Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[CH:3]=1.[H-].[Na+].[H][H].[C:28]1([CH:34]([CH3:38])[C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[C:28]1([CH:34]([CH3:38])[C:35]([O:1][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:20])[F:21])[CH:13]=3)[C:4](=[O:23])[CH:3]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C(=O)Cl)c1ccccc1
Reactant: O=c1cc(O)c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Reactant: [H][H]
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)Oc1cc(=O)n(-c2cccc(OC(F)(F)F)c2)c2ncccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (967 mg, 3.0 mmol) in DMF (24 mL) was added sodium hydride (purity of about 60%, 120 mg, 1.0 eq.). The mixture was stirred until no more hydrogen was generated, to obtain a solution. Then, 2-phenylpropionyl chloride (1.2 eq.) was added thereto, and the mixture was stirred at a room temperature for 1 hour. To the mixture was added a saturated sodium hydrogencarbonate aqueous solution, and the resulting precipitate was separated by filtration, washed with water, and dried to give 4-(2-phenylpropionyloxy)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one as a form of crystal (1.14 g, yield 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](Cl)(=O)[C:10](Cl)=O.C(Cl)Cl>C1(C)C=CC=CC=1>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[CH:10][CH2:9]1
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C1=Nc2ccccc2OC1
Temperature: 25 °C
Yield: 110.9 %

Procedure:
To a mixture of 2.29 g (21.0 mmol) of o-aminophenol in 25 mL of dry toluene was added portion wise 11 mL of 2N oxalyl chloride/CH2Cl2 (22.0 mmol) solution. The mixture was refluxed for 4 h, cooled to room temperature, filtered and the solid was washed with xylene and water, and dried to leave 3.10 g (90%) of 2a as pale-green solid. The analytical sample was obtained by crystallization from acetone, mp 263°-264° C. (lit, 264°-266° C.; Bernard et al, J. Med. Chem. 28:240 (1985)). 1H NMR (CDCl3 +DMSO-d6), 6.932 (m, 4), 11.970 (m, 1).
Reaction SMILES: [C:1]1(=[O:15])[N:6]2[CH2:7][CH2:8][C:9]3[CH2:10][C:11](=O)[CH:12]=[CH:13][C:4]([C:5]=32)=[CH:3][NH:2]1.[N:16]([O-])=[O:17].[Na+].CN(C)C=[O:23].Cl.CC(C)=O>C(O)(C)C.O>[NH:6]1[C:7]2=[CH:8][CH:9]=[CH:5][C:4]3=[C:3]2[N:2]([CH2:10][CH2:11][C:12](=[N:16][OH:17])[C:13]3=[O:23])[C:1]1=[O:15]
Reactant: O=C1C=CC2=CNC(=O)N3CCC(=C23)C1
Reactant: CN(C)C=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: O
Product: O=C1C(=NO)CCn2c(=O)[nH]c3cccc1c32
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
8,9-Dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione (50 g; 92.4% purity; 0.228 mol) prepared in accordance with the procedure in Example 1 was dried and mixed with isopropanol (7.23 g; 0.12 mol; 0.53 eq) and water (3.01 g; 0.167 mol; 0.73 eq) (in alternative experiments and in production, 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione prepared in accordance with the procedure in Example 1 was instead used as centrifuge-wet material without the addition of water and isopropanol). The resulting wet 8,9-dihydro-2H-7H-2,9a-diazabenzo[cd]azulene-1,6-dione was combined with sodium nitrite (19.05 g at 99.3% purity; 0.274 mol; 1.2 eq) and N,N-dimethylformamide (800 g; 10.945 mol; 47.9 eq) in a stirred-tank reactor. The mixture was heated to 50° C., and then 32% HCl (41.65 g; 0.366 mol HCl; 1.6 eq HCl) was added over a 30 minute period. Toward the end of the HCl addition (i.e., after greater than 1 eq HCl had been added), the temperature quickly increased to 60-70° C. After all the HCl was added, the mixture was stirred at 60° C. for an additional 30 minutes. The mixture then was cooled to 35° C. over a 2- hour period. Next, water (224.71 g; 12.473 mol; 54.6 eq) was added over a 2-hour period. The resulting mixture was then cooled to 0° C. over a 2-hour period, and maintained at that temperature for 2 hours. Afterward, the solid 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime product was removed by filtration and washed 4 times with water (70.1 ml each time; 15.566 mol total; 68.13 eq total) and once with acetone (115.9 g; 99.9% purity; 1.994 mol; 8.73 eq). All the above steps were conducted under a N2 atmosphere.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:23][O:24][CH:25]([O:33][CH3:34])[CH2:26][NH:27][C@@H:28]([CH2:30][CH2:31][CH3:32])[CH3:29]>>[CH3:23][O:24][CH:25]([O:33][CH3:34])[CH2:26][N:27]([C@@H:28]([CH2:30][CH2:31][CH3:32])[CH3:29])[C:17](=[O:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12][C:11]1[CH:20]=[CH:21][CH:22]=[C:9]([C:7]2[CH:6]=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=2)[CH:10]=1
Reactant: CCC[C@@H](C)NCC(OC)OC
Reactant: CC(C)n1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Product: CCC[C@@H](C)N(CC(OC)OC)C(=O)CCOCCc1cccc(-c2cnn(C(C)C)c2)c1

Procedure:
The subtitled compound (100 mg) was prepared from 3-(3-(1-isopropyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 20 Step iii)] and ((R)—N-(2,2-dimethoxyethyl)pentan-2-amine [Preparation 10] using a similar method to that described in Example 18, Step iii). MS [M+H-MeOH]+=428 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.01 and 8.00 (2×s, 1H), 7.79 (s, 1H), 7.42-7.34 (m, 2H), 7.23 (t, J=7.7 Hz, 1H), 7.05 (d, J=7.7 Hz, 1H), 4.56 and 4.40 (2×t, J=5.3 Hz, 1H), 4.53 (septet, J=6.7 Hz, 1H), 4.26-4.16 and 3.96-3.86 (2×m, 1H), 3.75-3.64 (m, 4H), 3.34 (s, 3H), 3.32 (s, 3H), 3.25-3.10 (m, 2H), 2.84 (t, J=6.5 Hz, 2H), 2.72-2.50 (m, 2H), 1.60-1.14 (m, 4H), 1.51 (d, J=6.9 Hz, 6H), 1.10 and 1.09 (2×d, J=6.7 Hz, 3H), 0.86 (t, J=7.3 Hz, 3H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [Y:1].[CH:2]([OH:5])([CH3:4])[CH3:3]>[Cl-].[Cl-].[Zn+2].[Zn]>[CH3:3][CH:2]([CH3:4])[O-:5].[Y+3:1].[CH3:3][CH:2]([CH3:4])[O-:5].[CH3:3][CH:2]([CH3:4])[O-:5]
Reactant: [Y]
Reactant: CC(C)O
Agent: [Cl-]
Agent: [Zn+2]
Agent: [Zn]
Product: CC(C)[O-]
Product: [Y+3]
Yield: 70 %

Procedure:
The same procedure described in Example 3 was utilized except that ZnCl2 was substituted for zinc metal but was not milled with the yttrium. The milled yttrium, without zinc metal or zinc chloride, was reacted with a solution of isopropanol (500 cc) and 3 grams of ZnCl2 over a 24 hour period. Work-up of the reaction mixture yielded 41.6 grams (a 70% yield) of yttrium isopropoxide.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].O>CN(C)C=O>[CH:15]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)([CH3:17])[CH3:16]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reaction time: 0.83 h
Yield: 70 %

Procedure:
A 300 ml glass-made three-neck flask was charged with 0.134 mol of p-vinylphenol, 0.343 mol of imidazole and 90 ml of dimethylformamide as a solvent, and a solution prepared by dissolving 0.174 mol of triisopropylsilyl chloride in 90 ml of dimethylformamide was dropwise added thereto at 0° C. in 50 minutes. Then, the reaction temperature was elevated up to room temperature to carry out reaction for 10 hours in the same condition. Water was added thereto, and the reaction product was extracted with chloroform. The solvent was distilled off, and the residue was dissolved in diethyl ether and washed with a sodium hydroxide aqueous solution and water. The product was dried on magnesium sulfate and filtered, and then it was further dried on a calcium hydride. Then, the reaction product was distilled at a reduced pressure under nitrogen flow to obtain aimed p-triisopropylsilyloxystyrene at a yield of 70%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[CH:14](=O)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:12])[CH:11]=[CH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccncc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1ccncc1)c1ccc([N+](=O)[O-])cc1

Procedure:
41.25 G. of 4'-nitroacetophenone are suspended in 500 ml. of water and heated at 70° C. with stirring. Then, 24 ml. of isonicotinaldehyde are added and the reaction mixture is treated three times at intervals of 30 minutes with 5 ml. each time of a 6% NaOH solution in water/methanol (2:1). Subsequently the reaction mixture is left to react at 70° C. for 8 hours. The crystals which form are filtered off, boiled up twice with 500 ml. of ethanol each time and subsequently washed with ether to yield 4'-nitro-3-(4-pyridyl)-acrylphenone with a melting point of 218°-221° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH:10]([NH2:13])[CH2:11][S:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=O)[CH3:15].C(Cl)[Cl:22]>>[ClH:22].[ClH:22].[CH2:14]([NH:13][CH:10]1[CH2:9][C:8]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[S:12][CH2:11]1)[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2c1CC(N)CS2
Reactant: ClCCl
Product: CCNC1CSc2cccc(OC)c2C1
Product: Cl
Reaction time: 0.25 h

Procedure:
A mixture of 500 mg of 3,4-dihydro-5-methoxy-2H-[1]-benzothiopyran-3-amine and 361 mg of acetic anhydride in 10 mL of methylene chloride is kept at room temperature of 15 min. The solvent is removed in vacuo and the resulting 3,4-dihydro-N-acetyl-5-methoxy-2H-[1]-benzopyran-3-amine is dissolved in 10 mL of 1M diborane in tetrahydrofuran. After 3 hr reflux, the reaction mixture is poured into 6N hydrochloric acid, washed with ether, basified with 45% potassium hydroxide and reextracted with ether. After drying over magnesium sulfate, the solvent is removed in vacuo. Acidification with ethanolic hydrochloric acid affords 3,4-dihydro-N-ethyl-5-methoxy-2H-[1]-benzothio-pyran-3-amine hydrochloride melting at 222°-224°.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:17][F:18])[CH2:8][C:7](=O)[C:6]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4]1.C[Si]([C:23]#[N:24])(C)C.P(Cl)(Cl)(Cl)=O.Cl>[I-].[Zn+2].[I-].N1C=CC=CC=1.C1C=CC=CC=1>[F:1][CH2:2][C:3]1([CH2:17][F:18])[CH:8]=[C:7]([C:23]#[N:24])[C:6]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:5]=2[O:4]1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
To a mixture of 4.05 g of 2,2-bisfluoromethyl-3,4-dihydro-6-nitro-2H-1-benzopyran-4-one and 10 ml of dry benzene were added 2.52 ml of trimethylsilyl cyanide and 0.82 g of zinc iodide with stirring under ice-cooling, and the mixture was stirred at room temperature for 12 hours. The mixture was further combined with 8 ml of pyridine and 4.41 ml of phosphorus oxychloride and heated to reflux for 6 hours. The reaction mixture was acidified with ice water and aqueous hydrochloric acid and extracted with methylene chloride. The organic layer was washed with water and dried, then concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent; methylene chloride:hexane=7:3) to give 0.99 g of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carbonitrile; m.p. 136-137° C.;
Reaction SMILES: Cl[C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([CH3:8])[N:7]=1.ClC1C(C#N)=NC(C)=C(CC)N=1.Cl.[CH2:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH2:30][CH2:29][NH:28][CH2:27]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:9]([C:5]1[N:4]=[C:3]([C:11]#[N:12])[C:2]([N:28]2[CH2:27][CH2:26][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][CH2:29]2)=[N:7][C:6]=1[CH3:8])[CH3:10]
Reactant: c1ccc2c(c1)CCNCC2
Reactant: CCc1nc(C#N)c(Cl)nc1C
Agent: CCc1nc(Cl)c(C#N)nc1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C#N)c(N2CCc3ccccc3CC2)nc1C
Temperature: 0 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
A solution of 0.300 g (1.65 mmol) of the 1:1 mixture of the 3-chloro-6-ethyl-5-methyl-pyrazine-2 -carbonitrile and the 3-chloro-5-ethyl-6-methyl-pyrazine-2-carbonitrile, of 0.395 g (1.30 mmol) of 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) and of 0.566 g (2.60 mmol) of N-ethyl-diisopropylamine in 1.0 ml of N,N-dimethylformamide was stirred at room temperature for 60 hours and then at 60° C. for 18 hours. The reaction mixture was subsequently poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of ethylacetate. The combined ethylacetate phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was then chromatographed on silica gel using dichloromethane as eluent giving 0.086 g (0.29 mmol, 18% of theory) of the 6-ethyl-5-methyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as yellowish solid after crystallization from dichlormethane/pentane; MS: 293 (M+H)+; and 0.074 g (0.25 mmol, 15% of theory) of the 5-ethyl-6-methyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as yellowish solid; MS: 293 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].Cl[C:12]([CH3:16])([CH3:15])[C:13]#[CH:14].O.[OH-].[Na+]>C(Cl)Cl.CO>[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:10][C:12]([CH3:16])([CH3:15])[CH2:13][CH2:14][C:8]=2[CH:9]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: C#CC(C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 144 h
Yield: 34.3 %

Procedure:
To a solution of 95% 4-hydroxyacetophenone (13.6 g, 100 mmol), 3-chloro-3-methyl butyne (17.4 g, 170 mmol) in methylene chloride (75 ml) was added water (75 ml), sodium hydroxide (6.4 g, 160 mmol), and Triton B (40% in methanol, 23.0 g, 52 mmol). The reaction mixture was stirred at room temperature for six days. The organic layer was separated, the aqueous phase was reextracted with methylene chloride (2×200 ml). The combined extracts were concentrated in vacuo, the residue was taken up in ethyl acetate (500 ml) washed with 1N sodium hydroxide (3×250 ml), brine (200 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was dissolved in 1,2-dichlorobenzene (40 ml) and heated at reflux temperature for four hours. The solvent was removed by distillation at atmospheric pressure using a vigreaux column and the residue was distilled under reduced pressure (b.p. 140°-150° C. at 2.0 mm) to provide the title A compound (7.0 g) as a light yellow solid. 1H NMR (CDCl3) δ7.75 (dd, J=2.3 & 8.8 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 6.35 (d, J=10.0 Hz, 1H), 5.66 (d, J=9.9 Hz, 1H), 2.53 (s, 3H), 1.45 (s, 6H); 13C NMR (CDCl3) δ196.7, 157.4, 131.1, 130.2, 126.8, 121.6, 120.6, 116.0, 77.5, 28.3, 26.2.
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1)=[O:5])C.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:4]([CH:6]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[S:7]2)=[O:5])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1Sc2ccccc2N(C)C1=O
Reactant: Nc1ccc(F)cc1
Product: CN1C(=O)C(C(=O)Nc2ccc(F)cc2)Sc2ccccc21
Reaction time: 5 h
Yield: 31.1 %

Procedure:
A mixture of 2-ethoxycarbonyl-4-methyl-2H-1,4-benzothiazin-3(4H)one (2.4 g) and 4-fluoroaniline (1.59 g) was stirred for 5 hours at 180° to 185° C. After standing at room temperature, the reaction mixture was crystallized from diisopropyl ether and purified by recrystallization from diisopropyl ether to afford 0.94 g of 2-(4-fluorophenylcarbamoyl)-4-methyl-2H-1,4-benzothiazin-3(4H)one as a white crystal.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[NH3:9].[CH3:7][C:8]1[N:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=[CH:11][N:12]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccnc1C
Product: N
Reaction time: 0.5 h

Procedure:
Potassium carbonate (8.42 g, 61 mmol) was added to a solution of 2-methylimidazole (5 g, 61 mmol) in tetrahydrofuran (100 mL) and the suspension was stirred for 30 minutes. Ethyl bromoacetate (6.75 mL, 61 mmol) was added and the reaction was stirred for a further 30 minutes at room temperature. The mixture was filtered, washing through with dichloromethane:methanol (90:10). The filtrate was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (93:7:0.5) as eluant to afford the title compound as an oil, 5.28 g.
Reaction SMILES: [C:1](=[O:6])([O:4]C)[O:2]C.[CH3:7][N:8]([CH3:10])[CH3:9]>O>[C:1](=[O:2])([O-:6])[OH:4].[CH3:7][N+:8]([CH3:1])([CH3:10])[CH3:9]
Reactant: COC(=O)OC
Reactant: CN(C)C
Solvent: O
Product: C[N+](C)(C)C
Product: O=C([O-])O
Reaction time: 6 h

Procedure:
604 g of dimethyl carbonate, 394 g of trimethylamine and 250 g of water were introduced in a 3,000-milliliter Tefron-lined reactor and heated with stirring. After the temperature in the reactor reached 100° C., the reaction was continued for 6 hours at 100° C. Tetramethylammonium hydrogencarbonate was obtained in a yield of 90.1 mol % (based on trimethylamine).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CNc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N(C)c2ccccc2)cc1
Reaction time: 6 h
Yield: 102.2 %

Procedure:
The above general procedure was followed using 4-bromoanisole (187 mg, 1.00 mmol) and N-methylaniline (107 mg, 1.00 mmol) with 1 mol % Pd(dba)2 and 0.8 mol % tri-t-butylphosphine in 1.0 mL of toluene. After 6 hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 5% ethyl acetate/hexanes to give 218 mg (>99%) of N-(4-methoxyphenyl)-N-methylaniline. 1H NMR (500 MHz, CDCl3) δ 7.21 (dd, J=8.9, 7.0 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 6.80 (t, J=7.0 Hz, 1H), 3.83 (s, 3H), 3.28 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 156.3, 149.8, 142.4, 128.9, 126.1, 118.5, 115.9, 114.8, 55.5, 40.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:24])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C=Cc2cc(O)c(O)c([N+](=O)[O-])c2)cc1

Procedure:
The procedure described in Example 8 was repeated using 1.8 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.5 g of 4'-methoxyacetophenone in 20 ml of tetrahydrofuran. Yield 1.88 g (60%), m.p. 222°-228° C.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[CH2:11]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH2:11]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:23])=[CH:25][CH:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCc1ccc(C(=O)O)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCc1ccc(C(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.264 g (1.2 mol) of 4-heptylbenzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)\[CH2:4][C@H:5]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[CH3:29][NH:30][CH2:31][CH2:32][OH:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:33][CH2:32][CH2:31][N:30]([CH3:29])[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[CH2:4]/[C:3](=[N:2]\[OH:1])/[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=2)=[CH:21][CH:20]=1
Reactant: CNCCO
Reactant: Cc1cc(/C(C[C@H](c2ccc(C(=O)O)cc2)c2ccccc2C)=N/O)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(/C(C[C@H](c2ccc(C(=O)N(C)CCO)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 207, step 2, 4-[(R)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-benzoic acid (example 272) was coupled with 2-(methylamino)ethanol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a light yellow solid, MS (ESI+): m/z=432.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][CH2:28][C:29](Cl)=O)[CH3:26].C1(C)C=CC=CC=1>N1C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:26]([CH2:25][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Temperature: 25 °C

Procedure:
The preparation of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine is described in Parts A-F of Example 1. A concentrated solution of ethoxyacetyl chloride (12.2 g, 99.2 mmol) was added dropwise to a solution of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (29 g, 90 mmol) in 50:50 toluene:pyridine. The temperature of the reaction reached 40° C., and a precipitate formed. Triethylamine (15-20 g) and pyridine were added to help dissolve the precipitate. The reaction was heated at reflux for three hours and then allowed to cool to ambient temperature overnight. The solvents were removed under reduced pressure, and the black residue was dissolved in dichloromethane. The resulting solution was washed several times with aqueous sodium carbonate (150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 29.2 g of 7-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a tan solid.