Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12]([NH2:14])=O)=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21].O.[OH-].[NH4+]>C(#N)C>[CH3:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12]#[N:14])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21]
Reactant: Cc1c([N+](=O)[O-])cc(C(N)=O)cc1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1c([N+](=O)[O-])cc(C#N)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 75.3 %

Procedure:
Phosphorus pentachloride (1.082 g) is added over about 30 minutes into a mixture of 4-methyl-3,5-dinitrobenzamide (6) (1.04 g) in acetonitrile (20 mL, 15 g). The mixture is then heated to about 60° C. for about 4 hours. The solution is then cooled to ambient temperature and is slowly added to an ice and water mixture (20 mL). The mixture is cooled to about 5° C., whereupon ammonium hydroxide is added until a pH of about 8 is attained. The product that precipitates is filtered, washed with water (10 mL), and dried to provide 4-methyl-3,5-dinitrobenzonitrile (4) (0.72 g, 75% Yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[N:11][N:12]2[CH:17]([CH2:18]OS(C)(=O)=O)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[N:11][N:12]2[C:17]([CH3:18])=[CH:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2COS(C)(=O)=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)c1nn2c(C)cn(C)c(=O)c2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-benzyloxy-5-methyl-7-methylsulfonyloxymethyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (57 mg, 0.14 mmol) in anhydrous DMF under an atmosphere of nitrogen was added piperidine (133 μL, 1.35 mmol). The reaction was stirred at room temperature for 2 hours, heated to 50° C. for 2 hours, and stirred at room temperature overnight. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. ES MS (M+H)=328.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[C:7](OC)=[O:8].[BH4-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: COC(=O)c1cc(Cl)sc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCc1cc(Cl)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a 0° C. solution of methyl 2,5-dichlorothiophene-3-carboxylate (1.5 g, 7.1 mmol) in anhydrous methanol (50 mL) was added sodium borohydride (1.35 g, 35.7 mmol). The reaction mixture was stirred at room temperature overnight. After cooling to 0° C., a saturated ammonium chloride solution (50 mL) was added. The resultant mixture was extracted with DCM (3×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The product was purified by flash chromatography (0-15% EtOAc/hexanes), affording (2,5-dichlorothiophen-3-yl)methanol (286 mg, 22% yield).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]([N:36]([C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[CH3:37])=[O:35])[CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][C:34]([N:36]([C:38]2[CH:44]=[CH:43][C:41]([NH:42]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:40][CH:39]=2)[CH3:37])=[O:35])[CH2:31][CH2:32]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C(=O)CN1CCOCC1)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C(=O)CN1CCOCC1)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(N-morpholinomethylcarbonyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4]COC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.ClCCN(C)C>C(Cl)Cl.CO>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[CH:38][CH:39]=1
Reactant: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Agent: CN(C)CCCl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCOc1ccc(Nc2ncc(-c3ccsc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using 1-chloro-2-dimethylaminoethane hydrochloride. Title compound: ES-MS: 346.0 [M+H]+; single peak at tR=5.89 min (System 1); Rf=0.34 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=1)[C:13]([O:15][CH3:16])=[O:14]>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:11][CH:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:18][NH:19]1
Reactant: COC(=O)c1ccnc(-c2cc(F)c(F)cc2F)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(c2cc(F)c(F)cc2F)C1
Reaction time: 6 h
Yield: 94.9 %

Procedure:
Methyl 2-(2,4,5-trifluorophenyl)isonicotinate (2.509 g, 9.39 mmol) was dissolved in acetic acid (25 mL) and platinum(IV) oxide (0.107 g, 0.47 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 6 h. The catalyst was filtered off, washed with MeOH and the eluate evaporated. DCM and 10% K2CO3 were added and the phases separated. The organic layer was washed with brine, passed through a phase separator and evaporated to yield methyl 2-(2,4,5-trifluorophenyl)piperidine-4-carboxylate (2.434 g, 95%) as a brown oil. MS m/z 274 (M+H)+
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]1([CH2:11][CH2:12][CH:13]=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1>[C:5]1([CH2:11][CH2:12][CH:13]([OH:14])[CH:1]=[CH2:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CCCc1ccccc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To vinyl magnesium bromide (550 ml of a 1.0M solution) was added 3-phenylpropionaldehyde (36.68 g, 0.273 mol) in tetrahydrofuran (300 ml) under argon at 0°. This mixture was stirred for one hour at room temperature, quenched with aqueous ammonium chloride and ice, and extracted into ethyl ether. The organic portion was washed with 5% sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the desired alcohol which was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[C:12]([C:15]([OH:17])=[O:16])#[C:13]C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]1[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[N:7]=[N:6]1
Reactant: CC#CC(=O)O
Reactant: [N-]=[N+]=NCc1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(O)c1cn(Cc2ccccc2Cl)nn1
Temperature: 25 °C

Procedure:
A solution of 16.75 g (100 mmol) of o-chlorobenzyl azide, 7.35 g (100 mmol) of propynecarboxylic acid and 200 ml of toluene is stirred for 24 hours at 50°. After being cooled to room temperature, the precipitated product is filtered off with suction and washed first with toluene and then with diethyl ether. In this manner there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid having a melting point of 175° (with decomposition). After concentration of the filtrates by evaporation and washing the residue with a little toluene, 1-(o-chlorobenzyl)-1H-1,2,3-triazole-5-carboxylic acid having a melting point of 120° (with decomposition) remains.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19](Cl)=[O:20])=[CH:11]1>>[N:1]1([CH2:7][CH2:8][NH:9][C:19]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCCC1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Product: O=C(NCCN1CCCCC1)c1c[nH]c2ccccc12

Procedure:
1-Piperidineethylamine was reacted with 1H-indole-3-carboxylic acid chloride using the method described in Description 1 to afford the title compound (D2) as a beige solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][CH:9]=1)(=O)C.S(=O)(=O)(O)O>CO>[CH3:1][O:4][C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][S:8][CH:9]=1
Reactant: COC(=O)c1cscc1OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cscc1OC

Procedure:
Methyl 4-acetoxy-3-thiophenecarboxylate (81 g, 0.40 mol) and concentrated sulphuric acid (5 ml) in methanol (1.25 l) was heated under reflux for 3 days. The solvent was evaporated and the residue diluted with water (300 ml) and extracted with ether (5 times). The ether extracts were combined, washed with 1N sodium hydroxide (3 times) and dried over sodium sulfate. Evaporation of the solvent gave the title compound, 52 g, m.p. 66°-68° (lit. m.p.68°-70°).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][OH:20])[CH:14]=1)=[O:11]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cccc(CO)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1Br)Nc1cccc(CO)c1
Reaction time: 2 h

Procedure:
To a stirring solution of 2-(2-bromophenyl)acetic acid in dichloromethane (0.2 M) was added (3-aminophenyl) methan-1-ol (1.2 eq), triethylamine (1.5 eq), and EDAC (1.5 eq). After 2 hrs, the solution was washed with water, 10% HCl, 10% sodium carbonate, and water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a colorless solid. EI-MS m/z 320/322 (M+H)+
Reaction SMILES: [N:1]1([C:16]([O:18][CH2:19][CH:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:5][CH2:4][CH:3]2[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH:2]12.[ClH:33]>CO>[ClH:33].[N:1]1([C:16]([O:18][CH2:19][CH:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:5][CH2:4][CH:3]2[CH2:6][NH:7][CH2:8][CH:2]12
Reactant: CC(C)(C)OC(=O)N1CC2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)C2C1
Agent: Cl
Solvent: CO
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC2CNCC21

Procedure:
1-(9H-fluoren-9-yl)methyl 5-tert-butyl hexahydropyrrolo[3,4-b]pyrrole-1,5-dicarboxylate (810 mg, 1.86 mmol) was treated with HCl in MeOH (5 mL) for 2 hours and then concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][S:7][C:8]1[C:16]2[C:12](=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:14][C:15]=2[S:17][CH3:18])[CH2:11][CH2:10][C:9]=1[CH:24]=O)=[O:5])[CH3:2]>C(OC(=O)C)(=O)C>[CH3:18][S:17][C:15]1[S:14][C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]2[CH2:11][CH2:10][C:9]3[CH:24]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=3[C:16]=12
Reactant: CCOC(=O)CSC1=C(C=O)CCc2c(C(=O)OCC)sc(SC)c21
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(s1)-c1c(SC)sc(C(=O)OCC)c1CC2
Yield: 52.4 %

Procedure:
Ethyl 4-ethoxycarbonylmethylthio-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (0.30 g) was dissolved in acetic anhydride (10 ml) and refluxed under heating for 11 hours, after which it was concentrated under reduced pressure. The residue was poured over water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:7, v/v) to yield diethyl 4,5-dihydro-8-methylthiobenzo[2,1-c:3,4-b′]dithiophene-2,6-dicarboxylate (0.15 g, 52%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 107-108° C.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:15][CH2:14][C:13]([F:17])([CH3:16])[C:12]3[S:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:24]([C@:26]1([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32])#[CH:25]>>[F:17][C:13]1([CH3:16])[C:12]2[S:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:9][C:8]=2[C:6]2[CH:7]=[C:2]([C:25]#[C:24][C@:26]3([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]3=[O:32])[C:3]([F:23])=[CH:4][C:5]=2[O:15][CH2:14]1
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: CCOC(=O)c1nc2c(s1)C(C)(F)COc1cc(F)c(Br)cc1-2
Product: CCOC(=O)c1nc2c(s1)C(C)(F)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-hydroxy-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (170 mg) was reacted similarly to as described in General Procedure P with non-critical modifications to afford 130 mg (76%) of ethyl 9-bromo-4,8-difluoro-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate. Ethyl 9-bromo-4,8-difluoro-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (122 mg) was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford ethyl 4,8-difluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-methyl-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxylate which was directed subjected to General Procedure M to afford 7.2 mg and 6.9 mg (11% overall yield) after reverse phase purification then chiral separation. The absolute stereochemistry at the 4-fluorine substitution position for each isomer was not determined.
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]=2[CH2:6][CH2:5]1)=[O:3].[C:23]1([C@H:29]([OH:31])[CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:21]([O:20][C:18]([CH2:17][N:8]1[C:7]2[CH2:6][CH2:5][CH:4]([C:2]([O:31][C@@H:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:30])=[O:3])[CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CC(C(=O)Cl)CC2
Reactant: C[C@@H](O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cn1c2c(c3ccccc31)CC(C(=O)O[C@H](C)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
Crude ethyl (±)-(3-chlorocarbonyl-1,2,3,4-tetrahydro-carbazol-9-yl)-acetate (5 mmol) is dissolved in dry CH2Cl2 and treated with (R)-1-phenyl-ethanol (0.55 g, 5.4 mmol), DIEA (1.94 g, 15 mmol) and DMAP (61 mg, 0.5 mmol). The resulting yellow solution is stirred at rt overnight, diluted with EtOAc and successively washed with 0.1 N HCl, saturated aqueous NaHCO3, H2O and brine. The organic layer is dried over Na2SO4, filtered and evaporated. The residue is purified by column chromatography on silica gel (hexane/EtOAc 5:1) to provide the subtitle compound as yellow oil (1.36 g) in 76% yield.
Reaction SMILES: [CH2:1]1[S:25][C:4]2([CH2:8][CH2:7][C:6]([CH3:9])=[C:5]2[CH2:10][CH:11]([OH:24])[C:12]#[C:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[S:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].[OH-].[K+].[CH2:43](Cl)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.O>[CH2:2]1[S:3][C:4]2([CH2:8][CH2:7][C:6]([CH3:9])=[C:5]2[CH2:10][CH:11]([O:24][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)/[CH:12]=[CH:13]/[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[S:25][CH2:1]1
Reactant: COc1cccc(CCC#CC(O)CC2=C(C)CCC23SCCS3)c1
Reactant: ClCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CC/C=C/C(CC2=C(C)CCC23SCCS3)OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A solution of about 9.20 g (24.6 mmol) dl-3-methyl-2-[6-(m-methoxy-phenyl)-2-hydroxy-3-hexynyl]-2-cyclopentenone ethylene dithioketal in 53 ml tetrahydrofuran was added dropwise over a period of about 20 minutes to a suspension of 1.86 g (49 mmol) lithium aluminium hydride in about 80 ml tetrahydrofuran under a nitrogen atmosphere. The mixture was stirred in a water-bath at about 60° C. for about 4 hours. After cooling to about 0° C., the following consecutive dropwise additions were cautiously made to the suspension: 1.86 ml water, 1.86 ml 15% sodium hydroxide solution and 5.50 ml water. Sodium sulphate (5 g) was added and the whole was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue (7.35 g) was dissolved in about 100 ml tetrahydrofuran. The following consecutive additions were made to this solution under nitrogen: 20.0 g (370 mmol) powdered potassium hydroxide and 20.0 ml (214 mmol) benzyl chloride. The whole was then stirred for about 16 hours at room temperature. After filtering, the filtrate was evaporated to dryness under reduced pressure. The residue was filtered through about 100 g silica gel with hexane/acetone 9:1 by weight (500 ml) giving 8.70 g product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.O[C:21]1[CH:34]=CC=C(OC)[C:22]=1C(C1C=CC=CC=1)=O>>[CH:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)([CH3:34])[CH3:22]
Reactant: COc1cccc(O)c1C(=O)c1ccccc1
Reactant: O=[N+]([O-])c1oc2ccc(O)cc2c1-c1ccccc1
Product: CC(C)Oc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
Using the procedure described in Example 3 and starting with 5-hydroxy- 2-nitro-3 -phenylbenzofuran and isopropyl iodide one obtains 5-isopropoxy-2-nitro-3-phenylbenzofuran.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]=[C:8]1[C:14]2[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:18][C:13]=2[CH:12]=[CH:11][C:10]2[CH:24]=[CH:25][CH:26]=[CH:27][C:9]1=2>CCOCC>[O:7]=[C:8]1[C:14]2[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[CH2:20][OH:21])=[CH:18][C:13]=2[CH:12]=[CH:11][C:10]2[CH:24]=[CH:25][CH:26]=[CH:27][C:9]1=2
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(CO)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 2 h

Procedure:
0.5 G. of lithium aluminum hydride is added to a solution of 2.78 g. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2 -yl)propionic acid in 200 ml. of anhydrous ether. The mixture is stirred for 2 hours and then excess hydride is destroyed by sequential addition of ethyl acetate, methanol and water. The ethereal solution is separated and filtered and to it is added 15 g. of activated manganese dioxide. The mixture is stirred for 8 hours, then filtered through 10 g. of silica gel and the elute evaporated to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propan-1-ol (m.p. 63°-66°C).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13]C)=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2]>CO.[OH-].[Na+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cccc(CC(=O)O)c1
Yield: 103.4 %

Procedure:
A solution of methyl 3-etho xyphenylacetate (92.6 g, 0.4 mole) in methanol (600 ml ) and 6.25 N NaOH (400 ml ) was stirred overnight at room temperature and then filtered and concentrated in vacuo to remove the methanol. The solution was ad justed to pH 1 with concentrated HCl, the resulting precipitate filtered, washed with ice water, and dried under high vacuum to give 3-ethoxyphenyl acetic acid (74.5 g). M.p=89-90° C. 1H NMR (DMSO-d6, 200 MHz) δ: 1.30 (6, J=7 Hz, 3H, CH3), 3.50 (s, 2H, ArCH 2), 3.98 (q, J=7 Hz, 2H, ethyl CH2), 6.75-6.80 (m, 3H, Ar), 7.14-7.23 (m, 1H, Ar). (Lit. ref.: J. Med.Chem, 1980, 23(4) 437-444.
Reaction SMILES: C(OC([N:11]([CH2:24][CH:25]([OH:50])[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33](=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:28][CH:27]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=O)C1C=CC=CC=1>CO.[H][H].[C].[Pd]>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[CH2:13][CH2:12][NH:11][CH2:24][CH:25]([OH:50])[C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33](=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:28][CH:27]=1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCC(=O)Oc1ccc(C(O)CN(CCc2ccc(OC)c(OC)c2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)Oc1ccc(C(O)CNCCc2ccc(OC)c(OC)c2)cc1
Yield: 111.7 %

Procedure:
2.0 g of N-benzyloxycarbonyl-α-(3,4-dimethoxyphenethylaminomethyl)-4-palmitoyloxybenzylalcohol were dissolved in 40 ml of methanol, and 0.4 g of 10% palladium-carbon was added thereto. The mixture was shaken at room temperature in hydrogen atmosphere for one hour under atmospheric pressure. The reaction mixture was filtered to remove the catalyst, and the filtrate was evaporated to remove solvent. The residue thus obtained was recrystallized from methanol. 1.8 g of α-(3,4-dimethoxyphenethylaminomethyl)-4-palmitoyloxybenzylalcohol were obtained as colorless needles.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2].[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:34][CH2:33][C:23]2[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[S:26][C:22]=2[CH3:21])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OCC)OCC
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)cc1OCC)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol [PCT Int. Appl. (2002), WO 02/18355 A1] in tetrahydrofuran in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 e], to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless oil.