Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:8]3[CH2:12][CH:11]=[CH:10][CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[O-].[Na+].O>C(O)C.C(OCC)C>[CH:2]12[CH2:3][CH:4]([CH2:5][CH2:6]1)[CH2:7][CH:1]2[C:8]1[CH:12]=[CH:11][C:10](=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1=CCC(C23CCC(CC2)C3)=C1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1C1CC2CCC1C2
Yield: 99.5 %

Procedure:
A 500 mL round bottom flask was charged with a solution of norbornylcyclopentadiene (7.39 g, 46.1 mmol) and benzophenone (8.41 g, 46.2 mmol) in 100 mL absolute ethanol. NaOMe (5.50 g, 102 mmol) was added and the orange solution was stirred for 61 days before 100 mL H2O and 100 mL diethyl ether were added. The organic layer was isolated and the aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and rotavapped to provide 14.88 grams of red oily material. This was subjected to Kugelrohr distillation under high vacuum at 80-100° C., leaving behind 9.30 grams of red oil. This was Kugelrohred at 100-160° C. to afford 7.05 grams of product as a viscous red oil (47.1%).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:35])[F:34])[CH:26]=2)[C:32]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(F)c(Cl)nc2n(-c2cccc(C(F)(F)F)c2)c(=O)n1OCc1ccccc1
Yield: 69.1 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 3-trifluoromethylphenyl isocyanate (1.31 mL, 9.51 mmol) in DMA afforded 2.04 g of the title compound as a solid, mp 207-208° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[BrH:11].[CH2:12]([N:15]([CH2:28][CH2:29][CH3:30])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][C:20]([NH2:27])=[C:21]([OH:26])[CH:22]=2)[CH2:17]1)[CH2:13][CH3:14]>C(OCC)C>[BrH:11].[CH2:28]([N:15]([CH2:12][CH2:13][CH3:14])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][C:20]([NH:27][CH:8]=[O:10])=[C:21]([OH:26])[CH:22]=2)[CH2:17]1)[CH2:29][CH3:30]
Reactant: CCCN(CCC)C1CCc2cc(O)c(N)cc2C1
Reactant: O=CO
Agent: Br
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCCN(CCC)C1CCc2cc(O)c(NC=O)cc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.7 ml of acetic anhydride is added to 3 ml of 98% formic acid, kept at 0° C., and the whole is left for 15 minutes at 0° C. 2.2 g of 2-dipropylamino-7-amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide are then added thereto and the mixture is then stirred for one hour at 0° C. After 50 ml of diethyl ether have been added and the solid has been filtered off, the latter is recrystallised from a 50/50 methanol/ethyl acetate mixture. This gives 1 g of the final product melting at 213° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=[O:13].[K+].[K+].CS(C)=O.OO>O>[F:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]([NH2:11])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: N#CCOc1cncc(F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)COc1cncc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.1 %

Procedure:
To a mixture of 2-((5-fluoropyridin-3-yl)oxy)acetonitrile (0.55 g, 3.62 mmol), K2CO3 (0.60 g, 4.34 mmol) and DMSO (0.55 mL) in H2O (8 mL) was added H2O2 (0.55 mL, 30%) dropwise in an ice bath and the mixture was stirred at rt for 5 min. It was then concentrated in vacuo and the residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as a white solid (0.37 g, 60%).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]3)[N:5]=[C:4]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[C:28](Cl)([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].C([O-])(O)=O.[Na+]>CCOC(C)=O>[C:24]([C:4]1[CH:3]=[C:2]([C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29])[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:11][CH2:10]3)[N:5]=1)([CH3:26])([CH3:27])[CH3:25]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-n3nc(C(C)(C)C)cc3N)ccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(-n3nc(C(C)(C)C)cc3C(=O)OCC(Cl)(Cl)Cl)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
To a stirring solution of t-butyl 6-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (see WO 2006/071940A2, 0.075 g, 0.20 mmol) and Troc-Cl (0.028 ml, 0.21 mmol) in EtOAc (2 ml) was added sat'd. NaHCO3 (0.82 ml, 0.61 mmol). The resulting biphasic solution was stirred at RT overnight. The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were washed with brine (1×), dried (MgSO4) and concentrated in vacuo to give crude t-butyl 6-(3-t-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.110 g, 100% yield). 1H NMR (DMSO-d6) δ 9.93 (brs, 1H), 7.29-7.24 (m, 2H), 6.83-6.80 (m, 1H), 6.27 (s, 1H), 4.85 (s, 2H), 4.52 (brs, 2H), 3.57-3.53 (m, 2H), 2.82-2.79 (m, 2H), 1.44 (s, 9H), 1.27 (s, 9H); MS (ESI) m/z: 545.0 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2noc3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2ccccc12)N1CCNCC1
Yield: 95.3 %

Procedure:
A solution of tert-butyl 4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazine-1-carboxylate (16.5 g, 47.6 mmol) in trifluoroacetic acid (200 ml) was stirred at room temperature for 2 hours, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and diethyl ether to give 16.3 g (95.3%) of the desired product.
Reaction SMILES: Cl.C([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]N)=[CH:6][CH:5]=1)#N.Cl.[C:13]([C:16]1C=CC(CN)=CC=1)(O)=O.C#CCN1C=CN=N1>>[C:7]1([CH2:8][C:13]#[CH:16])[CH:6]=[CH:5][CH:4]=[CH:11][CH:10]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(CN)cc1
Agent: C#CCn1ccnn1
Agent: Cl
Product: C#CCc1ccccc1

Procedure:
Replacing 4-cyanobenzylamine hydrochloride in Example 4, Step (1), with 4-carboxy-benzylamine hydrochloride, and replacing the 1-propyn-3-yl-1H-[1,2,3]triazole in Example 4, Step (2), with 3-phenyl-propyne yielded 4-[[3-3-phenethylethynyl-benzoylamino]-methyl}-benzoic acid; 1H-NMR (DMSO-d6) δ 9.2 (m, 1H), 8.0 (s, 1H), 7.8 (m, 4H), 7.6 (d, 1H) 7.2-7.4 (m, 7H), 4.5 (d, 2H), 3.9 (s, 2H) ppm. Mp 209° C.-211° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][C@@H:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].O=[C:22]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:25][C:23]([CH:22]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][C@@H:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C[C@H](N)C(=O)N1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)O
Reactant: O=C(CCc1ccccc1)C(=O)OCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: C[C@H](NC(CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)O

Procedure:
A solution of 200 mg. of 1-(L-alanyl)-4-(S)-(phenylthio)-L-proline and 1.1 grams of benzyl 2-oxo-4-phenylbutyrate in 8 ml. of ethanol is stored at room temperature with 3 grams of powdered molecular sieves (type 4A). Over the course of three hours, 75 mg. of sodium cyanoborohydride is added. The reaction mixture is filtered and concentrated under reduced pressure. The residue is purified by absorption on a strong cation exchange resin and elution with 2% pyridine in water. After passage through a gel filtration column, the desired product, 1-[N-(1-benzyloxycarbonyl-3-phenylpropyl)-L-alanyl]-4-(S)-(phenylthio)-L-proline, is obtained as a mixture of isomers that can be separated by high performance liquid chromatography.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([O:10]CC2C=CC=CC=2)=[C:3]1[CH:18]([O:21][CH3:22])[CH2:19][CH3:20].[ClH:23]>CO.O.[Pd]>[ClH:23].[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([OH:10])=[C:3]1[CH:18]([O:21][CH3:22])[CH2:19][CH3:20]
Reactant: CCC(OC)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CCC(OC)c1c(O)c(=O)cc(C)n1C
Yield: 79.3 %

Procedure:
1,6-Dimethyl-2-(1-methoxypropyl)-3-benzyloxy-pyridin-4-(1H)-one (1.65 g, 5.5 mmol) was dissolved in methanol (30 ml)/water (10 ml) and adjusted to pH 1 with concentrated hydrochloric acid prior to hydrogenolysis for 4 hours in the presence of 5% Pd/C catalyst (0.35 g). Filtration followed by rotary evaporation gave the crude product as a white solid. Recrystallization from methanol/diethyl ether gave the pure title compound (1.08 g, 79.3%) as a white crystalline solid. m.p. 225-227° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].S(=O)(=O)(O)O.[CH3:24]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(F)c(Cl)c1
Yield: 97 %

Procedure:
A mixture of 3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionic acid (3.10 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(3-chloro-4-fluorophenyl)-4-isoxazolyl]propionate (3.18 g, yield 97%) was obtained as a pale yellow oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). NMR (CDCl3) δ: 2.60–2.72 (2H, m), 2.91–3.03 (2H, m), 3.69 (3H, s), 7.22–7.33 (1H, m), 7.52–7.66 (1H, m), 7.74–7.82 (1H, m), 8.23 (1H, s).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]([CH3:35])[CH2:30][C:31](=[O:34])[NH:32][N:33]=3)=[CH:24][C:22]=2[N:23]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([C:28]3[CH:29]([CH3:35])[CH2:30][C:31](=[O:34])[NH:32][N:33]=3)=[CH:24][C:22]=2[N:23]=1)#[N:2]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: CC1CC(=O)NN=C1c1ccc2oc(NCCCN)nc2c1
Product: CC1CC(=O)NN=C1c1ccc2oc(NCCCNCC(O)COc3ccccc3C#N)nc2c1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[2-(3-aminopropylamino)benzoxazol-5-yl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2([OH:20])[CH2:19][CH2:18][NH:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:21].[Na+]>CO.O.CCOCC>[C:8]([N:17]1[CH2:18][CH2:19][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([OH:20])[CH2:16]1)(=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2ccccc2Cc2ccccc2)CCNC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)N1CCC(O)(c2ccccc2Cc2ccccc2)C1
Reaction time: 2 h

Procedure:
A suspension of 5.0 g of 3-(α-phenyl-2-tolyl)-3-pyrrolidinol hydrochloride, Example 14, in 40 ml of methanol is diluted with water until a solution forms. The solution is treated with an excess of a 5% sodium hydroxide solution and then the methanol removed on a rotary evaporator leaving a suspension. The suspension is diluted with 50 ml of water and extracted successively with a 100 ml and a 20 ml portion of chloroform. The combined chloroform extracts are washed once with 50 ml of a 5% sodium hydroxide solution and twice with 50 ml portions of water and dried and the chloroform removed. The residue is subjected to azeotropic distillation with benzene and then dried in vacuo at 40° C. for 2 hours before being suspended in 30 ml of warmed chloroform containing 2.2 g of triethylamine. To this suspension is added dropwise 2.60 g of benzoyl chloride. After total addition, the resulting solution is stirred for 2 hours and then permitted to stand for 48 hours. The solution is diluted with 30 ml of chloroform, washed successively with a 50 ml portion of water and similar amount of a 5% sodium hydroxide and dried and the solvent removed leaving a tacky foam. The foam is dissolved in 60 ml of ether (warming may be required), and the solution filtered through glass wool. A precipitate forms which is collected by suction filtration and dried in vacuo at ambient temperature leaving a colorless solid, mp 113°-116° C. of 1-benzoyl-3-(α-phenyl-2-tolyl)-3-pyrrolidinol.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Mg+].[Br-]>C1COCC1>[OH:7][C:1]([C:3]1[CH:2]=[C:1]([OH:7])[CH:6]=[CH:5][CH:4]=1)([CH2:6][CH3:5])[CH2:2][CH3:3]
Reactant: Oc1ccccc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cccc(O)c1

Procedure:
Following the procedure described for Phenol 13, Step 2 and for Phenol 7, Step 3 but substituting EtMgBr in THF (Aldrich) for MeMgBr, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:28][CH:29]=2)[CH2:16][CH:17]([CH3:18])[CH3:19])[CH:10]=1
Reactant: COc1ccccc1-c1cc(C(CC(C)C)Nc2ccc(C(=O)O)cc2)c(C)o1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1cc(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A solution of 4-({1-[5-(2-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)benzoic acid (197 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (212 mg, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]2[C:19](=O)[C:18](=[CH:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH2:17][O:16][CH2:15]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:34][C:35]1[S:36][CH2:37][CH2:38][N:39]=1.CCO>C(Cl)(Cl)Cl>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:13]2[N:39]3[CH2:38][CH2:37][S:36][C:35]3=[N:34][C:19]3[C:18](=[CH:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][O:16][CH2:15][C:14]2=3)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C=C2COCC(=Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc(OC)c1OC
Reactant: NC1=NCCS1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1cc(C=C2COCC3=C2N=C2SCCN2C3c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC

Procedure:
A stirred solution of tetrahydro-3,5-bis[(3,4,5-trimethoxyphenyl)methylene]-4H-pyran-4-one (3.0 g, 6.5 mmole) and 2-amino-2-thiazoline (0.8 g, 7.8 mmole) in 75 ml of CHCl3 is heated at reflux for 44 hours. After cooling, the solution is filtered to remove a small amount of insoluble material. The solvent is evaporated to give an oily residue which solidifies when treated with a small amount of EtOH. The yield is 2.2 g, m.p. 166°-168°. Crystallization from 10 ml of MeCN gives 1.5 g (42%) of light yellow solid, m.p. 153°-155°. The m.p. of a sample of this material does not change when recrystallized from MeCN.
Reaction SMILES: NC1C=CC=CC=1.Cl.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+].Cl[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C(#N)C.O>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([NH:24][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(COc2cccc(N)c2)cc1
Reactant: COC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: O
Solvent: CC#N
Product: COC(=O)CNc1cccc(OCc2ccc(C)cc2)c1

Procedure:
A mixture of the aniline (Intermediate 82, 20 g, 94 mmol), sodium bicarbonate (11.8 g, 141 mmol) and methyl chloroacetate (9.1 ml, 103 mmol) in acetonitrile (30 ml) was heated at 90°-100° for 24 h. Water (200 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were washed with 2N hydrochloric acid (2×100 ml), water (2×100 ml) and brine (100 ml) before drying (Na2SO4) and evaporating to an orange solid. Trituration with ether, followed by evaporation of the triturate gave the title compound (Intermediate 83) as a pale grey solid (16 g; 60%), m.p. 78°-80°.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>O>[CH2:18]([NH:22][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: CCCCN
Solvent: O
Product: CCCCNc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (8.4 g), n-butylamine (8.7 g), and water (25 ml) was stirred at 90° C for 1.5 hours. After cooling, the pH was adjusted to pH 2, and the precipitated 4-butylamino-3-nitro-5-sulphamyl-benzoic acid was collected by filtration. After several recrystallizations from aqueous methanol the melting point was 192.5° C.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:43][CH2:44]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:34]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:35]=[CH:36][C:31]([C:29]2[O:30][C:26]([CH3:25])=[C:27]([CH2:43][CH2:44][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=4)([CH3:14])[C:4]([OH:3])=[O:24])=[CH:8][CH:9]=3)[N:28]=2)=[CH:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)c(F)c2)C(=O)O)cc1

Procedure:
A mixture of 2-(3,4-difluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 1, Part I) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-(3,4-difluoro-phenoxy)-2-methyl-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 2H, J=8.4 Hz), 7.36 (d, 2H, J=8.4 Hz), 7.63 (dd, 2H, J=7.6, 1.2 Hz), 7.49–7.45 (m,2H), 7.41–7.37 (m, 1H), 7.18 (d, 2H, J=8.8 Hz), 7.00 (q, 1H, J=9.5 Hz), 6.84 (d, 2H, J=8.8 Hz), 6.76 (ddd, 1H, J=11.2, 6.4, 2.8 Hz), 6.64–6.59 (m, 1H), 4.22 (t, 2H, J=6.2 Hz), 3.23 and 3.11 (d of ABq, 2H, J=14.0 Hz), 3.07 (t, 2H, J=6.2 Hz), 2.44 (s, 3H), 1.39 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([F:34])[CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:27]([F:34])[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1ccc(Cl)cc1F
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3F)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and corresponding 4-chloro-2-fluorophenyl boronic acid (175 mg, 1.0 mmol) to afford after chromatographic purification the title compound (128 mg, 60%). 1H NMR (CDCl3, 300 MHz) δ 7.28-7.29 (m,1H), 7.05-7.15 (m, 4H), 3.6-4.2 (m, 3H), 2.80-3.50 (m, 7H), 1.80-1.90 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 429 [M+H+].