Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([I:12])[CH:6]=1.C1(C)C=CC(S(O[CH2:23][CH2:24][Cl:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:25][CH2:24][CH2:23][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][C:7]=1[I:12]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: OCCCc1ccc(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCCc1ccc(OCCCl)c(I)c1
Temperature: 50 °C

Procedure:
A mixture of 4-(3-hydroxypropyl)-2-iodophenol (Step A) (2.94 g, 10.57 mmol), 2-chloroethyl p-toluenesulfonate (2.88 ml, 15.86 mmol), and potassium carbonate (3.65 g, 26.4 mmol) in DMF (11 ml) was heated at 50° C. under nitrogen overnight. EtOAc was added and the mixture was washed 2 times with water, followed by brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.62 (d, J=2.1 Hz, 1H); 7.18-7.13 (m, 1H); 6.85 (d, J=8.3 Hz, 1H); 4.24 (t, J=5.5 Hz, 2H); 3.86 (t, J=5.5 Hz, 2H); 3.54 (t, J=6.4 Hz, 2H); 2.59 (t, J=7.7 Hz, 2H); 1.77 (p, J=7.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[C:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:20])[CH3:19].FC1C=CC(C2C=C3C(=CC=2)N=CN=C3O)=CC=1>>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]3[CH:26]=[CH:27][C:22]([NH:21][C:18](=[O:20])[CH3:19])=[CH:23][CH:24]=3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(OCC2CC2)c2cc(Br)ccc2n1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: Oc1ncnc2ccc(-c3ccc(F)cc3)cc12
Product: CC(=O)Nc1ccc(-c2ccc3nc(N)nc(OCC4CC4)c3c2)cc1
Yield: 86 %

Procedure:
This compound, synthesized from 2-amino-6-bromo-4-(cyclopropyl-methoxy)-quinazoline and 4-acetamido-phenylboronic acid in 86% yield using the procedure described for the synthesis of 6-(4-fluorophenyl)-4-hydroxy-quinazoline, was characterized by its mass spectrum as follows: MS (m/z): 349 ([M+H]+, 100).
Reaction SMILES: C.CCCCCCC[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14](O)=[CH:15][CH:16]=1.[CH2:18]1OC1>>[CH3:18][C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:9]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: C1CO1
Agent: C
Product: C=C(C)c1ccccc1
Yield: 69 %

Procedure:
A pigment preparation consisting of 35% of carbon black (surface area, measured by the BET method, of 230 m2 /g), 5% of a reaction product of 1 mol of nonylphenol and 6 mols of ethylene oxide, 6% of a reaction product of 1 mol of nonylphenol and 10 mols of ethylene oxide and 54% of a copolymer obtained from 69% of α-methylstyrene and 31% of acrylonitrile is produced as follows:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]1([F:25])[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]1[NH2+:16][C@@H](C1C=CC=CC=1)C.[H][H]>[Pd].CO>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]1([F:25])[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]1[NH3+:16]
Reactant: [H][H]
Reactant: C[C@@H]([NH2+][C@@H]1[C@@H](O)CCCC1(F)F)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: [NH3+][C@@H]1[C@@H](O)CCCC1(F)F

Procedure:
(1R,6S)-2,2-difluoro-6-hydroxy-N-[(1R)-1-phenylethyl]cyclohexanaminium trifluoroacetate (74) in a solution of methanol (1.5 mL) was exposed to Pd/C (409 mg, 0.384 mmol) and hydrogen atmosphere (1 atm). The heterogeneous reaction mixture was filtered through a plug of celite and washed three times with 30 mL of methanol. The filtrate was concentrated under reduced pressure to yield (1R,6S)-2,2-difluoro-6-hydroxycyclohexanaminium trifluoroacetate (75) in quantitative yield. 1H NMR (500 MHz, CD3OD) δ 3.68 (s, 1H), 3.34 (t, J=16.6, 2H), 2.19 (s, 1H), 2.06 (s, 1H), 1.87 (d, J=56.3, 2H), 1.49 (s, 2H), 19F NMR (470 MHz, cd3od) δ −77.30 (s, 3F), −99.95 (d, J=242.9, 1F), −114.48-−116.71 (m, 1F).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[C:13](=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:27])[N:6]=1)[CH2:3][CH3:4].Cl[C:29]1[C:30]2[CH:37]=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:32]1[C:31]2[NH:35][CH:36]=[CH:37][C:30]=2[C:29]([NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:23])[F:24])[CH:16]=3)[C:13](=[O:26])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:27])[N:6]=2)[CH2:3][CH3:4])=[N:34][CH:33]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(CC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 38.3 %

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethyl)phenyl)quinazolin-4(3H)-one (38 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (18 mg, 0.12 mmol, 1.2 equiv) and diisopropylethylamine (35 μL, 0.20 mmol, 2.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 19 mg of the title compound (38% yield).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:29])[CH:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:25]3[S:24][C:23]([NH2:26])=[N:22][C:21]=3[C:20]([O:27][CH3:28])=[CH:19][CH:18]=2)[CH2:13]1>>[CH3:10][N:11]([CH3:29])[CH:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:25]3[S:24][C:23]([NH:26][C:7]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)=[O:8])=[N:22][C:21]=3[C:20]([O:27][CH3:28])=[CH:19][CH:18]=2)[CH2:13]1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: COc1ccc(N2CCC(N(C)C)C2)c2sc(N)nc12
Product: COc1ccc(N2CCC(N(C)C)C2)c2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
Using 5-methyl-thiophene-2-carbonyl chloride and 7-(3-dimethylamino-pyrrolidin-1-yl)-4-methoxy-benzothiazol-2-yl-amine the title compound was prepared using the general method of example 1 as yellow solid (90%), MS: m/e=417 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([NH:17][C:18]3[C:19]([O:24]C)=[N:20][CH:21]=[CH:22][CH:23]=3)[N:12]=2)[CH3:9])=[N:6][CH:7]=1>Br>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:12]=[C:13]([NH:17][C:18]3[C:19](=[O:24])[NH:20][CH:21]=[CH:22][CH:23]=3)[CH:14]=[N:15][CH:16]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncccc1Nc1cncc(N[C@@H](C)c2ccc(F)cn2)n1
Agent: Br
Product: C[C@H](Nc1cncc(Nc2ccc[nH]c2=O)n1)c1ccc(F)cn1
Temperature: 100 °C
Yield: 103.6 %

Procedure:
A suspension of N-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N′-(2-methoxypyridin-3-yl) pyrazine-2,6-diamine (Preparation 12b, 100 mg, 0.29 mmol) in 48% aqueous hydrogen bromide solution (1 mL) was stirred and heated at 100° C. for 3 hours. After cooling to ambient temperature, the solvent was evaporated under reduced pressure. The residue was treated with acetonitrile and the solid that formed was filtered and dried to give the hydrobromide salt of the title compound (98 mg, 68%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][C:4]([OH:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=[C:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>Cl(O)(=O)(=O)=O.CCOCC>[CH3:43][C:37](=[CH:36][C:32]1[O:31][C:35]([C:4](=[O:6])[CH2:3][CH:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:34][CH:33]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)C(C)=Cc1ccco1
Reactant: CC(C)CCCC(C)CCCC(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)C(C)=Cc1ccc(C(=O)CC(C)CCCC(C)CCCC(C)C)o1
Temperature: 0 °C

Procedure:
A mixture of 24.2 g (0.1 mole) of 3,7,11-trimethyldodecanoic acid and 21.0 g (0.1 mole) of trifluoroacetic anhydride is stirred at reflux for 1/2 hour. The mixture is cooled and 18.0 g (0.1 mole) of ethyl 3-(2-furanyl)-2-methylpropenoate is added. The mixture is cooled to about 0° C. and 5 drops of 70% perchloric acid is added. The mixture is stirred at 0° C. for 2 hours, then diluted with anhydrous ether and treated with saturated aqueous sodium carbonate solution until basic. The layers are separated and the ether layer washed with water, brine and evaporated to dryness. The residue is distilled at reduced pressure to give ethyl 2-methyl-3-[5-(1-oxo-3,-7,11-trimethyldodecyl)-2-furanyl]-2-propenoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](Cl)[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:18][CH3:17])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cl[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Solvent: CCO
Product: CN[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
Crude 4-[(2R)-2-(4-Bromophenyl)-2-chloroethyl]morpholine (34.5 g) was dissolved in 200 mL of EtOH at room temperature with magnetic stirring. The resulting solution was cooled to 0° C. and treated with MeNH2 (71 mL, 33 wt % in EtOH) under N2. The reaction flask was capped with a rubber septum and the reaction mixture maintained at room temperature for 48 h. The mixture was then concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated to yield the title compound as a yellow solid (32 g, 93%). MS (ES) m/e 300 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=O.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:3]=1[C:4]([Cl:24])=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14]
Reactant: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1cccc(Cl)c1C(Cl)=Nc1ccnc(Cl)c1F
Temperature: 25 °C
Yield: 87 %

Procedure:
A stirred solution of 2-chloro-N-(2-chloro-3-fluoropyridin-4-yl)-6-nitrobenzamide (4.27 g, 12.9 mmol) in thionyl chloride (60 mL) was heated at 85° C. for 2 days under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in petroleum ether (40-60° C.), to afford the title compound as a cream solid (3.90 g, 87% yield). 1H NMR (400 MHz, CDCl3): δ 8.27-8.20 (m, 2H), 7.88 (dd, J=1.1, 8.1 Hz, 1H), 7.66 (t, J=8.2 Hz, 1H), 6.95 (t, J=5.2 Hz, 1H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(Cl)Cl>CCOCC>[CH:7]1[C:11]2[C:11](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])Cl
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc2ccccc2c1
Yield: 69.7 %

Procedure:
To a one-neck 50 mL round-bottomed flask equipped with a septum pierced with a needle and a stir bar, was added pyridinium chlorochromate (2.31 g, 10.7 mmol) and DCM (20 mL) with stirring. Alcohol S10 (0.600 g, 5.35 mmol) was added all at once via syringe, and the reaction turned dark brown and thick. The reaction was stirred at rt for 3.5 h until complete by TLC, followed by addition of Et2O (25 mL) and silica gel (10 g). The suspension was stirred for 30 min, filtered through a pad of silica gel with Et2O washings, and then concentrated under reduced pressure to yield the aldehyde xx as a yellow oil (0.478 g, 81%). The crude product was carried on without further purification. Compound S11 was previously characterized.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](=[O:20])[N:30]2[CH2:31][CH2:32][N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29]2)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Reactant: c1ccc(N2CCNCC2)cc1
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCN(c2ccccc2)CC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with N-phenyl-piperazine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.
Reaction SMILES: [CH2:1]([Si:3]([CH2:19][CH3:20])([CH2:17][CH3:18])[O:4][C@H:5]([CH2:14][CH2:15][CH3:16])[C@@H:6]([CH3:13])[C@@H:7]1[O:12][C@:8]1([CH3:11])[CH2:9][OH:10])[CH3:2].C([Li])CCC.[I-].[I-].[Sm+2].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.O.CCOCC>[CH2:19]([Si:3]([CH2:1][CH3:2])([CH2:17][CH3:18])[O:4][C@H:5]([CH2:14][CH2:15][CH3:16])[C@@H:6]([CH3:13])[C@H:7]([OH:12])[C@H:8]([CH3:11])[CH:9]=[O:10])[CH3:20]
Reactant: CCC[C@@H](O[Si](CC)(CC)CC)[C@@H](C)[C@@H]1O[C@]1(C)CO
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC[C@@H](O[Si](CC)(CC)CC)[C@@H](C)[C@H](O)[C@H](C)C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(2R,3S,4S,5R)-5-(Triethylsilyloxy)-2,3-epoxy-2,4-dimethyl-1-octanol (21.0 mg, 69.4 μmol) in 300 μl of THF at 0° C. was deprotonated with 1.05 eq of n-butyllithium. After 15 min, 0.1M samarium diiodide (764 μmol, 1.1 eq) was added and the reaction was allowed to warm to 25° C. over night. Then 1 ml of 1/2 saturated Rochelle's salt was added, stirred an additional 1 h, and poured onto 5 ml of Et2O and 1 ml of H2O. The layers were separated, extracted with ether (3×5 ml), washed with 5% NaHCO3 (2×1 ml), brine (1×1 ml), dried over MgSO4 and concentrated to give 31 crude.
Reaction SMILES: [I-].[Na+].C[Si](Cl)(C)C.[NH2:8][C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=1.C(N(CC)CC)C.[Cl:22][C:23]1[N:28]=[C:27]([O:29][CH3:30])[N:26]2[N:31]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:33]=[C:25]2[CH:24]=1>C(#N)C.CS(C)=O>[CH3:14][N:11]1[CH:12]=[CH:13][C:9]([NH:8][S:34]([C:32]2[N:33]=[C:25]3[N:26]([C:27]([O:29][CH3:30])=[N:28][C:23]([Cl:22])=[CH:24]3)[N:31]=2)(=[O:35])=[O:36])=[N:10]1
Reactant: COc1nc(Cl)cc2nc(S(=O)(=O)Cl)nn12
Reactant: Cn1ccc(N)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1nc(Cl)cc2nc(S(=O)(=O)Nc3ccn(C)n3)nn12

Procedure:
Sodium iodide (3.6 g, 24 mmol) and trimethylsilyl chloride 92.6 g, 24 mmol) were added to a solution of 3-amino-1-methylpyrazole (2.3 g, 24 mmol) and triethylamine (2.5 g, 25 mmol) in 20 mL of acetonitrile at ambient temperature with stirring and under dry nitrogen. The mixture was allowed to react until the 3-amino-1-methylpyrazole was essentially all consumed as determined by gas-liquid chromatography. The solvent was then removed by evaporation under reduced pressure and the residue was taken up in diethyl ether. The resulting mixture was filtered to remove solids and the ether was removed by evaporation under reduced pressure. The residue was dissolved in 10 mL of acetonitrile and the resulting solution was combined with 7-chloro-5-methoxy-1,2,4-triazolo[1,5-c]-pyrimidine-2-sulfonyl chloride (2.0 g, 7.0 mmol) and to this was added with stirring at ambient temperature about 0.2 mL of dimethyl sulfoxide catalyst. The resulting mixture was allowed to react for 24 hours and was then concentrated under reduced pressure and the residue was diluted with first water and then methylene chloride. The organic layer was recovered, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure to obtain the title compound as a white solid, which, after drying, amounted to 2.4 g (98 percent of theory) and melted at 185°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:30]([CH2:37][CH2:38]O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>>[ClH:1].[O:17]([CH2:18][CH2:20][O:24][C:23]([C:18]1([C:20]([O:22][CH2:38][CH2:37][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[C:16]1[CH:26]=[CH:27][CH:13]=[CH:14][CH:15]=1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCCOc1ccccc1
Agent: Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCCOc1ccccc1)(C(=O)OCCOc1ccccc1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-phenoxyethanol according to the procedure of Example 1 as an off-white gummy solid; 1H NMR (300 MHz, CDCl3): δ 1.23-1.40 (brs, 3H), 2.70-2.90 (brm, 1H), 3.05-3.30 (brm, 2H), 3.31-3.52 (brm, 2H), 4.12 (t, J=4.4 Hz, 4H), 4.57 (t, J=4.8 Hz, 4H), 5.38-5.60 (brs, 2H), 6.70-7.0 (complexm, 10H), 7.15-7.47 (complex m, 7H), 8.60-8.80 (brs, 1H), 9.90-10.20 (brs, 1H).; MS (ES) m/z (relative intensity): 662 (M+ -HCl, (100), 594 (20), 498 (35).
Reaction SMILES: C1(C)C=CC=C(CC[O:9][C:10]([C:12]2[CH:20]=[C:19]([O:21][CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=2)=[O:11])C=1.[OH-].[Na+].C1COCC1.O>CO>[C:26]1([CH3:30])[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][CH2:22][O:21][C:19]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[C:12]([C:10]([OH:11])=[O:9])[CH:20]=2)[CH:25]=1
Reactant: Cc1cccc(CCOC(=O)c2cc(OCCc3cccc(C)c3)c3c(c2)OCO3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(CCOc2cc(C(=O)O)cc3c2OCO3)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
4.5 g of 7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid 2-m-tolyl-ethyl ester and 650 mg of sodium hydroxide were dissolved in 50 ml of methanol, 50 ml of THF and 5 ml of water. The mixture was kept at room temperature for 20 h, then stirred at 50° C. for 5 h and evaporated. The residue was dissolved in 300 ml of a 0.1 M aqueous solution of sodium hydroxide and washed three times with 50 ml each of diisopropyl ether. The pH was adjusted to 2 with sodium hydrogensulfate and the mixture stirred for 30 min at room temperature. The product was collected by filtration, washed and dried in vacuo to yield 3.1 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19]([C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[CH:26][C:24]=2[CH:25]=1)=[O:20])C>>[O:10]=[C:6]1[C:5]2[CH:11]=[CH:12][C:2]([O:1][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][C:27]3[CH:28]=[CH:29][C:23]4[O:22][C:21]([C:19]([OH:20])=[O:18])=[CH:25][C:24]=4[CH:26]=3)=[C:3]([CH2:13][CH2:14][CH3:15])[C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)c1cc2cc(OCCCCCBr)ccc2o1
Product: CCCc1c(OCCCCCOc2ccc3oc(C(=O)O)cc3c2)ccc2c1OCCC2=O

Procedure:
Starting with 0.207 g (1.00 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.355 g (1.00 mmol) of 5-[(5-bromopentyl)oxy]-2-benzofurancarboxylic acid ethyl ester, there was obtained 0.093 g (20.5%) of the title compound as an off-white solid, mp 192°-195° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:8][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])C.O.[OH-].[Li+]>C1COCC1.CO.O.C(Cl)Cl>[CH:11]1([C:10]2[N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:22])[F:23])[CH:15]=3)[N:8]=[C:7]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[C:6]=2[C:4]([OH:5])=[O:3])[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Temperature: 80 °C

Procedure:
To a solution of 5-cyclopropyl-3-pyridin-4-yl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (154 mg, 0.37 mmol) in 2 ml THF, 1 ml methanol and 1 ml water, was added lithium hydroxide monohydrate (26 mg, 1.11 mmol). The solution was heated at 80° C. for 2 h. The reaction mixture was cooled, diluted with CH2Cl2 and washed with water. The aqueous phases were extracted with three portions of CH2Cl2. The combined organic layers were dried over magnesium sulfate, and evaporated to deliver a white solid (128 mg, 89%) of the tide compound. MS: 388.2 (M−H−).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]#[N:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.O>[C:7]([C:5]1[S:6][C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])=[CH:3][CH:4]=1)#[N:8]
Reactant: N#Cc1ccc(Br)s1
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1ccc(C#N)s1
Reaction time: 0.08 h
Yield: 95.7 %

Procedure:
A solution of 5-bromothiophene-2-carbonitrile (1.25 g, 6.65 mmol) in 50 ml of dioxane is degassed with argon, tetralkis(triphenylphosphine)palladium(0) (768 mg, 0.665 mmol) is added and the mixture is stirred for 5 minutes. 2-Methoxybenzene boronic acid (2.02 g, 13.3 mmol) and aqueous 2 N sodium carbonate (13.3 ml) are successively added and the mixture is stirred for 16 hours at 85° C. Extractive work-up (2×50 ml dichloromethane and 2×30ml water). The organic phase is dried over sodium sulfate, filtrated and evaporated. The residue (4.05 g) is purified via flash chromatography on silica (eluent: 100% hexane>hexane/ethyl acetate 96:4 gradient) to give 1.37 g of 2-(5-cyanothien-2-yl)anisole (96%). M+=215.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]([C:18]([F:21])([F:20])[F:19])[C:12]([C:22]([O:24]CC)=[O:23])=[CH:11]3)=[CH:4][CH:3]=1.[OH-].[Li+].Cl.C(OCC)C>CO.O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]([C:18]([F:20])([F:21])[F:19])[C:12]([C:22]([OH:24])=[O:23])=[CH:11]3)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(F)cc3)ccc2NC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: O=C(O)C1=Cc2cc(-c3ccc(F)cc3)ccc2NC1C(F)(F)F
Temperature: 25 °C
Yield: 88.2 %

Procedure:
Ethyl 6-(4-fluorophenyl)-2-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylate (189 mg, 0.51 mmol) was suspended in methanol-tetrahydrofuran-water (10 mL, 7:2:1). Lithium hydroxide (42 mg, 0.1.53 mmol) was added, and the mixture was gently heated to reflux for two hours. The reaction was cooled to room temperature and 1 N aqueous hydrochloric acid added until pH=1. The organic solvent was removed in vauco to afford a suspension of a crude yellow solid. Diethyl ether (20 mL) was added, and the solution was washed with water (2×20 mL), saturated ammonium sulfate (2×20 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 6-(4-fluorophenyl)-2-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylic acid (152 mg, 0.45 mmol) as a yellow solid (88% yield). 1H NMR (CD3OD3, 300 MHz) 7.81 (s, 1H), 7.40-7.56 (m, 4H), 7.10 (t, 1H, J=9.1 Hz), 6.78 (d, 1H, J=8.3 Mz), 5.12 (m, 1H). HRMS m/z 337.0732; calcd 337.0726.