Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1.[CH3:27][S:28][C:29]1[CH:30]=[CH:31][C:32]2[N:36]=[C:35]([SH:37])[NH:34][C:33]=2[CH:38]=1>C(O)(C)C>[ClH:1].[CH3:9][C:8]1[C:3]([CH2:2][S:37][C:35]2[NH:36][C:32]3[CH:31]=[CH:30][C:29]([S:28][CH3:27])=[CH:38][C:33]=3[N:34]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: CSc1ccc2nc(S)[nH]c2c1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Solvent: CC(C)O
Product: CSc1ccc2[nH]c(SCc3nccc(SCCCSc4ccc5ncc([N+](=O)[O-])n5n4)c3C)nc2c1
Product: Cl
Yield: 145.5 %

Procedure:
0.79 g (1.93 mmol) of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitro-imidazo[1,2-b]pyridazine and 0.41 g (1.1 mmol) of 6-methylsulfanyl-1H-benzoimidazole-2-thiol in 35 ml of isopropanol are reacted as described in Example 2. 0.97 g (97%) of the title compound of m.p. 193-195° C. is isolated.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[N:10]2)[CH:6]=[CH:5][N:4]=1.[CH:18]1C=C(Cl)C=C(C(OO)=O)C=1.[S:29]([O-:33])([O-])(=[O:31])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:18][S:29]([C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[N:10]2)[CH:6]=[CH:5][N:4]=1)(=[O:33])=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CSc1nccc(-n2nnc3ccccc32)n1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1nccc(-n2nnc3ccccc32)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
1-(2-Methylsulfanyl-pyrimidin-4-yl)-1H-benzotriazole (27.05 g, 111 mmol) was dissolved/suspended in 600 mL of CHCl3 in a 2 L round bottom flask. The mixture was cooled with an ice bath and m-CPBA (58.03 g, 259 mmol, ca. 77%) was slowly added portionwise, while maintaining the reaction temperature below 15° C. The reaction mixture was slowly warmed to RT and stirred for 16 hours, then refluxed for 1 hour. It was cooled and treated with aqueous sodium thiosulfate; the organic layer was separated and washed with 3 portions of aqueous sodium bicarbonate. It was then dried over sodium sulfate, filtered and concentrated under reduced pressure until the formation of a suspension, which was filtered and dried to give the 1-(2-methanesulfonyl-pyrimidin-4-yl)-1H-benzotriazole as a white solid (20.78 g, 68% yield), mp=201.8-202.5° C.; MS=276 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[CH:5]=[C:6](Br)[N:7]=1.C([N:24](CC)[CH:25]([CH3:27])[CH3:26])(C)C.[NH2:30][C@@H:31]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:32]1[CH2:37][CH2:36][N:35](C(OCC2C=CC=CC=2)=O)[CH2:34][CH2:33]1.C1(N)CC1.C1([Mg]Br)CCCC1>O1CCCC1.C(OCC)(=O)C.C(O)C>[CH:25]1([NH:24][C:12](=[O:14])[C:11]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:9]([N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH:30][C@@H:31]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH:32]4[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]4)[C:3]3=[O:20])[CH:10]=2)[CH2:27][CH2:26]1
Reactant: CCN(C(C)C)C(C)C
Reactant: N[C@@H](c1ccccc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Agent: Br[Mg]C1CCCC1
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N[C@@H](c2ccccc2)C2CCNCC2)c1=O
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 0.1 g) in tetrahydrofuran (1.5 mL) within a microwave vial was added N,N-diisopropylethylamine (130 μL) and 4-[(R)-aminophenylmethyl]-1-piperidinecarboxylic acid, phenylmethyl ester (98 mg). The reaction was heated at 110° C. for 60 minutes within a microwave. The reaction was cooled to room temperature before the addition of cyclopropylamine (0.13 mL) and cyclopentylmagnesium bromide (2M in diethyl ether, 1 mL) dropwise. After stirring for 30 minutes, ethanol (1 mL) was added followed by ethyl acetate. The solvent was washed with water, and brine, then dried (Na2SO4), filtered and the solvent removed. The product was dissolved in t-butanol (2 mL) followed by the addition of 1,4-cyclohexadiene (1 mL) and 10% Pd on carbon (30 mg). The reaction mixture was heated within a microwave at 120° C. for 30 minutes, cooled to room temperature, filtered and purified by preparative HPLC (Gemini column, 0.1% trifluoroacetic acid: acetonitrile eluent) to afford N-cyclopropyl-4-methyl-3-[2-oxo-3-[[(R)-phenyl-4-piperidinylmethyl]amino]-1(2H)-pyrazinyl]-benzamide (58 mg) and 4-[(R)-4-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]phenylmethyl]-1-piperidinecarboxylic acid, phenyl ester (19 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:32]1(O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OC1CCCCC1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(O)cc3)oc2C)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(OC4CCCCC4)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
To a 0° C. solution of 2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy)-phenoxy}-2-methyl-propionic acid ethyl ester (0.60 g, 1.41 mmol), cyclohexanol (0.212 g, 2.11 mmol) and triphenyl phosphine (0.55 g, 2.10 mmol) in THF (18 mL) was added diisopropyl azodicarboxylate (0.43 g, 2.12 mmol) in THF (2 mL). The reaction was warmed to room temperature and stirred under N2 for 18 h. Silica gel was added directly to the reaction mixture and the solvent removed in vacuo to absorb the crude product onto the silica gel. The crude product was then purified by flash chromatography (3/1 hexanes/EtOAc) to afford 0.339 g (47%) 2-(4-{2-[2-(4-cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. 1H NMR (500 MHz, CDCl3) δ 7.94-7.85 (m, 2H), 6.92 (d, 2H, J=9.0 Hz), 6.82-6.75 (m, 4H), 4.32-4.23 (m, 1H), 4.21-4.16 (m, 4H), 2.98-2.90 (m, 2H), 2.39 (s, 3H), 2.05-1.95 (m, 2H), 1.85-1.78 (m, 2H), 1.62-1.51 (m, 3H), 1.52 (s, 6H), 1.42-1.25 (m, 3H), 1.27 (t, 3H, J=7.23 Hz); MS (ES+) Calc'd for C30H38NO6: Found m/e 508.3 (M+1, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:29])[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][C:26](=[O:28])[NH2:27])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30].O1CCOCC1>CCO>[ClH:30].[C:26]([CH2:25][O:24][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([O:22][CH3:23])[CH:19]=1)[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:29])(=[O:28])[NH2:27]
Reactant: COc1cc(OCC(N)=O)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc(OCC(N)=O)cc(C(=O)NC2CCNCC2)c1
Temperature: 25 °C

Procedure:
2.20 g (5.4 mmol) of 4-(3-carbamoylmethoxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester was suspended under argon in 40 mL of EtOH at rt; while stirring, 6.75 mL of HCl/dioxane (4 molar) was added; the heterogeneous reaction mixture was heated up to reflux to achieve a clear solution. After cooling down to rt, the solvents were removed by evaporation i.V. and the residue was dried in high vacuum at rt for 5 hours. This crude product was recrystallised from MeCN to yield 1.53 g of 3-carbamoylmethoxy-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride as colorless solid [MS: 308.3 (MH+)]; the mother liquor contained 0.80 g of [3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-acetic acid ethyl ester hydrochloride as light yellow amorphous solid. MS: 337.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1Br.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1B(O)O>COCCOC.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=1[F:10]
Reactant: COc1cccc(F)c1B(O)O
Reactant: Clc1ccc(Br)c(Cl)c1
Solvent: O
Solvent: COCCOC
Product: COc1cccc(F)c1-c1ccc(Cl)cc1Cl
Yield: 62.7 %

Procedure:
Treatment of 2,4-dichlorobromobenzene (13.8 g, 61.2 mmol) with 2-fluoro-6-methoxybenzene boronic acid (5.0 g, 29.4 mmol) in DME-water (5:1, 150 mL) according to the procedure described for Example 69, Step 1 provided 5.0 g (63%) of 2,4-dichloro-2′-fluoro-6′-methoxybiphenyl as a colorless oil.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][CH2:4][OH:5].[C:7]1(O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH3:6][C:2](=[CH2:1])[CH2:3][CH2:4][O:5][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=C(C)CCO
Reactant: Oc1ccccc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)CCOc1ccccc1
Temperature: 70 °C

Procedure:
To a stirred solution of 3-methyl-3-buten-1-ol (1.17 ml) in tetrahydrofuran (30 ml) were added sequentially phenol (1.32 g), triphenylphosphine (3.85 g) and di-tert-butyl azodicarboxylate (3.27 g). The mixture was heated at 70° C. overnight and then was concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0→70:30) to give (3-methyl-but-3-enyloxy)-benzene (2.06 g, quant.) as a colourless semi-solid which crystallized on standing.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>>[Cl:18][C:15]1[CH:14]=[C:13]2[C:12](=[CH:17][CH:16]=1)[NH:11][C:8](=[O:10])[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[C:19]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(O)Cc1ccccn1
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1ccccn1
Yield: 23 %

Procedure:
Synthesized from (2-pyridyl)-acetic acid and (2-amino-5-chloro-phenyl)-phenyl-methanone according to general procedure 2 Yield 23%.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10](O)[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2>CCCCCCCC>[C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10]([C:22]3[CH:21]=[CH:20][C:19]4[N:18]([CH3:17])[C:30]5[C:25]([C:24]=4[CH:23]=3)=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Reactant: Cn1c2ccccc2c2ccccc21
Solvent: CCCCCCCC
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc2c(c1)c1ccccc1n2C
Yield: 18.3 %

Procedure:
A mixture of 2.2 g (10.0 mmol) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (compound (202), Example 1a, Table 2), 1.8 g (10.0 mmol) of N-methylcarbazole and 0.2 g of Fulcat 22B and 20 ml of n-octane is refluxed for 5 hours under nitrogen. The Fulcat 22B catalyst is subsequently removed by filtration and excess n-octane is distilled off on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system dichloromethan/hexane=1:2 to 1:1 and subsequent crystallisation of the pure fractions from methanol yields 0.70 g (10%) of 7-tert-butyl-5-methyl-3-(9-methyl-9H-carbazol-3-yl)-3H-benzofuran-2-one, m.p. 84°-90° C. (compound (120), Table 1). The product may additionally contain minor amounts of other structural isomers in accordance with the substitution at the carbazole ring.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:18].[OH:19]OS([O-])=O.[K+].[OH2:25]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:18])(=[O:19])=[O:25]
Reactant: Cc1ccc(C)c(CSc2c(C)ccc[n+]2[O-])c1
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Product: Cc1ccc(C)c(CS(=O)(=O)c2c(C)ccc[n+]2[O-])c1
Temperature: 24 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4.0 g of 2-[((2,5-dimethylphenyl)methyl)thio]-3-methylpyridine-1-oxide in 50 mL of methanol, cooled to 3° C., was added a solution of 14.1 g of Oxone® in 50 mL of water over a period of 50 minutes. The reaction mixture was stirred at 24° C. overnight and then diluted with 200 mL of water. The product was extracted into chloroform and dried over magnesium sulfate. Evaporation of solvent under reduced pressure gave 4.1 g of 2-[((2,5-dimethylphenyl)methyl)sulfonyl]-3-methylpyridine-1-oxide as a white crystalline solid, having a melting point of 171–173° C. The 1H NMR spectrum (CDCl3) was in agreement with the expected structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.CO.C[C:12](C)([O-:14])C.[K+]>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:14][CH3:12])=[N:3][CH:4]=1
Reactant: CC(C)(C)[O-]
Reactant: Brc1ccc(Br)nc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,5-dibromopyridine (6.95 g, 29 mmol) in N,N-dimethylformamide (5 ml) was added methanol (3.56 ml) and 1M potassium tert-butoxide (32.3 ml) and the resulting mixture was stirred at room temperature for 18 hours. The resulting slurry was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluting with a 1:9 mixture of ether and hexane to afford the 5-Bromo-2-methoxypyridine compound as an oil.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[Br:30])[CH2:24][CH2:25]Br.FC1C=C(C=CC=1Br)CCO.CC(C)([O-])C.[K+].C([C:50]1([CH:56]2[CH2:61][CH2:60][CH:59]([CH2:62][CH:63]=O)[CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)C>CCOCC.C1COCC1.C1(C)C(C)=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23](/[CH:24]=[CH:25]\[CH2:63][CH2:62][CH:59]2[CH2:58][CH2:57][CH:56]([CH:50]3[CH2:51][CH2:52][CH:53]([CH2:1][CH3:2])[CH2:54][CH2:55]3)[CH2:61][CH2:60]2)[CH:27]=[CH:28][C:29]=1[Br:30]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Fc1cc(CCBr)ccc1Br
Reactant: CCC1(C2CCC(CC=O)CC2)CCCCC1
Agent: CC(C)(C)[O-]
Agent: OCCc1ccc(Br)c(F)c1
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC1CCC(C2CCC(CC/C=C\c3ccc(Br)c(F)c3)CC2)CC1
Reaction time: 2 h
Yield: 42 %

Procedure:
Into a flask, were placed triphenylphosphine (2.9 g, 11 mmol) and 3-fluoro-4-bromophenethylbromide (2.2 g, 11 mmol) prepared from 3-fluoro-4-bromophenethylalcohol, followed by adding and dissolving xylene (15 ml), heating under reflux for 10 hours, adding THF (10 ml) to the reaction solution and stirring under ice-cooling, adding potassium-t-butoxid (1.1 g, 10 mmol) slowly to the reaction solution, stirring the reaction solution after the completion of dropping at room temperature for 2 hours, adding THF (10 ml) solution of 4-(ethylcyclohexyl) cyclohexylacetoaldehyde (2.4 g, 10 mmol), further stirring for 5 hours, adding ether after the completion of reaction, filtering off white solid deposited, concentrating the filtrate under reduced pressure, purifying the obtained brown oil by means of silica gel chromatography, to obtain a mixture (1.8 g, 4.2 mmol) of 1-(3-fluoro-4-bromophenyl)-4-(4-(4-ethylcyclohexyl)cyclohexyl)-2-Z-butene with its E-isomer.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35]([O:37]CC)=O)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:40](Cl)Cl.[CH2:43](O)[CH3:44]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:7]=[CH:33][CH:32]=[C:31]([NH:34][C:35](=[O:37])[CH2:40][CH2:43][CH3:44])[C:30]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCCl
Reactant: CCO
Reactant: CCCCc1nc2ccc(NC(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCCc1nc2c(NC(=O)CCC)cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-6-ethoxycarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate amorphous substance, Rf value: 0.30 (Silica gel: methylene chloride/ethanol=19:1)
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([Cl:8])=[O:7])[CH:3]=[N:2]1.[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[N:11]=1>>[ClH:8].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[C:12]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:4]3[CH:3]=[N:2][S:1][CH:5]=3)=[O:7])[CH2:26][CH2:25]2)[N:11]=1
Reactant: O=C(Cl)c1cnsc1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)c4cnsc4)CC3)nc(N)c2cc1OC
Product: Cl

Procedure:
The title compound was prepared from isothiazole-4-carbonyl chloride (1.01 g.) and 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline (1.99 g.) following previously described procedures. The product had a m.p. of 286°-287° C. with decomposition.
Reaction SMILES: [CH3:1][CH:2](C)[C:3]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1)([CH3:7])[C:4]([O-:6])=[O:5].[CH3:24]O>[Pd]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]([CH3:7])([CH2:2][CH3:1])[C:4]([O:6][CH3:24])=[O:5])=[CH:10][CH:11]=1
Reactant: CC(C)C(C)(Oc1ccc(OCc2ccccc2)cc1)C(=O)[O-]
Reactant: CO
Agent: [Pd]
Product: CCC(C)(Oc1ccc(O)cc1)C(=O)OC

Procedure:
A solution of methyl-(4-(benzyloxy)phenoxy)-2-methylbutanoate (32 g) in 100 mL MeOH was hydrogenated using 10% Pd/C at 40 psi. The mixture was filtered through a pad of celite to remove the catalyst. The filtrate was concentrated to afford thick oily residue (21 g, quantitative).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C([O:8][C:9]1[C:14]2[CH:15]([C:21]#[N:22])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1)(=O)C.C(O)C.Cl.CN1CCCCC1>CN1CCCCC1>[OH:8][C:9]1[C:14]2[CH:15]([C:21]3[NH:22][N:3]=[N:2][N:1]=3)[CH2:16][C:17]([CH3:19])([CH3:20])[O:18][C:13]=2[CH:12]=[C:11]([C:23]([CH3:30])([CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:10]=1
Reactant: CCCCCCC(C)(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)CC2C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CN1CCCCC1
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)CC2c1nnn[nH]1
Reaction time: 1 h

Procedure:
Finely ground sodium azide (325 mg, 5 mmole) is added to a solution of 5-acetoxy-4-cyano-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran (1.855 g, 5 mmole) in 10 ml ethanol-free chloroform containing 271 mg (2 mmole) N-methylpiperidine hydrochloride and 5 drops of N-methylpiperidine. The mixture is heated at reflux for one hour, another 2 mmoles of N-methylpiperidine hydrochloride is added, refluxing is continued for one hour and the mixture is allowed to stand overnight at room temperature. The mixture is partitioned between chloroform and aqueous sodium carbonate solution, the aqueous phase is adjusted to pH 5 and extracted again with chloroform. The combined organic layers are washed with water, dried (MgSO4) and the solvent evaporated in vacuo to afford the title compound.
Reaction SMILES: [CH2:1]([N:5]([CH2:45][CH2:46][CH2:47][CH3:48])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][C:22]=2[C:31]([N:33]2[C@H:42]([CH2:43][OH:44])[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34]2)=[O:32])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C1COCC1.CO.O.O[Li].O>O>[CH2:45]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[C:31]([N:33]2[C@H:42]([CH2:43][OH:44])[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34]2)=[O:32])[N:11]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)=[O:7])[CH2:46][CH2:47][CH3:48]
Reactant: CCCCN(CCCC)C(=O)c1cn(CCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCN(CCCC)C(=O)c1cn(CCc2ccccc2)c(-c2ccc(C(=O)O)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of methyl 4-(4-(dibutylcarbamoyl)-1-phenethyl-1H-imidazol-2-yl)-3-((S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (110 mg, 0.169 mmol) in mixed solvents (2:2:1 THF/MeOH/H2O, 5.0 mL) was treated with LiOH H2O (21 mg, 0.507 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature over 30 min and stirring was continued for 1 h. The reaction mixture was concentrated to give crude product, which was diluted with water and extracted with MTBE. The aqueous layer was neutralized with 0.5N HCl and extracted with DCM (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title product (100 mg, 91%), which was used without purification. MS(ESI+) m/z 637.2 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(O)(=O)C.C(N(CC)CC)C.[CH:35]1([C:38]2[N:43]=[C:42]([C:44](=N)OCC)[CH:41]=[CH:40][N:39]=2)[CH2:37][CH2:36]1>C(O)C>[CH:35]1([C:38]2[N:43]=[C:42]([C:44]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:23][CH2:22][CH2:21][CH2:20]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH:41]=[CH:40][N:39]=2)[CH2:37][CH2:36]1
Reactant: CCOC(=N)c1ccnc(C2CC2)n1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1)N1CCCC1
Temperature: 40 °C

Procedure:
To a suspension of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (1.0 g, 2.76 mmol) and acetic acid (2.5 mL, 43.4 mmol) in ethanol (7 mL) was added triethylamine (1.5 mL, 10.8 mmol). A solution of ethyl 2-cyclopropylpyrimidine-4-carbimidate (530 mg, 2.77 mmol) in ethanol (3 mL) was added. The reaction mixture was heated at reflux for 30 min, then was cooled. The solvent was removed under reduced pressure and ethyl acetate (100 mL) was added to the residue followed by water (10 mL) and a saturated aqueous solution of ammonium chloride (50 mL). The layers were separated and the organics were washed with a saturated aqueous solution of sodium bicarbonate (75 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the resulting residue was added dichloromethane (4 mL) and methyl tert-butyl ether (35 mL). The mixture was stirred at 40° C. unit it was homogeneous. The solution was cooled to room temperature and stirred for 18 h. The resulting solids were filtered and rinsed with ether to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 1.10-1.17 (m, 2H) 1.18-1.23 (m, 2H), 1.57-1.70 (m, 1H) 1.82-2.05 (m, 7H) 2.27-2.34 (m, 1H) 2.63-2.72 (m, 1H) 2.97-3.07 (m, 1H) 3.14-3.22 (m, 1H) 3.43-3.54 (m, 3H) 3.58-3.67 (m, 1H) 4.37 (d, 1H) 4.53 (d, 1H) 6.76 (d, 1H) 7.95 (m, 2H) 8.67 (d, 1H) 10.46 (br, 1H). MS (ES+) (M+H) 418.5; LCMS retention time 2.72 min (Method L).