Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Br[CH:4]([CH:7]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[OH:8])[CH2:5][OH:6]>O.C(O)C>[O:8]1[CH:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)[CH:4]1[CH2:5][OH:6]
Reactant: OCC(Br)C(O)c1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCC1OC1c1ccsc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
0.8 g of sodium hydroxide in 15 ml of water is added to a solution of 2.4 g of (2RS,3SR)-2-bromo-3-(thiophen-3-yl)-propane-1,3-diol in 25 ml of ethanol. The reaction mixture is stirred for 40 minutes at room temperature, the ethanol is evaporated off in vacuo and the residue is diluted with 400 ml of water. Extraction is carried out with dichloromethane (3×100 ml), the extracts are dried over sodium sulfate and the solvent is evaporated off. The residue is chromatographed on silica gel with dichloromethane/acetone (9:1). The title compound is obtained in the form of light-yellow crystals, m.p.=63°-65° C.
Reaction SMILES: [CH:1]([C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8])=O.[C:16]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:18][CH2:19][CH3:20])=[O:17]>O1CCOCC1>[CH2:19]([O:18][C:16]([CH:21]=[CH:1][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8])=[O:17])[CH3:20]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)C=Cc1c(C)oc2c([N+](=O)[O-])cccc12
Yield: 84.2 %

Procedure:
A solution of 3-formyl-2-methyl-7-nitrobenzo[b]furan (200 mg) and (carboethoxymethylene)triphenylphosphorane (434 mg) in dioxane (3 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel. The obtained oil was crystallized from diisopropyl ether to give 3-(2-ethoxycarbonylethenyl)-2-methyl-7-nitrobenzo[b]furan (226 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:26]2[C:27]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])=[CH:28][C:29]3[O:33][C:32]([C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)=[C:31]([C:41]([NH:43][CH3:44])=[O:42])[C:30]=3[CH:45]=2)=[N:13][C:14]=1[C:15]1[C:23]([CH2:24][OH:25])=[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]2[N:16]=1)C1C=CC=CC=1>CO.[Pd]>[F:40][C:37]1[CH:36]=[CH:35][C:34]([C:32]2[O:33][C:29]3[CH:28]=[C:27]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:48])=[O:49])[C:26]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[C:14]([C:15]5[C:23]([CH2:24][OH:25])=[C:18]6[CH:19]=[CH:20][CH:21]=[CH:22][N:17]6[N:16]=5)[N:13]=4)=[CH:45][C:30]=3[C:31]=2[C:41]([NH:43][CH3:44])=[O:42])=[CH:39][CH:38]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(-c4nn5ccccc5c4CO)n3)cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(-c4nn5ccccc5c4CO)n3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A mixture of compound 5-(5-(benzyloxy)-6-(3-(hydroxymethyl)pyrazolo[1,5-a]pyridin-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (250 mg, 0.35 mmol) and Pd/C (20 mg) in MeOH (2 mL) was stirred at room temperature under H2 for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified using prep-TLC (EA:MeOH=20:1) to provide the product of compound 2-(4-fluorophenyl)-5-(5-hydroxy-6-(3-(hydroxymethyl)pyrazolo[1,5-a]pyridin-2-yl)pyridin-2-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, yield: 46%). 1H-NMR (Methanol-d4, 400 MHz) δ 8.50 (d, J=6.8 Hz, 1H), 7.98 (dd, J=5.2, 8.4 Hz, 2H), 7.84 (s, 2H), 7.78 (d, J=9.2 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.29˜7.23 (m, 3H), 6.93 (t, J=6.8 Hz, 1H), 4.77 (s, 2H), 3.26 (s, 3H), 2.93 (s, 3H), 2.90 (s, 3H). MS (M+H)+: 616.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)(=[O:30])=[O:29])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 3-fluorobenzenesulfonyl chloride (390 μl). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(3-fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (919 mg).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18].[Cl-].[NH4+]>C1COCC1>[F:6][C:7]1[C:8]([F:13])=[CH:9][CH:10]=[CH:11][C:12]=1[CH:14]([OH:19])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC=O
Reactant: Fc1ccccc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC(O)c1cccc(F)c1F
Reaction time: 8 h

Procedure:
n-Butyllithium (50 cm3, 10.0M in hexanes, 0.5 mol) was added dropwise to a stirred, cooled (-78° C.) solution of 1,2-difluorobenzene (57 g, 0.5 mol) in dry THF (600 cm3) under an atmosphere of dry nitrogen. The mixture was maintained under these conditions (3 h) then a solution of pentanal (43.1 g, 0.5 mol), in dry THF (50 cm3) added dropwise at -78° C. The temperature of the reaction mixture was allowed to reach room temperature overnight. An aqueous solution of ammonium chloride (27 g in 160 cm3 water) was added and the product extracted into diethyl ether (2×150 cm3), the combined extracts washed with water (2×150 cm3) and dried (MgSO4). The solvent was removed in vacuo to give the product as a colourless oil which was purified by distillation under reduced pressure.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:18]=[C:17]4[C:13]([CH2:14][CH2:15][CH2:16]4)=[CH:12][C:9]=3[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:19]([O-:24])([N+]([O-])=O)=[O:20]>C(Cl)(Cl)Cl>[N+:19]([C:11]1[O:10][C:9]2[CH:12]=[C:13]3[C:17](=[CH:18][C:8]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:16][CH2:15][CH2:14]3)([O-:24])=[O:20]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: c1ccc(-c2coc3cc4c(cc23)CCC4)cc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1oc2cc3c(cc2c1-c1ccccc1)CCC3

Procedure:
To a solution of 2.3 g. (0.01 mole) of the product of step B in 100 ml. of chloroform is added 1.8 g. (0.02 mole) of dinitrogen tetraoxide, and the mixture is stirred at about 20° C. for 20 hours. The mixture is evaporated, and the residue is triturated with isopropyl ether to provide a precipitate. The precipitate is separated by filtration and recrystallized from methanol to provide 6,7-dihydro-2-nitro-3-phenyl-5H-indeno-[5,6-b]furan, m.p. 161°-164° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Nc1ccccc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: c1ccccc1
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccccc2)C(=O)OC1=O

Procedure:
To a boiling solution of 3.0 g. (0.014 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 25 ml. of benzene is added 1.4 g. (0.015 m.) of aniline and the resulting mixture is refluxed overnight. The reaction mixture is cooled and filtered to give 5-acetyl-4-hydroxy-3-[1-(phenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 184° -186° C.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:20]/[O:21][CH2:22][CH2:23][I:24])/[C:17]([OH:19])=O)[N:15]=1.[NH2:25][C@H:26]1[C@@H:29]([CH2:30][O:31][C:32](=[O:34])[NH2:33])[N:28]([S:35]([OH:38])(=[O:37])=[O:36])[C:27]1=[O:39]>C(N(CC)CC)C>[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:20]/[O:21][CH2:22][CH2:23][I:24])/[C:17]([NH:25][C@H:26]2[C@@H:29]([CH2:30][O:31][C:32](=[O:34])[NH2:33])[N:28]([S:35]([OH:38])(=[O:36])=[O:37])[C:27]2=[O:39])=[O:19])[N:15]=1
Reactant: Nc1nc(/C(=N/OCCI)C(=O)O)cs1
Reactant: NC(=O)OC[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Product: NC(=O)OC[C@@H]1[C@H](NC(=O)/C(=N\OCCI)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Reaction time: 2 h
Yield: 50 %

Procedure:
7.7 g of 2-chloro-1-methyl-pyridinium iodide are added to a solution of 6.8 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-iodoethoxy)imino]-acetic acid, 4.8 g of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid and 8.4 g of triethylamine in 50 ml of dimethylformide and the mixture is stirred for 2 hours. After removal of the solvent under reduced pressure at about 25° C., the residue is taken up in 250 ml of water and washed with 100 ml of ethyl acetate and twice with 100 ml of dichloromethane. After the addition of 20.3 g of tetra-n-butylammonium hydrogen sulphate, the mixture is adjusted to pH 6-7 using 70 ml of saturated sodium bicarbonate solution and extracted four times with 100 ml of dichloromethane each time. The combined extracts are washed with 50 ml of water. The product is then precipitated by the addition of 7.5 ml of formic acid. After washing with acetone and ether, there are obtained 5.6 g of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(2-iodoethoxy)imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:34][OH:35]>CCO.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1](=[N:34][OH:35])[NH2:2])=[CH:8][CH:7]=3)[NH:10][C:11]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:15][CH:16]=1
Reactant: NO
Reactant: N#Cc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Yield: 92.4 %

Procedure:
To a mixture of 2-(4-cyanophenyl)-4-(4-fluorophenyl)-5-(4-pyridyl)-1H-imidazole (3.0 g, 8.7 mmol) [See Ex. 1 above] and K2CO3 (2.4 g, 17 mmol) in EtOH (120 mL) and H2O (6 mL) was added hydroxylamine hydrochloride (1.2 g, 17 mmol). After heating at reflux for 24 h, the reaction mixture was poured into H2O. The precipitate was collected, washed with H2O and air-dried. The crude product was dissolved in acetone, silica gel was added and the solvent was evaporated. The impregnated silica gel was added to the top of a flash column and the column was eluted with a solvent gradient of 2-10% MeOH/CHCl3 to afford the title compound as a white solid (3.0 g, 91%): ESMS (m/z): 374 (M+ +H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][C:11]([CH3:17])=[CH:12][C:13](OC)=[O:14].CS(O)(=O)=O>O>[CH3:10][C:11]1([CH3:17])[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=2[CH3:8])[O:9][C:13](=[O:14])[CH2:12]1
Reactant: Cc1cc(C)cc(O)c1
Reactant: COC(=O)C=C(C)C
Agent: CS(=O)(=O)O
Solvent: O
Product: Cc1cc(C)c2c(c1)OC(=O)CC2(C)C
Yield: 92.4 %

Procedure:
3,5-Dimethylphenol (5.00 g, 0.0409 mol) and methyl 3,3-dimethylacrylate (5.14 g, 0.045 mol) were added to methanesulfonic acid (5 mL) at room temperature followed by heating at 70° for 17 hours. The reaction was cooled, diluted with water (750 mL), extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with saturated aqueous sodium hydrogencarbonate (2×100 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification by silica gel flash chromatography eluting with methylene chloride afforded the title compound as a beige solid (7.73 g, 0.0378 mol, 92%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.43 (s, 6 H) 2.27 (s, 3 H) 2.46 (s, 3 H) 2.59 (s, 2 H) 6.74 (s, 2 H). MS (DCI) m/z 205 (M+H)+, 222 (M+NH4)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][N:15]([C@H:24]([CH2:35][CH:36]2[CH2:39][CH2:38][CH2:37]2)[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:12]([C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][N:15]([C@H:24]([CH2:35][CH:36]2[CH2:39][CH2:38][CH2:37]2)[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:14]1)=[O:11]
Reactant: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CO)[C@@H](c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.6 %

Procedure:
A solution of 1.29 mL (14.8 mmol) of oxalyl chloride in 15 mL of CH2Cl2 at −78° C. was treated with 2.10 mL (29.7 mmol) of DMSO maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 5 min. A solution of 2.33 g (5.9 mmol) of 2-(R)-(3-(R)-(hydroxymethyl)-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propionic acid, benzyl ester (from Step B) in 10 mL of CH2Cl2 was added maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 30 min. The mixture was treated with 10.3 mL (59.3 mmol) of DIEA maintaining the temperature at less than −60° C. The reaction was warmed to 0° C., stirred for 20 min and quenched with H2O. The mixture was partitioned between 250 mL of CH2Cl2 and 100 mL of H2O and the layers were separated. The aqueous layer was extracted with 250 mL of CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated. Flash chromatography on 100 g of silica gel using 4:1 v/v hexanes/ether as the eluant afforded 2.30 g (97%) of the title compound: 1H NMR (300 MHz) δ 1.54-2.08 (m, 8H), 2.31 (m, 1H), 2.75 (t, J=8.6 Hz, 1H), 2.96 (m, 1H), 3.11-3.35 (m, 4H), 3.56 (q, J=7.9 Hz, 1H), 5.16 (s, 2H), 7.19-7.39 (m, 1OH), 9.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([O:14][CH2:15][CH2:16]OC1C=CC=C(C)C=1C)=[O:13].CC1C(C)=CC=CC=1OCC(OCC)=O.[CH3:41][C:42]1[C:47]([CH3:48])=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:49]CC(OC)=O>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([O:14][CH2:15][CH2:16][CH2:49][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([CH3:48])[C:42]=1[CH3:41])=[O:13]
Reactant: COC(=O)CCc1cccc(C)c1C
Reactant: Cc1cccc(OCCOC(=O)N2CCCc3c(Br)cccc32)c1C
Agent: CCOC(=O)COc1cccc(C)c1C
Product: Cc1cccc(CCCOC(=O)N2CCCc3c(Br)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 2-(2,3-dimethylphenoxy)ethyl 5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate except that ethyl 2-(2,3-dimethylphenoxy)acetate was replaced by methyl 3-(2,3-dimethylphenyl)propanoate. LCMS, [M+Na]+=426.0.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[H-].[Na+].[CH3:11]I>CN(C)C=O.C(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:11])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(I)cc[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1ccc(I)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A solution of 4-iodo-2-pyridone (500 mg), sodium hydride (109 mg) and methyl iodide (482 mg) in dimethylformamide (5.0 mL) was stirred at room temperature for 4 hr. Additional sodium hydride (109 mg) and methyl iodide (482 mg) were added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution. After extraction with chloroform, the organic phase was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=98:2-96:4) to afford the title compound (341 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.Cl[CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl.[I-].[Na+].O.[Cl-].[Na+].O>CN(C)C=O.C(N(CC)CC)C>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:1]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: ClCCOCCCl
Reactant: Cc1cc(C)nc(N)c1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)nc(N2CCOCC2)c1
Temperature: 150 °C
Yield: 56 %

Procedure:
2-Amino-4,6-dimethylpyridine (50 g), bis(2-chloroethyl)ether (57.5 mL), sodium iodide (6.13 g) and triethylamine (137 mL) were mixed in dry N,N-dimethylformamide (1 L) under argon and heated to 150° C. for 16 hours. Water/brine/saturated aqueous sodium bicarbonate (2:1:1, 750 mL) were added to the cooled reaction mixture and it was extracted with ethyl acetate (5×200 mL). The combined organic phases were concentrated in vacuo to app. 500 mL. Water (500 mL) and concentrated aqueous hydrochloric acid (35 mL) were added, the phases separated and the aqueous phase washed with ethyl acetate (200 mL). The aqueous phase was made basic with the addition of concentrated aqueous sodium hydroxide (50 mL) and extracted with isopropyl acetate (5×200 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo to furnish 44.0 g (56% yield) of the title compound as a black oil. The crude product was used without further purification. GC-MS (m/z) 192 (M); tR=5.60. 1H NMR (500 MHz, DMSO-d6): 2.08 (s, 3H), 2.26 (s, 3H), 3.39 (m, 4H), 3.68 (m, 4H), 6.05 (s, 1H), 6.44 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Br)cc1
Temperature: 77 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a solution of methyl 2-(4-bromophenyl)acetate (9 g, 39.5 mmol) in carbon tetrachloride was added N-bromosuccinimide (7.1 g, 40 mmol), benzoyl peroxide (1.2 g, 6.7 mmol). The mixture was heated to reflux, and then stirred at the 77° C. for 4 hours. Thin layer chromatography showed full conversion. Then the mixture was concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20/1) to give methyl 2-bromo-2-(4-bromophenyl)acetate (12 g, 91%). 1H NMR (300 MHz, CDCl3) δ 7.68-7.65 (m, 2H), 7.52-7.49 (m, 2H), 5.35-5.31 (m, 1H), 3.89 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]CC)=O)=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH:6]=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:4]=1.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33]>C(O)(C)C>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][N:33]1[C:9](=[O:11])[C:8]2[C:3](=[N:4][C:5]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:6][C:7]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH2:2]1
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)cc(-c2ccccc2)nc1CBr
Solvent: CC(C)O
Product: CN(C)CCN1Cc2nc(-c3ccccc3)cc(-c3cccc([N+](=O)[O-])c3)c2C1=O
Yield: 35.8 %

Procedure:
A mixture of ethyl 2-bromomethyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (1.5 g) and 2-dimethylaminoethylamine (0.6 g) in isopropyl alcohol (15 ml) was refluxed for 1 hour. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of water (20 ml) and chloroform (40 ml). The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off. The residue was subjected to a column chromatography on silica gel, eluting with a mixture of chloroform and methanol (50:1 V/V). The fractions containing the desired compound were combined and evaporated in vacuo. The crystalline residue was recrystallized from ethanol to give 6-(2-dimethylaminoethyl)-4-(3-nitrophenyl)-5-oxo- 2-phenyl-5,7-dihydro-(6H)-pyrrolo[3,4-b]pyridine (0.49 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Br[CH2:20][CH2:21][CH2:22][C:23]#[N:24]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:17][CH2:18]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(N3CCNCC3)c2c1
Reactant: N#CCCCBr
Product: COc1ccc2cccc(N3CCN(CCCC#N)CC3)c2c1

Procedure:
This compound was prepared according to the process described in Example 1, Stage C, from 4-(7-methoxy-1-naphthyl)piperazine and 4-bromobutyronitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[C:17]([N:25]1[CH2:30][CH2:29][NH:28][C@H:27]([CH3:31])[CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:25]1[CH2:30][CH2:29][N:28]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][N:5]=3)[NH:9][CH:8]=2)=[O:15])[C@H:27]([CH3:31])[CH2:26]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Cl)ccnc12
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Agent: [K+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2c(Cl)ccnc12

Procedure:
Precursor 5d, 1-benzoyl-3-(R)-methyl-4-[(7-chloro-4-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a, starting from Potassium (7-chloro-4-azaindol-3-yl)-oxoacetate, Precursor 4e, and 1-benzoyl-3-(R)-methyl piperazine. MS m/z: (M+H)+ calcd for C21H20ClN4O3 411.12, found 411.04. HPLC retention time: 1.10 minutes (column A).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](N)=[CH:24][CH:23]=1)([CH3:19])[CH2:9][C:8]2=[O:29])(=[O:3])[CH3:2].[ClH:30].N([O-])=O.[Na+].[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH:36]=[CH2:37]>O.C1C=CC=CC=1.CC(C)=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:37][CH:36]([Cl:30])[C:35]([O:39][CH2:40][CH3:41])=[O:38])=[CH:24][CH:23]=1)([CH3:19])[CH2:9][C:8]2=[O:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2=O
Reactant: Cl
Reactant: C=CC(=O)OCC
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3cc(OC(C)=O)c(C(C)(C)C)cc3O2)cc1
Reaction time: 0.5 h

Procedure:
In a similar manner to Preparation 45, to a mixture of 0.42 g of 6-acetoxy-2-(4-aminophenoxymethyl)-7-t-butyl-2-methylchroman-4-one and 5 ml of acetone were added dropwise, whilst cooling with ice, 0.2 ml of concentrated hydrochloric acid and then a solution of 0.09 g of sodium nitrite in 0.5 ml of water. 1.1 g of ethyl acrylate were then added dropwise, after which 16 mg of cuprous oxide were added gradually to the mixture, whilst keeping its temperature at 40°-43° C. Evolution of nitrogen ceased after about 30 minutes. Benzene was added to the reaction mixture, and the organic layer was separated. The resulting benzene extract was washed with water and dried over anhydrous sodium sulfate. The residue after evaporation of the benzene was subjected to silica gel column chromatography, eluted with a 20:1 by volume mixture of benzene and ethyl acetate, to give the desired ethyl 3-[4-(6-acetoxy-7-t-butyl-2-methyl-4-oxochroman-2-ylmethoxy)phenyl]-2-chloropropionate.