Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][CH:10]=[O:11].C[Mg+].[Br-].[CH3:16]COCC>C1COCC1>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:12])[C:2]=1[CH2:9][CH:10]([OH:11])[CH3:16]
Reactant: CCOCC
Reactant: Cc1cc(C)c(CC=O)c(C)c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cc(C)c(CC(C)O)c(C)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 68.3 %

Procedure:
Mesitylacetaldehyde (0.68 g, 4.19 mmol) was dissolved in THF (5.0 mL, dry) and MeMgBr in Et2O (3.0M, 0.75 g, 6.29 mmol)) was added slowly at 0° C. The cooling bath was removed and the reaction mixture was stirred at rt for 4.5 h. The mixture was cooled to 0° C. and excess Grignard reagent was hydrolyzed with HCl (1N). The mixture was diluted with water and extracted with Et2O. The organic layer was dried over Na2SO4, evaporated and the residue was purified by column chromatography on silica gel using MTBE, heptane and DCM as eluant giving the title compound (0.51 g, 61%). 1H NMR (CDCl3, 500 MHz) δ 6.88-6.85 (m, 2H), 4.08-3.99 (m, 1H), 2.87-2.72 (m, 2H), 2.32 (s, 6H), 2.26 (s, 3H), 1.29 (d, 3H).
Reaction SMILES: [C-]#N.[K+].FC(F)(F)S(O[C:10]1[C:20]2[O:19][CH2:18][CH2:17][C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=O)=O.[CH2:28]([N:30](CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Zn].Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O.C(OCC)(=O)C>[C:28]([C:10]1[C:20]2[O:19][CH2:18][CH2:17][C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)#[N:30]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C1=Cc2cccc(OS(=O)(=O)C(F)(F)F)c2OCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cccc(C#N)c2OCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of zinc (69.2 mg, powder) and potassium cyanide (0.12 g) in N,N-dimethylformamide (10.5 ml) was stirred for 10 minutes under nitrogen atmosphere at ambient temperature and thereto was added successively ethyl 2,3-dihydro-9-trifluoromethanesulfonyloxy-1-benzoxepin-4-carboxylate (0.53 g), triethylamine (0.25 ml), and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium (0.12 g, complex with dichloromethane (1:1)). The reaction mixture was stirred at 60° C. for 2 hours. Thereto was added a mixture of ethyl acetate and water, basified by aqueous potassium carbonate, and filtered off. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by medium pressure liquid chromatography (silica gel) using a mixture of ethyl acetate and n-hexane (1:9) to give a solid of ethyl 9-cyano-2,3-dihydro-1-benzoxepin-4-carboxylate (310 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[NH:8][C:7]=12.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl.[Pd](Cl)Cl>[C:13]1([C:11]([C:9]2[NH:8][C:7]3=[CH:2][N:3]=[CH:4][CH:5]=[C:6]3[CH:10]=2)=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)c1cc2ccnc(Cl)c2[nH]1
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Temperature: 60 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
(7-Chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanone (Example 29) (1.09 g, 4.25 mmol), palladium(II)chloride (15.4 mg, 3 mol %) and triethylamine (1.3 mL) were combined in N,N-dimethylformamide (25 mL). The reaction mixture was heated at 60° C. under an atmosphere of hydrogen for 8 h, then at room temperature for an additional 16 h. The reaction mixture was diluted with methylene chloride (25 mL) and filtered through a pad of diatomaceous earth. Evaporation of the solvents provided 1.3 g of crude orange solid. Purification by chromatography (SiO2; 0-10% methanol in methylene chloride, 1400 mL) afforded phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (196 mg, 0.893 mmol, 21%) as an off-white solid: mp 245-247° C.; 1H NMR (300 MHz, CD3OD) δ 7.18 (1H, s), 7.55-7.63 (2H, m), 7.65-7.77 (2H, m), 7.95-8.04 (2H, m), 8.17 (1H, d, J=5.7 Hz), 8.87 (1H, s); ESI MS m/z 223 [C14H10N2O+H]+; HPLC (Method A) >99% (AUC), tR=13.4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)=[O:10])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23]>CO>[NH2:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:22]([F:25])([F:23])[F:24])[CH:4]=1)=[O:10]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CO
Product: Nc1cccc(CNC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a round bottom flask was added urea 26 (700 mg, 1.87 mmol, 1.0 eq.) and methanol (15 mL). The flask was then flushed with N2 before adding 10% Pd/C (35 mg, 5% by wt.). The reaction was placed under atmospheric H2 and allowed to stir at RT for 2 h before filtering over celite and rinsing with methanol. Concentration via rotary evaporation followed by column chromatography with silica gel and 1:1 EtOAc:Hexanes afforded pure urea 27 as a white solid (415 mg, 65% yield). LC/MSD (BP Series 1100 MSD) MS (ES+) m/z 344.1 (M+H)+1 1H-NMR, Varian 400 M DMSO-d6) δ 9.05 (br. s, 1H), 8.09 (d, 1H), 7.55 (m, 2H), 6.93 (t, 1H), 6.48 (s, 1H), 6.40 (d, 2H), 5.05 (s, 2H), 4.20 (s, 2H) ppm.
Reaction SMILES: [NH2:1][CH:2]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][CH2:5][CH:6]([NH2:16])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[CH2:34][O:35][CH2:36][C:37](Cl)=[O:38]>ClCCl>[CH2:19]([O:18][CH2:17][CH:2]1[CH2:3][NH:4][CH2:5][CH:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:16][C:37](=[O:38])[CH2:36][O:35][CH2:34][C:33](=[O:40])[NH:1]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(CNCC(N)COCc1ccccc1)COCc1ccccc1
Reactant: O=C(Cl)COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1COCC(=O)NC(COCc2ccccc2)CNCC(COCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,5-diamino-1,5-dibenzyloxymethyl-3-aza-pentane (0.57 g, 1.7 mmol) (Example 6 (d)) and triethylamine (0.34 g, 3.4 mmol) in dichloromethane (10 ml) and a solution of diglycolic acid dichloride (0.29 g, 1.7 mmo11 in dichloromethane (10 ml1 were added simultaneously over 2.5 hours to vigorously stirred dichloromethane (10 ml) at 0° C. The solution was stirred at ambient temperature overnight, washed with water (2×30 ml), dried with sodium sulphate and evaporated. yield 0.59 g (78%).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([C:16]1[N:20]=[C:19]([NH:21][C:22]3[C:27]([O:28][C:29]4[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:26][C:25]([S:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)=[CH:24][N:23]=3)[S:18][N:17]=1)[CH2:12]2)=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+].[ClH:49]>CCO>[ClH:49].[OH:4][CH2:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([C:16]1[N:20]=[C:19]([NH:21][C:22]3[C:27]([O:28][C:29]4[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:26][C:25]([S:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)=[CH:24][N:23]=3)[S:18][N:17]=1)[CH2:10]2)=[O:7]
Reactant: CC(=O)OCC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)CO)ns1
Temperature: 50 °C
Yield: 83.1 %

Procedure:
2-(3-(5-(3-(2-Methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl acetate (95 mg, 0.157 mmol) was dissolved in EtOH (3 mL) and K2CO3 (excess) was added and heated to 50° C. for 1.5 hr. The reaction was partitioned between CH2Cl2 and saturated aqueous NH4Cl, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (15% methanol in EtOAc) to afford 2-hydroxy-1-(3-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone hydrochloride (78.2 mg, 0.131 mmol, 83.1% yield) as a solid after HCl salt formation. Mass spectrum (apci) m/z=562.2 (M+H—HCl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>O(C(C)=O)C(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1
Reactant: CC(=O)Nc1ccc(F)cc1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(C)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a mixture of N-(4-fluoro-2-methylphenyl)acetamide (19 g, 113.1 mmol, 1 eq) and (CH3CO)2O (190 mL) was added HNO3 (11.4 mL, 1.0 eq) dropwise at 0° C. The reaction mixture was allowed to warm to RT overnight and was subsequently poured onto ice and extracted with DCM. The organic phase was washed with aqueous NaHCO3 until the pH of the aqueous layer was >7. The organic phase was washed with water and then dried over Na2SO4. The solvent was evaporated to give the title compound as a crude solid (20 g, 84%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.82 (1H, s), 7.71 (1H, dd, J1=2.8 Hz, J2=8.0 Hz), 7.56 (1H, dd, J1=2.8 Hz, J2=9.2 Hz), 2.32 (3H, s), 2.02 (3H, s).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][CH2:41][CH2:42]O>>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:42][CH2:41][O:40][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][O:34]3)[CH:26]=2)=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCOC1CCCCO1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCOC4CCCCO4)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 61F and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (purchased from Fluka) were processed as described in Example 62A to provide the title compound.
Reaction SMILES: C([N:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH2:31])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:11])(=O)C.Br.O>O1CCOCC1>[NH2:31][C:25]1[C:21]2[C:22](=[O:24])[CH:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:11])=[C:13]([F:32])[CH:14]=3)[O:19][C:20]=2[C:28]([F:29])=[CH:27][C:26]=1[F:30]
Reactant: CC(=O)N(CCCCCCBr)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCCCCBr)c(F)c3)cc(=O)c12
Yield: 63.2 %

Procedure:
6.10 g (11.9 mmol) of the resulting 2-[4-[N-acetyl-N-(6-bromohexyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one was dissolved in 60 ml of dioxane, 40 ml of 47% aqueous HBr was added and the mixture was heated at reflux for 3 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed once with 5% aqueous sodium bicarbonate and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 3.53 g (63%) of 5-amino-2-[4-(6-bromohexylamino)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:9][CH:8]=3.[CH2:23]=O.C[O-].[Na+].[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:16]([O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH3:23])=[CH:14][C:13]2=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc2[nH]c3ccc(OCc4ccccc4)cc3c2c1
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc2[nH]c3ccc(OCc4ccccc4)cc3c2c1
Temperature: 80 °C
Yield: 99.2 %

Procedure:
To a suspension of 3-amino-6-(benzyloxy)-9H-carbazole 3 (90 mg, 0.31 mmol) and paraformaldehyde (47 mg, 1.57 mmol) in MeOH (20 mL) was added a solution of NaOMe in MeOH (0.32 mL, 1.56 mmol). The resulting mixture was heated at 80° C. for 1 h, then NaBH4 (59 mg, 1.55 mmol) was added. The resulting mixture was heated at 80° C. for 2 hrs, and then cooled to room temperature. To this solution was added NaOH (1 N, 30 mL). The mixture was then extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo to give a brown solid (93 mg, 100%). It was used directly in the next step without any further purification. 1H NMR (acetone-d6, 400 MHz) δ: 9.68 (br s, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.53 (d, J=7.6 Hz, 2H), 7.20-7.42 (m, 6H), 7.03 (dd, J=8.8, 2.4 Hz, 1H), 6.79 (dd, J=8.4, 2.4 Hz, 1H), 5.17 (s, 2H), 2.85 (s, 3H). MS: m/z=303 (M+H+)+.
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20]Cl>CCCCC>[C:1]([N:5]=[N:6][C:7]([Cl:20])([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCl
Reactant: CC(CC(C)C)=NNC(C)(C)C
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CC(C)CC(C)(Cl)N=NC(C)(C)C
Temperature: -15 °C

Procedure:
Into a 5 liter, 4-neck round bottom flask equipped with a low temperature thermometer, a chlorine inlet tube, a mechanical stirrer, and a gas exit tube protected from the atmosphere with a CaCl2 tube, was added 510 grams (3.0 moles) of methyl isobutyl ketone t-butylhydrazone, 303.6 grams (3.0 moles) of triethylamine and 2400 ml of pentane. The contents were cooled to -15°C with a dry ice-isopropanol bath. Then with rapid stirring 213 grams (3.0 moles) of chlorine were passed into the reaction mixture as fast as it was possible to control the temperature at 5°C or below. After all of the chlorine had been added the reaction temperature was adjusted to -5°C to 0°C and the reaction mixture filtered to remove the triethylamine hydrochloride. The triethylamine hydrochloride filter cake was washed with fresh pentane and the filtrate added to the original pentane solution.
Reaction SMILES: C(OC1C=C(C=C(OCC)C=1F)C[N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)C.[CH:35]([O:38][C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([O:47][CH:48]([CH3:50])[CH3:49])[CH:46]=1)[CH:42]=O)([CH3:37])[CH3:36].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH:35]([O:38][C:39]1[CH:40]=[C:41]([CH:44]=[C:45]([O:47][CH:48]([CH3:50])[CH3:49])[CH:46]=1)[CH2:42][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:37])[CH3:36]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OCC)c1F
Reactant: CC(C)Oc1cc(C=O)cc(OC(C)C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Oc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OC(C)C)c1

Procedure:
In analogy to the procedure described in example 50k), N-piperidin-4-yl-3-(1H-tetrazol-5-yl)-benzamide (example 178) was reacted with 3,5-diisopropoxy-benzaldehyde (example 126b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 479.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Reaction time: 12 h
Yield: 93 %

Procedure:
To a solution of (4-bromo-2-ethyl-phenyl)-methanol in anhydrous DMF was added TBSCl (1.5 eq.) and imidazole (1.5 eq). The mixture was stirred at that temperature for 12 hours before it was diluted with water. The mixture was extracted with Et2O and the combined organic layers were washed with H2O, brine, dried over MgSO4. The solvent was removed in vacuo to give the desired product. (93% yield). 1H NMR (300 MHz, CDCl3): δ 0.09 (s, 6H), 0.92 (s, 9H), 1.20 (t, J=7.5 Hz, 3H), 2.57 (q, J=7.5 Hz, 2H), 4.67 (s, 2H), 7.29 (s, 3H).
Reaction SMILES: [Cl-].[OH:2][CH2:3][C@@H:4]([NH3+:9])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO.CCOC(C)=O>[CH2:17]([NH:9][C@@H:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@H]([NH3+])CO
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CO)NCc1ccccc1
Reaction time: 0.17 h

Procedure:
To (2R)-3-hydroxy-1-methoxy-1-oxopropan-2-aminium chloride (1 eq.) in MeOH (1.3 M) at 0° C. was added triethylamine (1 eq.). The reaction mixture was stirred for 10 minutes and benzaldehyde (1 eq) was added. The reaction mixture was stirred for 2 hours and NaBH4 (1.5 eq.) was added portionwise to the reaction mixture over 30 min. The reaction mixture was stirred at rt for 5 hours and poured into a 1:1 mixture of saturated aqueous NH4Cl and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine and water, dried over Na2SO4, filtered and concentrated. The crude product was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (43.4 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[N:14]=[C:13](Cl)[C:12]([CH3:16])=[C:11]([CH3:17])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].C(=[NH:79])(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])=O.[Na+].Cl.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:79][C:13]1[C:12]([CH3:16])=[C:11]([CH3:17])[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([Cl:1])[N:14]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1c(Cl)nc(Cl)c(C(=O)OC(C)(C)C)c1C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(N)nc(Cl)c(C(=O)OC(C)(C)C)c1C
Temperature: 90 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
tert-Butyl 2,6-dichloro-4,5-dimethylnicotinate (1.9 g, 6.9 mmol, 1 equiv), Pd2(dba)3 (0.63 g, 0.69 mmol, 0.1 equiv), xantphos (0.80 g, 1.38 mmol, 0.2 equiv), and Cs2CO3 (5.4 g, 16.5 mmol, 2.4 equiv) was slurried in dioxane (deoxygenated by bubbling nitrogen through it for 10 min) added. Benzophenone imine (1.4 mL, 8.3 mmol, 1.2 equiv) was added and the mixture was heated at 90° C. for 2 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was taken up in MeOH (80 mL) and NaOAc (1.69, 20.6 mmol, 3 equiv) and hydroxlamine hydrochloride (0.96 g, 13.8 mmol, 2 equiv) was added. After 18 h, the reaction was added to 1 N NaOH and extracted with DCM (×2). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc/hex) to afford the product (1.1 g, 62%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.57 (br. s., 2H), 2.24 (s, 3H), 2.03 (s, 3H), 1.60 (s, 9H); LCMS (ESI, M+1): 257.15.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([OH:19])[CH3:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:20](I)[CH2:21][CH3:22]>C(Cl)(Cl)Cl.[Ag].[Ag]=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([O:19][CH2:20][CH2:21][CH3:22])[CH3:18])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(CC(C)O)cc2)cc1
Reactant: CCCI
Agent: O=[Ag]
Agent: [Ag]
Solvent: ClC(Cl)Cl
Product: CCCOC(C)Cc1ccc(-c2ccc(C(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 360 h
Yield: 30.4 %

Procedure:
Into a four-necked flask provided with a stirrer and a thermometer, 25.4 g of (-)-4-acetyl-4'-(2-hydroxypropyl)biphenyl (XXIII-43) [0.1 mol, [α]D20 =-11.2° (C=1, CHCl3)], 69.5 g (0.3 mol) of silver oxide and 255 g (1.5 mol) of propyl iodide were charged, and then stirred at room temperature for 15 days. Thereafter, the reaction mixture was diluted with 300 ml of chloroform, and silver salt was filtered off, and thereafter, the filtrate was concentrated under a reduced pressure. The resulting residue was subjected to a silica gel column chromatography (elution medium: toluene/ethyl acetate=10/1) to obtain 9.0 g of (-)-4-acetyl-4'-(2-propoxypropyl)biphenyl (XXII-43) [yield=30.5%, [α]D20 =-10.2° (C=1, CHCl3), m.p.=53°-55° C.] and 17.4 g of the starting material (XXIII-43) with recovery of 68.5%.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1[Cl:33]>CN(C=O)C>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH:9]2[CH2:10][CH2:11][CH2:12][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]2=[O:13])=[C:27]([Cl:33])[CH:28]=1
Reactant: O=C1CCCCN1C1CCCCC1
Reactant: Clc1cc(Br)ccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCCN1C1CCCCC1
Temperature: -78 °C
Yield: 37.8 %

Procedure:
Dissolve 1-cyclohexyl-piperidin-2-one (0.2 g, 1.10 mmol) in dry DMF (11 mL) cool to −78° C. and add lithium bis(trimethylsilyl)amide (1.66 mL of 1.0 M solution in THF, 1.66 mmol). After 15 min add 1-bromomethyl-2-chloro-4-bromobenzene (0.63 g, 2.21 mmol), and allow the mixture to warm to room temperature over 15 h. Partition the mixture between ether and brine, dry the organic layer over sodium sulfate and evaporate. Purify the residue by chromatography on silica gel (eluting 0% to 100% ethyl acetate in hexane) to give the desired product (0.16 g, 38%). MS (ES+) m/z=384, 386 (M+H)+.