Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:28][CH3:29])=[C:8]([C:14]([CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3C)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2]1.C1(S(CC2C(C(OCC)=O)=C(OC)C(Br)=CC=2)(=O)=O)C=CC=CC=1.[N:54]1C=CC=C(B(O)O)[CH:55]=1>>[C:21]1([S:18]([CH2:17][C:14]2[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:28][CH3:29])[C:6]([C:3]3[CH:2]=[N:54][CH:55]=[CH:5][CH:4]=3)=[CH:16][CH:15]=2)(=[O:19])=[O:20])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(-c2ccoc2)c1OC
Reactant: OB(O)c1cccnc1
Agent: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2cccnc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 28, starting from ethyl 6-benzenesulphonylmethyl-3-bromo-2-methoxybenzoate (Intermediate 61) and 3-pyridylboronic acid.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]2[C:8]([CH:13]([O:21][C:22](=[O:24])[CH3:23])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][N:10]=[C:11]([CH3:12])[C:4]=2[O:3]1>C(O)(C(F)(F)F)=O.O>[CH3:12][C:11]1[C:4]([OH:3])=[C:5]([CH2:6][OH:7])[C:8]([CH:13]([O:21][C:22](=[O:24])[CH3:23])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][N:10]=1
Reactant: CC(=O)OC(c1ccc(Cl)cc1)c1cnc(C)c2c1COC(C)(C)O2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC(c1ccc(Cl)cc1)c1cnc(C)c(O)c1CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
0.24 g (0.66 mmoles) of (+)-2,2,8-trimethyl-5-(4-chloro-α-acetoxybenzyl)-pyrido-[4,3-e]-1,3-dioxane are poured into a 10 ml round bottomed flask and dissolved in 3.3 ml of TFA/H2O (10:1). The reaction is allowed to stir at room temperature for 1.5 hours, the solvent is then removed by rotary evaporation. 1 ml of methanolic ammonia is added to the crude product (the excess of TFA being neutralized), then evaporated to dryness under high vacuum. The crude product was shown to contain 90% of the desired diol-acetate by HPLC along with 4.4% of unreacted starting material.
Reaction SMILES: CC1(C)[O:10][C@H:9]2[C@H:4]([C@@H:5]([CH2:16][OH:17])[O:6][C@@H:7]3[O:13]C(C)(C)[O:11][C@@H:8]32)[O:3]1.[C:19](O)(=[O:42])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[C:29][C:30]#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:19]([O:17][CH2:16][CH:5]1[CH:4]([OH:3])[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:13])[O:6]1)(=[O:42])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[C:29][C:30]#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Reactant: CC1(C)O[C@H]2[C@@H](O1)[C@@H](CO)O[C@@H]1OC(C)(C)O[C@@H]12
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OCC1OC(O)C(O)C(O)C1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,2;3,4-di-O-isopropylidene-D-galactopyranose (2.6 g, 10 mmol) and 10,12-tricosadiynoic acid (3.5 g, 10 mmol) were dissolved in 25 ml methylene chloride. 1-Ethyl-3(3-dimethylaminopropyl)carbodiimide (2 g, >10 mmol) was added neat. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted to 100 ml, extracted with water (2×25 ml), dried over MgSO4 and the solvent was removed in vacuo. The crude product was treated with trifluoroacetic acid (10 ml) at room temperature for 30 minutes, evaporated in vacuo, and purified by straight phase chromatography on a CHROMATOTRON, eluted with methanol/chloroform (5:95). The product was characterised by NMR.
Reaction SMILES: [O:1]=[C:2]([C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([OH:13])[C:10]([OH:11])=[CH:9][CH:8]=1)[NH2:5])[OH:3].C([O-])([O-])=O.[Na+].[Na+].[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23].Cl>O>[C:21]([NH:5][C@H:4]([C:2]([OH:3])=[O:1])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:12]([OH:13])[CH:14]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
1.15 g (5.69 mmol) of Na2B4O7 was dissolved in 30 ml of water. The solution was degassed with Ar for 30 minutes, after which 0.592 g (3.0 mmol) of L-DOPA was added and stirred for 15 minutes. 0.317 g (3.0 mmol) of Na2CO3 was then added, the solution was cooled to 0° C., and 0.3 ml (3.0 mmol) of methacryloyl chloride was slowly added with stirring. The pH of the solution was maintained above 9 with Na2CO3 during the reaction. After stirring for 1 hour at room temperature, the solution was acidified to pH of 2 with concentrated HCl. The mixture was extracted with ethyl acetate three times. After washing with 0.1 N HCl and drying over anhydrous MgSO4, the solvent was removed in vacuo to yield crude light brown solid. The product was further purified by elution from a silica gel column with dichloromethane (DCM) and methanol (95:5). After evaporating the solvent, a white, sticky solid was obtained with a product yield of 35%. 1H NMR (500 MHz, acetone-d6): ÿ 7.1 d(1H, —NH—); 6.6-6.8 (3H, C6H3(OH)2—); 5.68 s (1H, CHH═); 5.632 s (unknown peak); 5.33 s (1H, CHH═); 4.67 m (1H, —CH—); 2.93-3.1 m (2H, CH2—); 1.877 s (3H, —CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:8]1[NH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:7]=1[CH2:6]2.[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][C:30](Cl)=[O:31].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([N:9]1[C:8]2[C:20]3[C:5]([CH2:6][C:7]=2[C:11]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:10]1)=[CH:4][C:3]([O:2][CH3:1])=[C:22]([O:23][CH3:24])[CH:21]=3)=[O:31]
Reactant: COc1cc2c(cc1OC)-c1[nH]nc(Nc3cccc(F)c3)c1C2
Reactant: COC(=O)CCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)n1nc(Nc2cccc(F)c2)c2c1-c1cc(OC)c(OC)cc1C2

Procedure:
To a mixture of (6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (Compound 14) (0.50 g, 1.5 mmol), 3-Chlorocarbonyl-propionic acid methyl ester (Compound 26a) (0.277 g, 1.8 mmole) and DMF (1.5 mL) was added Duisopropylethylamine (DIEA) (0.52 mL, 3.0 mmole) at room temperature with stirring. The reaction was stirred at room temperature over night. The reaction was quenched with water and extracted with EtOAc. The solvent was removed via rotovap and the crude material was prepped on the reverse phase HPLC. Lyophilization gave the title compound as-a white powder. MS m/z 439.9 (M+H)+;
Reaction SMILES: [NH2:1][C@H:2]([C:14]([NH:16][C:17]1[CH:18]=[N:19][N:20]([CH3:23])[C:21]=1[NH2:22])=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][C:41](ON1C(=O)CCC1=O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(Cl)(Cl)Cl>[NH2:22][C:21]1[N:20]([CH3:23])[N:19]=[CH:18][C:17]=1[NH:16][C:14](=[O:15])[C@@H:2]([NH:1][C:41](=[O:42])[CH2:40][CH2:39][NH:38][C:36]([O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:37])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Reactant: Cn1ncc(NC(=O)[C@@H](N)CCCNC(=O)OC(C)(C)C)c1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl (4S)-4-amino-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-oxopentylcarbamate (4.90 g) and triethylamine (1.52 g) in chloroform (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (4.26 g). The mixture was stirred at room temperature for 17 hours. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-oxopentylcarbamate as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:31][O:32][CH2:33]Cl.[Cl-].[NH4+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][O:21][CH2:31][O:32][CH3:33])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(CCO)ccc1OCc1ccccc1
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCCc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of methyl 2-benzyloxy-5-(2-hydroxyethyl)benzoate (1.43 g) in dichloromethane (20 ml) were added N,N-diisopropylethylamine (1.0 ml) and chloromethyl methyl ether (460 μl) under ice-cooling, and the mixture was stirred for 17 hours at room temperature. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=4/3) gave methyl 2-benzyloxy-5-(2-methoxymethoxyethyl)benzoate (1.19 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:13].[K+]>CO>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][OH:13])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=C[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CO)c1ccc(Cl)cc1

Procedure:
A mixture of 2-bromo-1-(4-chloro-phenyl)-ethanone (100 mmoles) and potassium formate (130 mmoles) in MeOH (100 ml) is stirred at reflux for 3 hours. The reaction mixture is poured onto crushed ice. The solid formed is filtered off, washed with cold MeOH and then dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[O:7])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].C([O-])([O-])=O.[K+].[K+].[C:29]1([CH3:41])[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CN(C=O)C>[N+:20]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:2]=1[N:38]1[CH2:39][CH2:40][N:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH3:41])[CH2:36][CH2:37]1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])=[O:7])([O-:22])=[O:21]
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=C(NCCCN1CCCC1=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-Fluoro-3-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide (2.0 g, 6.47 mmol) in DMF (10 mL), K2CO3 (1.7 g, 12.94 mmol) was added followed by 1-o-tolyl-piperazine (1.7 g, 9.7 mmol), and the reaction mixture was stirred at room temperature for 16 h. DMF (2.0 mL) was added and filtered. The solid was washed with MeOH (300 mL) and methanol layer was evaporated to give the acid 3-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide in the first crop (1.8 g, 62%).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH2:9]([NH2:13])[CH:10]([CH3:12])[CH3:11].[BH4-].[Na+]>CO>[Br:1][C:2]1[O:6][C:5]([CH2:7][NH:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)CN
Reactant: O=Cc1ccc(Br)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CNCc1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a stirred solution of 5-bromo-2-furaldehyde (500 mg) in methanol (5 mL) was added isobutylamine (209 mg). The mixture was stirred overnight at r.t. Sodium borohydride (162 mg) was added and the mixture was stirred for 2 h. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to give the crude (5-bromo-furan-2-ylmethyl)-isobutyl-amine (686 mg) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(O)(=O)C.ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:13]([N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: c1ccc(Cn2cccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1C=C(c2cccn2Cc2ccccc2)C(=O)c2ccccc21
Yield: 18 %

Procedure:
3.16 millimol of 1,4-naphthoquinone were stirred with 25 millimol of N-benzylpyrrole and 3.16 millimol of copper acetate in 50 ml of acetic acid in a round-bottomed flask at room temperature for 1 hour. The reaction mixture was diluted with 300 ml of dichloromethane and the resulting mixture was then poured into a large volume of water (300 ml). The organic phase was then separated out and washed four times with 100 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 2-(1-benzyl-1H-pyrrol-2-yl)-[1,4]-naphthoquinone was thus isolated in a yield of 18% after purification by chromatography on a column of silica.
Reaction SMILES: [C:1](=[N:14]O)([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3]>[Pd].C(O)(=O)C>[NH2:14][CH:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3]
Reactant: CCC(=NO)c1ccc2ccccc2n1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCC(N)c1ccc2ccccc2n1
Reaction time: 5 h
Yield: 96.8 %

Procedure:
Example P-11: 4.0 g of 2-propionylquinoline-oxime and 2 g of 5 % Pd/C catalyst in 40 ml of glacial acetic acid are placed in a hydrogenation apparatus. The batch is hydrogenated for 5 hours at 20°-25° C. under normal pressure. Filtration is then carried out, the glacial acetic acid is removed under a water-jet vacuum and the residue is purified by means of flash chromatography on silica gel (eluant: ethanol/ether 1:1 ) to yield 3.6 g of 2-(1-aminopropyl)quinoline in the form of a red oil (1H-NMR).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH2:13]([O:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:14]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:16]([O:15][CH2:13][CH3:14])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CCONCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CCON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 92 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with O-ethyl-N-4-fluorobenzyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (92% yield): mp 95–96° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (3H, t, J=7.07 Hz, CH3), 1.77 (6H, s, CH3), 3.90 (2H, q, J=7.07 Hz, OCH2), 4.81 (2H, s, NCH2), 6.41 (1H, s, CH), 7.03 (2H, m, aromatics), 7.37 (2H, m, aromatics). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.50; H, 5.60; N, 4.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].CC([O-])=O.[Na+].[Br:21]Br>CC(O)=O.C(OCC)C>[Br:21][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1c(Br)cc(C(=O)O)c(OC)c1OC
Temperature: 80 °C

Procedure:
To a solution of 2,3,4-trimethoxybenzoic acid (4.7 g, 22 mmol) and NaOAc (5.5 g, 40 mmol) in 35 ml AcOH was added a solution of bromine (1.5 ml, 29 mmol) in 35 ml AcOH. The reaction became red in color, which quickly faded. The mixture was heated to 80° C. for 1 h, at which point it was cooled to ambient temperature. The material was partitioned between dichloromethane and water. The organic layer was removed and the aqueous layer was extracted once with dichloromethane. The combined organic layers were dried with Na2SO4, filtered, and concentrated to give an oil which solidified on standing. The material was dissolved in diethyl ether and hexanes. Concentration to ½ the volume resulted in precipitation of a white solid. Filtration provided the title compound as a white solid. MS m/z: 293 (M+H+); calc'd for C10H11BrO5: 291.1
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][NH:4][CH2:3]1.[C:8]([N:15]1[CH2:18][C:17](=O)[CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CC(O)=O>[C:11]([O:10][C:8]([N:15]1[CH2:18][CH:17]([N:4]2[CH2:5][CH2:6][NH:7][C:2](=[O:1])[CH2:3]2)[CH2:16]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(N2CCNC(=O)C2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a mixture of 3-oxopiperazine 4a (490 mg, 4.89 mmol) and N-Boc-azetidin-3-one 1a (922 mg, 5.38 mmol) in 1,2-dichloroethane (10 mL) and HOAc (0.5 mL) was added Na(OAc)3BH (1141, 5.38 mmol). The reaction was stirred at room temperature overnight. Additional 1a (335 mg, 1.96 mmol) and Na(OAc)3BH (415 mg, 1.96 mmol) was added. The reaction was stirred for another 24 h before it was quenched with aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by column chromatography (silica gel, 4% MeOH/CH2Cl2) gave intermediate 4b as white solid (860 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)(Cl)Cl>[CH2:28]([NH:36][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 61 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -13° C. and -16° C. during 25 minutes. After stirring for 5 minutes, 11.37 g (0.088 mol) of octylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -13° C. and -16° C. during 40 minutes. The reaction mixture is stirred at the same temperature for 1 hour and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to obtain 15.4 g (61.0%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 108°-110° C.
Reaction SMILES: C([C:3]1[C:4]([N:15]2[CH2:19][CH2:18][C@@H:17]([C:20]3([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:21]3)[CH2:16]2)=[C:5]([O:13][CH3:14])[C:6]([F:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:27]([O:26][C:24]([NH:23][C:20]1([C@@H:17]2[CH2:18][CH2:19][N:15]([C:4]3[CH:3]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:12])[C:5]=3[O:13][CH3:14])[CH2:16]2)[CH2:22][CH2:21]1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCc1cc(C(=O)O)c(F)c(OC)c1N1CC[C@@H](C2(NC(=O)OC(C)(C)C)CC2)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(N2CC[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)ccc(C(=O)O)c1F
Temperature: 50 °C

Procedure:
Ethyl 4-[(3R)-3-(1-tert.-butoxycarbonylaminocyclopropyl)-pyrrolidin-1-yl]-2-fluoro-3-methoxybenzoic acid (3.61 g) was dissolved in 28 mL of ethanol, 1N aqueous sodium hydroxide solution (34.5 mL) was added to the solution, and the mixture was heated to 50° C. with stirring. After completion of the reaction, 10% aqueous citric acid solution was added to the mixture followed by extraction with chloroform. An organic layer was dried with anhydrous sodium sulfate and filtered, and then the solvent was distilled away. The title compound was obtained as residual crystals (4.45 g). The crystals were used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1B1OC(C)(C)C(C)(C)O1)[C:5]#[N:6].Br[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1)[C:5]#[N:6]
Reactant: Cc1cc(Br)ccn1
Reactant: CC1(C)OB(c2ccc(C#N)cc2F)OC1(C)C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(C#N)cc2F)ccn1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (14.0 g), 4-bromo-2-methylpyridine (5.84 mL), tetrakis(triphenylphosphine)palladium(0) (5.24 g) and 2N aqueous sodium carbonate solution (91 mL) in 1,2-dimethoxyethane (20 mL) was stirred at 80° C. for 30 min under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was separated, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.41 g).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:7]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH2:14]2)=[CH:6][C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCCCl
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2CNC(=O)C2)cc1OCCN1CCN(c2ccccc2)CC1
Yield: 15.2 %

Procedure:
20 mmol of 4-[3-(2-chloroethoxy)-4-methoxyphenyl]-2-pyrrolidone is dissolved in 50 ml. of dimethylformamide. After adding 22 mmol of 1-phenylpiperazine (95% strength) and 20 mmol of triethylamine, the reaction mixture is heated for 6 hours to 100 ° C. After the reaction has ceased, the solvent is withdrawn at 40° under a high vacuum. The residue is taken up in 50 ml. of ethyl acetate, washed with semisaturated sodium chloride solution, and the solvent, after drying over sodium sulfate, is distilled off under vacuum, thus obtaining in a 15.2% yield 4-{4-methoxy-3-[2-(4-phenylpiperazin-1-yl)ethoxy]-phenyl}-2-pyrrolidone, m.p. 140°-141°. The dihydrochloride, m.p. 219°-221°, is precipitated from ethereal hydrochloric acid.