Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[NH:7][CH2:6]1)=[O:4].[CH2:11]([O:13][C:14](=[O:27])[CH2:15][O:16][C:17]1[C:18]([N+:24]([O-:26])=[O:25])=[N:19][C:20](Br)=[CH:21][CH:22]=1)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O1CCOCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:27])=[C:18]([N+:24]([O-:26])=[O:25])[N:19]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CNC(=O)C1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(N2CC(C(=O)OC)CC2=O)nc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 5 h
Yield: 75.9 %

Procedure:
A mixture of 5-oxopyrrolidin-3-carboxylic acid methyl ester (synthesized with reference to Tetrahedron Asymmetry, 2001, vol. 12, pages 3241-3250; 1.0 g, 6.99 mmol), [(6-bromo-2-nitropyridin-3-yl)oxy]acetic acid ethyl ester (synthesized with reference to WO2004/2992; 2.13 g, 6.99 mmol), palladium acetate (157 mg, 0.699 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (417 mg, 0.699 mmol), potassium phosphate (4.83 g, 21 mmol) and 1,4-dioxane (50 ml) was stirred under a stream of nitrogen gas at 100° C. for 5 hours. After cooling, ethyl acetate was added to the reaction solution, the insoluble material was removed by filtration, the obtained filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to yield 1.95 g (76%) of the title compound in the form of a light brown syrup.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH3:25][Sn](C)(C)C.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(I)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 120 °C
Yield: 58.2 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-1-iodo-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (117 mg, 0.27 mmol), tetramethyltin (0.2 mL, 1.34 mmol), and PdCl2(PPh3)2 (38 mg, 0.054 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (5-35% EtOAc/hexanes) to give 51 mg of the title compound. MS: (+) m/z 325.09 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1.O1CCOCC1.[H][H].[ClH:22]>CO.[Pd]>[ClH:22].[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH2:12])[CH:6]=1
Reactant: COC(=O)Cc1cccc(C#N)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc(CN)c1

Procedure:
To a solution of (3-cyano-phenyl)-acetic acid methyl ester (18.06 g, 103 mmol) in MeOH (150 mL) and 4M HCl in dioxane (30.0 mL, 120 mmol) was added 10% palladium on carbon (2 g). The mixture was placed on a Parr shaker and was hydrogenated at 50 psi hydrogen for 24 h. The catalyst was removed via filtration through Celite® and the organic solution was concentrated in vacuo. The resulting solid was stirred in EtOAc and filtered to provide the title compound as a white solid (20.42 g). 1H NMR (400 MHz, CD3OD) δ 7.42-7.32 (m, 4H), 4.09 (s, 2H), 3.69 (s, 2H), 3.67 (s, 3H); MS 180 (M+1). mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([CH3:29])=[CH2:28])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](OCCCC)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].O.[NH2:31][NH2:32]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([CH3:29])=[CH2:28])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH:31][NH2:32])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)OCCCC)nn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)NN)nn1

Procedure:
Butyl 6-[N-(5-bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 4) (4.3 g, 9.3 mmol) was dissolved in ethanol (170ml) with hydrazine hydrate (17 ml, 330 mmol) and heated at reflux for 16 hours. The solvent was removed in vacuo, and the residue treated with ethyl acetate/water (200 ml of each). The organic phase separated off and the aqueous phase reextracted with ethyl acetate (2×200 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the title compound as an oil which crystallised on standing (3.66 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](N)[CH:10]=1)[N:7]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15])[CH2:6][CH2:5]2>CO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:16][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:7]3[CH2:6][CH2:5][C:4]([CH:3]=1)=[C:8]23
Reactant: NC(=O)c1ccccc1N1CCc2cc(Cl)cc(N)c21
Solvent: ClCCl
Solvent: CO
Product: O=C1Nc2cc(Cl)cc3c2N(CC3)c2ccccc21
Reaction time: 2 h

Procedure:
2-(5-chloro-7-aminoindolin-1-yl)benzamide of Example 1c (28.7 g, 0.10 mole) was dissolved in methanol/dichloromethane (DCM) solution (1:9 v/v) at 35° C. Silica gel (510 gm) was added to absorb the starting material, then the solvent was removed as much as possible under vacuum (50° C., 25 mmHg pressure for 1 hr.) The reaction mixture was then heated at 145°-155° C. and mechanically stirred for 11/2 hours. The heating was stopped when the mixture started to turn brown. The combined material was placed onto a flash chromatography column (1 kg, silica gel 60, slurry packed with DCM), eluted with DCM (16 l) and 2% CH3OH in DCM (10 l). The fractions containing the desired product were pooled and concentrated to yield a solid, 16 gm, (59%), m.p. 252°-255° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]([C:14]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:3]=1Br.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[NH2:1][C:2]1[C:3]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[CH:4][C:5]([C:14]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)C1(c2cc(Br)c(N)c(OCC(F)(F)F)c2)CCCC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Yield: 69.1 %

Procedure:
A mixture of ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (5.1 g, 14 mmol), 4-trifluoromethylphenylboronic acid (3.36 g, 17 mmol), CsF (0.28 g, 1.84 mmol) and Pd(PPh3)4 (0.410 g, 0.4 mmol) in 75 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 75 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentanecarboxylate (4.6 g) as a yellow oil.
Reaction SMILES: [N:1]1([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>C1COCC1>[N:1]1([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[C:20]4=[N:21][CH:22]=[CH:23][CH:24]=[C:25]4[NH:26][C:27]3=[O:28])=[CH:17][CH:18]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccnc1Nc1ccc(N2CCn3c2nc2ccccc23)cc1
Solvent: C1CCOC1
Product: O=c1[nH]c2cccnc2n1-c1ccc(N2CCn3c2nc2ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A mixture of N2-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]pyridine-2,3-diamine (20 mg) and 1,1′-carbonyldiimidazole (19 mg) in THF (5 mL) was stirred at ambient temperature overnight. After this time, the solids that formed were collected by filtration to afford 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (12 mg) as off-white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9]#[C:10][C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=1.FC1C=CC(N2C(C(OCC)=O)=CN=C2I)=CC=1.C(C1C=CC=CC=1[C:54]([F:57])([F:56])[F:55])#C.C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([N:12]2[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:15]=[C:11]2[C:10]#[C:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:54]([F:57])([F:56])[F:55])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Reactant: C#Cc1ccccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCOC(=O)c1cnc(I)n1-c1ccc(F)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C#Cc2ccccc2C(F)(F)F)n1-c1ccc(F)cc1

Procedure:
Ethyl 1-(4-fluorophenyl)-2-((2-(trifluoromethyl)phenyl)ethynyl)-1H-imidazole-5-carboxylate (46) was prepared in a similar manner as that described for the synthesis of compound 42 using ethyl 1-(4-fluorophenyl)-2-iodo-1H-imidazole-5-carboxylate (38) (900 mg, 2.5 mmol), 1-ethynyl-2-(trifluoromethyl)benzene (0.42 mL, 3.0 mmol), PdCl2(PPh3)2 (88 mg, 0.13 mmol), copper (I) iodide (23 mg, 0.13 mmol), diisopropyl amine (7 mL), and THF (50 mL).
Reaction SMILES: CC1OC(SCC2C(C)=C(OC)C(C)=C[N+]=2[O-])=NN=1.[CH3:20][C:21]1[O:25][C:24]([S:26]([CH2:28][C:29]2[C:34]([CH3:35])=[C:33]([O:36][CH3:37])[C:32]([CH3:38])=[CH:31][N+:30]=2[O-])=[O:27])=[N:23][N:22]=1>>[CH3:35][C:34]1[C:29]([CH2:28][S:26]([C:24]2[O:25][C:21]([CH3:20])=[N:22][N:23]=2)=[O:27])=[N:30][CH:31]=[C:32]([CH3:38])[C:33]=1[O:36][CH3:37]
Reactant: COc1c(C)c[n+]([O-])c(CS(=O)c2nnc(C)o2)c1C
Agent: COc1c(C)c[n+]([O-])c(CSc2nnc(C)o2)c1C
Product: COc1c(C)cnc(CS(=O)c2nnc(C)o2)c1C

Procedure:
The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×50 ml), dried (Mg2SO4) and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate to CH2Cl2 /MeOH (20/1) to give 2-(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl-5-methyl-1,3,4-oxadiazole (70) (5.44 g, 19%, mp 114°-115° C.) along with unreacted starting material (3.82 g) and the N-oxidized products 2-(5-methyl-1,3,4-oxadiazol-2-yl)thiomethyl-3,5-dimethyl-4-methoxypyridine-N-oxide and 2-(5-methyl-1,3,4-oxadiazol-2-yl)sulfinylmethyl-3,5-dimethyl-4-methoxypyridine-N-oxide (15.76 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].F[C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]>C1COCC1.CN(C=O)C>[F:17][C:15]1[CH:16]=[CH:9][C:10]([C:11]#[N:12])=[C:13]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)[CH:14]=1
Reactant: c1c[nH]nn1
Reactant: N#Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1-n1nccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.6 %

Procedure:
To a solution of 1H-1,2,3-triazole (3.5 g, 50.7 mmol) in THF (10 mL) and DMF (20 mL) was added portionwise, NaH (1.3 g, 51 mmol, 95%). The mixture was stirred at room temp for 30 min. Added to this was 2,4-difluorobenzonitrile (7.6 g, 55 mmol) and the mixture was stirred at 85° C. for 3 h. The white mixture was concentrated and purified by flash chromatography eluting with 0%-5%-10% EtOAc/hexane to give the title compound as white needles (0.34 g, 3% yield). 1H-NMR (300 MHz, CDCl3) δ: 7.92 (2H, s), 7.88-7.79 (2H, m), 7.19-7.12 (1H, m). LCMS [M+H]+calcd for C9H6N4F: 189.05; found: 189.12.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[C:9]([CH3:18])=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11]2.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1>CS(C)=O>[CH3:18][C:9]1[C:8]([O:7][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=2)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2=[O:17]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1c(O)ccc2c1CCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(Oc2ccc(C#N)cn2)ccc2c1CCC2=O
Temperature: 25 °C
Yield: 76.9 %

Procedure:
Add K2CO3 (1.24 g, 9.00 mmol) to a mixture of 5-hydroxy-4-methyl-1-indanone (973 mg, 6.00 mmol), 6-chloronicotinonitrile (831 mg, 6.00 mmol) and DMSO (15 ml) stirring at ambient temperature under nitrogen. Heat the mixture at 55° C. for three days. Quench the reaction with saturated aqueous NH4Cl and extract with EtOAc (2×). Wash extract with water and brine, dry (MgSO4) and concentrate on rotary evaporator to a brown foam. Purify on silica gel (10% EtOAc/DCM) to give 1.22 g of 6-(4-Methyl-1-oxo-indan-5-yloxy)-nicotinonitrile as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[CH:20]([N:23]=[C:24]=[O:25])([CH3:22])[CH3:21]>CN(C=O)C.CCOC(C)=O>[CH2:8]([O:7][C:5](=[O:6])[C:4]1[CH:10]=[CH:11][N:12]=[C:2]([NH:1][C:24]([NH:23][CH:20]([CH3:22])[CH3:21])=[O:25])[CH:3]=1)[CH3:9]
Reactant: CCOC(=O)c1ccnc(N)c1
Reactant: CC(C)N=C=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccnc(NC(=O)NC(C)C)c1
Temperature: 140 °C

Procedure:
To a solution of ethyl 2-aminoisonicotinate (500 mg, 3.01 mmol) in DMF (10 ml) is added triethylamine (1.26 ml, 9.03 mmol) and then isopropyl isocyanate (512 mg, 6.02 mmol). The reaction mixture is heated in a microwave at 140° C. for 2 hours. The reaction mixture is diluted with EtOAc, washed with water (×5), brine, dried (MgSO4) and concentrated in vacuo. Chromatography (SiO2, MeOH/DCM) affords 2-(3-Isopropyl-ureido)-isonicotinic acid ethyl ester; [M+H]+ 252
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Li])CCC.IC.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][CH3:18])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: C#Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CI
Solvent: C1CCOC1
Product: CC#Cc1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 97.1 %

Procedure:
Under argon condition, tert-butyl((4-ethynylbenzyl)oxy)dimethyl-silane (247 mg, 1.00 mmol) was dissolved in 5 mL of dry THF, cooled to −78° C., and n-butyl lithium (805 μL, 2.49 M solution in n-hexane, 2.00 mmol) was slowly added thereto. After stirring for 20 minutes at −78° C., iodomethane (313 μL, 5.00 mmol) was added again thereto. Thereafter, the temperature was raised to room temperature and the reaction mixture was stirred for 30 minutes at room temperature. Upon completion of the reaction, the reaction was terminated by adding 10 mL of aqueous saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (5 mL×4) and the organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out, and the resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 253 mg (0.971 mmol, 97%) of the desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24](O)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[CH2:23][C:24]([N:37]1[CH2:38][CH2:39][N:34]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:35][CH2:36]1)=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
To solution (15 ml) of 2,4-dibenzyloxyphenyl acetic acid (760 mg) and 1-benzylpiperazine (440 mg) in N,N-dimethylformamide are added triethylamine (0.6 ml) and diethyl cyanophosphate (420 mg) at 5° C. under stirring and stirring is continued for 15 minutes. To the reaction solution is added water and the product is extracted with dichloromethane. The dichloromethane layer is washed with water and dried. The solvent is distilled off to yield 1-(2,4-dibenzyloxyphenylacetyl)-4-benzylpiperazine (968 mg).
Reaction SMILES: C[CH:2]([CH2:11][CH2:12][CH:13]=[C:14](C)C)[CH2:3][CH2:4][CH2:5][C:6](=O)[C:7]([O-:9])=O.[O:17]=[C:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]CCCCCCCC)[C:19]([O:21]CCC(C)CCC=C(C)C)=O.CC(CCCCCCCCCCCC)C(=O)C(OCCC(C)CCC=C(C)C)=O.C1(C(=O)C(OCCCCCCCCCC)=O)CCCCC1.CC(CCC=C(C)C)CCC(C)C(=O)C([O-])=O.CC(CC)C(=O)C(OCCC(C)CCC=C(C)C)=O.O=C(C1C=CC=CC=1)C(OCCC(C)CCC=C(C)C)=O.O=C(CCC)C(OCCC(C)CCC=C(C)C)=O.C1(C(=O)C(OCCC(C)CCC=C(C)C)=O)CCCCC1.C1(C(=O)C(OCC2C=CC(OC)=CC=2)=O)CCCCC1>>[CH:32]1([C:18](=[O:17])[C:19]([O:9][CH:7]2[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:2][CH2:11][CH2:12][CH2:13][CH3:14])=[O:21])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CC(C)=CCCC(C)CCCC(=O)C(=O)[O-]
Reactant: CCCCCCCCCCCCCCC(=O)C(=O)OCCC(C)CCC=C(C)C
Agent: CC(C)=CCCC(C)CCC(C)C(=O)C(=O)[O-]
Agent: CC(C)=CCCC(C)CCOC(=O)C(=O)C1CCCCC1
Agent: CC(C)=CCCC(C)CCOC(=O)C(=O)c1ccccc1
Product: CCCCCC1CCCC1OC(=O)C(=O)C1CCCCC1

Procedure:
MS (EI): 167 (1); 140 (1); 139 (8); 138 (7); 123 (1); 112 (1); 111 (11); 110 (1); 109 (1); 98 (2); 97 (25); 96 (2); 95 (3); 84 (7); 83 (100); 82 (5); 81 (4); 79 (2); 71 (4); 70 (2); 69 (22); 68 (2); 67 (9); 66 (1); 65 (1); 57 (11); 56 (2); 55 (29); 54 (3); 53 (2); 43 (4); 42 (1); 41 (12); 39 (3); 29 (3); 27 (1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH3:20]>CC(C)=O>[CH2:19]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:20]
Reactant: COc1ccc(C#N)c(O)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(OC)ccc1C#N

Procedure:
30.0 g (201 mmol) of 2-hydroxy-4-methoxybenzonitrile are refluxed with 83.4 g of potassium carbonate (603 mmol) and 32.88 g (301 mmol) of bromoethane in 550 ml of acetone for 18 hours. After filtration, the solvent is removed under reduced pressure and the residue is purified by silica gel chromatography (cyclohexane:ethyl acetate=10:1): 35.9 g of an oil Rf=0.37 (cyclohexane:ethyl acetate=3:1)
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[CH:10]=[CH:9]2)([O-:5])=[O:4]>>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)[CH:10]=[CH:9]2)([O-:5])=[O:4]
Reactant: COC(=O)c1ccc(Cn2ccc3cc([N+](=O)[O-])ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(Cn2ccc3cc([N+](=O)[O-])ccc32)cc1

Procedure:
4-[(5-Nitro-1H-indol-1-yl)methyl]benzoic acid was prepared by NaOH hydrolysis of methyl 4-[(5-nitro-1H-indol-1-yl)methyl]benzoate: MS (ESI) m/z 295;
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[CH2:7]([NH:14][CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([N:14]([CH2:15][CH2:16][OH:17])[C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCNCc1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
N,N-dimethyl carbamoyl chloride (2.55 g, 0.0238 mol) was added drop by drop at 0° C. to a solution of N-benzyl ethanol amine (3 g, 0.0198 mol) and triethylamine (3 g, 0.0298 mol) in 25 ml of DCM (dry) and stirred at RT for 3 h under nitrogen atmosphere. The reaction was quenched with water, extracted with dichloromethane, washed with water, brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by column chromatography over silica gel using 3.5% methanol in dichloromethane as eluent afforded 4 g of the sub-title compound as a liquid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[OH-].[K+].CCO>[CH:20](=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:10]=2)[C:15]1=[O:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 87.8 %

Procedure:
According to the method of Example 8, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.505 g, 1.97 mmol) was reacted with benzaldehyde (0.312 g, 2.94 mmol) in 3.0 mL of 4% KOH in EtOH overnight at room temperature to afford 0.596 g (88%) of the title compound as a cream-colored solid: CI-MS m/e 344 (M+), 345 (M++1);
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([N:15]([CH2:24][CH:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:26])[C:16](=[O:23])[CH2:17][CH:18](OC)OC)[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(N(CC)CC)C>C(Cl)Cl.C(OCC)C.O>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([N:15]1[C:16](=[O:23])[CH2:17][CH2:18][N:27]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[CH:25]([CH3:26])[CH2:24]1)[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)[C@H](CCOCc1ccccc1)N(CC(C)Nc1ccc(Cl)c(Cl)c1)C(=O)CC(OC)OC
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@H](CCOCc1ccccc1)N1CC(C)N(c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
A cooled solution (0° C.) of 1.75 g (3.23 mmol) of (S)-4-benzyloxy-2-[[2-(3,4-dichloro-phenylamino)-propyl]-(3,3-dimethoxy-propionyl)-amino]-butyric acid methyl ester in 30 ml CH2Cl2 was treated with 3.71 ml (48.48 mmol) of trifluoroacetic acid and after 2 h at RT with 2.57 ml (16.16 mmol) of triethylsilane. The reaction was stirred at RT for 16 h, cooled (0° C.) and neutralized with 6.76 ml (48.48 mmol) of triethylamine. The residue was dissolved in diethyl ether and cold water. The reaction was extracted with 10% aq. KHSO4 solution/diethyl ether (3×). The organic phases were washed with sat. aq. NaHCO3 solution, dried over Na2SO4 and evaporated. Flash silica gel column (n-heptane/EtOAc 4:1→1:1) afforded 0.79 g (46%) of the title compound as a 71:29 mixture of the (R) and (S) diastereomers. Orange oil, MS: 479.1 (MH+, 2Cl).