Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].C([O-])(O)=O.[Na+]>Br>[N:19]1([CH2:18][CH2:17][CH2:16][N:11]2[C@@H:12]3[C@@H:8]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([OH:2])[C:15]=4[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCN1CCOCC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCN1CCOCC1
Temperature: 0 °C
Yield: 89.1 %

Procedure:
3.75 g (0.01135 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-morpholin-4-yl-propyl)-1H-benzo[e]indole were dissolved in 0.13 l of 48% aqueous HBr and boiled under reflux for 5 hours. The mixture was poured into an ice-cold aqueous solution of 46.3 g (1.16 mol) of NaOH. After the addition of solid NaHCO3 the mixture was extracted three times with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with Na2SO4, filtered and concentrated. By chromatography over silica gel with methanol there were obtained 3.20 g (89%) of oily rac-cis-2,3,3a,4,5,9b-hexahydro-3-(3-morpholin-4-yl-propyl)-1H-benzo[e]indol-6-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14](=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[OH:13][CH2:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Br)cc(CO)c1
Agent: [Pd]
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)cc(CO)c1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3-bromo-5-(hydroxymethyl)benzoate (4.53 g, 18.5 mmol) in dioxane (74 mL) is added cesium carbonate (6.0 g, 18.5 mmol), potassium carbonate (5.1 g, 37 mmol), and palladium(0) tetrakis(triphenylphosphine) (2.1 g, 1.85 mmol), followed by trimethyl boroxine (5.1 mL, 37 mmol). The reaction mixture is refluxed for 12 h, cooled to room temperature, and then partitioned between water and ethyl acetate. The organic layer is washed with water and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The black oil is adsorbed onto silica gel followed by purification by flash column chromatography (silica, 25% ethyl acetate/hexanes) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), 7.65 (s, 1H), 7.39 (s, 1H), 5.31 (br s, 1H), 4.53 (s, 1H), 3.84 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1F.C(=O)([O-])[O-].[Cs+].[Cs+].[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[S:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1ccc(Br)c(Sc2ccccc2)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of 4-bromo-3-fluoro-N-methyl-2-nitroaniline (0.30 g, 1.20 mmol) in N,N-dimethylformamide (2.45 mL) was treated with cesium carbonate (0.472 g, 1.45 mmol) and benzenethiol (0.149 mL, 1.45 mmol). The resultant reaction mixture was warmed to 80° C. and stirred at 80° C. for 30 min, after which time the reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with 10% solution of K2CO3 and brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by flash column chromatography (100% hexanes to 40% EtOAc/hexanes) gave the desired product (396 mg, 97%) as an orange solid. LCMS calculated for C13H12BrN2O2S (M+H)+: m/z=339.0, 341.0. found: 338.9, 340.9.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[N:31]=[C:18]4[C:19]([C:23]5[CH:28]=[CH:27][C:26](F)=[C:25]([F:30])[CH:24]=5)=[CH:20][CH:21]=[CH:22][N:17]4[N:16]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[O-:32][CH2:33][CH3:34].[Na+]>CCO>[CH2:33]([O:32][C:26]1[CH:27]=[CH:28][C:23]([C:19]2[C:18]3[N:17]([N:16]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[CH:2][CH:7]=5)[CH2:13][CH2:12]4)[N:31]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:24][C:25]=1[F:30])[CH3:34]
Reactant: Fc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)c5)CC4)nc23)cc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(-c2cccn3nc(NC4CCN(c5ccncc5)CC4)nc23)cc1F
Temperature: 150 °C

Procedure:
To a solution of N-(1-(2-chloropyridin-4-yl)piperidin-4-yl)-8-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 169c) (88 mg, 0.20 mmol) in EtOH (1 mL) was added sodium ethoxide solution (21% in ethanol, 75 L, 0.2 mmol) and the reaction mixture was heated in the microwave to 150° C. for 30 minutes and then sodium ethoxide solution (21% in ethanol, 75 L, 0.2 mmol) was added and the resulting mixture heated to 150° C. for another 30 minutes. The mixture was then evaporated.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:12]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)#[N:2]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)c(C#N)c1
Temperature: 150 °C
Yield: 81.2 %

Procedure:
The following reaction was split into two batches with half the amounts: methyl 3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (D25) (1.5 g, 4.85 mmol), phenylboronic acid (1.183 g, 9.70 mmol), potassium carbonate (2.011 g, 14.55 mmol) and palladium tetrakistriphenylphosphine(0) (0.561 g, 0.485 mmol) were taken up in DMF (24 ml) and the mixture heated in the microwave for 30 min at 150° C. The two reactions were combined and diluted with ethyl acetate (50 mL) and the mixture filtered through kieselguhr to remove palladium residues. The filtrate was concentrated in vacuo to reduce the amount of DMF and then the residue partitioned between saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL). The organic phase was washed with further sodium bicarbonate (50 mL) and then water (50 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The brown solid was purified by silica chromatography, eluting 0-25% EtOAc in iso-hexane over 35 minutes to give the title compound as a white solid (935 mg, 3.94 mmol). δH (d6-DMSO, 400 MHz): 8.42 (1H, d), 8.29 (1H, dd), 7.81 (1H, d), 7.65 (2H, m), 7.60-7.50 (3H, m), 3.92 (3H, s). MS (ES): no mass ion observed.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][CH2:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[CH:22]=[CH:21][S:20][C:19]=3[CH2:18][CH2:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCc1cccs1)C1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(CN2CCC(C3=NCCc4sccc43)CC2)cc1
Reaction time: 4 h

Procedure:
A solution of 2 g of the product obtained in Step C in 8 ml of toluene, and 12 mmol of POCl3, are heated at reflux. After 4 hours, the reaction mixture is poured onto ice, rendered basic by the addition of a 20% sodium hydroxide solution and then extracted with dichloromethane. The organic phase is dried and filtered and then evaporated, enabling the expected product to be isolated.
Reaction SMILES: [Br-].[CH2:2]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:33]([CH:35]1[CH2:40][CH2:39][CH:38]([CH:41]=O)[CH2:37][CH2:36]1)#[N:34].O>COC(C)(C)C>[CH2:2]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:41][CH:38]2[CH2:39][CH2:40][CH:35]([C:33]#[N:34])[CH2:36][CH2:37]2)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: N#CC1CCC(C=O)CC1
Reactant: CCCCCc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCCc1ccc(C=CC2CCC(C#N)CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
A mixture of 2.51 g of (p-pentylphenyl)methyl-triphenylphosphonium bromide and 615 mg of 4-cyanocyclohexanecarboxaldehyde (cis/trans mixture about 1:1) in 30 ml of t-butyl methyl ether was placed at 0° C. in a sulphonation flask while gassing with argon, the mixture was treated within 2 minutes with 673 mg of solid potassium t-butylate and the mixture was subsequently stirred at 0° C. for a further 1.5 hours. The red-brown, heterogeneous mixture was then poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was suspended in 150 ml of hexane, freed from precipitated triphenylphosphine oxide by filtration (back-washing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.4 bar) of the resulting oil (1.36 g) on silica gel with 3% ethyl acetate/petroleum ether as the eluant gave 1.02 g (81%) of 4-[2-(p-pentylphenyl)ethenyl]cyclohexanecarbonitrile as a colourless oil; Rf values of this isomer mixture (10% ethyl acetate/petroleum ether): 0.27 and 0.36.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:34])[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:27][C@H:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25]2)[C:10]1=[O:33].C(=O)(O)[O-].[Na+].[CH3:40][N:41](C)C=O>[C-]#N.[Zn+2].[C-]#N>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:34])[C:17]2[C:12](=[CH:13][C:14]([C:40]#[N:41])=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:27][C@H:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25]2)[C:10]1=[O:33]
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(C#N)cc3C(F)(F)F)C1
Reaction time: 2 h

Procedure:
To a solution of the compound of Example 1-2 (68 mg, 0.11 mmol) in N,N-dimethylformamide (1.1 mL) were added zinc cyanide (15 mg, 0.13 mmol) and tetrakistriphenylphosphine palladium (25 mg, 0.02 mmol), and the reaction was carried out at 80° C. for 2 hours. To the reaction solution was added saturated aqueous sodium bicarbonate, and the mixture was extracted with toluene-ethyl acetate (1:1). The organic layer was dried over magnesium sulfate and filtered, and then evaporated and purified by silica gel column chromatography (chloroform/methanol/ammonia water=50/1/0 to 10/1/0 to 100/10/1) to give the titled compound (54 mg, 94%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]23[NH:38][CH2:37][CH2:36][N:25]2[C:26](=[O:35])[C:27]2[N:28]([C:30]([C:33]#[N:34])=[CH:31][CH:32]=2)[CH2:29]3)=[CH:20][CH:19]=1>CN(C=O)C.C(Cl)Cl.N1C=CC=CC=1.O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]23[N:38]([C:13]([C:12]4[C:8]([CH3:7])=[N:9][O:10][CH:11]=4)=[O:15])[CH2:37][CH2:36][N:25]2[C:26](=[O:35])[C:27]2[N:28]([C:30]([C:33]#[N:34])=[CH:31][CH:32]=2)[CH2:29]3)=[CH:20][CH:19]=1
Reactant: COc1ccc(C23Cn4c(C#N)ccc4C(=O)N2CCN3)cc1
Reactant: Cc1nocc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C23Cn4c(C#N)ccc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.7 %

Procedure:
To generate the acid chloride, oxalyl chloride (150 μL, 1.61 mmol) and DMF (1 drop) were added to a suspension of 3-methyl-1,2-oxazole-4-carboxylic acid (65 mg, 0.51 mmol) in CH2Cl2 (1 mL) at 0° C. The suspension was allowed to stir for a further 15 minutes at 0° C. followed by 1 hour at room temperature. The resulting solution was concentrated in vacuo (without heating) to give an oil that was dissolved in CH2Cl2 and concentrated in vacuo. To a chilled (ice bath) suspension of the acid chloride (generated as above, 0.51 mmol) in pyridine (1 mL) was added a cloudy mixture of 10a-(4-methoxyphenyl)-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-8-carbonitrile (45 mg, 0.1 mmol) in pyridine (1 mL). The reaction mixture was warmed to room temperature and stirred for 1.5 hour. The reaction mixture was then diluted with water (5 mL) and extracted with CH2Cl2 (3×2 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to yield a crude residue that was purified by flash chromatography (Biotage SP4, 4 g cartridge, gradient 0-100% EtOAc in hexanes) and reverse phase chromatography (Biotage SP4, 12 g cartridge, C18, 5-50s-55-100% acetonitrile in water; water contained 0.1% formic acid) to give 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-8-carbonitrile (106) as a white solid (17 mg, yield 40%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=3)[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[NH:35][C:36](Cl)=[O:37].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[NH:35][C:36](=[O:37])[O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:16]2
Reactant: Oc1ccc2c(c1)CN(Nc1ccncc1)C2
Reactant: O=C(Cl)NN1CCc2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NN1CCc2ccccc2C1)Oc1ccc2c(c1)CN(Nc1ccncc1)C2
Temperature: 25 °C
Yield: 30.2 %

Procedure:
To a mixture of 2,3-dihydro-2-(4-pyridinylamino)-1H-isoindol-5-ol (1.50 g), triethylamine (1.47 g), and chloroform (15 ml), 1,2,3,4-tetrahydroisoquinolin-2-ylcarbamyl chloride (1.55 g) in chloroform (10 ml) was added dropwise with stirring, under nitrogen, at ambient temperature. The reaction mixture was stirred under reflux for 3 hrs, at ambient temperature overnight and poured into dilute sodium bicarbonate solution. The layers were separated. The aqueous phase was extracted with chloroform, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The residue was chromatographed on silica, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane-methanol-ammonium hydroxide. The appropriate fractions were collected and evaporated. The residue was recrystallized from ethanol-toluene to give 800 mg (31%) of product, mp 162-163° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[C:13]3[C:9]([CH2:10][C:11](=[O:15])[NH:12]3)=[CH:8][CH:7]=2)=[CH:2]1.[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.N1CCCCC1>C(O)C>[OH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:7][CH:8]=2)[NH:12][C:11]1=[O:15]
Reactant: O=Cc1ccccc1O
Reactant: O=C1Cc2ccc(-c3ccsc3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(-c3ccsc3)ccc2C1=Cc1ccccc1O
Yield: 68.9 %

Procedure:
A mixture of 6-thiophen-3-yl-1,3-dihydroindol-2-one (100 mg, 0.5 mmol), 2-hyroxy-benzaldehyde (60 mg, 0.5 mmol) and piperidine (0.23 mL) in ethanol (4 mL) was stirred at reflux overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 110 mg (69%) of 3-(2-hydroxybenzylidene)-6-thiophen-3-yl-1,3-dihydroindol-2-one as yellow-red crystals.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]([OH:25])[C:22]([OH:24])=O)=[CH:19][C:18]=1[O:28][CH3:29].ON1C(=O)CCC1=O.[CH3:38][CH2:39][CH2:40][CH:41]([NH2:45])[CH2:42][CH2:43][CH3:44].C(=O)(O)[O-].[Na+].Cl>O1CCOCC1.O>[CH3:38][CH2:39][CH2:40][CH:41]([NH:45][C:22](=[O:24])[CH:21]([OH:25])[C:20]1[CH:26]=[CH:27][C:17]([OH:16])=[C:18]([O:28][CH3:29])[CH:19]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCC(N)CCC
Reactant: COc1cc(C(O)C(=O)O)ccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CCC)NC(=O)C(O)c1ccc(O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A solution of dicyclohexyl carbodiimide (DCC) (5.5 g, 26.7 mmol) in 1,4-dioxane (50 ml) was added to a stirred solution of 4-hydroxy-3-methoxymandelic acid (5 g, 25.3 mmol) and N-hydroxysuccinimide (3 g, 26.1 mmol) in 1,4-dioxane (100 ml) at room temperature. The resulting white suspension was stirred at room temperature for 16 hours. Then the reaction mixture was filtered. The filtrate was poured into a stirred solution of 4-heptylamine in water (20 ml) and sodium bicarbonate (2.5 g, 20 mmol) was added. The resulting solution was heated to 50° C. and stirred at this temperature for 1.5 hour. The cooled solution was acidified to pH<2 using aq. HCl 5% solution and extracted three times with ethyl acetate (100 ml). The combined organic layers were washed with brine, dried with sodium sulfate, filtered and the filtrate concentrated by evaporation under reduced pressure. The residue was purified by crystallization from ethyl acetate/heptane to yield the title product (5.5 g, 73.6%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.O.[NH2:61][C:62]1[NH:66][N:65]=[N:64][N:63]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:61][C:62]3[N:63]=[N:64][NH:65][N:66]=3)=[O:28])=[CH:24][CH:23]=2)[C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1ccc(CN(c2ccc(Cl)cc2)c2nc(-c3ccc(Cl)cc3)cs2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nn[nH]n1)c1ccc(CN(c2ccc(Cl)cc2)c2nc(-c3ccc(Cl)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
4-({(4-Chlorophenyl)-[4-(4-chlorophenyl)thiazol-2-yl]amino}methyl)benzoic acid (0.15 g, 0.33 mmol) was dissolved in DMF (5 mL) and 1-hydroxybenzotriazol (49 mg, 0.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg, 0.36 mmol), and triethylamine (51 μL, 0.36 mmol) were added and the resulting mixture was stirred at room temperature for 15 minutes. 5-Aminotetrazole hydrate (34 mg, 0.33 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. Water was added and the mixture was stirred at room temperature for 1 hour and filtered. Washing with water and drying in vacuo afforded 145 mg (84%) of the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:32]1[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 89 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 89%). 1H NMR (200 MHz, DMSO-db): δ 3.57-3.59 (m, 4H), 3.64-3.66 (m, 4H), 4.04 (s, 3H), 7.05 (d, J=9.5 Hz, 2H), 7.44 (dt, J=8.9 and 2.9 Hz, 1H), 7.54 (dd, J=9.8 and 2.8 Hz, 1H), 7.81 (dd, J=9.1 and 5.9 Hz, 1H), 8.08 (d, J=9.4 Hz, 2H), 9.35 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=3)[CH:20]=2)[C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:4][CH2:3]1.O.O.[Sn](Cl)Cl>C(O)C.ClCCl.[OH-].[Na+]>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[CH:9]([O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][CH2:26][C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1
Reactant: CN1CCC(OC(c2cccc(OCc3cccc([N+](=O)[O-])c3)c2)c2nc3ccccc3s2)CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CN1CCC(OC(c2cccc(OCc3cccc(N)c3)c2)c2nc3ccccc3s2)CC1

Procedure:
A suspension of 2-{(1-methylpiperidin-4-yloxy)[3-(3-nitro-benzyloxy)phenyl]methyl}benzothiazole (example 196, 55 mg) and tin(II) chloride dihydrate (250 mg) in ethanol (2 mL) is refluxed for 1 h. The cooled mixture is diluted with dichloromethane and aqueous 1N sodium hydroxide. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure to afford 3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylamine which is then converted into its oxalate salt in acetone to give 3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxymethyl}-phenylamine, oxalate as an orange solid. TLC of the base (eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5): Rf=0.14.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][N:14]=[N+:15]=[N-:16])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[C:22]([F:39])=[C:23](/[CH:27]=[C:28](/[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[F:38])\[C:29]#[N:30])[CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[C:22]=2[F:39])[C:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[F:38])([C:29]#[N:30])[CH:9]([CH2:10][C:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][N:14]=[N+:15]=[N-:16])[NH:8]1)=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C/C=N/CC(=O)OC(C)(C)C)CCN=[N+]=[N-]
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 35.3 %

Procedure:
In a manner similar to the method described in Example 100b, [5-azido-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 120a (0.65 g, 2.45 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (0.76 g, 2.45 mmol) prepared in Example 52a, AgF (0.47 g, 3.7 mmol), and triethylamine (0.55 mL, 6 mmol) in dichloromethane (80 mL) at room temperature for 18 h, followed by the reaction with DBU (3 ml) in tert-butanol (3 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a yellow gum (0.5 g, 36%).