Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[CH:25]=[C:26]([S:30]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:31])=[O:32])[CH:27]=[CH:28][CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (322 mg, 1.0 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (370 mg, 1.2 mmol) according to general procedure II. Obtained as a yellow solid (244 mg, 44%). MS (ISP) 549.3 [(M+H)+]; mp 226–229° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:15](Cl)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18]>ClCCl>[C:15]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: NCCCC(=O)O
Reactant: CC(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)NCCCC(=O)O
Reaction time: 0.17 h
Yield: 22 %

Procedure:
To a solution of 20 gm (194 mMol) 4-aminobutyric acid in dichloromethane (700 ml) was added 56.8 ml (407 mMol) triethylamine and the mixture was stirred for 10 minutes. To the reaction mixture was then added a solution of 47.4 ml (388 mMol) isovaleryl chloride in dichloromethane (200 ml) dropwise and the resulting mixture was then stirred at room temperature for 2 hours. The reaction mixture was then filtered and the volatiles removed under reduced pressure. The residue was dissolved in 1N aqueous sodium hydroxide (150 ml) and the solution was stirred for 1.5 hours at room temperature. The aqueous solution was extracted with diethyl ether and the combined ether extracts were washed with water. All aqueous phases were combined and then acidified with concentrated hydrochloric acid. This mixture was then extracted well with ethyl acetate. These organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was slurried in hexane and the hexane decanted from the residue. Remaining residue was distilled in a bulb to bulb apparatus at 220° C. at 0.05 mmHg to give 8.0 g (22%) N-isovaleryl-4-aminobutyric acid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.Cl>C(OC)(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:22]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Yield: 93.3 %

Procedure:
Ethyl trifluoroacetate (23.52 g, 166 mmol) was dissolved in methyl tert-butyl ether (75 mL). To the stirred solution was added 25 weight % sodium methoxide (40 mL, 177 mmol). Next 4'-chloroacetophenone (23.21 g, 150 mmol) was dissolved in methyl tert-butyl ether (20 mL), and added to the reaction dropwise. After stirring overnight (15.75 hours), 3N HCl (70 mL) was added. The organic layer was collected, washed with brine (75 mL), dried over MgSO4, filtered, and concentrated in vacuo to give a 35.09 g of yellow-orange solid. The solid was recrystallized from isooctane to give 31.96 g (85%) of the dione: mp 66-67° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[OH-].[K+].Cl[C:12]1[N:13]=[C:14]2[CH:20]=[N:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]2=[N:16][CH:17]=1>CS(C)=O>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:12]2[N:13]=[C:14]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]3=[N:16][CH:17]=2)=[CH:1][CH:2]=1
Reactant: Clc1cnc2c(cnn2-c2ccccc2)n1
Reactant: Oc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Brc1ccc(Oc2cnc3c(cnn3-c3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
In 3 ml of dimethyl sulfoxide were dissolved 2.00 g (0.0115 mole) of p-bromophenol and 0.5 g (0.009 mole) of potassium hydroxide, and 1.00 g (0.0043 mole) of 5-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyrazine was added to the solution. The mixture was maintained at 100° C. for 2 hours. The post treatments were conducted in the same manner as described in Example 39, and the resulting residue was recrystallized from hexane to obtain 1.41 g (the yield was 89%) of 5-(4-bromophenoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyrazine in the form of a colorless scaly crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]2=O)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[H][H]>[Pd].CC(O)=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCc2ccc(OC)cc2C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C1CCc2ccc(OC)cc2C1
Yield: 70.4 %

Procedure:
A slurry of methyl 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (6.0 g, 26 mmol) and 10% palladium on carbon (100 mg) in AcOH (120 mL), and concentrated sulfuric acid (780 μL) was allowed to stir under 30 psi of hydrogen for 2.5 h. The reaction mixture was diluted with chloroform, and filtered through Celite. The filtrate was washed with water (5×), dried over Na2SO4 and evaporated. The residue was purified by filtration through a pad of silica, to give methyl 7-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylate as an oil (4.03 g, 71%). 1H NMR (300 MHz, CD3OD): δ 6.94 (d, 1H), 6.67-6.62 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 2.94-2.91 (m, 2H), 2.78-2.70 (m, 3H), and 2.18-2.09 (m, 1H), and 1.86-1.73 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.C(N(CC)CC)C.[CH3:21][NH:22][CH2:23][CH2:24][OH:25]>C(#N)C>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][OH:25])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CNCCO
Reactant: COc1ccc(CBr)cc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CN(C)CCO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 5 mL round bottom flask was charged with 4-(bromomethyl)-1-methoxy-2-nitrobenzene (0.6 g, 2.44 mmol) and acetonitrile (2 mL). The solution was treated with triethylamine (1 mL, 7.32 mmol) and 2-(methylamino)ethanol (0.585 mL, 7.32 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to provide the title compound. MS (DCI(+)) m/e 241.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]([CH3:14])=[CH:3][C:4]([O:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5].[N+:15]([C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[CH:21]=[C:22]([C:27](OC)=[O:28])[C:23]([O:25][CH3:26])=[O:24])([O-:17])=[O:16].C(N(CC)CC)C>CC(O)C>[OH:28][C:27]1[NH:1][C:2]([CH3:14])=[C:3]([C:4]([O:6][CH2:7][CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:5])[CH:21]([C:20]2[CH:31]=[CH:32][CH:33]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[C:22]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(N)=CC(=O)OCCc1cccs1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)C1=C(O)NC(C)=C(C(=O)OCCc2cccs2)C1c1cccc([N+](=O)[O-])c1
Yield: 26.5 %

Procedure:
A mixture of 2-(2-thienyl)ethyl 3-amino-2-butenoate (1.8 g) and dimethyl 3-nitrobenzylidenemalonate (2.25 g) was dissolved in anhydrous 2-propanol (80 ml) and, after addition of triethylamine (27 ml), the mixture was refluxed for 21 hours. After the solvent was distilled off under reduced pressure, the residue was purified by thin-layer silica gel chromatography (developing solvent: chloroform/methanol=19/1; elution solvent: chloroform/acetone=2/1) so as to obtain 1.0 g (26%) of the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[C:10](Cl)[N:9]=[C:8]([Cl:16])[N:7]=1)=[O:5])[CH3:2].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:9]=[C:8]([Cl:16])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1OCC
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1nc(Cl)nc(N2CCOCC2)c1OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
2,6-dichloro-5-ethoxy-pyrimidine-4-carboxylic acid ethyl ester (2 g, 1 eq.) was stirred in toluene (80 ml) and a solution of morpholine (0.73 ml, 1.1 eq.) in toluene (20 ml) was added dropwise in about 10 minutes at −10˜0° C., after stirring the resulting solution for 3 h at r.t. Water was added and extracted with EA. The combined organic layers were washed with brine, dried and evaporated in vacuo. Purification by flash chromatography gave a product (1.79 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(Cl)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(CO)ccc1Cl
Temperature: 25 °C

Procedure:
Methyl 4-chloro-3-methoxybenzoate (5 g, 25 mmol, 1 equiv) in 15 mL of THF and 15 mL of DCM was cooled to 0° C. and treated with LiAlH4 (2.8 g, 3 equiv) overnight and was allowed to warm to rt. The reaction was then quenched with saturated sodium sulfate. Removal of the solid by filtration through celite followed by evaporation of the filtrate gave 4-chloro-3-methoxybenzyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CN1CCCN(C)C1=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:16][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: Clc1ccc(C(=Cn2cncn2)OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.2 %

Procedure:
670 mg (2.62 mmol) of 1-(2,4-dichlorophenyl)-2-[1,2,4]triazol-1-yl-ethanone in 12 ml of tetrahydrofuran and 4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone were added to a suspension of 171 mg (3.92 mmol) of sodium hydride (55% in mineral oil) in 15 ml of tetrahydrofuran and 5 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and stirred at room temperature for 3 hours. Thereafter, 396 mg (5.24 mmol) of benzyl bromide were added and the mixture was stirred at room temperature for a further 16 hours. The tetrahydrofuran was removed under a vacuum, the residue was added to 50 ml of water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were dried over magnesium sulphate and the diethyl ether was removed in a vacuum. The crude product was purified by column chromatography on silica gel (diethyl ether/pentane 1:4). In addition to mixed fractions with the C-alkylation product there were obtained 65 mg (7%) of pure 1-[2-(2,4-dichloro-phenyl)-2-benzyloxy-vinyl]-1H-[1,2,4]triazole as a colourless oil. [M+H]+ =345, 347.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH:8]([N+:12]([O-:14])=[O:13])[N+:9]([O-:11])=[O:10])(=[O:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].[OH-].[Na+]>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([N:15]=[N+:16]=[N-:17])([N+:12]([O-:14])=[O:13])[N+:9]([O-:11])=[O:10])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCCCC([N+](=O)[O-])[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)OCCCC(N=[N+]=[N-])([N+](=O)[O-])[N+](=O)[O-]
Reaction time: 5.25 h

Procedure:
A divided electrochemical H-cell was charged with 4,4-dinitro-1-butyl acetate (10.2 g), 30% aqueous NaN3 (25 ml) and 12N NaOH (4 ml) in the anode compartment and 30% NaN3 (35 ml) in the cathode compartment. This solution was electrolyzed at 650 mA using a platimum foil anode (6.5 cm2) and a stainless steel cathode. After 5.25 h the reaction was stopped, and the anolyte was extracted with CH2Cl2 (3×25 ml). Brine-washing, drying, and concentrating the extracts yielded a product which displayed a weak hydroxyl absorption in the infrared spectrum. The product was reacetylated by stirring with acetyl chloride (1 ml) in CH2Cl2 (30 ml) for 2 h. This reaction was quenched in ice water, dried, and concentrated. The crude yellow oil was purified by column chromatography on silica gel eluting with 10% ethyl acetate in hexanes. The purified product was a clear light yellow oil which was greater than 95 % pure by HPLC: nD =1.4649 (25C); IR: 2165, 1735, and 1590 cm-1 ; NMR (CDCl3): 4.07 (q, 2H), 2.58 (m, 2H), 2.07 (s, 3H), 1.73 (m, 2H). Elemental analyses calcluated for C6H9N5O6 : C, 29.15; H, 3.64; N, 28.34. Found: C, 29.59; H, 3.90; N, 27.89.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][N:4]=1.CC([O-])(C)C.[K+].C1(P(O[NH2:37])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[NH2:37][N:5]1[N:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:13]
Reactant: O=c1[nH]nc(C(F)(F)F)c2ccccc12
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 1 h

Procedure:
A mixture of Example 11A and KOtBu (1 M in THF, 2.8 mL, 2.8 mmol) in THF (5 mL) was stirred for 60 min, and O-(diphenylphosphoryl)hydroxylamine (0.680 mg, 0.348 mmol) was added and stirred for 1 hour. The mixture was diluted with EtOAc, washed with 1 N NaOH and water, dried (Na2SO4), and concentrated to give the title compound as a white solid (402 mg) which was used without purification. 1H NMR (300 MHz, DMSO-d6) δ 8.45-8.35 (m, 1H), 8.10-7.92 (m, 3H), 6.58 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1cncc(Br)c1
Product: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1

Procedure:
23 g (105 mmol) of methyl 5-bromonicotinate and 26 g (126 mmol, 1.2 eq.) of 4-trifluoromethoxyphenylboronic acid were reacted according to the General Method 1A. Yield: 14 g (41% of theory)
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=2)[NH:14][N:13]=1>C1COCC1>[CH2:1]([NH:8][C:9]([NH:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2[nH]nc(I)c2c1
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Nc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
Benzyl isocyanate (0.25 mL, 2.0 mmol) was added to 3-iodo-1H-indazol-5-ylamine (Preparation #28, 0.50 g, 1.9 mmol) in THF (10 mL). After stirring at ambient temperature for about 2.5 hours, the mixture was filtered and washed with Et2O to give 1-benzyl-3-(3-iodo-1H-indazol-5-yl)-urea (0.41 g, 55%) as an ivory solid; RP-HPLC (Table 1, Method e) Rt 0.98 min, m/z (ESI+) 393.0 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8](Cl)=[O:9].CCOC(C)=O>C1COCC1>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8]([N:2]([CH3:3])[CH3:1])=[O:9]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(OC)c1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of dimethylamine (42 mL, 84 mmol) in THF at 0° C. is added 2,6-dimethoxybenzoyl chloride (5.58 g, 27.8 mmol) and it is warmed to RT and stirred for 18 h. The mixture is poured to EtOAc, washed with water, 1 N HCl solution and brine. The solvent is removed and concentrated to give the title compound and it is used in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>CC#N>[O:19]([CH2:18][CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1
Yield: 79.5 %

Procedure:
To a stirred suspension of 4-hydroxybenzaldehyde (0.500 g, 4.012 mmol) and anhydrous potassium carbonate (0.833 g, 6.019 mmol) in dry MeCN (15 ml) at room temperature was added 2-bromo-1-tert-butyldimethylsiloxyethane (83%, 1.730 g, 6.019 mmol), and the reaction mixture was heated under reflux for 20.5 h. Water (25 ml) was added and the reaction mixture was extracted with Et2O (4×25 ml). The combined organic extracts were washed with brine (50 ml), dried (Na2SO4), and the solvent was removed under reduced pressure to give a pale yellow oil that was purified by flash chromatography (3:1 Hexane/Et2O) to give the title compound (0.895 g, 79.5%) as a colourless oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:21])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[NH:18][C:17](=[O:20])[CH2:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9](=[O:21])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[N:18]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:17](=[O:20])[CH2:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C1Cc2cccc(CC(=O)OCc3ccccc3)c2N1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2C(=O)Cc3cccc(CC(=O)OCc4ccccc4)c32)cc1
Temperature: 70 °C

Procedure:
A solution of 28.1 g (0.1 mole) 2,3-dihydro-2-oxo-1H-indole-7-acetic acid phenylmethyl ester in 400 ml of toluene is treated with 17.1 g (0.1 mole) of 4-methoxybenzoyl chloride. The mixture is heated at 70° C. with stirring and a solution of 10.2 g (0.1 mole) of triethylamine in 100 ml of toluene is added dropwise.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=O)[NH:14][C:15]=2[CH:16]=1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[S:30])[NH:14][C:15]=2[CH:16]=1)=[O:4]
Reactant: COC(=O)CCc1ccc2c(c1)NC(=O)C1CCCC21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)CCc1ccc2c(c1)NC(=S)C1CCCC21
Yield: 117.8 %

Procedure:
Analogously to Example 4, 7-(methoxycarbonylethyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (120 mg, 0.44 mmol) is reacted with Lawesson's reagent (195 mg, 0.48 mmol) to form 150 mg of product.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:26]2[CH2:25][CH2:24][N:23]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[CH:22]([CH3:21])[CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2C)c1

Procedure:
106 mg (77%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 2-methyl-1-m-tolylpiperazine (52 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: [CH2:1]=O.[CH2:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1)[CH3:4]>C(O)=O>[CH2:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:21])=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH3:1])[CH2:19][CH2:20]3)[N:13]=2)[C:8](=[O:22])[C:7]([C:23]([OH:25])=[O:24])=[CH:6]1)[CH3:4]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)nc21
Reactant: C=O
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)nc21

Procedure:
To a solution of 37% formalin (12 ml) and formic acid (18 ml) was added 6.0 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, and the mixture was heated at 120°-125° C. for 4 hours with stirring. The mixture was then concentrated to dryness under reduced pressure. The residue was adjusted to pH 8 by addition of aqueous 7% sodium bicarbonate, and extracted with chloroform. The extract was dried and the solvent was evaporated. The crystalline residue was recrystallized from a mixture of dichloromethane and ethanol to give 5.0 g of 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 228°-230° C.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:34]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([NH:40][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: CN[C@H](Cc1ccccc1)CN1CC=C(c2cc(F)ccc2OC)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)NC2CCCCC2)CC1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,3,6-tetrahydropyridin-1-yl]-ethyl}-methyl-amine (0.17 g, 0.48 mmole, described as intermediate 12 above) and triethylamine (0.15 mL, 1.0 mmole) in dichloromethane (10 mL) was cooled to 0° C. and a solution of cyclohexyl isocyanate (0.070 mL, 0.51 mmole) was added dropwise. The resulting mixture was stirred at 0° C. to room temperature (ice melt) overnight. The solvent was evaporated and the residue dissolved in EtOAc (25 mL) and water (25 mL). The layers were separated and the organics washed with water (25 mL), brine (30 mL) and dried over Na2SO4. Filtration and concentration gave the crude product which was purified by flash chromatography (elution with EtOAc) to yield 0.19 g (83% yield) of 1-{(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydro-4H-pyridin-1-yl]-ethyl}-3-cyclohexyl-1-methyl-urea. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid.