Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].CCCCCC>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Nc1cc(F)ccc1Br
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
To an ice-cold solution of 2-bromo-5-fluoroaniline (50.0 g, 263.14 mmol) in DCM (400 mL) was added triethyl amine (48.0 mL, 342.10 mmol). The resulting mixture was stirred at 0° C. for 10 min followed by addition of pivaloyl chloride (36.0 mL, 289.50 mmol) then stirred at rt for 3 h. After completion of reaction (by TLC), the reaction mixture was diluted with DCM and washed with saturated solution of NaHCO3. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 1.0% EtOAc:hexane to obtain the product as an off white solid (66.0 g, 92% yield).
Reaction SMILES: CO[C:3](=[O:21])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([O:11][CH3:12])[CH2:7]1.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH:8]([O:11][CH3:12])[CH2:7]2)[C:3]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: COC(=O)C(CC1CCC(OC)C1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: COC1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Yield: 6.7 %

Procedure:
2-(3,4-Dichloro-phenyl)-3-(3-methoxy-cyclopentyl)-propionic acid methyl ester (118.3 mg, 0.36 mmol) and 2-aminothiazole (35.8 mg, 0.36 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 2.6 mL, 1.79 mmol). The resulting reaction mixture was then heated under reflux for 30 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate, and the filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 40% ethyl acetate/hexanes) afforded the 2-(3,4-dichloro-phenyl)-3-(3-methoxy-cyclopentyl)-N-thiazol-2-yl-propionamide (9.6 mg, 7%) as a white glass: (ES)+-HRMS m/e calcd for C18H20Cl2N2O2S (M+H)+ 399.0696, found 399.0700.
Reaction SMILES: Cl[Si:2]([CH3:18])([CH3:17])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:15])=[C:4]1[CH3:16].CCN(CC)CC.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>CCCCCC>[CH3:27][C:26]([NH:30][Si:2]([CH3:18])([CH3:17])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([CH3:15])=[C:4]1[CH3:16])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N
Reactant: CC1=C(C)C([Si](C)(C)Cl)c2cc3c(cc21)CCC3
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1=C(C)C([Si](C)(C)NC(C)(C)C)c2cc3c(cc21)CCC3
Reaction time: 16 h
Yield: 92.7 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2,3-dimethyl-s-indacen-1-yl) silane (3.537 g, 0.01217 moles) was stirred in hexane (50 mL) as NEt3 (1.94 g, 0.01916 moles) and t-butylamine (1.12 g, 0.01533 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a light yellow oil (3.537 g, 88.6 percent).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[C:19][Si](C)(C)C)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]#[CH:19])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)C#CCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
To a solution of methanol (20 mL) of (3-(4-benzyloxy-phenyl)-prop-1-ynyl)-trimethyl-silane (910 mg) described in Manufacturing Example 12-1 was added potassium carbonate (850 mg) at room temperature, which was stirred for 4 hours and 10 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain the titled compound (620 mg).
Reaction SMILES: Cl[P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4](Cl)[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[C:15]([C:19]1[CH:20]=[C:21]([CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[OH:31])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[C:15]([C:19]1[CH:20]=[C:21]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[O:31][P:2]1[N:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[P:4]([O:31][C:30]2[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:28][C:29]=2[C:32]([CH3:35])([CH3:34])[CH3:33])[N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)(C)N1P(Cl)N(C(C)(C)C)P1Cl
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cc(C(C)(C)C)c(OP2N(C(C)(C)C)P(Oc3c(C(C)(C)C)cc(CCC(=O)OC)cc3C(C)(C)C)N2C(C)(C)C)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 2,4-dichloro-1,3-di-tert-butyl-1,3,2,4-diazadiphosphetidine, methyl 3,5-di-tert-butyl-4-hydroxyhydrocinnamate and triethylamine to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl.[CH3:13]N(C)CCCN=C=NCC.CO>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:10][C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.8 %

Procedure:
A mixture of 4-nitro-1H-pyrazole-3-carboxylic acid (2.0 g, 12.7 mmol) in dichloromethane at 25° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.68 g, 14.0 mmol), methanol (8.2 mL), and 4-dimethylaminopyridine (155 mg, 1.27 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane and was washed with a 1N aqueous hydrochloric acid solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 45:55 ethyl acetate/petroleum ether) afforded 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.06 g, 48.8%) as a white solid: LR-MS for C5H5N3O4 (M−H)+ at m/z=170.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39](Cl)=[CH:38][C:37]=2[C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH2:53]([Sn](CCCC)(CCCC)C=CC)[CH2:54][CH2:55]C.[F-].[Cs+]>CN(C=O)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[CH:40][C:39](/[CH:53]=[CH:54]/[CH3:55])=[CH:38][C:37]=2[C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-c4cccc(S(C)(=O)=O)c4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Reactant: CC=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C/C=C/c1ccc([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)c(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 130 °C

Procedure:
To a solution (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (500 mg, 0.65 mmol) in DMF (10 mL) was added tributyl(prop-1-enyl)stannane (258 mg, 0.78 mmol), Pd(t-Bu3P)2 (33 mg, 0.065 mmol), and CsF (217 mg, 1.43 mmol). The reaction was heated to 130° C. in a sealed tube for 3 h, then cooled to RT, and partitioned between water and CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-5-((E)-prop-1-en-1-yl)-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:47]([O:51][C:52]([N:54]1[CH2:58][CH2:57][CH:56]2[NH:59][CH2:60][CH:61]([C:62](=[O:74])[NH:63][C:64]3[C:73]4[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=4)[CH:67]=[CH:66][CH:65]=3)[CH:55]12)=[O:53])([CH3:50])([CH3:49])[CH3:48]>CN1C(=O)CCC1.CCOC(C)=O>[C:47]([O:51][C:52]([N:54]1[CH2:58][CH2:57][CH:56]2[N:59]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH2:60][CH:61]([C:62](=[O:74])[NH:63][C:64]3[C:73]4[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=4)[CH:67]=[CH:66][CH:65]=3)[CH:55]12)=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC2NCC(C(=O)Nc3cccc4ccccc34)C21
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
A solution of Cbz-Gly-OH (250 mg, 1.20 mmol) in NMP (2 mL) was cooled to 0° C. and treated with HATU (502 mg, 1.32 mmol) followed by NMM (0.2 mL). After 10 min, 54 (360 mg, 0.95 mmol) in NMP (2 mL) was added. The reaction mixture was allowed to warm to ambient temperature overnight. The solution was diluted with EtOAc, washed successively with 1M HCl, saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. Purification by reverse phase HPLC (2″ Dynamax® C18, 10-70% ACN in H2O with 0.1% HOAc over 30 min) afforded 55 as a white solid (400 mg). Mass spectrum, m/z [573.2] (M+H)+.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:21][CH:20]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:54]([O:61][C:62]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)=[O:63])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C=O)C.C(OCC)(=O)C.O>[CH2:54]([O:61][C:62]([N:64]1[CH2:69][CH2:68][N:67]([C:27](=[O:29])[CH2:26][CH2:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][NH:17][C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])=[CH:24][CH:23]=2)[CH2:66][CH2:65]1)=[O:63])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCC(=O)O)cc1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(CCC(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Yield: 73 %

Procedure:
A mixture of 11.4 ml of ethyldiisopropylamine in 20 ml of DMF is mixed successively with 3.11 g of 3-(4-tert-butyloxycarbonylaminomethylphenyl)propionic acid (starting material B4) and 4.64 g HBTU, with stirring. After ten minutes 2.45 g of 1-benzyloxycarbonylpiperazine are added and the mixture is stirred at RT for 5 h. The mixture is diluted with ethyl acetate and water. After phase separation, the organic phase is washed with 1N hydrochloric acid solution, 1N aqueous sodium hydroxide solution and water. After drying over magnesium sulfate, the organic solution is concentrated and the residue is chromatographed over silica gel (petrolether/ethyl acetate/acetone 4:5:1). Concentration of the pure fractions and drying in vacuo gives 3.91 g of the title compound as a yellowish powder. The mass spectrum shows the molecular peak MH+ at 481.8 Da.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][CH:10]=[CH:9][CH2:8]1)([O-])=O.C1(C)C=CC=CC=1.[SH-].[Na+]>O>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Agent: [Na+]
Agent: [SH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 100 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone in 400 parts of toluene, 1000 parts of toluene-containing mother liquor and a solution of 8.8 parts of sodium bisulfide in 400 parts of water are charged simultaneously to a tube reactor (volume: 100 ml) with static mixing elements. The average residence time is c. 3 minutes. The feed temperature of the components is regulated such that the reaction mixture leaves the reactor at 160° C. and is separated continuously in a separating vessel under pressure (10 bar) into an aqueous and an organic phase. The pressure is relaxed in the working up reactor containing the organic phase, which is cooled to room temperature. The product is isolated by filtration, washed with toluene and dried under vacuum at 80° C. The aqueous phase is extracted with the mother liquor, a portion of which is recycled to the reactor. In stationary operation, 86 parts of 1-aminoanthraquinone are obtained per hour in 99% purity (layer chromatography), corresponding to a yield of 98% of theory, based on 5-nitrotetrahydroanthraquinone.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15](=O)[CH2:14][C:13]2([CH3:26])[CH3:25])[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].Cl.[CH3:28][O:29][NH2:30].N1C=CC=CC=1>C(O)(C)C.C(OCC)(=O)C>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)/[C:15](=[N:30]/[O:29][CH3:28])/[CH2:14][C:13]2([CH3:25])[CH3:26])[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1)C(n1cncc1C(=O)OC(C)C)C(C)(C)CC2=O
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CO/N=C1\CC(C)(C)C(n2cncc2C(=O)OC(C)C)c2cc(OC)ccc21
Temperature: 50 °C

Procedure:
To a solution of 3-(7-methoxy-2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester, which can be prepared as described in Example 14, (0.053 g, 0.147 mmol) and methoxyamine hydrochloride (0.038 g, 0.442 mmol) in isopropanol (1 mL) is added pyridine (0.118 g, 1.472 mmol). The mixture is heated to 50° C. and after 2 hours, is diluted with ethyl acetate, and washed twice with 1M aqueous sodium bisulfate, water, and brine. The organic phase is dried over MgSO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (elution with heptane-ethyl acetate, 4:1 to 7:3) to give 3-{7-methoxy-4-[(E)-methoxyimino]-2,2-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl}-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 386.0 (M+H)+. The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-{7-Methoxy-4-[(E)-methoxyimino]-2,2-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl}-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, MeOD) δ ppm 0.96 (s, 3 H), 1.12 (s, 3 H), 1.47 (d, J=6.1 Hz, 3 H), 1.49 (d, J=6.3 Hz, 3 H), 2.43 (d, J=17.9 Hz, 1 H), 3.01 (d, J=17.9 Hz, 1 H), 3.82 (s, 3 H), 4.04 (s, 3 H), 5.40 (sept, J=6.3 Hz, 1 H), 6.65 (s, 1 H), 6.79 (d, J=2.5 Hz, 1 H), 7.09 (dd, J=9.1, 2.5 Hz, 1 H), 8.16 (d, J=9.1 Hz, 1 H), 8.30 (s, 1 H), 8.53 (s, 1 H).
Reaction SMILES: C(OC1C=C(C)C=CC=1C(OC)=O)(=O)C.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1/[CH:30]=[CH:31]/[C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[C:34]([OH:42])[CH:33]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OC1C=CC=CC=1/C=C\C1C=CC(C(OC)=O)=C(O)C=1)C1C=CC=CC=1.C(OC1C=CC=CC=1C=CC1C=CC(C(OC)=O)=CC=1F)C1C=CC=CC=1.FC1C=C(C=CC=1C)C(OC)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1/[CH:30]=[CH:31]/[C:32]1[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[C:34]([OH:42])[CH:33]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccccc2OCc2ccccc2)cc1O
Agent: COC(=O)c1ccc(/C=C\c2ccccc2OCc2ccccc2)cc1O
Agent: COC(=O)c1ccc(C)c(F)c1
Agent: COC(=O)c1ccc(C)cc1OC(C)=O
Product: O=C(O)c1ccc(/C=C/c2ccccc2OCc2ccccc2)cc1O

Procedure:
Methyl 2-acetoxy-4-methylbenzoate was converted to a mixture of methyl 4-[2-(2-benzyloxyphenyl)-(E)-ethenyl]-2-hydroxybenzoate and methyl 4-[2-(2-benzyloxyphenyl)-(Z)-ethenyl]-2-hydroxybenzoate using the procedures described in Example 8 for the synthesis of methyl 4-[2-(2-benzyloxyphenyl)ethenyl)-3-fluorobenzoate from methyl 3-fluoro-4-methylbenzoate (using 2 equivalents of lithium hexamethyldisilazide in the final step). The isomers were separated by subjecting to chromatography on silica gel using a dichloromethane:hexane (1:2) as eluant. Further purification of the isomers was achieved by crystallisation.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>O1CCCC1>[NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([O:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[O:32])=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCOC(=O)/C=C/c1c(Oc2ccc(N)cc2)ccnc1N
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccnc1N

Procedure:
Ethyl(E)-3-[2-amino-4-(4-aminophenoxy)-3-pyridyl]-2-propenoate (230 mg), p-fluorophenyl isocyanate (0.11 ml) and tetrahydrofuran (6 ml) were stirred at room temperature for 30 minutes. After adding NH type silica gel to the reaction solution, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (ethyl acetate). The solvent was distilled off under reduced pressure to obtain 200 mg of a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:32])[O:13][C:14](=O)[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]=2)=[CH:3]1.[NH3:33]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:32])[NH:33][C:14](=[O:13])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cn(-c4ccccc4)c4ccccc34)C(=O)OC2=O)c2ccccc21
Reactant: N
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(-c4ccccc4)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
150 mg of 3-(1-methyl-3-indolyl)-4-(1-phenyl-3-indolyl)furan-2,5-dione were treated with 3 ml of DMF and 10 ml of 33% aqueous ammonia at 80° C. for 4 hours. The mixture was cooled and extracted with ethyl acetate. The ethyl acetate extract was dried and concentrated. The residue was crystallized from ethyl acetate/hexane to give 120 mg of 3-(1-methyl-3-indolyl)-4-(1-phenyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 135°-137° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([N:27]=[C:28]=[O:29])=[O:26]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH2:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:28]([NH:27][C:25]([C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)=[O:26])=[O:29])[CH2:3][CH2:4]2)=[CH:14][CH:15]=1
Reactant: O=C=NC(=O)c1ccco1
Reactant: NC1CCN(CCCC(=O)c2ccc(F)cc2)CC1
Product: O=C(NC(=O)c1ccco1)NC1CCN(CCCC(=O)c2ccc(F)cc2)CC1

Procedure:
Using a procedure analogous to Example 1, 4-amino-1-(4-[4-fluorophenyl]-4-oxobutyl)piperidine is reacted with 2-furoyl isocyanate to give the title compound.
Reaction SMILES: [C:1]1([C@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[Cl:15][C:16]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Cl:15][C:16]1[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:9][CH2:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10]
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: C[C@H](CN)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](CNCc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Yield: 45.4 %

Procedure:
To a solution of (S)-2-phenyl propylamine (0.5 g, 3.7 mmol) in dry dichloromethane was added acetic acid followed by 2-chloro-3-trifluoromethylbenzaldehyde (1.1 g, 5.5 mmol) and sodium triacetoxyborohydride (1.5 g, 7.4 mmol). After the resulting mixture was stirred for 1.5 h at RT water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified by column chromatograph (Ethyl acetate:Hexane/25:75) to give the title compound as an oil (0.55 g, 45%). MS (ESI) 327.6 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH2:12](I)[CH3:13]>CN(C=O)C>[CH2:12]([N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]2)=[N:1]1)[CH3:13]
Reactant: CCI
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
To a solution of indazole (6.2 g, 52.5 mmol) in DMF (30 mL) was added sodium hydride (60% dispersion in mineral oil, 3.0 g, 75.0 mmol) at 0° C. After stirring at 0° C. for 20 min., ethyl iodide (5 mL, 62.5 mmol) was added dropwise at 0° C. The mixture was stirred at rt for 1 h, and then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phases were washed with brine, and dried over anhydrous magnesium sulfate. TLC indicated that a 2:1 mixture of two isomers was formed. The mixture was purified by flash chromatography (hexanes:ethyl acetate=4:1, then 1:1) to give 2.34 g of the title compound as a viscous oil (slow moving isomer).