Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[C:3]([CH2:5][CH2:6][O:7][P:8](Cl)[N:9]([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])#[N:4].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:64]2[CH:69]=[CH:68][C:67]([O:70][CH3:71])=[CH:66][CH:65]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:26][CH2:27][C@H:28]2[O:32][C@@H:31]([N:33]3[CH:41]=[N:40][C:39]4[C:34]3=[N:35][CH:36]=[N:37][C:38]=4[O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C@@H:30]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@@H:29]2[OH:57])=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.CN1C=CN=C1>CCOC(C)=O.CCCCCC.C(N(CC)CC)C.O1CCCC1>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:64]2[CH:65]=[CH:66][C:67]([O:70][CH3:71])=[CH:68][CH:69]=2)([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[O:26][CH2:27][C@H:28]2[O:32][C@@H:31]([N:33]3[CH:41]=[N:40][C:39]4[C:34]3=[N:35][CH:36]=[N:37][C:38]=4[O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C@@H:30]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@@H:29]2[O:57][P:8]([O:7][CH2:6][CH2:5][C:3]#[N:4])[N:9]([CH:10]([CH3:11])[CH3:12])[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(OCC[Si](C)(C)C)ncnc43)[C@@H](OCc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Agent: Cn1ccnc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(OCC[Si](C)(C)C)ncnc43)[C@@H](OCc3ccccc3)[C@@H]2OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Under the protection of N2, 2-cyanoethyl-N,N-diisopropylchlorophosphoramidite (0.69 mL, 3.10 mmol) was added drop-wise to a 0° C. anhydrous tetrahydrofuran (12 mL) solution of 9-{5-O-[bis(4-methoxyphenyl)(phenyl)methyl]-2-O-benzyl-β-D-arabinofuranosyl}-6-[2-(trimethylsilyl)ethoxy]-9H-purine (1.18 g g, 1.55 mmol), N,N-diisopropylethylamine (0.81 mL, 4.65 mmol)), and 1-methylimidazole (0.06 mL, 0.78 mmol). The reaction was gradually warmed to room temperature and stirred for 60 min. The reaction was then quenched with methanol (5 mL) and stirred for 5 min. After the solvent was removed under the reduced pressure, the residue was purified by flash chromatography (gradient: hexane with EtOAc 0-50%, with 1% triethylamine in both hexane and EtOAc) to produce 1.41 g (94.6%, 1.47 mmol) final product. LCMS: for C52H65N6O5PSi calculated 961.167. found 961.6 [M+H]+. 31P NMR (600 MHz, CD3CN) δ: 150.65, 150.24.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ccc(N)cn1
Reaction time: 0.67 h

Procedure:
To a solution of 12-2 (6.0 g, 22.0 mmol) in 50 mL DMF at 0° C. was added NaH gradually. After the mixture was stirred for 40 min, CH3I (3.4 g, 24.0 mmol) was added in one portion. The reaction mixture was stirred for 5 hr, treated with 300 mL water and extracted three times with ethyl ether. The combined organic layers were washed with brine and dried over Na2SO4. After solvent removal, the residue was purified by silica gel flash chromatography (CHCl3/hexanes 6:1) to afford the desired product 12-3 as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([OH:12])([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH2:7])[CH3:2].[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4](=[O:13])[C:5]([O:12][CH2:18][CH:17]=[CH2:16])([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH2:7])[CH3:2]
Reactant: C=CC(O)(C(=O)OCC)C(F)(F)F
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: C=CCOC(C=C)(C(=O)OCC)C(F)(F)F

Procedure:
To a solution of 2-hydroxy-2-trifluoromethyl-but-3-enoic acid ethyl ester (3.6 g) in THF (100 mL) at 0° C. was added sodium hydride (1.1 g of 60% in oil), followed by addition of allyl bromide (2.3 mL) and tetrabutyl ammonium iodide (1.35 g). The resulting mixture was then heated to reflux for 5 h. The reaction was carefully quenched with NH4Cl (aq), extracted with EtOAc, and dried over Na2SO4. After concentration, the resulting crude material was filtered through a plug of silica gel and rinsed with 20% CH2Cl2/hexanes, then concentrated to yield the title compound as a yellow oil.
Reaction SMILES: [ClH:1].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:9]2[CH2:14][CH2:13][O:12][CH:11]([CH:15]([O:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][CH2:22]4)O)[CH2:10]2)C=CC=CC=1>C(O)C>[ClH:1].[CH2:20]1[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[O:17][CH2:15][CH:11]2[O:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH:22]=[CH:21]1
Reactant: OC(Oc1cccc2c1CCC2)C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1
Agent: Cl
Solvent: CCO
Product: C1=Cc2cccc(OCC3CNCCO3)c2C1

Procedure:
In 500 ml. of ethanolic hydrochloric acid (350 ml. of 0.5 N hydrochloric acid and 150 ml. of ethanol) was dissolved 5.0 g. of 4-triphenylmethyl-2-(1-hydroxy-4-indanyloxymethyl)-morpholine and the solution was refluxed 17 hours. After cooling the reaction mixture, ethanol was distilled away under reduced pressure until the whole volume of the reaction mixture became about 350 ml. Sodium chloride was added to the reaction mixture to cause salting out and the mixture was extracted three times each time with 200 ml. of chloroform. The chloroform extracts were combined, dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. Then, by adding acetone to the syrupy residue formed, 2.0 g. of 2-(7-indenyloxymethyl)morpholine hydrochloride was obtained as a precipitate.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:27]=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=1>CN1CCCC1=O>[C:32]([C:29]1[N:30]=[CH:31][C:26]([N:22]2[CH2:23][CH2:24][CH:19]([N:5]([CH:2]3[CH2:4][CH2:3]3)[C:6](=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([C:13]4[O:17][CH:16]=[N:15][CH:14]=4)=[CH:11][CH:12]=3)[CH2:20][CH2:21]2)=[N:27][CH:28]=1)#[N:33]
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: N#Cc1cnc(Cl)cn1
Agent: Cl
Solvent: CN1CCCC1=O
Product: N#Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)cn1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 5-chloro-pyrazine-2-carbonitrile following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.46 min; Mass spectrum (ESI+): m/z=415 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:25]([CH3:26])[C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:16]3[CH2:15][CH2:14][N:13]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C@@H:12]([CH3:11])[CH2:17]3)=[CH:24][CH:23]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=C(Cl)c1cccc(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Cl)n3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid chloride from step 1 was dissolved in DCM (15 mL) and added to a mixture of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.500 g, 1.57 mmol) and triethylamine (0.284 mL, 2.04 mmol) in DCM (15 mL). The reaction mixture was stirred at room temperature overnight and then washed with water (×2) and brine. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography. Elution with 20-60% EtOAc/pentane yielded the title compound as a yellow oil/solid (0.658 g). δH (CDCl3, 400 MHz) 7.56 (1H, m), 7.46 (1H, m), 7.17 (2H, m), 6.99 (2H, m), 4.16 (1H, br.s), 3.79 (1H, d), 3.50 (3H, s), 3.46 (1H, d), 3.32 (1H, d), 3.07 (1H, m), 2.69 (1H, d), 2.50 (1H, d), 2.08 (1H, m), 1.97 (1H, m), 1.46 (9H, s), 1.19 (3H, d). MS (ES): MH+ 459/461.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][S:14][CH:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:32]>C(O)C>[ClH:32].[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:15]([S:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCCN(CCSC2c3ccccc3CCc3ccccc32)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCCN(CCSC2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
The above ester (1.23 g, 0.003 mol) was dissolved in ethanol (15 ml). 2 N Sodium hydroxide (4.0 ml) was added and the mixture was stirred for 1 h at room temperature. The solution was made acidic (pH 1) by addition of excess 1 N hydrochloric acid and concentrated in vacuo to remove ethanol. The remainder was extracted with diethyl ether (50 ml) and redissolved in dichloromethane (50 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo. Crystallisation of the remainder from acetone (20 ml) afforded 0.78 g (62%) of the title compound as a crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:5][C:6]=1[C:7](=[O:9])[CH3:8].[CH3:20][Mg]Br>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:5][C:6]=1[C:7]([OH:9])([CH3:20])[CH3:8]
Reactant: C[Mg]Br
Reactant: CC(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)(C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanone (0.58 g, 2.15 mmol) is stirred in tetrahydrofuran (25 mL) at zero deg. C. Methyl magnesium bromide (1.1 mL, 3.23 mmol, 3 M in ether) is added and the reaction stirred at room temperature 2 hr. The mixture is cooled on ice/water and quenched with saturated ammonium chloride (5 mL). The product is extracted with ethyl acetate (3×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to afford the product as a tan solid, 0.40 g, 65%). MS M++1 286. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(C)ccc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 8.8 mmol) and 2-amino-4-methylbenzamide (2.0 g, 13.2 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4-methylbenzamide was isolated as a white solid (2.81 g, 70% Yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3 H), 2.36 (s, 3 H), 6.65 (d, J=3.84 Hz, 1 H), 6.98 (s, 1 H), 7.47 (d, J=8.05 Hz, 2 H), 7.70 (s, 1 H), 7.74 (s, 1 H), 7.75 (d, J=2.93 Hz, 1 H), 7.98 (d, J=8.42 Hz, 2 H), 8.25 (s, 1 H), 8.33 (s, 1 H), 12.52 (s, 1 H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH2:26]P(=O)(OCC)OCC.[CH2:35]([C:38]1([CH:53]=O)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[CH2:42][CH2:41][C:40]2[CH:49]=[CH:50][CH:51]=[CH:52][C:39]1=2)[CH:36]=[CH2:37].[NH4+].[Cl-]>C1COCC1>[CH2:35]([C:38]1([CH:53]=[CH:26][O:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[C:39]2[CH:52]=[CH:51][CH:50]=[CH:49][C:40]=2[CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]1=2)[CH:36]=[CH2:37]
Reactant: C=CCC1(C=O)c2ccccc2CCc2ccccc21
Reactant: CCOP(=O)(COC1CCCCO1)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCC1(C=COC2CCCCO2)c2ccccc2CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
Dissolved diisopropylamine (9.2 g, 0.0910 mol) in 200 mL of dry THF. Cooled to 0° C. under a nitrogen atmosphere. Added 2.5M n-butyl lithium in hexane (35.2 mL, 0.0880 mol) via syringe. Stirred at 0° C. for 10 mins then cooled to -78° C. Added diethyl [(2-tetrahydropyranyloxy)methyl]phosphonate in 45 mL of dry THF via addition funnel. Stirred at -78° C. for 1 hour. Added 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-carboxaldehyde in 100 mL of dry THF via addition funnel. Warmed to room temperature then refluxed for 16 hours. Cooled to room temperature, and added 500 mL of saturated NH4Cl. Separated layers, and extracted aqueous solution with ether. Washed combined organic extracts with saturated NaHCO3, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 3% ether-hexane then 5% ether-hexane. Combined appropriate fractions and evaporated to give 12.7 g (46% yield) of 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl-(2-tetrahydropyranyloxy-ethene).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:13]1([S:19]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a stirred solution of 5-chloroindole (20 g, 131.93 mmol, 1 eq.) in dry DMF (250 mL) at 0° C., was added NaH (5.38 g, 134.57 mmol, 1.02 eq.). After stirring at room temperature for 1 h, benzenesulfonyl chloride (23.77 g, 134.57 mmol, 1.02 eq.) was added slowly. The reaction mixture was stirred for additional 1 h, then poured into 1 L of 5% aq. NaHCO3 and extracted with EtOAc (×3). The organic layers were combined, washed with H2O (×3), brine (×3), dried over (Na2SO4), filtered, and the filtrate was concentrated. The material was purified by flash chromatography to yield 30 g of 1-phenylsulfonyl-5-chloroindole as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:38](=[O:40])[CH3:39])[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([OH:34])[C:26]=3[CH2:35][CH2:36][CH3:37])=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[Na+]>CO>[C:38]([C:9]1[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([OH:34])[C:26]=2[CH2:35][CH2:36][CH3:37])=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:41])=[O:2])[CH:15]=[CH:14]2)(=[O:40])[CH3:39]
Reactant: CCCc1c(OCCCOCCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOCCCOc2ccc3ccc(OCC(=O)O)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 72.6 %

Procedure:
A mixture of 1.2 g of [[8-acetyl-7-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester and 21 ml of 1N sodium hydroxide in 42 ml of methanol was stirred at reflux for 1 hour. The methanol was removed in vacuo and the aqueous solution was washed with ethyl acetate. The aqueous layer was acidified with 3N hydrochloric acid to pH 3 and the oil was extracted with chloroform. The extract was dried (magnesium sulfate) and concentrated to give an oil which was triturated with ether-cyclohexane and filtered to yield 0.85 g, mp 101°-104° C. (73%) of [[8-acetyl-7-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-naphthalenyl]oxy]acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:5]([NH:7][C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:30])[CH2:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])=[CH:15][CH:14]=2)=[C:10]([F:33])[CH:9]=1)=[O:6].[BH4-].[Na+].O.[Cl-].[NH4+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:5]([NH:7][C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]([OH:30])[CH2:20][CH2:21][C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:18]=2)=[C:10]([F:33])[CH:9]=1)=[O:6]
Reactant: O=C(CCC(=O)N1CCOCC1)c1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2F)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(Oc2ccc(C(O)CCC(=O)N3CCOCC3)cc2)c(F)c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(4-{4-[4-(3,4-dichlorobenzoylamino)-2-fluorophenoxy]phenyl}-4-oxobutyryl)morpholine (1.00 g, 1.83 mmol) in THF (20 mL) and methanol (5 mL) was added sodium borohydride (0.0694 g, 1.83 mmol), and the resulting solution was stirred for 1 hour at room temperature. To this reaction solution were added water and saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). The obtained solid was recrystallized from water-containing isopropanol, to thereby yield 0.850 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:15])=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:2].[CH2:20]([O:22][C:23](Cl)=[O:24])[CH3:21].[NH4+].[Cl-]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:20]([O:22][C:23](=[O:24])[NH:12][C:11]1[CH:13]=[CH:14][C:8]([O:7][C:6]2[CH:16]=[CH:17][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[O:18][CH3:19])=[C:9]([F:15])[CH:10]=1)[CH3:21]
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OC)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc(Oc2ccc(CC)cc2OC)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (0.19 mmol; 50 mg) in 1 mL THF/NaHCO3 sat. (1/1), at 0° C. were added ethylchloroformate (0.38 mmol; 41 mg). The reaction was stirred overnight at room temperature. The mixture was hydrolysed with NH4Cl sat. (4 mL) and extracted with dichloromethane (3*2 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (36 mg; 56%) was obtained as a brown oil, after purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—70/30).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30](OCC)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:39][CH:36]3[CH2:38][CH2:37]3)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: NC1CC1
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NC3CC3)c(O)c3ncc(Cc4ccccc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopropylamine employing methods similar to those described in Example 2. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.04 (1H, br d, J=3.4 Hz), 8.61 (1H, s), 7.81 (2H, d, J=8.4 Hz), 7.29 (3H, m), 7.17 (2H, d, J=8.4 Hz), 7.05 (1H, s), 7.03 (2H, m), 5.39 (2H, br), 4.05 (2H, s), 3.01 (3H, s), 2.97 (1H, m), 0.90 (2H, m), 0.70 (2H, m); HRMS calcd for C27H25N3O5S+H+: 504.1593. Found: 504.1581.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7]2.[Li+].[OH-]>C1COCC1.CCO.O.Cl.CC#N.CN(C=O)C>[CH3:1][C:2]1[C:3]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2ccc(Oc3ccccc3)c(C)c2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCO
Product: Cc1c(Oc2ccccc2)ccc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 60 °C
Yield: 54.7 %

Procedure:
To 0.090 g (0.24 mmol) of ethyl 8-methyl-7-phenoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 5 mL THF:EtOH:H2O (7:2:1) was added 0.015 g (0.36 mmol) of LiOH. The mixture was heated at 60° C. for 2 hours. Removed volatiles in vacuo and diluted with HCl (10%), CH3CN, and DMF and purified by reverse phase chromatography to afford 0.046 g (55%) of a pale yellow solid: 11H NMR (CH3OD/400 MHz) 2.15 (s, 3H), 5.79 (q, 1H, J=7.2 Hz), 6.43 (d, 1H, J=8.4 Hz), 6.94-6.96 (m, 2H), 7.09-7.14 (m, 2H), 7.33-7.37 (m, 2H), 7.74 (s, 1H); MS (ES+) 351.2 (M+H, 100); HRMS (ES−) m/z calcd for (C18H13F3O4) 349.0688, found 349.0681.
Reaction SMILES: N#N.[CH:3](/[C:11]1[O:12][CH:13]=[C:14]([C:16](OCC)=[O:17])[N:15]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.C1(C)C=CC=CC=1.CC(=O)OCC>[CH:3](/[C:11]1[O:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)=[CH:4]\[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1coc(/C=C/c2ccccc2)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1coc(/C=C/c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (E)-ethyl 2-styryloxazole-4-carboxylate (WO 2009077990 A1) (8.5 g, 34.9 mmol) in THF (28.3 mL) was treated dropwise at 0° C. with DiBAL-H (85.0 mL of a 1.0 M solution in toluene, 85.0 mmol) and the resulting solution was stirred for 1.5 h at 0° C. Rochelle's salt solution was added followed by EA and the mixture was stirred for 24 h at rt. The aq. layer was extracted with EA (3×40 mL) and the combined org. layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound as an orange oil. TLC: rf (1:1 hept-EA)=0.20. LC-MS-conditions 07: tR=0.71 min, [M+H]+=202.15.