Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[CH2:11][CH2:10]3)=[CH:5][CH:4]=[C:3]1[C:17]#[N:18].[I-].[Sm+3].[I-].[I-].[C:23](Cl)(=[O:25])[CH3:24].Cl>C(#N)C>[C:23]([C:5]1[CH:4]=[C:3]([C:17]#[N:18])[N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10]2)(=[O:25])[CH3:24]
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)CCC2=O
Reactant: CC(=O)Cl
Agent: Cl
Agent: [I-]
Agent: [Sm+3]
Solvent: CC#N
Product: CC(=O)c1cc(C#N)n(C)c1-c1ccc2c(c1)CCC2=O
Temperature: 120 °C
Yield: 9 %

Procedure:
To a stirred solution of 1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile (0.25 g, 1.0 mmol) in acetonitrile (25 mL) was added samarium iodide (0.5 g, 1.2 mmol) and acetyl chloride (1.75 mL, 24.6 mmol). The reaction mixture was heated in microwave to 120° C. for 10 minutes. The mixture was treated with a 10% aqueous HCl solution (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (30% ethyl acetate in hexane) to give 4-acetyl-1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile as a tan solid (0.025 g, 8%). MS (ESI) m/z 279; HRMS: calcd for C17H14N2O2+H+, 279.1128; found (ESI, [M+H]+), 279.1125.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([CH2:26]O)[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].CS(Cl)(=O)=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C(Cl)Cl.C(N(CC)CC)C.C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([Si:22]([CH3:23])([CH3:24])[CH3:25])[CH:19]=[C:18]([CH2:26][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CO)cc([Si](C)(C)C)c1
Reactant: C1CCNC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CN2CCCC2)cc([Si](C)(C)C)c1
Reaction time: 8 h

Procedure:
398 mg of the ethyl (RS)-(4-cyano-phenylamino)-(3-hydroxymethyl-5-trimethylsilanyl-phenyl)-acetate described in Example 156.3 were dissolved in 6 ml of CH2Cl2 g and 0.41 ml of triethylamine followed by 0.1 ml of methanesulphonyl chloride were added dropwise at 0° C. The mixture was stirred overnight and an intermediate was then isolated by extraction. This was taken up in 5 ml of THF and stirred together with 0.41 ml of triethylamine and 0.32 ml of pyrrolidine. By repeat extraction there was obtained a crude product, which was purified by column chromatography (cyclohexan/ethyl acetate). There were obtained 130 mg of ethyl (RS)-(4-cyano-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-trimethylsilanyl-phenyl)-acetate as a light brown solid; MS: 460 ([M]+).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].C[O-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35])[C:27](OC)=[O:28])=[CH:21][CH:20]=1)#[N:12]>CO.O1CCOCC1>[CH2:32]([C:31]1[N:6]=[C:4]([CH:3]([CH3:7])[CH3:2])[NH:5][C:27](=[O:28])[C:26]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:13]([C:11]#[N:12])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:24][CH:23]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Reactant: CC(C)C(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCc1nc(C(C)C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 62.8 %

Procedure:
A solution of 2-methylpropanimidamide hydrochloride (10 g), 28% sodium methoxide (25 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (14 g) in methanol (140 mL) and 1,4-dioxane (70 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (9.7 g, 62%) as a pale-yellow solid.
Reaction SMILES: [C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[BH4-].[Na+]>CO.Cl[Ni]Cl>[C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([F:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C1CCCC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Oc1cc(N)c(F)cc1C1CCCC1
Reaction time: 0.17 h
Yield: 68.1 %

Procedure:
To a solution of 2-cyclopentyl-4-fluoro-5-nitrophenyl methyl carbonate (2022 mg, 7.14 mmol) and NiCl2 (925 mg, 7.14 mmol) in methanol (10 mL) cooled to 0° C. was added NaBH4 (810 mg, 21.42 mmol) portion-wise. The reaction was stirred for 10 min then quenched with NaHCO3. The mixture was diluted with ethyl acetate and filtered through a pad of Celite. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexanes) provided 5-amino-2-cyclopentyl-4-fluorophenyl methyl carbonate (1232 mg, 68% yield) as brown solid. 1H NMR (400.0 MHz, DMSO-d6) δ 6.94 (d, J=12.6 Hz, 1H), 6.50 (d, J=8.2 Hz, 1H), 5.17 (s, 2H), 3.81 (s, 3H), 2.84 (dd, J=8.4, 17.2 Hz, 1H), 1.87-1.80 (m, 2H), 1.75-1.67 (m, 2H), 1.62-1.53 (m, 2H), 1.45-1.36 (m, 2H). MS (ESI) m/z (M+H+): 255.1.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[CH:19]=1)=[C:8]2[C:12]([O:14]CC=C)=[O:13])[CH3:3].C(C(CCCC)C([O-])=O)C.[Na+:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[CH:19]=1)=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:36]
Reactant: C=CCOC(=O)C1=C(c2cccc(CO)c2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd]
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cccc(CO)c3)C[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate prepared in the above step, sodium 2-ethylhexanoate (242 mg) and triphenylphosphine (32 mg) were dissolved in THF (10 ml), and the solution was cooled to 0° C. Thereto tetrakis(triphenylphosphine) palladium(0) (70 mg) was added. Thirty minutes later, thereto hexane (3 ml) was added and then the solution was stirred for additional 30 minutes. The resulting crystals were filtered under nitrogen atmosphere, and dried under reduced pressure to give sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (217 mg).
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH:19]1[O:23][CH:22]([CH2:24][O:25]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]([O:45][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:20]1[F:54])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O>[C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH:19]1[O:23][CH:22]([CH2:24][OH:25])[CH:21]([O:45][C:46](=[O:53])[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:20]1[F:54])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ncnc2c1ncn2C1OC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(OC(=O)c2ccccc2)C1F)c1ccccc1
Solvent: CC(=O)O
Product: O=C(Nc1ncnc2c1ncn2C1OC(CO)C(OC(=O)c2ccccc2)C1F)c1ccccc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 56.8 %

Procedure:
Compound 55.3 (13.0 g, 17.4 mmol) was treated with 80% AcOH (100 mL) and stirred at 40° C. for 5 h. The solvent was removed in vacuo and the mixture was subjected to Combiflash purification (SiO2, 330 g, 0-100% EtOAc-hexanes gradient) which afforded 55.4 as a white solid (4.72 g, 45%).
Reaction SMILES: [CH2:1]([Li])CCC.[N:6]12[CH2:13][CH2:12][CH:9]([CH2:10][CH2:11]1)[C@H:8]([NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1[CH3:24])[CH2:7]2.CN(C)C=O.Cl>CCCCCC.O1CCCC1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13]1)[C@H:8]([N:14]1[CH:1]=[CH:24][C:17]3[C:16](=[CH:21][CH:20]=[CH:19][C:18]=3[O:22][CH3:23])[C:15]1=[O:25])[CH2:7]2
Reactant: [Li]CCCC
Reactant: COc1cccc(C(=O)N[C@@H]2CN3CCC2CC3)c1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc2c(=O)n([C@@H]3CN4CCC3CC4)ccc12
Temperature: -10 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of n-butyllithium (2.2 mmol) in hexane was added in a dropwise fashion to a stirred solution of (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-methylbenzamide (0.24 g, 0.87 mmol), from Example 1, Method B, in dry tetrahydrofuran (1.0 mL) at -70° C. The mixture was maintained at -10° C. and stirred for 1 hour. The mixture was then cooled to -70° C. and dimethylformamide (0.1 mL) added. The reaction mixture was allowed to warmto room temperature over 1.5 hours, then cooled to 0° C. and acidified with aqueous hydrochloric acid (10%). The layers were separated and the aqueous phase was washed with ethyl acetate. The aqueous layer wasthen made basic with aqueous sodium hydroxide (10N) and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. Evaporation of solvents gave (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-5-methoxy-1 (2H)-isoquinolinone as a white solid (0.23 g, 0.804 mmol). Preparation of the hydrochloride salt from ethanol-hydrogen chloride gave (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-5-methoxyl-1(2H)-isoquinolinone hydrochloride, m.p. 275°-277° C., [α]D25 -106.7° (c=0.30, H2O).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1.[CH:13]([N:16](CC)C(C)C)(C)C.S(Cl)(Cl)=O.[C-]#N.[Na+]>C1COCC1.CN(C)C1C=CN=CC=1.CC(OC)(C)C.O>[F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:13]#[N:16])=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: OCc1ccc(C(F)(F)F)nc1
Agent: CN(C)c1ccncc1
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: N#CCc1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of (6-trifluoromethyl-pyridin-3-yl)-methanol (4.93 g, 27.8 mmol) in THF (50 mL) were added N,N-diisopropyl ethyl amine (5.7 mL, 33 mmol) and 4-dimethylaminopyridine (17 mg, 0.14 mmol). After cooling to 0° C. thionyl chloride (4.8 mL, 56 mmol) was added dropwise over a period of 10 min. After stirring for 30 min. at 0° C., the ice bath was replaced with a water bath and stirred for 2 h at ambient temperature. The resulting brown reaction mixture was concentrated in vacuo, diluted with TBME (50 mL) and cooled to 0° C. before aqueous NaHCO3 (1M, 100 mL) was added. The mixture was stirred for 30 min., the aqueous layers were extracted with TBME (50 mL) and the combined organic layers were washed with aqueous NaHCO3 (1M, 50 mL) and brine (50 mL). Drying over sodium sulphate was followed by concentration. The resulting oil (6.44 g) was dissolved in DMSO (15 mL) and sodium cyanide (1.36 g, 27.8 mmol) was added. The resulting dark reaction mixture was stirred for 18 h at ambient temperature under a nitrogen atmosphere. It was diluted with TBME (50 mL) and treated with ice (30 g) and water (50 mL). The aqueous layer was separated and extracted with TBME (50 mL). The organic layers were washed twice with water (50 mL) and brine (30 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 50:50) afforded the title compound (3.59 g, 59%) as a light brown oil. MS m/e: 185.3 [M−H]−.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[CH:20]=3)[C:10]=2[O:9]1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CNCC1Cc2cccc(Br)c2O1
Product: CNCC1Cc2cccc(-c3cccc(Cl)c3)c2O1

Procedure:
The title compound was prepared (0.59 g, 53%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 3-chlorophenylboronic acid (0.194 g, 1.24 mmol). mp 177-178° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:8][CH:9]=2)[N:4]([CH:19]2[CH2:21][CH2:20]2)[CH:3]=1.[O:22]=[C:23]1[NH:28][CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[CH:19]1([N:4]2[C:5]3=[N:6][C:7]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)=[CH:8][CH:9]=[C:10]3[C:2]([N:28]3[CH2:27][CH2:26][N:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][C:23]3=[O:22])=[CH:3]2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)N1CCNC(=O)C1
Reactant: Brc1cn(C2CC2)c2nc(OCc3ccccn3)ccc12
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(c2cn(C3CC3)c3nc(OCc4ccccn4)ccc23)C(=O)C1
Temperature: 120 °C
Yield: 11.8 %

Procedure:
A mixture of 3-bromo-1-cyclopropyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridine (0.263 g, 765 μmol), ethyl 3-oxopiperazine-1-carboxylate (0.158 g, 0.918 mmol), N,N′-dimethylethane-1,2-diamine (33.8 μL, 0.313 mmol), copper(I) iodide (32 mg, 168 μmol), potassium phosphate (tribasic, n-hydrate) (0.179 g, 841 μmol) in DMF (10 mL) is heated at 120° C. for 15 h. The mixture is cooled to room temperature and further copper(I) iodide (0.145 g, 765 μmol), potassium phosphate (tribasic, n-hydrate) (0.536 g, 2.52 mmol) and N,N′-dimethylethane-1,2-diamine (165 μL, 1.53 mmol) are added, followed by ethyl 3-oxopiperazine-1-carboxylate (0.132 g, 0.765 mmol). After further heating for 24 h under nitrogen at 100° C., the mixture is concentrated in vacuo, diluted with MeOH and poured onto a SCX-2 ion-exchange column. This is washed with 3 column volumes of MeOH and then the product collected in the subsequent one column volume flush of 7 M methanolic ammonia. The solution is concentrated in vacuo and purified by column chromatography on silica, eluting with 0 to 100% EtOAc in isohexane, to give the title compound as a yellow oil (40 mg, 0.09 mmol). MS (m/z): 436 (M+1). 1H-NMR (400 MHz, CDCl3): 0.89-0.99 (m, 4H), 1.31 (t, 3H), 3.31-3.37 (m, 1H), 3.76-3.78 (m, 2H), 3.82-3.88 (m, 2H), 4.22 (q, 2H), 4.33 (s, 2H), 5.60 (s, 2H), 6.72 (d, 1H), 7.00 (s, 1H), 7.18-7.22 (m, 1H), 7.48-7.52 (m, 1H), 7.64-7.69 (m, 2H), 8.59-8.61 (m, 1H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:33]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:27]5[C:22]4=[CH:23][CH:24]=[CH:25][CH:26]=5)=[CH:17][CH:16]=3)=[N:13][CH:14]=2)O1.Br[C:36]1[CH:37]=[CH:38][C:39]([C:42]2[N:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:45]3[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=3[N:43]=2)=[N:40][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.CC(C)=O.C(Cl)Cl.C1COCC1>[C:47]1([N:46]2[C:45]3[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=3[N:43]=[C:42]2[C:39]2[N:40]=[CH:41][C:36]([C:9]3[CH:14]=[N:13][C:12]([C:15]4[CH:16]=[CH:17][C:18]([N:21]5[C:22]6[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=6[C:28]6[C:33]5=[CH:32][CH:31]=[CH:30][CH:29]=6)=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[CH:37][CH:38]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: c1ccc(-n2c(-c3ccc(-c4ccc(-c5ccc(-n6c7ccccc7c7ccccc76)cc5)nc4)cn3)nc3ccccc32)cc1
Yield: 69.8 %

Procedure:
Following the procedure for 19, 7 (0.757 g, 1.70 mmol), 13 (0.594 g, 1.70 mmol), tetrakis(triphenylphosphine)palladium(0) (98 mg, 85 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) yielded 21 (0.70 g, 70% yield) as a light yellow solid after flash chromatography (SiO2, 100% CH2Cl2 to 19:1 CH2Cl2-acetone).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].[CH2:25]([O:27][P:28]([CH2:33][NH:34][C:35]([C:37]1[N:38]=[C:39]([NH2:42])[S:40][CH:41]=1)=[O:36])(=[O:32])[O:29][CH2:30][CH3:31])[CH3:26]>>[CH2:25]([O:27][P:28]([CH2:33][NH:34][C:35]([C:37]1[N:38]=[C:39]([NH:42][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)[S:40][CH:41]=1)=[O:36])(=[O:32])[O:29][CH2:30][CH3:31])[CH3:26]
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Reactant: CCOP(=O)(CNC(=O)c1csc(N)n1)OCC
Product: CCOP(=O)(CNC(=O)c1csc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2)n1)OCC

Procedure:
The above prepared 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid is coupled with {[(2-amino-thiazole-4-carbonyl)-amino]-methyl}-phosphonic acid diethyl ester following the procedure described in Example 1, Step D to give [({2-[3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoylamino]-thiazole-4-carbonyl}-amino)-methyl]-phosphonic acid diethyl ester.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.O1CCCC1>O>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH:7]2[CH2:8][CH2:9][CH:4]([CH:3]=[O:2])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)#[N:15]
Reactant: COC=C1CCC(c2ccc(C#N)cc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CCC(C=O)CC2)cc1
Yield: 99 %

Procedure:
A mixture of 4.2 g of p-[4-(methoxymethylene)cyclohexyl]benzonitrile and 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 30 minutes in a round flask. The mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed once with 100 ml of water, dried over magnesium sulphate and concentrated. There were obtained 3.9 g (100%) of 4-(p-cyanophenyl)cyclohexanecarboxaldehyde as a colourless oil which was used in the next step without further purification: trans/cis ratio about 3:1, Rf-value (ethyl acetate/petroleum ether, vol. 3:7) 0.41. By recrystallization from hexane there could be obtained pure trans-4-(p-cyanophenyl)cyclohexanecarboxaldehyde; m.p. 57.1° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>CCOCC>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: c1ccsc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 8.4 g of thiophene in 200 ml of ether is stirred, cooled to 0° C. under nitrogen while 48.0 g of butyl lithium is added dropwise via syringe. After stirring for 1 hour, the reaction mixture is cooled to -78° C. and 35.0 ml of tributyl tin chloride is added dropwise via syringe. Following stirring at room temperature for 30 minutes, the reaction mixture is quenched with 60 ml of water, poured over crushed ice and extracted with ether (3×200 ml). The organic layer is dried and evaporated in vacuo to give 46.2 g of the desired product as a residue.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:34]=[CH:33][C:17]([CH2:18][S:19][C:20]3[N:29]([CH3:30])[C:28](=[O:31])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[CH3:32])[N:21]=3)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)=O)C.[Li+].[BH4-]>C1COCC1>[OH:3][CH2:4][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH2:18][S:19][C:20]3[N:29]([CH3:30])[C:28](=[O:31])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[CH3:32])[N:21]=3)=[CH:33][CH:34]=2)=[O:13])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCN(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc2nc(SCc3ccc(C(=O)N4CCC(CO)CC4)cc3)n(C)c(=O)c12
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
In THF (25 ml) was dissolved 2-[4-(4-ethoxycarbonylpiperidylcarbonyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (3.593 g) followed by addition of LiBH4 (254 mg), and the mixture was stirred for 30 minutes. This reaction mixture was washed with 1N-HCl and saturated aqueous NaCl solution in that order, dried, and concentrated. The residue was rinsed with ethyl acetate to provide the title compound as colorless-solid (1.871 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:16])=[CH2:15].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C.C(OCC)(=O)C.CCCCCC>C1C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12][CH2:13]1
Reactant: C=C(C)COc1cc(C(=O)OC)ccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(=O)c1ccc2c(c1)OCC2(C)C
Temperature: 120 °C
Yield: 36.2 %

Procedure:
A mixture of methyl 4-bromo-3-(2-methylallyloxy)benzoate (0.500 g, 1.754 mmol), tributyltin hydride (0.708 mL, 2.63 mmol), and AIBN (0.035 g, 0.210 mmol) in benzene (20 mL) was heated in a pressure tube at 120° C. for 22 h. The volatiles were removed under vacuum. The residue was diluted with ethyl acetate (100 mL) and shaken with 10% KF solution. The resulting precipitate was removed by suction filtration through CELITE®. The organic layer of the filtrate was separated, washed with saturated NaHCO3 solution and brine, and dried over anhydrous MgSO4. The desired product, methyl 3,3-dimethyl-2,3-dihydrobenzofuran-6-carboxylate (0.131 g, 0.635 mmol, 36.2% yield) was isolated as a colorless oil with ISCO (40 g silica gel, 1-10% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N:30]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[C:31]=[O:32]>O1CCCC1>[CH2:33]([NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Reactant: O=C=NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.69 mmol) in tetrahydrofuran (5 mL) and triethyl-amine (0.47 mL, 3.38 mmol) was added isocyanatomethyl-benzene (0.25 mL, 2.03 mmol) dropwise. The reaction mixture was stirred at 25° C. for 3 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(3-benzyl-ureido)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (215 mg, 29%) as a white solid: LC/MS m/e calcd for C26H27N3O3 (M+H)+: 430.52, observed: 430.1.