallized from ethanol, to obtain a title compound (0.39 g, yield 67%).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:17])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([OH:16])[CH:9]=2)[CH2:2][CH2:3][CH3:4].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]2)=[CH:21][CH:20]=1>C(OC(O)C)C>[CH2:1]([C:5]1[C:6](=[O:17])[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([O:16][CH2:32][CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:35][CH:34]=3)[CH2:25][CH2:26]1)[CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C)c2ccc(O)cc2[nH]c1=O
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: CCOC(C)O
Product: CCCCc1c(C)c2ccc(OCCCN3CCN(Cc4ccc(Cl)cc4)CC3)cc2[nH]c1=O
Yield: 57.5 %

Procedure:
In a manner analogous to that described in Example 1, 3-n-butyl-4-methyl-7-hydroxy-2-oxo-1,2-dihydroquinoline is reacted with 3-[4-(4-chlorobenzyl)-piperazin-1-yl]-propyl chloride in ethoxyethanol. There is obtained 3-n-butyl-4-methyl-7-{3-[4-(4-chlorobenzyl)-piperazin-1-yl]-propoxy}-2-oxo-1,2-dihydroquinoline in a yield of 57.5% of theory; m.p. 148°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:12]=[O:13])=[O:5]
Reactant: NC(=O)c1ccccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1ccccc1Cl

Procedure:
2-Chlorobenzamide was dissolved in dichloromethane, mixed with 1.5 eq. of oxalyl chloride and heated to reflux for 16 hours. The reaction mixture was concentrated under high vacuum and reacted in stage b without further purification.