Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13]O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]C(Br)(Br)Br>ClCCl>[Br:34][CH2:13][CH2:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]1
Reactant: CCCCC[C@H]1CC[C@H](CCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CCBr)CC1
Temperature: -20 °C
Reaction time: 5 h

Procedure:
A mixture of 20 g of 2-(trans-4-pentylcyclohexyl)ethanol, 27.5 g of triphenylphosphine and 350 ml of dichloromethane was treated portionwise while stirring at -30° C. over a period of 45 minutes under an inert gas atmosphere with 36.5 g of tetrabromomethane. The resulting mixture was then stirred at -20° C. for another 30 minutes and at room temperature for 5 hours. The mixture was subsequently concentrated and the residue was triturated with 500 ml of hexane. After cooling to 0° C., the precipitated triphenylphosphine oxide was filtered off and the filtrate was chromatographed on silica gel with hexane. The crude 1-bromo-2-(trans-4-pentylcyclohexyl)ethane obtained (29.0 g) was distilled at 92°-98° C./1.5 Torr. Yield: 21.9 g as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)\[CH3:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)\[CH2:7][Br:17])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(Cl)c1
Yield: 64.8 %

Procedure:
To a stirred mixture of (E)-3-(3-chloro-phenoxy)-but-2-enoic acid ethyl ester (3.45 g, 0.014 mol) in carbon tetrachloride (20 mL) under a nitrogen atmosphere was added N-bromosuccinimide (2.79 g, 0.016 mol) and benzoyl peroxide (347 mg, 0.001 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(3-chloro-phenoxy)-but-2-enoic acid ethyl ester (2.90 g, 63%) as a yellow oil.
Reaction SMILES: CC1NC2CCCCC=2N=1.FC1C=CC(C(Cl)=O)=CC=1.F[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:29](=[O:40])[CH2:30][C:31]1[NH:35][C:34]2[CH2:36][CH2:37][CH2:38][CH2:39][C:33]=2[N:32]=1>C(#N)C>[F:28][C:26]1[CH:25]=[CH:24][C:23]([C:29](=[O:40])[CH2:30][C:31]2[NH:32][C:33]3[CH2:39][CH2:38][CH2:37][CH2:36][C:34]=3[N:35]=2)=[CH:22][CH:27]=1
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccc(F)cc1F
Agent: Cc1nc2c([nH]1)CCCC2
Agent: O=C(Cl)c1ccc(F)cc1
Solvent: CC#N
Product: O=C(Cc1nc2c([nH]1)CCCC2)c1ccc(F)cc1

Procedure:
The compound is prepared as described in example XXXXIII with 2.00 g (14.68 mmol) 2-methyl-4,5,6,7-tetrahydro-1H-benzimidazole, 6.98 g (44.05 mmol) of 4-fluorobenzoyl chloride and 4.90 g (48.42 mmol) of TEA in 50 ml acetonitrile. The crude intermediate is directly transformed into 1-(2,4-Difluorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-ethanone to yield 737 mg (10.7% of th.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[CH:24][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:32]1([CH3:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>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:32]1([C:38]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:25]=[CH:24][C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[C:10]=4[CH:9]=3)=[CH:4][CH:3]=2)=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Brc1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1
Reactant: Cc1ccccc1
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: [K+]
Product: c1ccc(C(=C(c2ccccc2)c2ccc(-c3ccc4c5ccccc5c5ccccc5c4c3)cc2)c2ccccc2)cc1
Temperature: 60 °C
Yield: 82 %

Procedure:
The product B (1.25 g, 3.26 mmol), D (1.37 g, 3.58 mmol), potassium carbonate solution (K2CO3(aq), 2.0 M, 8.0 mL), and dried toluene (24 mL) were charged in a two-necked bottle. The bottle was deoxygenated and purged with nitrogen, and the mixture in the bottle was stirred at 60° C. until it was totally dissolved. The nitrogen pressure of the bottle was increased, and Pd(PPh3)4 (381 mg, 0.33 mmol) was rapidly added into the bottle. The reaction was heated to 110° C., and stirred for 48 hours. The resulting was filtered to remove metal. The filtrate was condensed to remove the solvent. The solid was washed by water and methanol, and then sublimated at a temperature of 260° C. to obtain TSTP (1.50 g, yield=82%) as white solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:31]/[CH:32]=[CH:33]/[CH2:34][NH2:35])[CH2:27][CH2:26]1.Cl>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:31]/[CH:32]=[CH:33]/[CH2:34][NH:35][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[CH:16][CH:15]=2)[CH2:29][CH2:30]1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: COc1ccccc1N1CCN(C/C=C/CN)CC1
Agent: Cl
Product: COc1ccccc1N1CCN(C/C=C/CNC(=O)c2ccc(-c3ccccn3)cc2)CC1
Yield: 65 %

Procedure:
Prepared from 4-pyridin-2-yl-benzoic acid hydrochloride and 4-(4-(2-methoxyphenyl)-piperazin-1-yl)-trans-but-2-enyl amine according to the general procedure. Yield: 65%. Mp. (hydrochloride): 168-170° C. 1H NMR (400 MHz, CDCl3): δ 2.70 (s, 4H), 3.12 (s, 6H), 3.86 (s, 3H), 4.13 (m, 2H), 5.78-5.85 (m, 2H), 6.43 (m, 1H), 6.85-7.02 (m, 4H), 7.27 (s, 2H), 7.77 (s, 2H), 7.90 (d, J 7.5, 2H), 8.06 (d, J 8.1, 2H), 8.72 (d, J 3.1, 1H). 13C NMR (101 MHz, CDCl3): δ 41.0, 50.9, 53.7, 55.8, 60.7, 111.6, 118.7, 121.3, 121.4, 123.2, 123.5, 127.5, 127.9, 129.1, 130.5, 135.0, 137.4, 141.6, 142.7, 150.3, 152.7, 156.7, 167.4. Anal. (O27H30N4O2.3HCl.4H2O) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](=[CH:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5]([O:7][CH3:8])=[O:6].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1COCC1.O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([CH:9]([S:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[F:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(=O)C(=Cc1c(F)ccc(F)c1F)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C(=O)OC)C(Sc1ccc(Cl)cc1)c1c(F)ccc(F)c1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-(2,3,6-Trifluoro-benzylidene)-malonic acid dimethyl ester (6.5 g, 23.7 mmol) and 4-chlorothiophenol (5.1 g, 35.5 mmol) were dissolved in 100 mL THF. K2CO3 (5 g, excess) was added, the reaction mixture was stirred at 60° C. for three hours. 300 mL of EtOAc and 300 mL of water were added. The organic layer was separated, washed with water, dried over Na2SO4 and concentrated. The product was purified by column chromatography using EtOAc/hexane as the eluent. (Gradient from 0/100 to 25/75 in 45 min, 7.1 g, 72%). 1H NMR (CDCl3 400 MHz) δ 7.26 (m, 4H), 7.03 (m, 1H), 6.75 (m, 1H), 5.08 (d, J=11.7 Hz, 1H), 4.34 (d, J=12.4 Hz, 1H), 3.84 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20](=[O:23])[CH2:21]Br.Cl>CS(C)=O>[CH3:18][O:19][C:20](=[O:23])[CH2:21][O:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6-Bromo-2-nitropyridin-3-ol (10.8 g, 49.1 mmol) was dissolved in dimethylsulfoxide (DMSO) (30 mL). Potassium carbonate (13.6 g, 98.6 mmol) and bromoacetic acid methyl ester (7.0 mL, 74 mmol) were added and the reaction mixture was stirred at 60° C. for two hours. Then, the reaction mixture was cooled to room temperature and neutralized with 1N HCl(aq). The aqueous solution was extracted twice with ethyl acetate, and the combined organic extracts were washed with brine. The product was purified by column chromatography (SiO2, EtOAc/hexanes) to afford (6-bromo-2-nitropyridin-3-yloxy)acetic acid methyl ester. Yield 10.9 g (37.5 mmol, 76%). LCMS (ESI): calc. C8H7BrN2O5=290, 292; obs. Low ionization.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH2:22])=[N:18][CH:19]=1.C(N(CC)CC)C.[O:30]1[C:39]2[CH:38]=[C:37]([CH:40]=O)[N:36]=[CH:35][C:34]=2[O:33][CH2:32][CH2:31]1.[BH4-].[Na+]>C(Cl)Cl.CCO>[O:30]1[C:39]2[CH:38]=[C:37]([CH2:40][NH:22][CH2:21][CH2:20][C:17]3[CH:16]=[CH:15][C:14]([C:7]4[C:6]5[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[N:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:19][N:18]=3)[N:36]=[CH:35][C:34]=2[O:33][CH2:32][CH2:31]1
Reactant: COc1ccc2nccc(-c3ccc(CCN)nc3)c2n1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2nccc(-c3ccc(CCNCc4cc5c(cn4)OCCO5)nc3)c2n1
Reaction time: 24 h
Yield: 168.7 %

Procedure:
To a stirred solution of (2-{5-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-pyridinyl}ethyl)amine hydrochloride salt (0.69 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added triethylamine (0.29 mL, 2.07 mmole) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (0.12 g, 0.73 mmole). After 24 h, the reaction contents were concentrated and dried under high vacuum. To a stirred solution of the crude imine in dry EtOH (25 mL) at RT was added NaBH4 (0.03 g, 0.73 mmole). After 24 h, Silica gel (5 g) was added to the reaction solution and the suspension was concentrated under vacuum to a dry solid. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (0.50 g, 72%) as light yellow solid: 1H NMR (400 MHz, CD3OD) δ 9.52 (d, J=1.8 Hz, 1H), 9.22 (d, J=5.6 Hz, 1H), 9.02 (d, J=8.3 Hz; 1H), 8.57 (m, 2H), 8.48 (d, J=5.6 Hz, 1H), 8.19 (d, J=9.3 Hz, 1H), 7.79 (s, 1H), 7.68 (d, J=9.3 Hz, 1H), 4.66 (m, 4H), 4.54 (s, 2H), 4.13 (s, 3H), 3.82 (m, 2H), 3.71 (s, 2H). LC-MS (ES) m/e 430 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:19]([Mg][Cl:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+:29]>O1CCCC1.C(OCC)C>[ClH:27].[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([NH2:29])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Cc1ccsc1C=O
Reactant: [NH4+]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccsc1C(N)Cc1ccccc1
Product: Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 50 g (0.40 mol) of 3-methyl-2-thiophenecarboxaldehyde in 150 ml of dry tetrahydrofuran at 0° C. was added dropwise 476 ml (0.47 mol) of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran over a 2 hour period. After stirring the mixture an additional 20 minutes at 0° C., 476 ml (0.47 mol) of a 1M solution of benzyl magnesium chloride in diethyl ether was added dropwise over a 2 hour period. The resulting mixture was allowed to warm to ambient temperature, stirred for 0.5 h longer, and poured into 2.5 L of saturated aqueous ammonium chloride. The mixture was extracted with chloroform (3×500 ml), organic layers combined, dried over MgSO4, and concentrated to dryness giving 85 g of the title amine as an oil. A sample of the product (4 g) was dissolved in isopropanol, made acidic with hydrogen chloride in isopropanol, decolorized with carbon, and reconcentrated to near dryness. The crude hydrochloride salt was recrystallized from a solvent mixture of ethyl acetate and methanol to give 2.5 g of white solid (mp 184°-186° C.).
Reaction SMILES: [CH:1]([N:4]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12]C)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2].[C:17]1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([N:4]([CH2:9][CH:10]1[O:14][CH:15]([CH2:16][CH3:17])[CH2:12][O:11]1)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CCOC(CN(C(=O)CCl)C(C)C)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC1COC(CN(C(=O)CCl)C(C)C)O1

Procedure:
N-Isopropyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), butandiol-1,2 (3.56 ml) and trace amounts of toluenesulfonic acid were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux until no more ethanol was given off. After this time sodium carbonate (1 gram) was added to the mixture with stirring and the resulting mixture was distilled to yield the desired product N-isopropyl-N-(4-ethyl-1,3-dioxolan-2-ylmethyl)-α-chloroacetamide having a boiling point of 140° C. at 1 mm of Hg pressure.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])[CH:2]=[CH2:3].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]#[N:8])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C#N)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1cc(C#N)ccc1OCc1ccccc1

Procedure:
Prepared analogously to Example 5d from 3-allyl-4-hydroxy-benzonitrile and benzylbromide/potassium carbonate in dimethylformamide.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1)(=O)C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[NH2:24].[OH-].[Na+].Cl>C(O)(C)C>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:17]2[C:18]3[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=1
Reactant: CC(=O)OCCCCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: OCCCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A solution of 5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)pentyl acetate (200 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (265 mg) in isopropyl alcohol (3.5 mL) was stirred at 80° C. for 14 hrs. 1N Aqueous sodium hydroxide solution (2.1 mL) was added at 0° C., and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer washed with aqueous sodium hydrogen carbonate and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=1:19) to give a colorless solid. Recrystallization from ethyl acetate-hexane gave the title compound (275 mg) as colorless crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)=[CH:53][CH:52]=[N:51]1>CN(C=O)C>[CH3:49][N:50]1[C:54]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)=[CH:53][CH:52]=[N:51]1
Reactant: Cn1nccc1-c1cccc(N)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 42.6 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.010 g of product in 44% yield: LCMS (ESI) m/z 362 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([I:9])=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CS(C)=O.C(OCC)C.O>[I:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([O:11][CH3:10])=[N:3][CH:4]=1
Reactant: C[O-]
Reactant: Cc1cc(I)cnc1Br
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: COc1ncc(I)cc1C
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution containing 2-bromo-5-iodo-3-methyl-pyridine (4.80 g, 16.0 mmol) in DMSO (15 mL) is added methanolic NaOMe (3.33 M, 5.3 mL, 17.7 mmol) at 0° C. The solution is allowed to warm to ambient temperature and then heated at 70° C. for 1 hour. The reaction mixture is diluted with diethyl ether (300 mL) and water (200 mL) and the layers are separated. The organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by silica gel flash column chromatography (hexane/diethyl ether, 19:1) to provide 2.86 g (71%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ2.12 (s, 3H), 3.90 (s, 3H), 7.60 (d, J=2.1 Hz, 1H), 8.14 (d, J=2.1 Hz, 1H) ppm; MS (EI): m/z 249 (M+).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][C@@H:16]([C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[CH2:15][N:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13]1)=O)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-].[C]>[NH2:11][C@H:12]1[CH2:17][C@@H:16]([C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[CH2:15][N:14]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H](C(=O)N2CCOCC2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.5 %

Procedure:
tert-Butyl (3S,5R)-3-{[(benzyloxy)carbonyl]amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (39 g) and palladium(II) hydroxide-carbon (4 g) were suspended in methanol (500 ml) and the mixture was stirred under a hydrogen atmosphere (1 atom) at room temperature for 15 hr. The palladium catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-amino-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (28 g).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1.[Na].[N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH:32]=1>CO.C(Cl)(Cl)Cl>[ClH:2].[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][N:31]4[CH:36]=[CH:35][C:34](=[O:37])[CH:33]=[CH:32]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=1)#[CH:29]
Reactant: O=C1C=CN=CC1
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCCl)cc23)c1
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCn4ccc(=O)cc4)cc23)c1

Procedure:
The free base of this product was prepared from the title product of Example 30 and the sodium salt of pyrid-4-one as described for Example 50. The free base was isolated by flash chromatography with 15% methanol/CHCl3 and converted to the title product according to the procedure described for Example 28 (32%; M.P. 155°-168° C. (dec); LC-MS: 457 (MH+); anal. RP-HPLC RT: 3.45 min).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([O:18][C:19]2[CH:20]=[C:21]([CH2:25][C:26]#N)[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:31])[CH3:30].CC[OH:35]>>[CH2:29]([O:31][C:26](=[O:35])[CH2:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([O:18][C:10]2[C:11]3[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[CH3:28])[CH:20]=1)[CH3:30]
Reactant: Cc1c(Oc2cccc(CC#N)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Reactant: CCO
Reactant: CC(=O)Cl
Product: CCOC(=O)Cc1cccc(Oc2c(C)n(Cc3ccccc3)c3cc(Cl)ccc23)c1

Procedure:
[3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-yloxy)-phenyl]-acetonitrile (0.065 g, 0.168 mmol) was dissolved in EtOH (3 mL) then acetyl chloride (0.240 mL, 3.36 mmol) was added and the reaction was heated to reflux for 3 days. After cooling the reaction was submitted to aqueous workup and silica gel chromatography to afford the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][CH2:14][OH:15])[CH3:11]>CS(C)=O>[CH2:10]([N:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:13][CH2:14][OH:15])[CH3:11]
Reactant: CCNCCO
Reactant: N#Cc1ccc(F)cc1
Solvent: CS(C)=O
Product: CCN(CCO)c1ccc(C#N)cc1
Temperature: 140 °C
Yield: 21335.1 %

Procedure:
A solution of 10 g (82.6 mmol) of 4-fluorobenzonitrile and 15 g (0.17 mmol) of 2-(ethylamino)ethanol in 30 ml of DMSO was stirred under heat at 140° C. for 3 hours, followed by extraction with ethyl acetate. The solvent was distilled out under reduced pressure, followed by washing with ethyl acetate, whereby 6.9 g of white powder were obtained (yield: 44%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)cc1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-methoxyphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (73%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1cc(C)cc(O)c1
Solvent: CO
Product: Cc1cc(C)cc(OCC(=O)c2ccccc2)c1
Yield: 86 %

Procedure:
Using 3,5-dimethylphenol and phenacyl bromide, the title compound was synthesized in the same manner as in Reference Example 177. Yield 86%. Melting point: 104-105° C. (methanol).