Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH2:19][CH3:20]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[N:8]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)[CH2:19][CH3:20])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Reaction time: 0.33 h

Procedure:
To a solution of 2-(BOC-amino)-5-bromopyridine (500 mg) in THF (20 mL) at 0° C. was added sodium hydride (88 mg) and the reaction stirred for 20 min. Then, iodoethane (0.18 mL) was added and the reaction stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted into ethylacetate (3×20 mL). The organic layers were dried (MgSO4) and reduced in vacuo to give (5-bromo-pyridin-2-yl)-ethyl-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=O)=O)=[CH:12][CH:11]=1>C(O)C>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:18]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)=[N:8][C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:1]=2)=[CH:14][CH:15]=1
Reactant: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Nc1ccccc1N
Solvent: CCO
Product: Oc1ccc(-c2nc3ccccc3nc2-c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Into a 250 ml round bottom flask equipped with a magnetic stirrer and reflux condenser was placed 1,2-diaminobenzene (2.3275 g, 0.0215 mol), 4,4'-dihydroxybenzil (5.2135 g, 0.0215 mol) and absolute ethanol (30 ml). The solution was stirred for one-half hour at room temperature, and a yellow precipitate formed. The mixture was heated to reflux overnight. The solvent was removed by vacuum distillation and the solid dried at 100° C. for two hours to give 6.6 g (97%) of yellow powder. The material was recrystallized from 1,4-dioxane/water mixture. Yield 6.0 g (89%) m.p. 336° C.-338° C. Anal. Calcd for C20H14N2O2 : C, 76.42%; H, 4.49%; N, 8.91%. Found: C, 76.54%; H, 4.44%; N,8.96%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:10]=[CH:11][N:12]2[C:17]=1[C:16](=[O:18])[N:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([C@@H:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])=[N:13]2.Cl.O1CCOCC1>>[NH2:27][C@H:25]([C:14]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:18])[C:17]2=[C:9]([S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[CH:10]=[CH:11][N:12]2[N:13]=1)[CH3:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nn2ccc(Sc3ccccc3O)c2c(=O)n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1nn2ccc(Sc3ccccc3O)c2c(=O)n1-c1ccccc1
Yield: 154.5 %

Procedure:
(S)-tert-Butyl (1-(5-((2-hydroxyphenyl)thio)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)carbamate (252 mg, 0.33 mmol) was treated with a solution of hydrochloric acid in dioxane (4M, 2 mL, 8 mmol) according to the method described in Preparation 1 to obtain 193 mg (99% yield) of the title compound. Purity 99%.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].Cl.[CH2:26]([O:29][NH2:30])[CH:27]=[CH2:28].C([O-])(=O)C.[K+].CO>O>[CH2:26]([O:29][N:30]=[C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[N:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[N:16]=2)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:2])[CH:27]=[CH2:28]
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)cccc1C(C)=O
Reactant: C=CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=CCON=C(C)c1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Reaction time: 5 h
Yield: 46.3 %

Procedure:
1.0 g of methyl 2-acetyl-6-[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoate, 1.0 g of allyloxyamine hydrochloride and 0.9 g of potassium acetate were added to 30 ml of methanol, and were refluxed with stirring for 5 hours. The reaction mixture was then poured into a cold water, and was extracted with ethyl acetate. The organic layer thus formed was washed with firstly dilute hydrochloric acid, then sodium hydrogencarbonate and water in sequence. The organic layer thus washed was then dried and concentrated. The residue oily product was purified by column chromatography to obtain 0.54 g of the aimed compound (melting point=76° to 78° C.) at a yield of 46% as a colorless transparent crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH3:19].CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:19]=[CH:22][N:23]([CH3:25])[CH3:24]
Reactant: COC(OC)N(C)C
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Solvent: CN(C)C=O
Product: CN(C)C=Cc1nc2ccccc2c(=O)n1-c1ccccc1Cl
Temperature: 140 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-2-methyl-3,4-dihydro-quinazolin-4-one (1.0 g, 3.69 mmol) and dimethylformamide dimethyl acetal (0.64 mL, 4.8 mmol) in dimethylformamide (4 mL) was heated to 140° C. for 24 hours. Additional dimethylformamide dimethyl acetal (0.32 mL, 2.4 mmol) was added and heating was continued for an additional 24 hours. The reaction was cooled to ambient temperature and concentrated at reduced pressure (60° C. bath temperature). The dark residue was triturated with methanol and the pale orange solid which formed was collected and dried to give 0.75 g (62%) of 3-(2-chloro-phenyl)-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one which had: mp 228-230° C.; 1H 1H NMR δ 8.19 (d, J=8 Hz, 1 H), 7.91 (d, J=12.3 Hz, 1 H), 7.71-7.18 (m, 7 H), 4.10 (d, J=12.3 Hz, 1 H), 2.81 (br s, 6 H). Analysis calculated for C18H16ClN3O: C, 66.36; H, 4.95; N, 12.90. Found: C, 66.20; H, 5.03; N, 12.79.
Reaction SMILES: [O:1]([CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30](O)[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:36]2)=[CH:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30]([O:10][C:9](=[O:11])[CH:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH3:13])[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[CH2:36]2)=[CH:23]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: CCC(Oc1ccccc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 92.7 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 0.66 g of (2RS)-2-phenoxybutyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as describe in Example B, above], to give 1.20 g of the title compound as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:6]=2[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: COc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1

Procedure:
A mixute of 12.9 g of 6-chloro-2[(4-methoxyphenyl)amino]-3-nitrobenzoic acid, 25 ml of chlorobenzene and 50 ml of phosphorus oxychloride was stirred and heated to reflux temperature over a period of one hour, and held under reflux for 4.5 hours. The mixture was cooled, filtered, and the filtrate concentrated to a viscous dark residue by evaporation under reduced pressure. The evaporation residue, and the precipitate collected previously were dissolved in 130 ml of acetic acid and cautiously treated with 15 ml of water, while stirring. The dark red title compound is collected, washed with water, and dried to 11.5 g (95%), mp 262-264 degrees.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]2[CH:39]=[CH:38][C:11]3[N:12]=[C:13]([N:15]4[CH2:20][CH2:19][N:18]([C:21](=[O:37])[C@@H:22]([NH:29]C(=O)OC(C)(C)C)[CH2:23][C:24]5[S:25][CH:26]=[CH:27][CH:28]=5)[CH2:17][CH2:16]4)[S:14][C:10]=3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(OCC)C>O1CCOCC1.Cl>[NH2:29][C@@H:22]([CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:13]2[S:14][C:10]3[CH:9]=[C:8]([CH2:7][NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:39]=[CH:38][C:11]=3[N:12]=2)[CH2:16][CH2:17]1)=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(CNC4CCCC4)cc3s2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(CNC4CCCC4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl 1-(4-(6-((cyclopentylamino)methyl)benzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (20 mg) was dissolved in dry 1,4-dioxane (2 ml) and HCl (4N in 1,4-dioxane). 5 mL) was added. The resulting mixture was stirred overnight at room temperature, then concentrated and chromatographed (94.5:5:0.5 dichloromethane:methanol:ammonium hydroxide) to yield a colorless oil, which was added to HCl/diethyl ether. The resulting white precipitate was collected and dried to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C=O)C.C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][C:2]2[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1ccc(O)c(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C)nc2CO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
1.39 g (10 mmol) of the commercial 3-hydroxy-6-methyl-2-pyridinemethanol in 15 ml DMF was cooled (0° C.), treated with 0.52 g (13.00 mmol) of NaH (55% in oil) and after 30 min, with 1.35 mL (10.00 mmol) p-methoxybenzylchlorid. The suspension was stirred 1 h at 0° C. and 2 h at RT. The reaction mixture was diluted with CH2Cl2 and washed with 1M NaOH and brine. The organic layers were dried over magnesium sulfate, evaporated, purified by silica gel column (AcOEt) and crystallized (AcOEt/n-n-heptane) to give 1.55 g (60%) of the title compound as a white solid. MS: 260.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23].FC(F)(F)C([O:28][CH2:29][C:30]([CH3:36])([CH3:35])[C:31](=[O:34])[CH2:32]Br)=O>CO>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:32][C:31](=[O:34])[C:30]([CH3:36])([CH3:35])[CH2:29][OH:28])[CH2:19][CH2:18]2)=[O:14])=[CH:4][C:3]=1[Cl:23]
Reactant: CC(C)(COC(=O)C(F)(F)F)C(=O)CBr
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Solvent: CO
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(=O)C(C)(C)CO)CC3)c2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 24.5 %

Procedure:
A mixture of 5-amino-6-chloro-2-ethyl-N-(piperidin-4-ylmethyl)imidazo[1,2-a]-pyridine-8-carboxamide (Example 4, step 4, 530 mg, 1.57 mmol) and 4-bromo-2,2-dimethyl-3-oxobutyl trifluoroacetate (Example 6, step 1, 777 mg, 2.67 mmol) in methanol (15 mL) was stirred at room temperature for 5 days. The reaction mixture was concentrated in vacuo. The residue was basified with aqueous potassium carbonate (20 mL) and extracted with dichloromethane (3×30 mL). The combined extract was washed with brine, dried over magnesium sulfate, and evaporated. Flash column chromatography (NH-silica gel) of the residue eluting with dichloromethane/methanol (200:1 to 50:1) afforded a white solid. This was recrystallized from ethanol to afford 173 mg (25%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: SCc1ccccc1Cl
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Na]
Product: Clc1ccc(/C=C\C(SC(/C=C\c2ccc(Cl)cc2)c2ccccc2Cl)c2ccccc2Cl)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-chlorostyryl 2-chlorobenzylsulfide. The title compound was obtained in 73% yield following oxidation. 1HNMR (CDC13) δ4.56 (2H, s), 6.70 (1H, d, JH,H=12.05), 7.18-7.64 (8H aromatic+1H ethylenic).
Reaction SMILES: [Cl:1][CH:2]=[CH:3][NH:4][C:5](=[O:14])[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13].S(=O)(=O)(O)O.[CH3:20][N:21]([CH3:37])[C:22](=[O:36])[S:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.O>ClCCl>[CH3:20][N:21]([CH3:37])[C:22](=[O:36])[S:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([CH:3]([NH:4][C:5](=[O:14])[C:6]3[C:7]([F:13])=[CH:8][CH:9]=[CH:10][C:11]=3[F:12])[CH2:2][Cl:1])=[CH:34][CH:35]=2)=[CH:26][CH:25]=1
Reactant: CN(C)C(=O)Sc1ccc(-c2ccccc2)cc1
Reactant: O=C(NC=CCl)c1c(F)cccc1F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)Sc1ccc(-c2ccc(C(CCl)NC(=O)c3c(F)cccc3F)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A solution of 1 g (4.59 mmol) N-(chloroethenyl)-2,6-difluorobenzamide in 2 mL of dichloromethane was added to 4 mL of concentrated sulfuric acid at 0° C. A portion of 1 g (3.89 mmol) of S-[1,1'-biphenyl]-4-yl dimethylcarbamothioate was added to the mixture and the mixture was stirred at 0° C. for 2 h. The mixture was stored in the refrigerator overnight. The mixture was poured into water (100 mL) and the mixture was filtered. The solid was washed with water (100 mL) and was dried overnight in vacuo at 70° C. to give the crude product 1.52 g (84% yield) as solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.[Zn]>[OH:14][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: CCCCCC=O
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCCCCC(O)CC(=O)OCC
Temperature: 83 °C

Procedure:
7.64 g (0.117 mol) of zinc pretreated as described in Reference Example 1 were suspended in 50 ml of toluene, the mixture was heated to 83° C., the heat source was subsequently removed and a mixture of 11.4 ml (0.103 mol) of ethyl bromoacetate and 11.23 ml (0.0935 mol) of hexanal was added dropwise over a period of 30 minutes. After a brief induction phase, rigorous foaming and heating of the reaction mixture to 110° C. was observed. After all the mixture had been added, the resulting suspension was cooled to 8° C. by means of an ice/water mixture, after which 15 ml of 50% strength sulfuric acid was added dropwise at such a rate that the temperature of the suspension did not exceed 35° C. After phase separation, the organic phase was washed twice with 15 ml of water and dried over sodium sulfate. After filtration and removal of all volatile constituents on a rotary evaporator at 50° C./5 torr, the residue obtained was distilled in an oil pump vacuum at 2.5 torr. The fraction comprising ethyl 3-hydroxyoctanoate went over at 88-93° C. Yield: 12.25 g (70%).
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:13])[CH2:9][CH2:10][CH2:11][CH3:12]>C1(C)C=CC=CC=1>[CH2:8]([NH:13][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCN
Reactant: COCC(Cl)C=O
Solvent: Cc1ccccc1
Product: CCCCCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-pentylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:32](Br)(Br)([Br:34])[Br:33].C(C1SC(C2SC=CC=2)=CC=1)=O.ClCCl>ClCCl.CCCCCC>[Br:33][C:32]([Br:34])=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: BrC(Br)=Cc1ccc(-c2cccs2)s1
Reaction time: 1 h

Procedure:
0.55 g of 5-formyl-2,2'-bithiophene was dissolved in 10 ml of dichloromethane. 1.95 g of PPh3 and 1.23 g of CBr4 were dissolved in 40 ml of dichloromethane and mixed with the 5-formyl-2,2'-bithiophene/dichloromethane solution under nitrogen gas atmosphere at 0° C. After the mixture was stirred for 1 hour and 10 ml of n-hexane was added to precipitate the triphenyl-phosphine oxide. And the reaction solution was filtered. Further, 100 ml of n-hexane was then added into the solution and the yellowish solid was obtained. The solid was further purified by column chromatography and crystallized with ethanol. The crystal product was thus obtained and the melting point thereof was 112°-113° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:9])[CH2:7][CH3:8].[Al+3].[Cl-].[Cl-].[Cl-].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:4]1[CH:3]=[C:2]([C:6](=[O:9])[CH2:7][CH3:8])[S:1][CH:5]=1
Reactant: CCC(=O)c1cccs1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCC(=O)c1cc(Br)cs1
Temperature: 0 °C

Procedure:
A 47.3 g (338 mmol) sample of 1-(2-thienyl)-1-propanone (Aldrich) was dissolved in 225 mL of CHCl3 and 101.3 g (760 mmol) of AlCl3 was added with stirring. To this mixture was added a solution of bromine (57.5 g, 360 mmol) in 375 mL of CHCl3. The mixture was stirred at room temperature over night then poured into 500 mL of ice water. The organic layer was separated, washed with water (2×200 mL), dried over MgSO4, filtered and evaporated to yield 81 g of the crude title compound, which was taken directly to the next step. mp 40°-41° C.; MS: 158 (M+H)+, 236 (M+NH4)+ ; NMR (CDCl3) δ: 1.22 (t, 3H, J=7.5 Hz), 2.91 (q, 2H, J=7.5Hz), 7.51 (d, 1H), 7.60 (d, 1H). IR (KBr): 2960, 1670, 1400, 1220 cm-1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Reactant: ICC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(CC4CCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and (1-iodomethyl)cyclopentane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12]>[Pd].O.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[O:12]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)NS(C)(=O)=O
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)cc1C(=O)NS(C)(=O)=O
Yield: 79.3 %

Procedure:
In the same way as that described in Example 11, Step 2, using 2-methyl-1-(methylsulphonylaminocarbonyl)-5-nitrobenzene (3 g, 11.6 mmol), 10% palladium on carbon (0.3 g, 10% (w/w)) in water (2 ml) and ethanol (100 ml), the title compound (2.1 g, 79%) was afforded as a pale yellow crystalline solid. mp 174°-176° C. 1H NMR (360 MHz, D6-DMSO) δ 2.17 (3H, s), 3.32 (3H, s), 6.61 (1H, dd, J=8.1 and 2.5 Hz), 6.67 (1H, d, J=2.4 Hz), 6.92 (1H, d, J=8.2 Hz).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]=[CH:5][C:6]1[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:8][C:7]=1[CH2:19][CH2:20][CH3:21].[Li+].[OH-]>C1COCC1.CO>[CH2:12]([C:11]1[CH:10]=[C:9]([C:15]([F:16])([F:18])[F:17])[CH:8]=[C:7]([CH2:19][CH2:20][CH3:21])[C:6]=1[CH:5]=[CH:4][C:3]([OH:22])=[O:2])[CH2:13][CH3:14]
Reactant: CCCc1cc(C(F)(F)F)cc(CCC)c1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1cc(C(F)(F)F)cc(CCC)c1C=CC(=O)O
Yield: 76.3 %

Procedure:
3-(2,6-Dipropyl-4-trifluoromethyl-phenyl)-acrylic acid methyl ester (343 mg) was reacted with 1N LiOH (5 ml) in THF (10 ml) and CH3OH (5 ml) for 1 hr. The reaction mixture was concentrated in vacuo. Water (30 ml) was added to the resulting residue, which was neutralized with 1N HCl solution. The mixture was extracted with ethyl acetate (30 ml×3). The combined organic layer was dried over MgSO4. The filterate was concentrated in vacuo to yield title compound (250 mg, 82%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH:2]=C.[CH2:20]([O:23]CCOCCOC1C=CC(C(OC)=O)=CC=1)[CH:21]=[CH2:22].[OH-].[Na+]>CO>[CH2:20]([O:23][CH2:2][CH2:1][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1)[CH:21]=[CH2:22]
Reactant: C=CCOCCOCCOc1ccc(C(=O)O)cc1
Reactant: C=CCOCCOCCOc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOCCOCCOCCOc1ccc(C(=O)O)cc1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
These compounds were synthesized by similar methods. The representative synthesis of 4-(2-(2-allyloxyethoxy)ethoxy)benzoic acid (11) is presented. A mixture of 8.39 grams (0.03 mole) of the obtained methyl 4-(2-(2-allyloxy-ethoxy)ethoxy)benzoate (7), 6 ml of 50% aqueous sodium hydroxide solution and 150 ml of methanol was stirred under reflux for three hours. Methanol was distilled off (100 ml) and water 600 ml was added. The reaction mixture was acidified with hydrochloric acid. After cooling to 0° C., a white solid was filtered and set aside. The filtrate was extracted with dichloromethane and the extracted material was evaporated to a white solid which was combined with the set-aside material. The combined material was dried under vacuum to yield 4.4 g of product (94.3%). 1H-NMR (CDCl3, TMS): d=3.81-4.25 (m, 10H, --CH2 --(OCH2CH2)2 -- ), 5.23 and 5.9 (m, 3H, CH2 =CH--), 6.95 and 8.05 (2d, 4 aromatic protons), 12.2 (s, 1H, --COOH).