Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:29][NH:30]2)=[CH:26][CH:25]=1>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:29]2[NH:30][C:31]3[C:27]([C:28]=2[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:26][CH:25]=[C:24]([F:23])[CH:32]=3)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)NCCc1c[nH]c2cc(F)ccc12
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Product: CC(=O)NCCc1c(C(C2=C(O)C(Cc3ccccc3)OC2=O)c2ccccc2)[nH]c2cc(F)ccc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-acetamide to give N-(2-{2-[(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl)-phenyl-methyl]-6-fluoro-1H-indol-3-yl}-ethyl)-acetamide as a white solid. MS: 497.4 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1O[C:17]([CH2:19][CH2:20][CH2:21][Cl:22])([CH3:18])OC1.B(F)(F)F.O>[N+](C)([O-])=O>[Cl:22][CH2:21][CH2:20][CH2:19][C:17]1([CH3:18])[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=2)[CH2:11][CH2:12][O:13]1
Reactant: COc1ccc(CCO)cc1OC
Reactant: CC1(CCCCl)OCCO1
Agent: FB(F)F
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COc1cc2c(cc1OC)C(C)(CCCCl)OCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 1404.6 %

Procedure:
A mixture of 3,4-dimethoxyphenylethyl alcohol (1.72 g, 0.01 mole), 5-chloro-2-pentanone ethylene ketal (1.64 g, 0.01 mole) and 0.5 ml of BF3 etherate in 20 ml of nitromethane is stirred at room temperature under N2 for 4 hours. The reaction mixture is then poured into cold water and extracted with CH2Cl2. The CH2Cl2 solution is washed with water, dried (Na2SO4) and concentrated to an oil. The oil is chromatographed on silica gel with 10% ethylacetate/Skellysolve B as eluate to give 40 g (54% yield) of 1-(3-chloropropyl)-6,7-dimethoxy-1-methyl-isochroman as a white crystalline product, m.p. 77°-79° C. The nmr of the product is consistent with the structure.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:15][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[N:9][C:8]=3[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:22])[C:5]=2[CH2:4]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C1C=CC=CC=1>[C:23]([O:1][CH2:2][CH:3]1[O:15][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[N:9][C:8]=3[N:7]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:6](=[O:22])[C:5]=2[CH2:4]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c2c(c3cccnc3n1-c1ccccc1)OC(CO)C2
Solvent: c1ccccc1
Product: CC(=O)OCC1Cc2c(c3cccnc3n(-c3ccccc3)c2=O)O1

Procedure:
The product of Example 2 is refluxed with acetic anhydride in benzene, and the resultant product is recrystallized from isopropyl acetate to give the title compound, m.p. 207°-208° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]([C@@H:16]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:17]([OH:24])[CH2:18][NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C(O)=O.C(=O)([O-])[O-].[K+].[K+].[O:44]1[C:48]2[CH:49]=[CH:50][C:51]([S:53](Cl)(=[O:55])=[O:54])=[CH:52][C:47]=2[O:46][CH2:45]1>O.O1CCOCC1.C(OCC)(=O)C>[O:44]1[C:48]2[CH:49]=[CH:50][C:51]([S:53]([N:19]([CH2:18][C@@H:17]([OH:24])[C@@H:16]([N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:54])=[O:55])=[CH:52][C:47]=2[O:46][CH2:45]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: CC(C)CNC[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
To a 5000 mL, 3-necked flask fitted with a mechanical stirrer was added N-[3(S)-[N,N-bis(phenylmethyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine.oxalic acid salt (354.7 g, 0.7 mole) and 1,4-dioxane (2000 mL). A solution of potassium carbonate (241.9 g, 1.75 moles) in water (250 mL) was then added. The resultant heterogeneous mixture was stirred for 2 hours at room temperature followed by the addition of 1,3-benzodioxole-5-sulfonyl chloride (162.2 g, 0.735 mole) dissolved in 1,4-dioxane (250 mL) over 15 minutes. The reaction mixture was stirred at room temperature for 18 hours. Ethyl acetate (1000 mL) and water (500 mL) were charged to the reactor and stirring continued for another 1 hour. The aqueous layer was separated and further extracted with ethyl acetate (200 mL). The combined ethyl acetate layers were washed with 25% brine solution (500 mL) and dried over anhydrous magnesium sulfate. After filtering and washing the magnesium sulfate with ethyl acetate (200 mL), the solvent in the filtrate was removed under reduced pressure yielding the desired sulfonamide as an viscous yellow foamy oil (440.2 g 105% yield). HPLC/MS (electrospray) (m/z 601 [M+H]+].
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=1[C:7]([NH:29][C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)=[O:8])[CH2:2][CH3:3]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Propoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Propoxy-N-(4-nitro-3-trifluoromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[H-].[Na+].[H][H].[CH3:30][O:31][CH2:32][CH2:33]Br>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:33][CH2:32][O:31][CH3:30])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Reactant: [H][H]
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(-c3ccc(OCCOC)cc3)cc3ccccc23)CC1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline (0.420 g) obtained in Example 7 was dissolved in N,N-dimethylformamide (5 ml), followed by the addition of 60% sodium hydride (0.06 g). After the evolution of hydrogen was ceased, 2-methoxyethyl bromide (178 μl) was added thereto, and the mixture was stirred 50° C. for 3.5 hr. After the reaction solution was cooled to room temperature, it was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(2-methoxyethoxy)phenyl]isoquinoline as a white powder. The compound was converted into a hydrochloride in a conventional manner, to give 0.457 g of the title compound as a yellow powder.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13].Br[CH2:15][CH2:16]Br>CN(C=O)C>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2([CH2:16][CH2:15]2)[C:5]1=[O:13]
Reactant: CN1C(=O)Cc2ccccc21
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
Add sodium hydride (60%, 1.4 g, 35.4 mmol) portionwise to the solution of 1-methylindolin-2-one (2.6 g, 17.7 mmol) in DMF (10 mL) at 0° C., stir for 30 min. Then add 1,2-dibromoethane (3.31 g, 17.7 mmol) to the mixture, stir the resulting mixture at room temperature overnight. Pour the reaction mixture to ice water, extract with ethyl acetate (100 mL×2), and wash the combined organic layers with brine (50 mL), dry over anhydrous sodium sulfate. Concentrate under reduced pressure, purify the residue by chromatography (silica gel, EtOAc:PE=1:3) to provide the title compound (1.5 g, 50.0%). MS: (M+1): 174.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>O.C(O)C>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:41]2[CH:40]=[CH:39][CH:38]=[C:37]([C:36]([F:47])([F:46])[F:35])[CH:42]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(C(F)(F)F)c3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
N,N-Dimethylformamide (1 ml), ethanol (0.5 ml), and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 3-trifluoromethylphenylboronic acid (67 mg) under an argon atmosphere, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (50 mg, yield 95%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16].O>CC#N>[CH:15]([NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (15 g, 64.7 mmol) in CH3CN (100 mL) was added dropwise a solution of isopropylamine in water (7.6 g, 0.13 mol) at 0° C. The resulting mixture was stirred at RT for 8 h. The organic solution was removed under reduced pressure and the residue was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (16.4 g, 99.6% yield), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1 H), 8.05 (d, J=7.6 Hz, 1 H), 4.31-4.22 (m, 3 H), 2.46 (s, 3 H), 1.27 (t, J=7.2 Hz, 3 H), 1.20 (d, J=6.4 Hz, 6 H).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:27]=[C:28]([CH:32]=[C:33]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=3)[C:34]=2[O:35][CH2:36][CH2:37]O)[C:29](O)=[O:30])[CH:23]=[CH:24][CH:25]=1.CCN(CC)CC.C1C=CC2N([OH:62])N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Cl:45][C:41]1[CH:40]=[C:39]([C:33]2[CH:32]=[C:28]([C:29](=[O:30])[NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)[CH:27]=[C:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)[C:34]=2[O:35][CH:36]([OH:62])[CH3:37])[CH:44]=[CH:43][CH:42]=1
Reactant: NCCCCCCCCn1ccc2ccccc21
Reactant: O=C(O)c1cc(-c2cccc(Cl)c2)c(OCCO)c(-c2cccc(Cl)c2)c1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)Oc1c(-c2cccc(Cl)c2)cc(C(=O)NCCCCCCCCn2ccc3ccccc32)cc1-c1cccc(Cl)c1
Yield: 87.4 %

Procedure:
To a flame dried round bottom flask-with 8-indol-1-yloctylamine (0.227 g, 0.930 mmol, preparation similar to step 1 of Example 54) in CH2Cl2 (10 mL) at room temperature was added 3,5-bis-(m-chlorophenyl)-4-(2-hydroxyethoxy)-benzoic acid (0.250 g, 0.620 mmol, prepared in step 2 of Example 55) followed by Et3N (0.259 mL, 1.86 mmol), HOBt (0.092 g, 0.682 mmol), and finally DCC (0.153 g, 0.744 mmol). After 3 days at this temperature, it was concentrated and then diluted with EtOAc (200 mL). The white solid (DCU) that formed was filtered off and washed with excess EtOAc. The organic layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (30 to 50% EtOAc/petroleum ether) to afford the product (0.341 g, 87%) as a solid; 1H NMR (CDCl3) δ 1.21-1.38 (m, 8H), 1.46-1.63 (m, 3H), 1.75-1.89 (m, 2H), 3.27-3.49 (m, 6H), 4.11 (t, J=8.1 Hz, 2H), 6.01-6.13 (m, 1H), 6.47 (d, J=2.2 Hz, 1H), 7.05-7.13 (m, 2H), 7.19 (t, J=8.8 Hz, 1H), 7.39-7.46 (m, 5H), 7.48-7.55 (m, 2H), 7.58-7.66 (m, 3H), 7.74 (s, 2H); mass spectrum [(+) ESI], m/z 629 (M)+.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])[C:14]=1C#N)#N.CCO.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C1(C)C=CC=CC=1>[C:1]([O:16][CH2:15][CH3:14])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=CC=Cc1ccccc1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C=Cc1ccccc1
Yield: 94 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), EtOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of AMBERLYST® 15 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with EtOH (10 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Ethyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C2H5) is isolated in 94% yield. 1H-NMR (CDCl3, 300 MHz) δ7.72 (1H, d, J=16.19 Hz), 7.43 (5H, m), 6.47 (1H, d, J=16.19 Hz), 4.28 (2H, q, J=7.09 Hz), 1.34 (3H, t, J=7.09 Hz); 13C-NMR (CDCl3, 75.4 MHz) δ166.9, 144.5, 130.1, 128.8, 128.5, 127.9, 118.2, 60.4, 14.2.
Reaction SMILES: CO[CH:3]1[CH:7]([CH:8]=[O:9])[CH2:6][CH:5](OC)O1.[C:12]([NH:15][CH2:16][CH2:17][NH2:18])(=[O:14])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>>[C:12]([NH:15][CH2:16][CH2:17][N:18]1[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:3]1)(=[O:14])[CH3:13]
Reactant: COC1CC(C=O)C(OC)O1
Reactant: CC(=O)NCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)NCCn1ccc(C=O)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
8.5 g (0.053 mol) of 2,5-dimethoxytetrahydrofuran-3-aldehyde and 5.4 g (0.053 mol) of 2-(acetylamino)-ethylamine are stirred at 60° C. for 1 hour. After addition of 0.05 g of p-toluenesulphonic acid hydrate, the mixture is stirred at 80° C. for 90 minutes and cooled, sodium bicarbonate solution is added and the mixture is extracted with methylene chloride and then with pentanol. The organic phases are concentrated and chromatographed over a silica gel column with methylene chloride/methanol =95:5 as the mobile phase. The product isolated is crystallized from ethyl acetate/ligroin.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:7][CH3:8].[CH3:22][OH:23].O>C1(C)C=CC=CC=1.ClCCl>[CH2:5]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[C:22]([O:2][CH3:1])=[O:23])=[CH:15][CH:14]=[CH:13][C:12]=2[C:18]([O:20][CH3:21])=[O:19])[CH2:6][CH2:7][CH3:8]
Reactant: CO
Reactant: CCCCc1cc2cccc(C(=O)OC)c2[nH]1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1[nH]c2c(C(=O)OC)cccc2c1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of phosgene in toluene (37 ml, 1.9M) was added to a solution of methyl 2-(n-butyl)indole-7-carboxylate (P) 11.5 g) (prepared, e.g., as described in Preparation 10), at 5° C. in dichloromethane (75 ml). The solution was stirred at room temperature for 16 hours, cooled in an ice bath, and treated with methanol (20 ml). Water was added, and the dichloromethane layer was separated and solvent evaporated under reduced pressure. Chromatography on silica gel, eluting with 20% ethyl acetate/hexane, afforded dimethyl 2-(n-butyl)indole-3,7-dicarboxylate (7.4 g), a compound of Formula (Q), as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)=[CH2:2].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(OCC)C>[CH:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1ccc(N)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=Cc1ccc(NS(C)(=O)=O)cc1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 500 g (4.2 moles) of 4-vinylaniline and 460 g (4.2 moles) of triethylamine in 1000 cc of anhydrous diethyl ether under a nitrogen atmosphere was added dropwise 478 g (4.2 moles) of methanesulfonyl chloride. The temperature of the reaction vessel was kept below 5° C by an ice bath during the course of the reaction. When addition was complete (40 min.), the mixture was stirred for an additional 2 hours and the contents of the flask then brought to room temperature. The mixture was filtered and extracted with 500 cc of 1.0 M HCl solution. The etheral portion was separated, dried and the ether removed on a rotary evaporator. The resulting oily solid was extracted with 500 cc of ethanol and recrystallized from ethane/water and then from toluene. 70-75% yield after recrystallization. M.P. = 97° C.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=O.C[O-:8].[Na+].[CH:10]([OH:13])([CH3:12])[CH3:11].ClCl>O>[CH3:6][O:5][CH2:3][C:2]([O:13][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)CCl
Reactant: CC(C)O
Reactant: C[O-]
Agent: ClCl
Agent: [Na+]
Solvent: O
Product: COCC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 77 %

Procedure:
434.1 g (4.0 mol) of methyl chloroacetate are initially introduced and stirred at 25° C. 756.3 g (4.2 mol) of 30% strength sodium methoxide solution are added dropwise in the course of 2.5 h such that a reaction temperature of 65° C. is not exceeded. After the addition, stirring is continued at reflux temperature for a further 3 h. 407.5 g of methanol are then separated from the reaction mixture by distillation. 480.8 g (8 mol) of isopropanol are added to the residue and the mixture is heated under reflux. In the course of this, methanol is removed through a 0.5 m long Multifil column at a reflux ratio of approximately 1:1 (291.9 g of distillate). After 6.5 h, the conversion of the methyl methoxyacetate to the isopropyl methoxyacetate is >98%. After cooling, the reaction mixture is filtered off with suction and the residue is washed with 450 g of isopropanol. A residue of 412.1 g and a liquid phase (filtrate and wash liquid) of 969.9 g are obtained. The liquid phase is fractionated through a 0.5 m long Multifil column. Isopropyl methoxyacetate (405.0 g, yield 77%) with an organic purity of >99%, a chlorine content of 10 ppm and a water content of <0.05% is obtained as the main fraction.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.P(Cl)(Cl)Cl>O>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: Nc1ccc(Cl)cc1
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=C(Nc1ccc(Cl)cc1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (3.78 g) of Preparation 1 and 4-chloroaniline (2.55 g) in 250 mL xylenes is heated to reflux. To this is added dropwise PCl3 (1.37 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected, washed with water and dried. The crude product is recrystallized from EtOAc/hexanes to yield 1.96 g of the title product as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].N(C1C=CC(O)=CC=1)[C:18]([CH3:20])=[O:19].CC(C)=O.C(Cl)(Cl)Cl>>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:13][CH:14]=1)[C:18]([CH3:20])=[O:19]
Reactant: CC(C)(Oc1ccc(N)cc1)C(=O)O
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
FIG. 2A illustrates a reaction scheme for preparing 2-(4-aminophenoxy)-2-methyl propionic acid, a compound that is useful as a precursor in the preparation of Group I compounds. In accordance with the scheme of FIG. 2A, 8 grams (g) (0.2 mol) of pulverized sodium hydroxide is added to a suspension of 5.28 g (0.035 mol) of p-acetaminophenol in 23 g (0.4 mol) of acetone. The reaction mixture is stirred at room temperature for 1/2 hour. Subsequently, 3.58 g (0.03 mol) of chloroform is added dropwise over the course of 30 minutes. The reaction mixture is stirred overnight at room temperature and acetone is removed under vacuum. The residue is dissolved in water (10 ml), followed by acidification with 37% hydrochloric acid (HCl) to produce a pale yellow precipitate of 2-(4-acetaminophenoxy)-2-methyl propionic acid (5 g, 60% yield), crystallized from methanol, mp 69°-71° C.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-:9].C[N+]1(C)CCCCC1.C(Cl)(Cl)=O.[ClH:22]>>[Cl:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([Cl:22])=[O:7].[C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl
Reactant: [Cl-]
Agent: C[N+]1(C)CCCCC1
Agent: O=C(Cl)Cl
Agent: O=C1CCCCCO1
Product: O=C(Cl)CCCCCCl

Procedure:
456 parts of 6-caprolactone and 9 parts of N,N-dimethylpiperidinium chloride are initially taken in the stirred reactor described in Example 1. 380 parts of phosgene and 70 parts of hydrogen chloride are passed in at 170°-175° C. in the course of 7 hours. The reaction mixture is then kept at this temperature for a further hour. Any phosgene and hydrogen chloride still present are blown out with nitrogen, and the reaction mixture is then worked up by distillation under reduced pressure. 424 parts of 6-chlorohexanoyl chloride and 86 parts of caprolactone are obtained. The conversion is 81% and the yield is 77.3%, based on lactone used.