Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C:9](=[O:22])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.CCOC(C)=O>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][O:21][C:15]1[CH:14]=[C:13]([CH:10]([C:9](=[O:22])[NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:24][CH:23]=2)[O:11][CH3:12])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(OC)C(=O)NCc2ccc(C#N)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
To a stirred solution of (RS)-N-(4-cyano-benzyl)-2-(3-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide (0.303 g) at rt in DMF (3 ml) were added K2CO3 (0.14 g) and ethyl bromoacetate (0.169 g). The reaction mixture was then stirred at rt under an argon atmosphere for 5 h 45. The mixture was diluted with EtOAc (25 ml), washed with water (25 ml) and brine (25 ml), dried (MgSO4), filtered and concentrated (rotavapor) to leave the crude product as a light yellow gum. The product was purified by chromatography (Silicagel (20 g) using a gradient profile: cyclohexane to cyclohexane/EtOAc 35:65) to give (RS)-{5-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-2-methoxy-phenoxy}-acetic acid ethyl ester (0.342 g) as a white solid.
Reaction SMILES: O1CCCC1.C([O:8][C:9](=[O:36])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20](=[O:35])[C:21]([S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:32]([CH3:34])[CH3:33])=[C:22]([OH:24])[CH:23]=2)=[CH:14][CH:13]=1)C.[OH-].[Na+].Cl>O>[OH:24][C:22]1[CH:23]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:9]([OH:36])=[O:8])=[CH:17][CH:16]=2)[O:19][C:20](=[O:35])[C:21]=1[S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]([CH3:33])[CH3:34]
Reactant: CCOC(=O)COc1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(OCC(=O)O)cc2)oc1=O
Reaction time: 1.5 h

Procedure:
To a tetrahydrofuran (10 ml) solution of 4-[4-Hydroxy-5-[(2-isopropylphenyl)thio]-6-oxo-6H-pyran-2-yl]phenoxy acetic acid ethyl ester (0.319 g. 0.75 mmol) was added 1N sodium hydroxide (1.80 mL, 1.81 mmol). The reaction was stirred for 1.5 h, and then water (10 ml) was added followed by acidification with conc. hydrochloric acid to pH 2. The aqueous layer was then extracted 2× with ethyl acetate (100 ml). the combined organic extracts were then washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by column chromatography (silica gel-230 to 400 mesh) using 94/5/1 methylene chloride/methanol/acetic acid as the eluent. m.p. 217° C.; (dec.); 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.42 (m, 1H), 4.79 (s, 2H), 6.75 (s, 1H), 6.90 (d, 1H), 7.06 (m, 4H), 7.26 (d, 1H), 7.79 (d, 2H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:16]([C:15]1[CH:18]=[CH:19][C:12]([O:11][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:13][CH:14]=1)=[O:17]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
Combine 6-chloronicotinamide (4.53 g, 28.9 mmol), 4-hydroxybenzaldehyde (3.5 g, 28.9 mmol), potassium carbonate (6 g, 43.4 mmol), and dimethylformamide (200 mL). Heat the reaction mixture to 130° C. under nitrogen, and stir for 18 h. Dilute the reaction mixture with 200 mL of water, extract with diethyl ether (4× 100 mL) and dichloroethane (2× 100 mL). Combine the organics, and dry over magnesium sulfate. Filter, and concentrate in vacuo. Adsorb the residue on silica, and purify by Biotage Flash 40L (elute with 50:50 hexanes/ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid (3.2 g, 46%): 1H NMR (DMSO-d6): 10.0 (s, 1H), 8.59 (d, 1H), 8.26-8.22 (dd, 1H), 7.98-7.95 (m, 2H), 7.10-7.07 (d, 1H), 6.15-5.65 (br m, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[C:10]([CH2:18][CH3:19])([CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:15][N:14]([CH3:16])[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH2:18][CH3:19])[CH3:17]
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1N(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCCC1N(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.7 g) and 1-benzyl-4-dimethylamino-3-ethyl-3-methyl piperidine (6 g, 23 mmol) in methanol (50 ml) was stirred in hydrogen atmosphere (1 atm.) for 48 hr at room temperature. The catalyst was filtered off, washed with methanol and filtrate was concentrated to afford 4-dimethylamino-3-ethyl-3-methylpiperidine. Yield 2.8 g (72%), C10H22N2, m/z 171 (M+1).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:25][O:26][C:27]([C:29]1([NH2:36])[CH2:34][CH:33]2[O:35][CH:30]1[CH2:31][CH2:32]2)=[O:28].[CH3:37][O:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][C:40]=1[O:48][CH2:49][CH2:50][C:51]1[CH:52]=[C:53]([CH3:57])[CH:54]=[CH:55][CH:56]=1>CN(C=O)C.CC(=O)OCC>[CH3:25][O:26][C:27]([C:29]1([NH:36][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([O:38][CH3:37])=[C:40]([O:48][CH2:49][CH2:50][C:51]3[CH:52]=[C:53]([CH3:57])[CH:54]=[CH:55][CH:56]=3)[CH:41]=2)[CH2:34][CH:33]2[O:35][CH:30]1[CH2:31][CH2:32]2)=[O:28]
Reactant: COC(=O)C1(N)CC2CCC1O2
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CC2CCC1O2
Yield: 100.1 %

Procedure:
550 mg of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 300 mg of 2-amino-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester and 410 mg of 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid (example 2) were stirred in 20 ml of anhydrous DMF for 15 h at room temperature. The mixture was diluted with 150 ml of EA and washed three times with 50 ml each of a saturated aqueous sodium carbonate solution and then three times with 50 ml each of a 10% aqueous sodium hydrogensulfate solution. The organic layer was dried with magnesium sulfate, evaporated to dryness and the residue purified by silica gel chromatography (HEP/EA gradient) to yield 630 mg of the title compound as a racemic mixture.
Reaction SMILES: [O:1]1[CH2:3][CH2:2]1.[F:4][C:5]([F:16])([F:15])[C:6]1[CH:7]=[C:8]([CH2:12][CH2:13]Br)[CH:9]=[CH:10][CH:11]=1.[Mg].S(=O)(=O)(O)O>C(OCC)C>[F:4][C:5]([F:15])([F:16])[C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][CH2:3][CH2:2][OH:1])[CH:9]=[CH:10][CH:11]=1
Reactant: C1CO1
Reactant: FC(F)(F)c1cccc(CCBr)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: OCCCCc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 75.3 %

Procedure:
5.5 g of oxirane in 20 ml of diethyl ether are added dropwise, at about 0° C., to a Grignard solution prepared from 28.5 g of 2-(3-trifluoromethylphenyl)-ethyl bromide and 2.9 g of magnesium in 200 ml of diethyl ether. After stirring the mixture for 1 hour and adding 100 ml of 10% strength sulphuric acid, it is extracted with diethyl ether and the residue is distilled. About 18.5 g of 4-(3-trifluoromethylphenyl)-butan-1-ol are obtained and are dissolved in 70 ml of toluene, 16 g of p-toluenesulphonyl chloride and 25 ml of pyridine are added and the mixture is stirred. After 2 days, the precipitate is filtered off and worked up by extraction. After concentrating the organic phase, 25.7 g of the tosylate of the substituted butanol remain and are taken up in 250 ml of ethanol and the mixture is added dropwise to a solution prepared from 11.5 g of diethyl malonate and 1.6 g of sodium in 220 ml of absolute ethanol. The mixture is heated under reflux for 24 hours and then concentrated and the residue is partitioned between water and methylene chloride. After several extractions, the organic phases collected are dried and concentrated. The residue is purified by chromatography over a 500 g silica gel column and gives 24.9 g of 4-(3-trifluoromethylphenyl)-butylmalonic acid diethyl ester, which is used in (d).
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].[C:19]([CH:21]([OH:35])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=1)#[N:20].N1C=CC=CC=1>CCOCC>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[C:5]([O:35][CH:21]([C:19]#[N:20])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of α-isopropyl-4-trifluoromethoxyphenylacetyl chloride (4.58 mmol) in ether (5 ml) is added to an ether (20 ml) solution of α-cyano-m-phenoxybenzyl alcohol (4.58 mmol) and pyridine (0.5 ml). The mixture is stirred overnight and filtered. The filtrate and the washings are evaporated and the residual oil is purified on 5×2 mm silica gel plates using 1:1 methylenechloride-hexane as eluent. The band with Rf=0.55 is extracted with ether and evaporated to give the desired ester (0.85 g).
Reaction SMILES: Cl.[O:2]=[C:3]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1>O1CCOCC1.CO>[N:19]1([C:3](=[O:2])[CH2:4][O:5][CH:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)N2CCCCC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(COC1CCNCC1)N1CCCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 4 N HCl solution in dioxane (6 mL) was added to a solution of tert-butyl 4-(2-oxo-2-(piperidin-1-yl)ethoxy)piperidine-1-carboxylate (111) (7.5 g, 22.98 mmol) in MeOH (20 mL) and the reaction mixture was stirred at room temperature for 6 hours. Removal of solvent afforded 1-(piperidin-1-yl)-2-(piperidin-4-yloxy)ethanone as its hydrochloride salt (2.300 g, 44.2%). This salt was then dissolved in methanol (50 ml) and MP-carbonate (14.88 g, 33.61 mmol) was added. The resulting mixture was filtered and the solvent removed to give the desired compound (2.300 g, 44.2%), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C(#N)C.CO.[Pt]>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(C)OC(=O)NNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)NNc1c(N)cnc2cc(Br)ccc12
Reaction time: 4 h
Yield: 80.2 %

Procedure:
A suspension of tert-butyl N′-(7-bromo-3-nitroquinolin-4-yl)hydrazinecarboxylate (50.0 g, 131 mmol) in 320 mL of acetonitrile (MeCN) and 80 mL of methanol was treated with platinum on carbon (5.0 g, 1.3 mmol, 5% w/w) and shaken under an atmosphere of hydrogen (3.8×105 Pa). After 4 h, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with portions of MeCN:MeOH (1:1) until the filtrate ran clear. The filtrate was concentrated under reduced pressure to yield 37.1 g of tert-butyl N′-(3-amino-7-bromoquinolin-4-yl)hydrazinecarboxylate as a tan solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH3:31])[N:18]=[C:17]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:39]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[Cl:30])=[C:19]([CH:31]=[O:39])[N:18]=[C:17]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Se]=O
Reactant: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(Oc2c(C=O)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 68.8 %

Procedure:
14.6 g of 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide and 15.9 g of selenium dioxide in 500 ml of dioxan were stirred in an autoclave at 170° C. for 6 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between chloroform and water. The organic phase was dried, the solvent was evaporated and the residue was recrystallized from dichloromethane-ethanol. There were obtained 10.3 g of 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-formyl-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, m.p. 235°-236° C., MS: M=561.
Reaction SMILES: [C:1]1(=[O:16])[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[H][H]>[Pd].C(O)C>[C:1]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: O=C1CCC=CCCCCCCC=CCC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1CC/C=C/CCCCCC/C=C/CC1
Agent: O=C1CC/C=C/CCCCCCCCCC1
Solvent: CCO
Product: O=C1CCC=CCCCCCCCCCC1

Procedure:
A flask was charged with cyclopentadeca-4E,12E-dien-1-one (0.10 g, 0.45 mmole), ethanol (5 ml) and 5% palladium-on-carbon (0.010 g). The mixture was stirred at room temperature under 1 atm of hydrogen gas for 30 minutes. The reaction mixture was filtered through celite and concentrated to provide crude cyclopentadec-4E-en-1-one (0.09 g, 88% yield). C15H30O (226.41 g/mole). 13CNMR (125 MHz, CDCl3): 21.65, 21.72, 25.85, 26.12, 27.86, 30.57, 31.02, 31.74, 31.82, 42.30, 42.49, 130.08, 132.00, 210.00 ppm. GC analysis indicates product to be a mixture of cyclopentadec-4E-en-1-one (39%), cyclopentadeca-4E,12E-dien-1-one (37%), and cyclopentadecanone (24%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[O:12][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: ClCCN1CCCC1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc([N+](=O)[O-])cc(C)c1OCCN1CCCC1

Procedure:
1-[2-(2,6-dimethyl-4-nitrophenoxy)ethyl]pyrrolidine was prepared in a manner analogous to the alkylation described in Example 1, from 2,6-dimethyl-4-nitrophenol (1.0 g, 5.98 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (1.52 g, 8.97 mmol) and caesium carbonate (5.83 g, 17.94 mmol) to give the desired product as a brown oil. 6H (CDCl3) 7.89 (2H, s), 3.96 (2H, t, J 6.1 Hz), 2.93 (2H, t, J 6.1 Hz), 2.65 (4H, m), 2.35 (6H, s) and 1.83 (4H, m). MS (ES+) 265 (MH+).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[CH3:13][C:12]1[C:11]2[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3cccc([N+](=O)[O-])c3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)oc2cccc(-c3cccc([N+](=O)[O-])c3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.9 %

Procedure:
To 300 mg of 3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carboxylic acid tert-butyl ester was added 4 mL of TFA/dichloromethane (1:1). The solution was stirred at room temperature for 5 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 232 mg (92% yield) of 3-methyl-4-(3-nitro-phenyl)-benzofuran-2-carboxylic acid as white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2][CH3:3].[CH3:15]C1C=C2C(=CC=1)NC(=O)C2=O.BrCCC>>[CH3:15][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:14])[C:6]2=[O:13]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Solvent: CCCBr
Product: CCCN1C(=O)C(=O)c2cc(C)ccc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using 5-methyl isatin (purchased from Fisher Scientific) and 1-bromo-propane (purchase from Fisher Scientific). 1H NMR δ 7.41 (m, 2H), 6.80 (d, 1H), 3.67 (t, 2H), 2.33 (s, 3H), 1.72 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[I-].[K+].Br[CH2:29][CH:30]1[O:34][CH2:33][CH2:32][O:31]1>CS(C)=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH2:29][CH:30]3[O:34][CH2:33][CH2:32][O:31]3)[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Reactant: BrCC1OCCO1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c2cccnc2sc(=Nc2ccc(Cl)cc2)n1CC1OCCO1
Yield: 9.6 %

Procedure:
In an atmosphere of argon, a mixture of 290 mg (1.0 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one and 1.4 ml of DMSO was put in a 30 ml flask. To the mixture was then added 113 mg (1.0 mmol) of potassium t-butoxide with stirring. The mixture was then stirred for 1 hour. To the mixture was then added 10 mg (0.06 eq) of potassium iodide. To the mixture was then added 484 mg of 2-bromomethyl-1,3-dioxolane. The mixture was then stirred for 15 hours. After the termination of reaction, the reaction mixture was extracted with water and ethyl acetate. The resulting organic phase was separated, washed with water and saturated brine, and then dried over sodium sulfate. The drying agent was then removed by filtration. The filtrate was then concentrated under reduced pressure. The resulting residue was then purified through silica gel column chromatography (eluant: 1/2 mixture of ethyl acetate and normal hexane). As a result, 36 mg of 2-[(4-chlorophenyl)imino]-3-([1,3]dioxolan-2-ylmethyl)-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 20 mg of 2-[N-(4-chlorophenyl)-N-([1,3]dioxolan-2-ylmethyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[C:5]([CH3:10])=[C:4]([Cl:11])[CH:3]=1.Cl[CH2:13][C:14](Cl)=[O:15].C([O-])([O-])=O.[K+].[K+]>>[Cl:11][C:4]1[C:5]([CH3:10])=[C:6]([Cl:9])[C:7]2[O:8][CH2:13][C:14](=[O:15])[NH:1][C:2]=2[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1c(Cl)cc(N)c(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(Cl)cc2c(c1Cl)OCC(=O)N2

Procedure:
6-Amino-2.4 dichloro-3-metylphenol (1.9 g, 10 mmol), 2-chloroacetyl chloride (1.2 g, 11 mmol) and K2CO3 (3.0 g, 22 mmol) were mixed according to GP1 to give the title compound as a crude (80MF2225) (2.33 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:42]([O:43][CH3:44])=[CH:41][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:42]([O:43][CH3:44])=[CH:41][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[O:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCOCC1)CC2
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CC(=O)N1CCOCC1)CC2
Yield: 60 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-morpholin-4-yl-ethanone. Product was isolated as a white foam (65 mg, 60%). mp: 100° C., MS (ESI+): 629.6 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.53 (s, 1H), 8.57 (d, J=9 Hz, 1H), 8.18 (s, 1H), 8.01 (s, 1H), 7.95 (d, J=8 Hz, 1H), 7.62 (t, J=8 Hz, 1H), 7.52 (s, 1H), 6.67 (s, 1H), 3.90 (s, 3H), 3.74 (s, 8H), 3.67 (d, 2H), 3.30 (m, 3H), 2.87 (m, 2H), 2.74-2.66 (m, 6H), 1.33 (d, J=7 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH:38]=O)=[N:30]1.N1CCCCC1>CO>[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](/[CH:38]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][CH2:14][CH2:15][N:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:30]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1CCCN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CCCN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
A solution of tert-butyl 4-[3-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)propyl]piperazine-1-carboxylate (0.0642 g, 0.164 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0264 g, 0.180 mmol) and piperidine (0.0112 g, 0.131 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-(3-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}propyl)piperazine-1-carboxylate (0.0393 g, 46%).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:25])([CH3:3])[CH3:2].I[CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:27][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:30][CH2:29]3)[CH2:21][CH2:20]2)=[O:16])[C:5]1=[O:25])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Reactant: Cc1cccc2c1cc(C(=O)NCC1CCNCC1)c(=O)n2C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc2c1cc(C(=O)NCC1CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC1)c(=O)n2C(C)C
Temperature: 80 °C
Yield: 32.5 %

Procedure:
To a solution of 1-isopropyl-5-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydroquinoline-3-carboxamide (300 mg, 0.88 mmol, step 4 in preparation 3) in N,N-dimethylformamide (30 mL), tert-butyl 4-(iodomethyl)piperidine-1-caroxylate (343 mg, 1.05 mmol, Villalobos Anabella et al., J. Med. Chem., 1994, 37, 2721) and potassium carbonate (610 mg, 4.4 mmol) were added at room temperature. The mixture was heated at 80° C. overnight. After cooled to room temperature, water (30 mL) was added and extracted with diethyl ether (50 mL×2). The combined organic layer was washed with water (20 mL×2), brine (20 mL), dried over magnesium sulfate and concentrated in vacuo gave yellow oil, which was chromatographed on a column of silica gel eluting with ethyl 25% ammonium oxide/methanol/dichloromethane (3:30:1000) to give 154 mg (32%) of the title compound as a clear colorless oil.