Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>CO>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([O-:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([O-:35])=[O:34]
Reactant: O=C(O)/C=C/C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 30 °C

Procedure:
Sunitinib (1.0g) was suspended in methanol (152 mL), followed by addition of fumaric acid (0.29 g) at 25-35° C. over a period of 15 minutes. After the stipulated time period, methanol was completely distilled off under vacuum below 45° C. The residue was treated with acetonitrile (38 mL) and refluxed. The reaction mass was maintained at reflux temperature for 60 minutes. The reaction mass was cooled to 25-35° C. for crystallization. The solid obtained was filtered, washed with acetonitrile, suck dried and dried under vacuum at 60° C. over 4-5 hr period to obtain sunitinib fumarate.(1.2 g; yield: 93%)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>ClCCl>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 1-(bromomethyl)-4-nitro-benzene (250 mg, 1.157 mmol) in dichloromethane (5 mL) was treated with triethylamine (200 μL, 1.39 mmol) and morpholine (110 μL, 1.27 mmol) then stirred at room temperature for 1.5 hrs. The solution was diluted with dichloromethane (20 mL) then washed with water (2×20 mL). The organic extract was dried (MgSO4), filtered and concentrated to give (i) which was used in subsequent reactions without further purification. 1H NMR (400 MHz, CDCl3) δ 8.21-8.16 (m, 2H), 7.56-7.50 (m, 2H), 3.76-3.69 (m, 4H), 3.59 (s, 2H), 2.49-2.42 (m, 4H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].CO>CC(C)=O>[C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
The free base (0.32 g; 0.2914 mmol) was dissolved in acetone (10 mL) and treated with 0.1M L-tartaric acid in MeOH (2.9 mL; 0.29 mmol). This mixture was concentrated and treated with dry ether to give a tartaric acid salt of the title compound as a white solid; mp 178°-180° C.; IR (KBr) 3440, 3064, 3030, 2934, 2802, 1662, 1610, 1582, 1518, 1486, 1452, 1372 cm-1 ; MS (FAB) MH+ m/z 1099, (M+Na)+ m/z 1121, (M+K)+ m/z 1137; 1H-NMR (CDCl3) δ 1.119 (s, 3H), 1.217 (s, 3H), 1.518 (m, 7H), 1.667 (s, 3H), 1.873 (m, H), 1.957 (s, 3H), 2.111 (m, H), 2.215 (s, 3H), 2.316 (m, H), 2.432 (s, 3H), 2.597 (m, H), 2.875 (m, 2H), 3.684 (m, 2H), 3.816 (d, H), 4.196 (d, H), 4.370 (d, H), 4.440 (m, H), 4.975 (d, H), 5.665 (m, 2H), 6.030 (m, H), 6.252 (t, H), 6.284 (S, H), 7.096 (d, NH), 7.200-8.700 (m, 19H) .
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[S:13][C:14]4[CH2:15][N:16]([C:21](=[O:24])[CH2:22][CH3:23])[CH2:17][CH2:18][C:19]=4[N:20]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:25]([OH:34])(=[O:33])[C@@H:26]([C@H:28]([C:30]([OH:32])=[O:31])[OH:29])[OH:27]>CO>[C:30]([CH:28]([CH:26]([C:25]([OH:34])=[O:33])[OH:27])[OH:29])([OH:32])=[O:31].[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[S:13][C:14]4[CH2:15][N:16]([C:21](=[O:24])[CH2:22][CH3:23])[CH2:17][CH2:18][C:19]=4[N:20]=3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CCC(=O)N1CCc2nc(OC3CCN(C4CCC4)CC3)sc2C1
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O
Reaction time: 1 h

Procedure:
A solution of 1-[2-(1-Cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-propan-1-one (0.8 grams, 2.3 mmol, obtained in above step) in methanol (10 mL) was treated with L(+)-Tartaric acid (0.34 grams, 2.3 mmol) at 0° C. Stirred the reaction mass for about 1 hour and the solvent was evaporated under vacuum to dryness. The solids were washed with diethyl ether and dried under vacuum to obtain the title compound (1.1 grams).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:15]=1)[C:7](=[O:14])[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2.C(N(CC)CC)C.CC(Cl)(Cl)Cl.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:33][C:11]([C:8]2[C:7](=[O:14])[N:6]3[CH:15]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[O:13])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc2ncc(C(=O)O)c(=O)n2c1
Reactant: NC1CCCC1
Solvent: ClC(Cl)Cl
Solvent: CC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2ncc(C(=O)NC3CCCC3)c(=O)n2c1
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
A mixture containing 1.22 g (0.006 mol) of 7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 0.84 ml (0.006 mol) of triethylamine in 40 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 0.46 ml (0.006 mol) of methyl chloroform, ,ate in 3 ml of chloroform is dropped to the above mixture at -18° C. during 10 minutes. After stirring for 5 minutes, 0.56 g (0.0066 mol) of cyclopentylamine dissolved in 6 ml of chloroform is dropped to the above solution which is then stirred at -10° C. for 1 hour and allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 15 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 15 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 0.8 g (49.2%) of the named compound as white crystals after recrystallization from ethanol, m.p.: 162°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH:5](C(OCC)=O)[C:6]([O:8]CC)=[O:7].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>Cl>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(Cc1ccccc1Cl)C(=O)OCC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Cl
Product: O=C(O)CCc1ccccc1Cl
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
To a 50 liter flask was added diethyl o-chlorobenzylmalonate (6067 g, 21.31 mol), glacial acetic. acid (1090 mL), and concentrated hydrochloric acid (16,000 mL). The reaction was then heated at reflux for 21 hours and 13 minutes. Additional concentrated hydrochloric acid (1840 mL, 5520 mL total) was added at 3.5, 13.5, and 17 hours into the reflux. The reaction was cooled to 0°±2° C. and the resulting solid was collected by suction filtration and washed with water (4 L). The solid was suspended in water (8 L) and the slurry was stirred for five minutes. The solid was collected by suction filtration and washed with water (20 L). The filtrate was pH 2 and tested positive for chlorine. The solid was then washed seven times in the following manner; the solid was suspended in water (8 L) and stirred for approximately ten minutes. The solid was collected by suction filtration and washed with water (4 L). The filtrate was tested for chloride ion and the pH was recorded. The final filtrate was pH 4.5-5 and tested negative to the presence of chloride ion. A total of 100 liters of water was used to wash the solid. The solid was dried under vacuum at 35°±3° C. for 70 hours to give crude β-2-chlorophenylpropionic acid (3653 g, 93.4%) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH:5]=[CH:4][CH2:3]1.N1C=CN=C1.[Si:12](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O.O.C(OCC)(=O)C>[C:25]([Si:12]([O:1][CH:2]1[CH2:6][CH:5]=[CH:4][CH2:3]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CC=CC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CC=CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89679.5 %

Procedure:
To an ice-cooled solution of 4-hydroxycyclopentene (50.0 g, 0.594 mol) and imidazole (80.9 g, 1.19 mol) in N,N-dimethylformamide (300 mL) was slowly added tert-butyldiphenylsilyl chloride (180 g, 0.65 mmol). The reaction mixture was warmed to room temperature. After 16 h, the reaction mixture was diluted with water (1 L) and ethyl acetate (500 mL). The aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organics were washed sequentially with water (3×300 mL) and saturated aqueous sodium chloride solution (2×200 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (15:1 petroleum ether/ethyl acetate) provided tert-butyl(cyclopent-3-en-1-yloxy)diphenylsilane (188 g, 98%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.69-7.66 (m, 4H), 7.43-7.38 (m, 6H), 5.63-5.60 (m, 2H), 4.58-4.53 (m, 1H), 2.46-2.38 (m, 4H), 1.61 (s, 9H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH:2]=[CH2:3].I[CH2:22]I>CCOCC>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][O:4][CH2:1][CH:2]2[CH2:22][CH2:3]2)=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ICI
Reactant: C=CCOCCc1ccc(OCc2ccccc2)cc1
Solvent: CCOCC
Product: c1ccc(COc2ccc(CCOCC3CC3)cc2)cc1

Procedure:
To a suspension of Zn/Cu couple (3.24 g) and dry ether (20 ml) was added to the compound of formula (7), (2 g, 0.0075 mol) in ether (10 ml) followed by the addition of diiodomethane (4.2 ml, 0.052 mol). The reaction mixture was refluxed under nitrogen atmosphere for 72 h (monitored by TLC) and filtered. The filtrate was washed with water, dried, concentrated and the residue purified by column chromatography on silica gel, eluting with light petroleum ether:ethyl acetate(2:50) to afford pure product of formula (8), as an oil 1.8 g (85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([OH:16])(=[O:15])[C:9]([CH2:11][C:12](O)=[O:13])=[CH2:10]>Cl>[O:13]=[C:12]1[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH:9]([C:8]([OH:16])=[O:15])[CH2:11]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccccc1
Agent: Cl
Product: O=C(O)C1CC(=O)N(c2ccccc2)C1
Temperature: 0 °C

Procedure:
In accordance with the method of “Journal of the American Chemical Society”, vol. 72, 1950, p. 1415, aniline was added to an itaconic acid aqueous solution and heated under reflux for 12Hours. After completion of the reaction, this was ice-cooled and mixed with 70 ml of 1 M hydrochloric acid, and the thus precipitated crystals were collected by filtration to obtain 5-oxo-1-phenylpyrrolidine-3-carboxylic acid. EP: 206.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[N:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>C1COCC1.CCOC(C)=O>[Cl:4][C:5]1[N:10]=[CH:9][C:8]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 92.7 %

Procedure:
To a mixture of 4.7 mL (9.43 mmol) of dimethylamine (2N in THF) and 2.6 mL (18.86 mmol) of TEA in 20 mL of THF is added dropwise, at 0° C., a solution of 2 g (9.43 mmol) of 6-chloropyridine-3-sulfonyl chloride (prepared according to patent WO 9840332) in 5 mL of THF. After stirring for 40 minutes at 0° C., the reaction medium is taken up in 40 mL of EtOAc, washed with water (2×40 mL) and brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. 1.93 g of 6-chloro-N,N-dimethylpyridine-3-sulfonamide are obtained in the form of a brown solid, which is used without further purification in the following step.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=[C:6]([O:18][CH:19]([CH3:21])[CH3:20])[CH:5]=1.CCO.O.[OH-].[Na+]>C1COCC1>[CH:19]([O:18][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=1)[C:3]([OH:22])=[O:2])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(OCCc2ccsc2)cc(OC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid methyl ester (5.24 g, 16.4 mmol) in THF (120 mL) was added EtOH (80 mL) and water (40 mL) at rt. Sodium hydroxide solution (1.0 M, 49.1 mL) was added slowly with some external cooling if needed. The mixture was stirred at rt overnight. On the second day organic solvents were removed by evaporation. The residue was partitioned between ether and water. After the ether layer was discarded, the aqueous layer was acidified with HCl (6.0 M, ˜8.2 mL) to pH<1, and extracted with EtOAc (3×). Combined EtOAc layers were washed with brine (1×), dried with anhydrous MgSO4, filtered, and concentrated to give 3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid (4.54 g, 90%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.29 (dd, J=5, 3 Hz, 1H), 7.22-7.24 (m, 2H), 7.09-7.10 (m, 1H), 7.04 (dd, J=5, 1 Hz, 1H), 6.69 (m, 1H), 4.59 (m, 1H), 4.21 (t, J=7 Hz, 2H), 3.14 (t, 0.1=7 Hz, 2H), 1.35 (d, J=6 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].CCCCCC.N>S(=O)(=O)(O)O.C(OCC)(=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[CH:5]=[N:4][CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1cncc2ccccc12
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1cccc2cncc(Br)c12
Yield: 48.5 %

Procedure:
With vigorous stirring, concentrated sulfuric acid (36 ml) was added with 4-bromoisoquinoline (10.0 g, Tokyo Kasei Kogyo) to such an extent that the temperature should not exceed 10° C. and stirred for a while to attain complete dissolution. Potassium nitrate (4.9 g, Kanto Chemicals) was dissolved in concentrated sulfuric acid (20 ml), added dropwise to the aforementioned solution at a temperature below −5° C. and further stirred for 2 hours while maintaining that temperature. Disappearance of 4-bromoisoquinoline was confirmed by thin layer chromatography (n-hexane:ethyl acetate=1:1), and then the reaction mixture was slowly poured into cold aqueous ammonia (200 ml, Wako Pure Chemical Industries) with vigorous stirring. The reaction mixture was stirred for 15 minutes and then extracted three times with ethyl acetate (150 ml for each time), and the combined organic layer was washed successively with water (250 ml) and saturated brine (250 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized with ethyl acetate to obtain the title compound (5.9 g) as thick yellow needle-like crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][NH2:12]>CO.O>[NH:11]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNc1ccc([N+](=O)[O-])cn1
Temperature: 10 °C

Procedure:
To a slurry of 47.6 g (0.3 mol) of 2-chloro-5-nitropyridine in a mixture of 400 ml methanol and 60 ml water and cooled to 10° C. was added with cooling below 30° 86 g hydrazine (95 percent) over about 10 minutes. The solids first went into solution, then a greenish-yellow precipitate separated. The mixture was stirred at reflux for 30 minutes. The greenish solid was filtered off and washed with cold methanol. The solid was slurried in 200 ml of cold water, washed and vacuum dried. The yield was 40.1 g (87 percent).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2cc(C)oc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2ccc(O)cc2o1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54.2 %

Procedure:
To a stirred solution of 6-Methoxy-2-methyl-benzofuran 125-A (1.76 g, 10.85mmol) in 45 ml of CH2Cl2 at −5° C. was added BBr3 (24 ml of 1M BBr3 in CH2Cl2, 16 28 mmol). The reaction was allowed to warm to 0° C. and stirred at that temperature for 1.5 hr. The reaction was poured into a mixture of ice and saturated aqueous NaHCO3 and layers were separated. The aqueous layer was re-extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to a brown oil. The residue was chromatographed on silica gel eluting CH2Cl2 to give 872 mg (54%) of 6-Hydroxy-2-methyl-benzofuran 125-B.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:26])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C[O:28][C:29](=O)[O:30]C>C1COCC1>[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH2:26][C:29]([OH:30])=[O:28])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)OC
Reactant: Cc1cc(C(C)(C)C)ccc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)c1ccc(C(=O)O)c(CC(=O)O)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a magnetically stirred solution of diisopropyl amine (0.75 g, 7.4 mmol) in THF (5 mL) at −30° C. is added BuLi (3.4 mL, 2.5 M in hexanes, 8.5 mmol). The mixture is stirred for 10 minutes at this temperature and cooled to −78° C. A solution of 4-tert-Butyl-2-methyl-benzoic acid [J. Am. Chem. Soc. 1944, 66, 154] (250 mg, 1.3 mmol) and dimethylcarbonate (150 mg, 1.67 mmol) in THF (3 mL) is added dropwise at −78° C. The mixture is allowed to stir at this temperature for 2 hours before it is allowed to warm to room temperature. The mixture is quenched with MeOH and water once it reached room temperature. After removal of THF, the water layer is extracted with ether. The water layer is acidified with HCl and the product is extracted from ether. After chromatography, the title compound is isolated pure (125 mg, 41%). MS (ESI): 237.1 (M+1)+1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>C(O)C>[CH3:12][C:10]1[O:11][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13][C:8]=2[N:9]=1
Reactant: COC(=O)c1ccc2nc(C)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc(C(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a solution of 2-methyl-benzoxazole-6-carboxylic acid methyl ester (301 mg, 1.57 mmol) in ethanol (10 mL) was added an aqueous solution of 2N sodium hydroxide (10 mL), and the mixture was stirred for 2 hours at room temperature. 2N Hydrochloric acid was added to the reaction mixture to adjust the pH to 4, and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, then, evaporated in vacuo, and the title compound (270 mg, 1.52 mmol, 97%) was obtained. This was used in the next reaction without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]([NH2:10])=[O:9]>CN(C)C1C=CN=CC=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].CC(N(C)C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:8]([NH2:10])=[O:9]
Reactant: Clc1ccccn1
Reactant: NC=O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccccn1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.255 g of bis(tricyclohexylphosphine)-palladium(II) dichloride, 3.923 g of 2-chloropyridine, 3.12 g of formamide, 4.64 g of 4-dimethylamino-pyridine and 25 ml of dimethyl acetamide are placed in a 200 ml glass autoclave. The autoclave is closed, flushed with nitrogen three times and then 5 bars carbon monoxide are applied. The reaction mixture is heated to 120° C. and stirred for 18 hours. It is then cooled, and the suspension is mixed with ethyl acetate and water, and extracted. The aqueous phase is extracted by shaking 3 times with ethyl acetate, and afterwards the organic phases are collected, dried over magnesium sulphate and concentrated, The oil obtained is chromatographed over silica gel. The yield of title compound is 18% (part of the product remains in the water phase).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C)C=O>[CH2:12]([C:19]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.2 %

Procedure:
To a stirred solution of p-nitrobenzyl chloride (15 g) and diethyl benzylmalonate (22 g) in N,N-dimethylformamide (150 ml) was added NaH (60% in oil, 3.8 g). After stirring at room temperature for 2 days, the reaction mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate. The ethyl acetate layer was washed with aqueous citric acid solution, water, saturasted aqueous sodium hydrogen carbonate solution and brine, and dried (MgSO4). The organic solvent was evaporated off and the residual oil was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:6, v/v) gave diethyl benzyl-4-nitrobenzylmalonate (24 g, 71%) as crystals. Melting point: 70-71°C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=1)[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O.[Cu](I)I>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]#[N:11])=[CH:2]2)[CH:17]=1)[CH3:13]
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: N#Cc1c[nH]c2ccccc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cccc(-n2cc(C#N)c3ccccc32)c1
Temperature: 75 °C
Reaction time: 72 h
Yield: 66.5 %

Procedure:
To a solution of 1H-indole-3-carbonitrile (0.28 g) in dimethyl sulfoxide (3 mL) were added 3-iodobenzoic acid ethyl ester (0.61 g), cesium carbonate (0.65 g), copper iodide (0.038 g) and N,N-dimethyl grycine (0.041 g), this mixture was stirred at 75° C. for 3 days. To this reaction mixture was added ethyl acetate, the insoluble material was removed by filtration and this filtrate was concentrated under reduced pressure. To this residue was added water, the precipitated solid was collected by filtration, and washed with water and n-hexane, and dried under reduced pressure at 40° C. to give the title compound (0.38 g).
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[CH:10](=[O:13])[CH:11]=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([CH2:12][CH2:11][CH:10]=[O:13])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCCOP([O-])CC
Reactant: C=CC=O
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CCC=O
Yield: 82.9 %

Procedure:
149 g (1 mol) of butyl ethylphosphonite (produced as in Example 2) and 67 g (1.2 mol) of 2-propenal in 217 g of toluene are heated to about 100° C. While stirring, 124 g of a 10% strength solution of WakoV65 in toluene are metered in. The solvent is distilled off in vacuo to obtain 171 g (78% of theory) of butyl ethyl-(2-formylethyl)phosphinate.