Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:7][CH2:8]N1C=NC2C1=NC(N)=NC=2)(=[O:3])[CH3:2].[NH2:24][C:25]1[N:33]=[C:32]2[C:28]([NH:29][C:30]([Cl:34])=[N:31]2)=[C:27]([Cl:35])[N:26]=1>>[C:1]([O:4][CH2:5][CH:6]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:7][CH2:8][N:31]1[C:30]([Cl:34])=[N:29][C:28]2[C:32]1=[N:33][C:25]([NH2:24])=[N:26][C:27]=2[Cl:35])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Reactant: Nc1nc(Cl)c2[nH]c(Cl)nc2n1
Product: CC(=O)OCC(CCn1c(Cl)nc2c(Cl)nc(N)nc21)COC(C)=O

Procedure:
Moreover, U.S. Pat. No. 5,138,057 discloses a process for preparing 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurine of Formula (I), in which 2-amino-6,8-dichloropurine of Formula (X) is reacted with 2-acetoxymethyl-4-halobut-1-yl-acetate of Formula (VII) to give 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-amino-6,8-dichloropurine of Formula (XI) which is then reduced under a pressurized condition in the presence of palladium, as shown in Scheme 3 below.
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1Br)[CH3:3].BrBr.Cl.[OH2:13]>CO>[CH3:8][C:4]1[O:5][CH:6]=[CH:7][C:3](=[O:13])[C:2]=1[OH:1]
Reactant: CC(O)c1occc1Br
Reactant: O
Agent: BrBr
Agent: Cl
Solvent: CO
Product: Cc1occc(=O)c1O
Temperature: 96 °C

Procedure:
To a sample of 2-(1-hydroxyethyl)-3-bromo-furan (0.54 g, 2.8 mmoles) in 15 ml water and 15 ml methanol at 0° C. was added 0.24 g (3.0 mmoles) of bromine. After allowing the reaction to come to room temperature, the reaction was treated with 3 ml of conc. HCl and heated to 96° C. for 2 hours, removing much of the methanol. After cooling, maltol was isolated by the method of Example 1.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)=O.C(OC(=O)C)(=O)C>[Pd]>[CH3:1][C:2]1[O:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: CC(=O)Oc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2ccccc2o1
Temperature: 190 °C

Procedure:
An autoclave is charged with 18.1 g. o-nitrophenyl acetate, 2.50 g. 5% palladium-on-carbon, 0.50 g. ferric chloride 25 ml. acetic anhydride and 75 ml. acetic acid, purged with nitrogen, pressurized to 5,000 psig. with carbon monoxide, and heated at 190° C. for 5 hours. Analysis of the reaction mixture by vapor phase chromatography indicates complete conversion of the o-nitrophenyl acetate to 2-methylbenzoxazole. The catalyst is separated by filtration and washed with acetone. The solvents are evaporated and the residual oil is dissolved in ether and the solution is washed with aqueous sodium bicarbonate and water. After evaporation of the ether, the crude product is distilled to obtain 2-methylbenzoxazole, b.p.30 mm. 102°-110° C. The product is identical with an authentic sample of 2-methylbenzoxazole by vapor phase chromatography and infrared spectrum.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:16]>Cl.CO.O1CCCC1>[ClH:16].[NH:5]1[CH2:6][CH2:7][S:2](=[O:15])(=[O:1])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=S1(=O)CCNCC1
Temperature: 25 °C

Procedure:
tert-Butyl 1,1-dioxothiomorpholine-4-carboxylate (2.03 g, 8.63 mmol) was dissolved in a mixture of hydrochloric acid-methanol 10 (20 ml) and tetrahydrofuran (20 ml); hydrochloric acid (4.0 ml) was added thereto during stirring at room temperature; and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated; methanol (20 ml), tetrahydrofuran (20 ml) and hydrochloric acid (4.0 ml) were added to the obtained crystals. Furthermore, water (10 ml) was added to this solution to perfectly dissolve the crystals; and this solution was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure; and the obtained crystals were suspended in methanol, filtered off, washed with methanol, and dried under aeration to yield the title compound as colorless crystals (1.49 g, 8.65 mmol, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:25])[CH3:24].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(#N)C.C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CC(=O)OCCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.5 g, 41 mmol), K2CO3 (7.2 g, 51 mmol), and 4-bromobutyl acetate (10 g, 51 mmol) in acetonitrile (200 ml) was heated at reflux for 3.5 hours. At the end of the reaction, the solution was cooled and filtered. The inorganic salt was washed with DCM (50 ml). The organic solvent was removed. The residue was purified on a flash chromatography column (packed with Sorbsil C30 silica gel, 100 g, eluted with DCM, 1 liter, increasing methanol from 2 to 4%, 2.51). The material thus purified weighed 12.92 g (89%). A small sample (1.67 g) was dissolved in ethanol and treated with 1 equivalent of fumaric acid (580 mg) in ethanol to yield white crystals: 1.8 g, m.p.=142°-143° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([I:25])=[CH:24][C:18]=2[N:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[I:25][C:23]1[CH:22]=[CH:21][C:19]2[NH:20][C:16]([C@@H:8]([NH2:7])[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:17][C:18]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2cc(I)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)c1nc2cc(I)ccc2[nH]1
Temperature: 0 °C

Procedure:
To a solution of [(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (1.0 g, 2.16 mmol) in dichloromethane (11 mL) at 0° C. under an atmosphere of nitrogen was added trifluoroacetic acid (6.0 mL, 81 mmol) and the mixture stirred at 0° C. with warming to room temperature over 2 hours. The reaction mixture was concentrated in vacuo then basified with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethylamine which was used in the subsequent step without further purification (750 mg, 96%).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:22][C:21]=3[C:29]([NH:31]C(C)(C)C)=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1>C1(OC)C=CC=CC=1>[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH:26]([CH3:27])[CH3:28])[S:22][C:21]=3[C:29]([NH2:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(C(=O)NC(C)(C)C)s1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(C(N)=O)s1
Reaction time: 30 h
Yield: 82.7 %

Procedure:
Trifluoroacetic acid was added (2.5 mL) to 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-carboxamide (165 mg, 0.417 mmol, see step (d) above), and one drop (ca. 0.05 mL) of anisol was added to the reaction mixture. The mixture was stirred under a N2 atmosphere for 30 hours and then evaporated and co-evaporated with acetonitrile. The crude product was purified by column chromatography (CH2Cl2:MeOH (85:15)) to give the sub-title compound (117 mg, 0.345 mmol) in 73% yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=O.[CH3:9][NH:10][C:11](=[S:14])[NH:12][NH2:13].C(=O)(O)[O-].[Na+].Cl>C(OCC)(=O)C.N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH3:9])[C:11]([SH:14])=[N:12][N:13]=1
Reactant: CNC(=S)NN
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cn1c(S)nnc1-c1ccco1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Furoyl chloride (0.76 ml, 7.66 mmol) was added in a dropwise manner to a solution of 4-methyl-3-thiosemicarbazide (732 mg, 6.96 mmol) and pyridine (7 ml) and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (100 ml), successively washed with water (3×100 ml) and brine (100 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The residue was suspended in sodium bicarbonate (70 ml, 69.6 mmol, 1 M water) and left stirring at 100° C. overnight. The reaction mixture was cooled to 0° C., then brought to pH about 6 using hydrochloric acid (70 ml, 1 N water). The title compound (298 mg) was collected by filtration as a white solid. 1H NMR (CDCl3), δ (ppm): 11.4 (bs, 1H), 7.63 (d, 1H), 7.02 (d, 1H), 6.60 (dd, 1H), 3.83 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[CH:26][CH:25]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 117 mg of 4-Acetylamino-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.16 (s, 3H), 7.26 (b, 1H), 7.33 (d, 1H, J=2.4 Hz), 7.39 (m, 6H), 7.46 (dd, 1H, J=8.4 Hz, 2.4 Hz), 7.55 (m, 3H), 7.71 (d, 1H, J=8.8 Hz), 9.74 (s, 1H). MS: m/z 429.0 (M++1).
Reaction SMILES: N1(O[C:11]([CH:13]=[CH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[O:12])C2C=CC=CC=2N=N1.CCN(CC)CC.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[NH2:37]>C(Cl)Cl>[CH3:44][O:43][C:39]1[CH:38]=[C:36]([NH:37][C:11]([CH:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)=[O:12])[CH:35]=[C:34]([O:33][CH3:32])[C:40]=1[O:41][CH3:42]
Reactant: COC(=O)c1ccc(C=CC(=O)On2nnc3ccccc32)cc1
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C=CC(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
To a stirred suspension at room temperature of VIII (150 mg, 0.46 mmol) in anhydrous CH2Cl2 (10 ml) under nitrogen were added Et3N (194 μl, 1.39 mmol) and 3,4,5-trimethoxyaniline (94 mg, 0.51 mmol) or ArNH2(1.1–1.2 equiv.), respectively. The reaction mixture was heated to 60° C. After 20 h, the reaction mixture was concentrated, diluted with AcOEt, and successively washed with a saturated aqueous solution of NH4Cl, H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (AcOEt/CH2Cl2:15/85→20/80) to give the title product IXa (130 mg, 0.35 mmol, 75% yield) as a yellow solid. 1H NMR (300 MHz, acetone-d6) δ(ppm): 9.42 (bs, 1H), AB system (δA=8.09, δB=7.78, J=8.1 Hz, 4H), 7.75 (d, J=15.6 Hz, 1H), 7.21 (s, 2H), 7.00 (d, J=15.8 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 6H), 3.73 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[H-].[Na+].[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19]Cl>>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccccc1Cc1ncc[nH]1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Product: Clc1ccc(COc2ccccc2Cc2ncc[nH]2)c(Cl)c1

Procedure:
Analogously to Example 1, 2.21 g. of (2,4-dichlorobenzyl)-[2-(1-imidazolymethyl)-phenyl]-ether, m.p. 108°-110°, is obtained from 1.74 g. of 2-(1-imidazolylmethyl)-phenol (Bull. Soc. Chim. France 1973, 1179), 300 mg. of sodium hydride suspension, and 1.41 g. of 2,4-dichlorobenzyl chloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1.[CH3:12][NH:13][C:14]([C:16]1[C:17](=[O:33])[C:18]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[C:19]([CH3:22])[NH:20][CH:21]=1)=[O:15]>>[CH3:12][NH:13][C:14]([C:16]1[C:17](=[O:33])[C:18]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[C:19]([CH3:22])[N:20]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=2)[CH:21]=1)=[O:15]
Reactant: CNC(=O)c1c[nH]c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Reactant: N#Cc1ccc(CBr)cc1F
Product: CNC(=O)c1cn(Cc2ccc(C#N)c(F)c2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O

Procedure:
Example 43 is prepared as described for example 2.1, substituting benzyl bromide with 4-bromomethyl-2-fluoro-benzonitrile and substituting preparation 5 with preparation 36a. ESI mass spectrum: [M+H]+=445; Retention time HPLC: 0.97 min (Z018_S04).
Reaction SMILES: [OH-].[Na+].[C:3]1(C)[CH:8]=CC=[CH:5][CH:4]=1.[C:10]([N:14]1[CH:18]([NH2:19])[CH:17]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])[C:16](=[O:28])[NH:15]1)([CH3:13])([CH3:12])[CH3:11]>O>[C:10]([N:14]1[CH:18]([NH2:19])[CH:17]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])[C:16](=[O:28])[N:15]1[CH:3]([CH2:4][CH3:5])[CH3:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)N1NC(=O)C(c2c(Cl)cccc2Cl)C1N
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)N1C(=O)C(c2c(Cl)cccc2Cl)C(N)N1C(C)(C)C
Temperature: 100 °C
Yield: 31 %

Procedure:
To 160 mg of sodium hydroxide (60% oil dispersion) were added 30 ml of toluene and 1.00 g of 1-tert-butyl-4-(2,6-dichlorophenyl)-5-amino-pyrazolin-3-one, and the mixture was heated for 2 hours at 100° C. To this was added 550 ml of isopropyl mathanesulfonate, and the mixture was heated for additional 3 hours at 100° C. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate anhydride, then, the solvent was distilled off under reduced pressure. The residue analyzed by 1H-NMR on the ratio of N-alkyl compound to O-alkyl compound being 31 to 69 was applied to column chromatography to obtain 353 mg (yield: 31%) of 1-tert-butyl-2-sec-butyl-4-(2,6-dichlorophenyl)-5-aminopyrazolin-3-one.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH3:2].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O>>[Br:8][C:9]1[CH:10]=[C:11]([CH2:12][C:6]2[S:5][CH:4]=[C:3]([CH2:1][CH3:2])[CH:7]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CCc1ccsc1
Product: CCc1csc(Cc2cccc(Br)c2)c1

Procedure:
3-Ethylthiophene and 3-bromobenzaldehyde were used and treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 281/283 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[N:16]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=[O:7].S(Cl)([Cl:28])=O>>[F:1][C:2]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[N:16]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([Cl:28])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F)C(=O)O
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F)C(=O)Cl
Reaction time: 5 h

Procedure:
2-[2-Fluoro-4-(6-chloroquinoxalin-2-yloxy)phenoxy]-propionic acid (1.73 g; 4.77 mmole) was treated with thionyl chloride and the mixture was heated under reflux with stirring for a period of 5 hours. The excess thionyl chloride was removed by distillation under reduced pressure to give 2-[2-fluoro-4-(6-chloroquinoxalin-2-yloxy)phenoxy]-propionyl chloride as a straw coloured oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([S:14][CH3:15])[C:5]=1[C:16]([CH3:18])=[CH2:17].C(O)C>O>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:14][CH3:15])[C:5]=1[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)c1c(Cl)ccc(C(=O)OC)c1SC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(C)c1c(Cl)ccc(C(=O)O)c1SC
Yield: 89.1 %

Procedure:
A solution of sodium hydroxide (7.0 g) in water was added to methyl 4-chloro-3-isopropenyl-2-(methylsulphenyl)benzoate (7.3 g) and the resulting mixture was heated at reflux for 2 hours. Ethanol was added and the mixture was heated at reflux for 1 hour. The ethanol was removed by evaporation and the aqueous residue was acidified to pH 1. It was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 4-chloro-3-isopropenyl-2-(methylsulphenyl)benzoic acid (6.15 g) NMR (CDCl3) 2.05 (s,3H), 2.4 (s,3H), 4.85 (s,1H), 5.35 (s,1H), 7.45 (d,1H), 7.85 (d,1H).
Reaction SMILES: CN(C)C(=N)N(C)C.[CH2:9]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[CH2:26]([O:28][CH:29]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:27]>ClCCl>[CH2:33]([O:32][C:30](=[O:31])[C:29]([O:28][CH2:26][CH3:27])=[CH:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:18]=1)[CH3:34]
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
Tetramethylguanidine (6.5 g; 56.6 mmole) was slowly added to a solution of 3-benzyloxybenzaldehyde (11.7 g; 55 mmole) and (1,2-diethoxy-2-oxoethyl)(triphenyl) phosphonium chloride (20.1 g; 46.8 mmole) in dichloromethane (200 ml) at 0° C. After stirring at room temperature overnight the solvent was evaporated in vacuo. Diethyl ether was added and insoluble material was filtered off. The filtrate was washed with sodium bicarbonate solution, dried (magnesium sulfate), filtered and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel using tetrahydrofuran (0.5%) in dichloromethane as eluant. The remaining aldehyde was removed by stirring with sodium bisulfite in water and diethyl ether for 2 days. The phases were separated and the organic phase was evaporated in vacuo to give 10.5 g (yield 69%) of 3-(3-benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[O:5][C:6]1[C:20]([O:21]C2C=CC(C#N)=CC=2)=[CH:19][C:9]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1)#[N:2].O[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[C:38]#[N:39]>>[C:1]([C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[O:5][C:6]1[C:20]([O:21][C:35]2[CH:42]=[CH:41][CH:40]=[C:37]([C:38]#[N:39])[CH:36]=2)=[CH:19][C:9]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2C#N)cc1
Reactant: N#Cc1cccc(O)c1
Product: N#Cc1cccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2ccccc2C#N)c1

Procedure:
The entitled compound was obtained as a brown solid in the same method as in Example 28 or in accordance with the method or by combining it with an ordinary method but using 4-fluoro-5-(2-cyano-phenoxy)-2-nitro-phenylamine obtained in Example 28 and 3-hydroxy-benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][CH3:10])[CH:3]=1.C(#N)C.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: COc1cc(Br)ccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
To a solution of 4-bromo-1-iodo-2-methoxybenzene (1.634 g, 5.221 mmol) in dry acetonitrile (20 mL) CuI (49.7 mg, 0.261 mmol) and Pd(Ph3P)2Cl2 (183.2 mg, 0.261 mmol) were added under Argon atmosphere and the mixture was degassed and backfilled with Argon for three times. TEA (0.728 mL, 5.221 mmol) and (ethynyl)trimethylsilane (1.48 mL, 1.03 g, 10.442 mmol) were added with a syringe and the reaction mixture, that darkened within 10 min, was stirred at room temperature for 1 h. The solvent was removed under vacuum and the residue was taken up with EtOAc (100 mL), washed with brine (3×20 mL), water (20 mL), dried over sodium sulphate and evaporated to dryness. The crude was purified by chromatography on silica gel (petroleum ether/diethyl ether 9/1) to yield the title compound as an orange solid (1.426 g, 96.5%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.F[C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].O>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])=[CH:10][CH:9]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
1.4 g of potassium carbonate were added to a solution of 1.29 g of 4-chlorophenol in 8 ml of DMF and, after stirring for 30 minutes, 1.6 g of 4-fluoro-3-nitroaniline were added, and the mixture was stirred at 100° C. for 3 hours. After cooling, 80 ml of water were added and, after brief stirring, the precipitate was filtered off with suction and dried in vacuo at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[S:13](=[O:16])(=[O:15])[NH2:14].N[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>C(O)CCCC>[Br:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:21]2[CH2:22][CH2:23][CH:18]([N:8]3[C:6](=[O:7])[C:5]4[C:4](=[CH:3][C:2]([Cl:1])=[C:12]([S:13]([NH2:14])(=[O:16])=[O:15])[CH:11]=4)[C:9]3=[O:10])[CH2:19][CH2:20]2)=[CH:30][CH:29]=1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Reactant: NC1CCN(Cc2ccc(Br)cc2)CC1
Solvent: CCCCCO
Product: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(C1CCN(Cc3ccc(Br)cc3)CC1)C2=O

Procedure:
Reaction of a mixture of 4-chloro-5-sulfamoylphthalimide (6.48 g., 0.025 mole) and 4-amino-1-(4-bromobenzyl)piperidine (6.7 g., 0.025 mole) in n-pentanol according to the procedure of Example 1(a) afforded the 1,3-dioxoisoindole product. Purification of the crude product by triturating with n-heptane and crystallization from DMF-methanol afforded 6.9 g. (54%) of 2-[1-[(4-bromophenyl)methyl]-4-piperidinyl]-6-chloro-2,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide, m.p. 246°-247° (dec.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1.[C-]#N.[K+].[I-].[K+].[CH3:25][N:26](C)C=O>O>[C:25]([CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)#[N:26]
Reactant: CN(C)C=O
Reactant: O=C(OCc1ccccc1)N1CCOC(CCCl)C1
Agent: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: O
Product: N#CCCC1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(2-chloroethyl)-4-benzyloxycarbonylmorpholine (16 g), potassium cyanide (6.3 g), potassium iodide (1 g), and dimethylformamide (50 ml) is heated at 100° C. with stirring for 5 hours. After cooling, the reaction mixture is diluted with water and extracted with diethyl ether. The organic layer is dried over sodium sulfate and evaporated. The residue is crystallized from diethyl ether-hexane to give the title compound (10.7 g), mp 59°-60° C.