Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH2:12][CH2:13][CH:14]=2)[C:7]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]=1[NH:19][C:20](=[O:22])[CH3:21]>C1COCC1.[Ni]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[C:7]([C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]=1[NH:19][C:20](=[O:22])[CH3:21]
Reactant: COC(=O)c1cc(C2=CCCO2)c(C(F)(F)F)cc1NC(C)=O
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C2CCCO2)c(C(F)(F)F)cc1NC(C)=O
Reaction time: 46 h
Yield: 56.5 %

Procedure:
A solution of 2-acetylamino-5-(4,5-dihydro-furan-2-yl)-4-trifluoromethyl-benzoic acid methyl ester (13.2 g, 40.1 mmol) in dry THF (250 mL) was shaken under H2 (5 bars) at r.t. in the presence of Raney nickel. (6.0 g, B113W, Degussa) for 46 h. The reaction mixture was then filtered through a sintered funnel and the filtrate was concentrated in vacuo to give the title product (7.5 g, 100%) as a yellow oil. API-ES: m/z 332 [M+H]+.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1)=[C:16]=[S:17].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([S:24][C:21]2[CH:22]=[CH:23][C:18]([N:15]=[C:16]=[S:17])=[CH:19][CH:20]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: S=C=Nc1ccc(S)cc1
Reactant: CCCCCc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCCc1ccc(C(=O)Sc2ccc(N=C=S)cc2)cc1

Procedure:
(18). Quantities: compound 17 (4.00 g, 0.021 mol), compound 3 (2.59 g, 0.016 mol), N,N'-dicyclohexylcarbodiimide (3.95 g, 0.019 mol), 4-(dimethylamino)pyridine (0.79 g, 0.019 mol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:14])[N:11]([CH3:13])[CH3:12])=[C:4]([CH2:15]O)[C:3]=1[Cl:17].O=S(Cl)[Cl:20].ClC1C=NC=C(Cl)C=1CCl>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C:10](=[O:14])[N:11]([CH3:13])[CH3:12])=[C:4]([CH2:15][Cl:20])[C:3]=1[Cl:17]
Reactant: O=S(Cl)Cl
Reactant: CN(C)C(=O)OCc1cnc(N)c(Cl)c1CO
Agent: ClCc1c(Cl)cncc1Cl
Product: CN(C)C(=O)OCc1cnc(N)c(Cl)c1CCl

Procedure:
Dimethyl-carbamic acid 6-amino-5-chloro-4-hydroxymethyl-pyridin-3-ylmethyl ester (18.5 mg, 0.071 mmol) was chlorinated with SOCl2 according to the synthesis of 3,5-dichloro-4-chloromethyl-pyridine. The resulting title compound was used for the next reaction without purification. MS (m/z): 278.0 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:27])([CH3:26])[CH2:4][C@H:5]([NH:18]C(=O)OC(C)(C)C)[CH2:6][N:7]([CH3:17])[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.C(O)C>[NH2:18][C@@H:5]([CH2:4][C:3]([O:2][CH3:1])([CH3:27])[CH3:26])[CH2:6][N:7]([CH3:17])[C:8](=[O:9])[O:10][CH2:11][CH2:12][Si:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: COC(C)(C)C[C@@H](CN(C)C(=O)OCC[Si](C)(C)C)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOCC
Product: COC(C)(C)C[C@H](N)CN(C)C(=O)OCC[Si](C)(C)C
Temperature: 62.5 °C

Procedure:
To a solution of (S)-tert-butyl 4-methoxy-4-methyl-1-(N-methyl-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)pentan-2-ylcarbamate (0.17 g, 0.42 mmol) in ether (2.0 mL) was added a solution of p-toluenesulfonic acid (80.7 mg, 0.43 mmol) in ethanol (1.0 mL). Transfer of the p-toluenesulfonic acid was completed with the aid of additional ether (1.0 mL). The solution was placed on a rotary evaporator and the ether was removed at rt. Then, with continuing evacuation, the bath temperature was raised to 60-65° C. for 20 min, during which gas evolution was evident. After cooling down to rt, the solid residue (S)-2-(trimethylsilyl)ethyl 2-amino-4-methoxy-4-methylpentyl(methyl)-carbamate was used without further purification as a p-toluenesulfonic acid salt. MS m/z 291 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16]C/C=C/C)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Si](Cl)(C)C.[OH-].[Na+]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH:11]([CH3:12])[CH:10]=[CH2:9])([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C=C/COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)C1(C(=O)O)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.2 %

Procedure:
To a solution of piperidine-1,3-dicarboxylic acid 3-((E)-but-2-enyl)ester 1-tert-butyl ester (105.7 g) in tetrahydrofuran (1000 ml) cooled to −68° C. was added lithium hexamethyl disilazide (1.1M tetrahydrofuran solution, 411 ml). The reaction mixture was warmed to 0° C. over 20 minutes, stirred at the same temperature for additional 30 minutes, and then cooled to −68° C. again. To the mixture was added trimethylsilyl chloride (56.6 ml). The reaction mixture was warmed to room temperature over 2 hours, and stirred at the same temperature for additional 2 hours. After ice-cooling, to the mixture were sequentially added water (1000 ml) and 2M aqueous sodium hydroxide solution (136 ml), and the mixture was washed with n-hexane (1000 ml). The separated aqueous layer was acidified by 2M aqueous hydrochloric acid solution, and then extracted with ethyl acetate (800 ml). The organic layer was sequentially washed with water (700 ml) and saturated aqueous sodium chloride solution (400 ml), and the separated aqueous layer was extracted with ethyl acetate (600 ml) again. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was slurry-washed with n-hexane/ethyl acetate solution (6/1, 700 ml) to give the titled compound (59.8 g). The filtrate was concentrated under reduced pressure, and the resulting residue was slurry-washed with n-hexane/ethyl acetate solution (4/1, 200 ml) again to give a solid (14.4 g). The solid was slurry-washed with n-hexane/ethyl acetate solution (5/1, 100 ml) again to give the titled compound (11.9 g). The resultant was combined to give the titled compound (71.7 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].[Br:8][C:9]1[CH:13]=[C:12](Br)[S:11][C:10]=1[CH3:15]>CCOCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:8][C:9]1[CH:13]=[C:12]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[S:11][C:10]=1[CH3:15]
Reactant: Cc1sc(Br)cc1Br
Reactant: Brc1cccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Mg]
Solvent: CCOCC
Product: Cc1sc(-c2cccs2)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A solution of 2-bromothiophene (1.44 g, 8.8 mmol) in anhydrous Et2O (25 mL) was treated with magnesium turnings (0.257 g, 10.6 mmol) and heated at reflux for 45 min under a nitrogen atmosphere. The heat source was removed and the reaction mixture was allowed to cool to room temperature when it was added to a cooled (0° C.) solution of 3,5-dibromo-2-methylthiophene (2.0 g, 8.8 mmol), Pd(dppf)Cl2 (13 mg, 0.018 mmol) and anhydrous Et2O (10 mL) dropwise via a canula. The reaction was stirred at this temperature for 1 h, the cooling bath was removed, the mixture was allowed to slowly come to room temperature and stirred for 16 h when it was quenched with 5% HCl (10 mL). The aqueous layer was separated and extracted with Et2O (2×20 mL). All organic extracts were combined, washed with H2O (3×20 mL), followed by brine (20 mL), dried (Na2SO4) and filtered. The solvent was evaporated under reduced pressure and the crude product was purified using column chromatography through silica gel (hexanes) yielding 1.69 g of pure product as a white solid.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH3:12].[O:13]1[CH2:15][CH2:14]1>O1CCCC1>[CH2:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:15][CH2:14][OH:13])[CH2:11][CH3:12]
Reactant: CCCc1ccccc1Br
Reactant: C1CO1
Agent: II
Solvent: C1CCOC1
Product: CCCc1ccccc1CCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Into a 250-mL 3-necked round-bottom flask, maintained with a nitrogen atmosphere, was placed I2 (10 mg, 0.04 mmol) and Mg (500 mg, 20.83 mmol, 2.07 equiv). Then 1-bromo-2-propylbenzene (2.0 g, 10.05 mmol, 1.00 equiv) dissolved in tetrahydrofuran (50 mL) was added dropwise into the flask and the mixture was heated to reflux. After the reaction was complete the resulting mixture was cooled to 0° C. and then oxirane (50 mL) was added in one portion. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 5 mL of NH4Cl (aq.). The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). Purification afforded 0.24 g (15%) of 2-(2-propylphenyl)ethan-1-ol as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:22])=O>ClCCl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7]([CH3:13])[C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(F)c(Cl)nc(Cl)c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(F)c(Cl)nc(Cl)c1C(=O)Cl
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A slurry of 30.8 g (0.147 moles) of 2,6-dichloro-4-methyl-5-fluoronicotinic acid in 200 mL of dichloromethane, containing a catalytic amount of dimethyl formamide, was treated dropwise over a 1-hour period with 19.2 mL (0.22 moles) oxalyl chloride. After 1 hour, the homogenous solution was evaporated in vacuo, diluted with an equal volume of dichloromethane, and evaporated in vacuo to yield 31.6 g of the title compound as an oil.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH:23]1[CH2:26][CH2:25][CH2:24]1.CO.C(Cl)Cl>CS(C)=O>[N:23]1([C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N1CCC1
Temperature: 60 °C
Yield: 44.4 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 38.0 mg, 0.090 mmol) and azetidine (Aldrich; 0.018 mL, 0.269 mmol) in DMSO (0.8 mL), heating at 60° C. for 40 min. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(3-(azetidin-1-yl)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (13.3 mg, 0.040 mmol, 44% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (1H, br. s.), 7.91 (1H, dd, J=7.5, 1.1 Hz), 7.59 (1H, dd, J=7.8, 1.0 Hz), 7.36 (1H, t, J=7.7 Hz), 7.14 (1H, d, J=2.2 Hz), 6.96 (1H, s), 4.41 (4H, t, J=7.6 Hz), 3.42 (2H, td, J=6.6, 2.1 Hz), 2.87 (2H, t, J=7.0 Hz), 2.60 (3H, s), 2.35-2.45 (2H, m). m/z (ESI, +ve) 334.1 (M+H)+.
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:6](=[O:8])[N:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:29])[CH2:27][OH:28])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]([NH:29][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[C:6](=[O:8])[N:7]=2)[CH2:27][OH:28])=[CH:24][CH:25]=1
Reactant: CSC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](CO)c2ccc(F)cc2)S/C1=C\c1c[nH]c2ncccc12

Procedure:
Then similar procedure as described in example 14b was used, starting from 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-thiazol-4-one (example 14a), 2-[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethylamine and DIEA to give 2-[(R)-1-(4-fluoro-phenyl)-2-hydroxy-ethylamino]-5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 383 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[O:18][CH2:19][CH3:20])=[O:10].Br[C:22]1[S:23][C:24]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:25]([C:27]2[CH:32]=[N:31][C:30]([Cl:33])=[CH:29][N:28]=2)[N:26]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1>[Cl:33][C:30]1[N:31]=[CH:32][C:27]([C:25]2[N:26]=[C:22]([N:15]3[CH2:16][CH2:17][C@@H:12]([NH:11][C:9]([C:3]4[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=4[Cl:1])=[O:10])[C@@H:13]([O:18][CH2:19][CH3:20])[CH2:14]3)[S:23][C:24]=2[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:28][CH:29]=1
Reactant: CCOC(=O)c1sc(Br)nc1-c1cnc(Cl)cn1
Reactant: CCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OCC)C2)nc1-c1cnc(Cl)cn1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To the stirred the solution of 3,4-dichloro-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Intermediate 26, 650 mg, 2.03 mmol) and ethyl 2-bromo-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate (Intermediate 47, 636 mg, 1.828 mmol) in N-methylpyrrolidine was added N,N-diisopropyl ethylamine and stirred at stirred at 60° C. for 3 h. The reaction mixture was cooled to room temperature and poured on to ice water. The precipitate was collected by filtration and dried to afford 950 mg (79%) of ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13](=O)[CH:14]([C:23]3([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:31]>>[ClH:21].[ClH:31].[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([C:23]3([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(C(c1ccc(Cl)c(Cl)c1)C1(O)CCCCC1)N1CCC(N2CCCCC2)CC1
Agent: Cl
Product: OC1(C(CN2CCC(N3CCCCC3)CC2)c2ccc(Cl)c(Cl)c2)CCCCC1

Procedure:
In an analogous manner to Example 1, step 2 1-[2-(1-(4′-bipiperidin-1′-yl)-1-(3,4-dichlorophenyl)ethyl]cyclohexanol dihydrochloride was prepared from 1-[2-(1,4′-bipiperidin-1′-yl)-1-(3,4-dichlorophenyl)-2-oxoethyl]cyclohexanol. MS m/z 439/441/443 ([M+H]+); HRMS: calcd for C24H36Cl2N2O.2.00 HCl, 510.1738; found (ESI), 439.2267.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.[F-].[Cs+]>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>[F:37][C:38]1[CH:43]=[C:42]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3)ccc2c1
Temperature: 85 °C
Yield: 61.3 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (2.0 g, 3.82 mmol), 3-fluorophenyl boronic acid (1.07 g, 7.64 mmol), trans-dichlorobis(triphenylphosphine)palladium II (536 mg, 0.76 mmol) and cesium fluoride (5.2 g, 34.4 mmol) along with 100 mL degassed acetonitrile and heat at 85° C. for 4 hours or until all the starting triflate is consumed. Cool the reaction, filter and purify on an SCX column eluting with 2N ammonia/methanol. The crude yield is 1.5 g (83%). Further purify the crude material on a silica column, eluting with 3% methanol/methylene chloride to give 1.1 g of the title compound (63%): 1H-NMR (CDCl3, 400 MHz) δ 7.81 (d, J=9.6 Hz, 1H); 7.73 (d, J=8.4 Hz, 1H); 7.39 (d, J=8.4 Hz, 1H); 7.28-7.25 (m, 1H); 7.19 (d, J=2.4 Hz, 1H); 7.11-7.06 (m, 2H); 7.04-7.01 (m, 2H); 6.88 (d, J=9.2 Hz, 2H); 6.75 (dd, J=6.4, 2.4 Hz, 2H); 4.34 (s, 2H); 4.07 (t, J=6.0 Hz, 2H); 3.93 (s, 3H); 2.81 (t, J=6.0 Hz, 2H); 2.57-2.57 (m, 4H); 1.67-1.61 (m, 4H); 1.48-1.46 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]([CH2:33][CH2:34][CH3:35])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH2:31][CH3:32])[C:11]2[CH:17]=[C:16]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:2][CH3:3]>CN.CO>[NH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:33][CH2:34][CH3:35])[N:10]([CH2:30][CH2:31][CH3:32])[C:11]=2[CH:17]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CN3C(=O)c4ccccc4C3=O)cc2n1CCC
Agent: CN
Solvent: CO
Product: CCCN(CCC)CCCCc1nc2ccc(CN)cc2n1CCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 103.5 %

Procedure:
The compound (173 mg) obtained in Example 125-5 was dissolved in a 40% methylamine/methanol solution (1.8 ml) and stirred at room temperature for 17 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (130 mg) as a pale-yellow viscous substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[N:7]2[C:8]3[CH:9]=[C:10]([C:15](O)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.N1C(C)=CC=CC=1C>CN(C=O)C.C1COCC1.C(Cl)Cl.C1COCC1>[S:28]1[CH:29]=[CH:30][N:31]=[C:27]1[NH:26][C:15]([C:10]1[CH:11]=[CH:12][C:13]2[CH:14]=[C:6]3[C:5](=[O:18])[NH:4][CH2:3][C:2]([CH3:1])([CH3:19])[N:7]3[C:8]=2[CH:9]=1)=[O:16]
Reactant: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)CNC(=O)c2cc3ccc(C(=O)Nc4nccs4)cc3n21
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a suspension of 24 mg (0.093 mmol) of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-7-carboxylic acid in 2:1 CH2Cl2/THF (3 mL) was added 16 μL (0.19 mmol) oxalyl chloride followed by two drops of 10% DMF in THF. After stirring for 1 h, the mixture was concentrated and 1 mL of CH2Cl2 was added followed by 19 mg (0.19 mmol) of 2-aminothiazole and 22 μL (0.19 mmol) of 2,6-lutidine. The mixture was stirred overnight, concentrated, and chromatographed (0-8% MeOH in CH2Cl2) to provide 17 mg of the title compound. ESI-MS m/z 340.9 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1>ClCCl>[C:1]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCCCCOc1ccccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCOc1ccccc1OC(C)=O
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Acetyl chloride (2.4 g, 30.1 mmol) was added dropwise to vigorously stirred mixture of 2-hexyloxyphenol (5.0 g, 25.8 mmol) and pyridine (5 ml) in dichloromethane (50 ml). The mixture was stirred for 1 hour and poured onto water. The organic layer was separated, dried (MgSO4), concentrated to give crude product which was purified by column chromatography on silica gel using dichloromethane petroleum spirit (1:3) as eluent to give title compound as a colourless oil (5.78 g, 95%). Found: C, 71.00; H, 8.35. C14H20O3 requires C, 71.19; H, 8.47. δH (CHCl3) 7.21-7.15 (m, 1H, ArH), 7.05-7.01 (m, 1H, ArH), 6.97-6.89 (m, 2H, ArH), 3.97 (t, J 6.5, 2H, OCH2), 2.30 (s, 3H, COCH3), 1.78-1.71 (m, 2H, ArOCH2CH2), 1.57-1.30 (m, 6H, CH2), 0.90 (t, J 6.9, 3H, CH2CH3). MS (FAB), 236 (M+, 53%), 194 (100%), 153 (27%), 110 (34%), 85 (7%), 55 (7%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[O:23])[CH:17]=2)=[C:11]([CH3:24])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].CC(C)=O>CO>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=2)=[C:11]([CH3:24])[CH:10]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 75.1 %

Procedure:
4′-((tert-Butyldimethylsilyl)oxy)-2′,6′-dimethylbiphenyl-3-carbaldehyde 3e (2.60 g, 38.10 mmol) was dissolved in 80 mL of methanol, followed by addition of sodium borohydride (1.66 g, 43.95 mmol). The reaction mixture was stirred for 3 hours. The resulting mixture was mixed with 50 mL of acetone and concentrated under reduced pressure. The residue was mixed with 200 mL of ethyl acetate, washed with water (60 mL×2), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (4′-((tert-butyldimethylsilyl)oxy)-2′,6′-dimethylbiphenyl-3-yl)methanol 3f (9.80 g, yield 98.0%) as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:14][C:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([N+:15]([O-])=O)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CCOC(C)=O>CO.[Pd]>[CH2:18]([C:13]1([NH2:15])[CH2:14][NH:8][CH2:9][CH2:10][NH:11][CH2:12]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])C1(Cc2ccccc2)CN(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC1(Cc2ccccc2)CNCCNC1
Yield: 75.7 %

Procedure:
In a 500 ml flask, compound 5 (16.0 g, 38.5 mmol) was dissolved in methanol (100 mL); Pd/C (10%, 3.0 g, moistened with 0.5 ml water) was added at once followed by ammonium formate (24.0 g, 0.385 mol). The mixture was stirred and heated to reflux for 3 h. When the reaction is complete (TLC PET/AcOEt 9/1), the catalyst was removed by filtration on Celite®, and the filtrate evaporated in vacuo. The residue is redissolved in dichloromethane and washed with 5% aq. NaOH. The organic phase was then dried (Na2SO4) obtaining 6 (5.98 g, 76%) as light yellow oil. M.p.: ESI-MS: 206 (MH+); (Calc. for C12H19N3: 205 u.m.a.).
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH:14]([OH:29])[CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.C(O)(=O)C.[N:34]([O-])=O.[Na+]>O>[ClH:1].[OH:29][CH:14]([CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[CH2:13][O:12][C:6]1[C:5]2[N:4]=[N:34][NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(CCNCC(O)COc2cccc(N)c2N)cc1OC
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CCNCC(O)COc2cccc3[nH]nnc23)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
14.1 g. 2,3-Diamino-1-[2-hydroxy-3-(3,4-dimethoxyphenethylamino)-propoxy]-benzene trihydrochloride are dissolved in 10 ml. water and 3.5 ml. glacial acetic acid, cooled to 5° C. and mixed with 2.07 g. sodium nitrite in 3.6 ml. water. The reaction mixture is then stirred for 2.5 hours at ambient temperature. The resultant sodium chloride is precipitated out by the addition of 480 ml. isopropanol. After filtration, the filtrate is evaporated, purified over a column of silica gel using methanol/ethyl acetate (2:1 v/v) as elution agent, mixed with ethereal hydrochloric acid and the hydrochloride so obtained is crystallized from ethanol. There are obtained 1.26 g. (10% of theory) 4-[2-hydroxy-3-(3,4-dimethoxyphenethylamino)-propoxy]-benzotriazole hydrochloride; m.p. 123°-124° C.