Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10](I)=[C:6]2[N:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:10]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:8][N:7]3[C:2]([C:16]4[CH:15]=[CH:14][C:13]([Cl:18])=[CH:12][CH:17]=4)=[CH:3][CH:4]=[N:5][C:6]=23)=[CH:22][CH:21]=1
Reactant: Clc1ccccc1-c1nn2c(Cl)ccnc2c1I
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1ccc(-c2c(-c3ccccc3Cl)nn3c(-c4ccc(Cl)cc4)ccnc23)cc1
Temperature: 72 °C

Procedure:
A mixture of 7-chloro-2-(2-chlorophenyl)-3-iodopyrazolo[1,5-a]pyrimidine (I-1A-1d; 50 mg, 0.13 mmol), 4-chlorophenylboronic acid (30 mg, 0.19 mmol), Na2CO3 (108 mg, 0.67 mmol), and tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) in ethanol (1 ml) and water (0.23 ml) was degassed (3×) by pulling a vacuum followed by refilling with nitrogen gas. The reaction was heated at 72° C. for 2 hr, cooled to room temperature, and then extracted from water with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo. Purification on a Chromatotron using 20% ethyl acetate in hexanes as eluant afforded compound 14A-1 (17 mg, 30%) as a solid: +ESI MS (M+1) 450.3; 1H NMR (400 MHz, CD2Cl2) δ 8.62 (d, J=4.1 Hz, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.51–7.36 (m, 6H), 7.28 (d, J=8.7 Hz, 2H), 7.04 (d, J=4.1 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[O:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:4][C:3]=1[O:19][CH3:20].Cl[CH2:22][C:23]1[N:24]=[C:25](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:26][C:27]=1C>>[CH3:20][O:19][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[O:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])[CH:6]=[CH:7][C:2]=1[O:1][CH2:22][C:23]1[N:24]=[C:25](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[S:26][CH:27]=1
Reactant: Cc1sc(/C=C/c2ccccc2)nc1CCl
Reactant: COc1cc(CCCCC2OC(=O)NC2=O)ccc1O
Product: COc1cc(CCCCC2OC(=O)NC2=O)ccc1OCc1csc(/C=C/c2ccccc2)n1

Procedure:
In substantially the same manner as in Working Example 9, 5-[4-(4-hydroxy-3-methoxyphenyl)butyl]-2,4-oxazolidinedione was reacted with 4-chloromethyl-5-methyl-2-[(E)-styryl]thiazole to obtain 5-[4-[3-methoxy-4-[2-[(E)-styryl]-4-thiazolylmethoxy]phenyl]butyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.167-168° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([F:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[OH-].[Na+]>CO>[C:14]([O:13][C:11]([N:6]1[CH2:7][CH:8]([F:10])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1CC(F)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(F)CC1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a stirred solution of methyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylate (1.2 g, 4.85 mmol) in MeOH (5 ml) was added 1N NaOH (5 ml) and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo, water was added thereto, and neutralized with 1N HCl. The mixture was extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo to give 1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (1.1 g, quant) as a colorless oil. 1H-NMR (CDCl3) δ1.47 (br s, 9H), 2.78-2.83 (br s, 3H), 4.37 (s, 2H), 6.73-6.76 (m, 3H), 7.17 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH:6]=1)=[O:4].[BH4-].[Na+].O1CCCC1.Cl>CO>[CH3:1][NH:2][C:3]([CH:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]([CH3:19])([CH3:18])[CH2:6]1)=[O:4]
Reactant: CNC(=O)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
A mixture of 0.53 g of N-methyl-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide, 0.38 g of sodium borohydride, 5 ml of tetrahydrofuran, and 5 ml of methyl alcohol was stirred at room temperature for 20 minutes. 2N Hydrochloric acid was added thereto, followed by extracting with dichloromethane. The extract was dried over magnesium sulfate and recrystallized from ethyl acetate and n-hexane to obtain 0.42 g of N-methyl-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.
Reaction SMILES: [Br:1]Br.[C:3]1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(N(C)C)=O>[Br-:1].[Br-:1].[C:16]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: [Br-]

Procedure:
Bromine (59.6 g, 0.373 mole) was added drop wise over a 30-min period to a stirred solution of triphenylphosphine (97.7 g, 0.373 mole) in anhydrous 486 ml of dimethylacetamide (DMAC) kept at about 10° C. (ice bath) and protected from atmospheric moisture. (Bromine remaining in the funnel was rinsed with 10 ml of DMAC). A smooth suspension containing finely divided, crystalline triphenylphosphine dibromide resulted. The 2,4-diamino-6-pteridinemethanol.HBr (2) (25.4 g, 0.093 mole) described above was added in one portion through a powder funnel (with the aid of 10 ml DMAC). The ice bath was removed, and the stirred mixture was allowed to warm to 20-25° C. After about 1 hr, complete solution had occurred. The solution, which gradually developed a dark-red color, was kept at 20-25° C. for 1 hr longer and was then chilled (ice bath) before it was treated with EtOH (72 ml). After overnight refrigeration, the solvents were removed by evaporation in vacuo. The dark, semisolid residue was stirred with two 300-ml portions of benzene (to remove triphenylphosphine oxide), and each portion was removed from the benzene-insoluble product by decantation. The solid that remained was dissolved with stirring in glacial AcOH (660 ml) which had been preheated to 80° C. The mixture was kept in a bath at 80° C. until solution was complete. A tan crystalline solid separated as the dark solution was allowed to cool. Overnight refrigeration caused the AcOH to partially freeze. When it had thawed, the solid was collected, washed with chilled AcOH followed by Et2O, and dried in vacuo (over P2O5 and NaOH pellets) at successive temperatures of 25° C., 56° C., and 110° C. (The higher temperature was necessary for complete removal of AcOH). The yield was 15.3 g (49%). (Some runs afforded 60% yield). This sample was further purified by reprecipitation from MeOH solution (Norit) by addition of Et2O followed by drying in vacuo (25° C., P2O5), yield 13.0 g (42%) of pale-yellow solid. Spectral data: λmax, nm (ε×10−3), 0.1 N HCl, 249 (17.3), 339 (10.5), 353 (sh); pH 7, 258 (21.2), 370 (6.87); 0.1 N NaOH, 258 (21.5), 370 (6.94); 1H NMR (CF3CO2D), δ 4.70 (s, 2, CH2) and δ 9.08 (s, 1, C7—H); estimated proportion relative to the methyl-substituted contaminant, 25:1. The preparation of 2 described above is typical of several runs that gave similar yields of material whose 1H NMR spectra differed only slightly in the estimated proportion of 2 with respect to the methyl-substituted contaminant. The proportions usually ranged from 16:1 to 25:1, which corresponds to a percentage of 2 of 94 to 96%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>C(OCC)C>[OH:1][C:2]1([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCOCC
Product: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A mixture of commercial tert-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10.0 mmol) and diethyl ether (30 ml) was cooled to 0° C. To this mixture was added dropwise a solution of (4-methoxyphenyl)magnesium bromide (0.5 M in diethyl ether, 30 ml, 15 mmol). After complete addition, the reaction mixture was allowed to warm to rt and stirred for 2 h. It was then slowly quenched with 150 ml of ice cold water and then the resulting mixture was extracted with 3×150 ml of DCM. The organic layers were combined, dried, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (30:70 ethyl acetate:hexane) to provide the desired product (3.0 g, 100% yield): LC-MS (ES-API): m/z 305.5 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 7.37 (q, J=1.0 Hz, 2H), 6.86 (q, J=1.0 Hz, 2H), 4.94 (s, 1H), 3.82 (d, J=11.5 Hz, 2H), 3.73 (s, 3H), 3.13 (br. s, 2H), 1.75 (td, J=12.9, 4.8 Hz, 2H), 1.56 (d, J=12.3 Hz, 2H), 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12]O)[C:6]=2[CH:14]=1.S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][Cl:17])[C:6]=2[CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2n1CCO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ccc(Cl)cc2n1CCCl
Reaction time: 7 h
Yield: 35.5 %

Procedure:
To a stirred mixture of 13 parts of 6-chloro-1,3-dihydro-1-(2-hydroxyethyl)-2H-benzimidazol-2-one in 225 parts of trichloromethane are added dropwise 32 parts of sulfinyl chloride. Upon completion, stirring is continued for 7 hours at reflux temperature. The reaction mixture is evaporated and the residue is triturated in water. The solid product is filtered off and crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. It is filtered off again and dried, yielding 5 parts (35.5%) of 6-chloro-1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one; mp. 164° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:17][O:18][CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22]Cl.C(N(CC)CC)C.S(=O)(=O)(O)O>ClCCl>[CH3:17][O:18][CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: COCCN(CCC#N)SCl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CCC#N)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A 19.9 g (0.09 mole) quantity of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate was poured into 100 ml of a dichloromethane solution containing 19.45 g (0.1 mole) of N-(2-methoxyethyl)-N-cyanoethylaminosulfenyl-chloride. The mixture was agitated by a stirrer and 18 g (0.18 mole) of triethylamine was added dropwise thereto at less than 10° C. over a period of 30 minutes. Thereafter the mixture was stirred at the same temperature for 2 hours. A 5% aqueous solution of sulfuric acid was added to the mixture until a pH of 6 was achieved. The dichloromethane solution was washed with a 5% aqueous solution of sodium hydrogencarbonate and with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated at reduced pressure, giving 31.8 g of a yellowish brown oily product in a yield of 84.0%.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][C@H:9]([O:13][CH2:14][C:15]#[CH:16])[CH2:8][O:7]2)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:21]=[CH:22][C:23]=1I.CCN(CC)CC>[Cu]I.CN(C=O)C>[F:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:21]=[CH:22][C:23]=1[C:16]#[C:15][CH2:14][O:13][C@@H:9]1[CH2:8][O:7][C:6]2=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]2[CH2:10]1
Reactant: C#CCO[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(C#CCO[C@@H]3COc4nc([N+](=O)[O-])cn4C3)c(F)c2)C(=O)O1
Yield: 37.3 %

Procedure:
To an oven dried round bottom flask was charged 2-Nitro-6(S)-prop-2-ynyloxy-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (75 mg, 0.34 mmol), N-[3-(3-Fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5(S)-ylmethyl]-acetamide (127 mg, 0.34 mmol), PhCl2(PPh3)2 (23 mg, 0.02 mmol) and CuI (3.2 mg, 0.017 mmol). The flask was flushed with nitrogen before degassed DMF (4 mL) and Et3N (0.15 mL, 1.05 mmol) were added. The resultant mixture was stirred at 80° C. for one hour before it was cooled down and partitioned into 50 mL EtOAc/50 mL water. The organic layer was washed with brine and dried over Na2SO4. Column chromatography (CH2Cl2/MeOH, v/v, 20:1 to 10:1) of the concentrated residue gave the titled compound (60 mg) as yellow solid. ESI MS m/z 474 (M+H). 1H NMR (400 MHz, MeCN-d3) 7.73 (s, 1H), 7.65 (dd, J=12.4, 2.4 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 7.39 (dd, J=8.8, 2.4 Hz, 1H), 6.84 (b, 1H), 4.20-4.99 (m, 1H), 4.76 (dt, J=12.4, 2.8 Hz, 1H), 4.67 (s, 2H), 4.53 (d, J=12.8 Hz, 1H), 4.45-4.51 (m, 1H), 4.26-4.42 (m, 2H), 4.17 (t, J=9.2 Hz, 1H), 3.85 (dd, J=9.6, 5.2 Hz, 1H), 3.56-3.68 (m, 2H), 1.98 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)=[O:4].[OH-].[NH4+:17]>C(OCC)C>[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:17])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(C)C(=O)c1ccc(C(N)=O)cc1

Procedure:
3.1 grams (14 mmoles) of 4-(2,2-dimethyl-1-oxopropyl) benzoyl chloride is dissolved in 15 milliliters of diethylether, and the resulting solution is added dropwise to concentrated ammonium hydroxide with vigorous stirring at 0°-10° C. The white crystalline precipitate which forms is filtered off and washed with water and with ether. The product is dried in vacuo to yield 4-(2,2-dimethyl-1-oxopropyl)-benzamide (m.p. 138°-140° C.) .
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C1(O)C=CC=CC=1.Cl.Br[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[N:20]1[CH:21]=[CH:22][C:17]([NH:1][N:2]2[CH2:6][CH2:5][CH2:4][C:3]2=[O:7])=[CH:18][CH:19]=1
Reactant: Brc1ccncc1
Reactant: NN1CCCC1=O
Agent: Cl
Solvent: Oc1ccccc1
Product: O=C1CCCN1Nc1ccncc1
Temperature: 140 °C
Yield: 16 %

Procedure:
A slurry consisting of 1-amino-2-pyrrolidinone (7.40 g), phenol (17.8 g), and 4-bromopyridine hydrochloride (15.8 g) was heated in a 140° C. oil bath for 70 minutes under nitrogen. The resulting solution was cooled to room temperature and purified via flash column chromatography (silica gel, 2% Et3N/0-50% MeOH/EtOAc) and preparative high performance liquid chromatography (HPLC) (silica gel, 10% MeOH/DCM). The resulting product fractions were concentrated and the product was redissolved in dichloromethane and sat. aqueous sodium bicarbonate. Exhaustive extraction of the aqueous layer afforded the pure product (free of triethyl amine salts). Recrystallization from dichloromethane/ether afforded 2.10 g (16%) of 1-(4-pyridinylamino)-2-pyrrolidinone, m.p. 177°-179.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:11][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCC(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
A mixture of 3,4-dimethoxyphenol (10 g), ethyl 4-bromo-butyrate (15.2 g), anhydrous potassium carbonate (11.7 g), potassium iodide (1.5 g) and N,N-dimethylformamide (40 ml) is stirred for 15 hours at 60° to 70° C. The reaction mixture is poured into ice-water and extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is dissolved in methanol (30 ml), to the solution is added a 2.5N aqueous solution of sodium hydroxide (67 ml), and the mixture is stirred for 40 mintues at 50° to 60° C. The reaction mixture is concentrated under reduced pressure. To the concentrate is added water, and the mixture is acidified (pH 3) with dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate - hexane to give 4-(3,4-dimethoxyphenyloxy)butyric acid as colorless prisms (12.5 g). To polyphosphoric acid (60 g) is added 4-(3,4-dimethoxyphenyloxy)butyric acid (6.0 g) obtained above, and the mixture is stirred for 30 minutes at 100° C. The reaction mixture is poured into ice-water and extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated. The residue is recrystallized from ethyl acetate - hexane to give 7,8-dimethoxy-3,4-dihydro-1benzoxepin-5(2H)-one as colorless prisms, m.p. 87°-88° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[CH:32]1([C:35]2[NH:36][CH:37]=[CH:38][N:39]=2)[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[N:36]([C:2]3[CH:3]=[CH:4][C:5]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:6]([C:8]([N:10]4[CH2:15][CH2:14][N:13]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)[CH2:12][CH2:11]4)=[O:9])[CH:7]=3)[CH:37]=[CH:38][N:39]=2)[CH2:34][CH2:33]1
Reactant: O=C(c1cc(Br)ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: c1c[nH]c(C2CC2)n1
Product: O=C(c1cc(-n2ccnc2C2CC2)ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Yield: 16 %

Procedure:
The title compound was prepared according to the procedure described for example 199 from (5-Bromo-2-morpholin-4-yl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CR) and 2-Cyclopropyl-1H-imidazole (CAS: 89532-38-7) (16% yield, white solid, MS (m/e): 526.3 (M+H, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[C:9](Br)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1Br.[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[C:9]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:18]1[S:17][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccsc1
Reactant: COc1c(Br)ccc2c(OC)c(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1c(-c2cccs2)ccc2c(OC)c(-c3cccs3)ccc12
Yield: 95 %

Procedure:
1,5-Dimethoxy-2,6-dibromonaphthalene (1.00 g., 0.0029 mol.) and 2-tributylstannyl)thiophene (4.314 g., 0.0116 mol.) were dissolved in 100 mL dry toluene in argon atmosphere. Pd(PPh3)4 (100 mg.) was introduced into the reaction flask using a Schlénk tube under argon. The resultant mixture was subsequently refluxed for 18 hrs. The brownish black solution was cooled and poured into 300 mL of petroleum ether to afford crude yellow solid. Upon recrystallization from CH2Cl2:petroleum ether (1:5), the desired product was obtained as a light yellow solid. Yield: 95%. M.p. 225-228° C. Anal. Calcd. for C20H16O2S2: C, 68.15%; H, 4.58%; S, 18.19%. Found: C, 67.98%; H, 4.53%; S, 18.03%. Mass spectrum: 351.84 (M+). 1H-NMR (CDCl3; in ppm): 3.88 (s, 3H), 7.16 (dd, 2H), 7.43 (dd, 2H), 7.63 (dd, 2H), 7.83 (d, 2H, 9 Hz), 796 (d, 2H, 9 Hz). 13C-NMR (CDCl3; in ppm): 61.3, 119.0, 123.2, 125.7, 126.5, 126.6, 126.9, 129.2, 138.9, 152.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:19])/[C:16]([OH:18])=[O:17])=[CH:10][C:9]=2[C:20]([F:23])([F:22])[F:21])=[CH:3][CH:2]=1.S[C:25]1C=CN=C[CH:26]=1>>[N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:19])/[C:16]([O:18][CH2:25][CH3:26])=[O:17])=[CH:10][C:9]=2[C:20]([F:21])([F:23])[F:22])=[CH:3][CH:2]=1
Reactant: C/C(=C\c1ccc(Sc2ccncc2)c(C(F)(F)F)c1)C(=O)O
Reactant: Sc1ccncc1
Product: CCOC(=O)/C(C)=C/c1ccc(Sc2ccncc2)c(C(F)(F)F)c1

Procedure:
E-3-[4-(4-Pyridylthio)-3-(trifluoromethyl)phenyl]-2-methyl-propenoic acid guanidide dihydrochloride ##STR9## 4 a) The ester from 3 a was reacted with 4-mercaptopyridine analogously to 3 b. Ethyl E-3-[4-(4-pyridylthio)-3-(trifluoromethyl)phenyl]-2-methyl-propenoate was isolated.
Reaction SMILES: C(O)CCC.Cl[C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][N:8]=1.O.[NH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>O>[NH:16]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][N:8]=1)[NH2:17]
Reactant: COc1cccnc1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: COc1cccnc1NN

Procedure:
To 50 ml of a butanol solution of 9.376 g of 2-chloro-3-methoxypyridine were added 16 ml of hydrazine monohydrate and 9.03 g of anhydrous potassium carbonate, and the mixture was heated under reflux for 20 hours. After cooling, the reaction mixture was poured into 200 ml of water and extracted with a mixed solvent of methanol-chloroform (1:9 by volume). The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation. The residue was subjected to silica gel column chromatography using a mixture of chloroform-methanol (20:1 by volume) as an eluate. The fraction containing the desired compound was concentrated to afford 5.952 g of the title compound.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23].C([O-])(=O)C.[NH4+:28]>C(O)C>[NH2:28][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CN)C1C
Temperature: 40 °C

Procedure:
A reaction mixture comprising 58.5 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester and 58.5 g. of ammonium acetate in 730 ml. of ethanol is heated to reflux for 10 min. The mixture is cooled to 40° C. and concentrated to a yellow solid. Th residue is taken up in 800 ml. of chloroform which is subsequently washed successively with water (1 × 450 ml.), 1N aqueous sodium hydroxide (2 × 450 ml.) and a brine solution (1 × 450 ml.). The chloroform layer is separated, dried over magnesium sulfate and concentrated to a yellow solid, 87.0 g., m.p. 86°-150° C. The crude product is further purified by recrystallization from ethyl acetate-hexane, 43.3 g., m.p. 160°-161° C.