Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([CH:15]=[O:16])=[C:10]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]=[CH:8]2>C(O)(=O)C>[Br:1][C:6]1[C:5]([O:4][CH3:3])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:11]2[CH:15]=[O:16]
Reactant: COc1ccc2c(C=O)c(OCc3ccccc3)ccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc2c(C=O)c(OCc3ccccc3)ccc2c1Br
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Bromine (3.22 mL, 62.5 mmol) was dissolved in 60 mL of glacial acetic acid and added, over a 20 minute period, to a soluton of 6-methoxy-2-(phenylmethoxy)-1-naphthalenecarboxaldehyde (17.4 g, 59.5 mmol, described in Example 5) in 270 mL of glacial acetic acid at 45° C. The resulting suspension was allowed to cool for 1 hour, then the precipitate was collected by filtration and washed thoroughly with absolute ethanol. The solid was suspended in 170 mL of toluene and concentrated by distillation at ambient pressure until about 30 mL remained then allowed to stand at room temperature overnight. The precipitate which formed upon cooling was collected by filtration and washed with hexane to give 18.14 g of the title compound as a yellow powder, m.p. 214°-220° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=O.[CH3:22][NH:23][CH3:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)CCl>[CH3:22][N:23]([CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN(C)Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 4-(2-formylphenyl)piperazinecarboxylate (Step 1)(0.6 g, 2.1 mmol), was added dimethylamine (Aldrich) (1.6 mL of a 2.0 M soln in THF, 3.2 mmol) in ClCH2CH2Cl (15 mL) and NaBH(OAc)3 (Aldrich) (0.66 g, 3.2 mmol). The reaction was stirred at RT for 2 h. The mixture was partitioned between CH2Cl2 and satd NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-{2-[(dimethylamino)methyl]phenyl}piperazinecarboxylate (0.68 g) as a yellow oil. MS m/z: 320 (M+H). Calc'd for C18H29N3O2: 319.44.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[O:10])[NH:8][CH:9]=1.I[CH2:13][CH2:14][CH2:15][O:16][CH3:17]>C(O)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]([O:11][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[C:7](=[O:10])[NH:8][CH:9]=1
Reactant: O=c1[nH]cc(Br)cc1O
Reactant: COCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COCCCOc1cc(Br)c[nH]c1=O
Reaction time: 0.25 h

Procedure:
To a 1.4M NaOH solution at 0° C. are added 0.9 mol 5-bromo-3-hydroxy-1H-pyridin-2-one [34206-49-0]. The mixture is allowed to stir for 15 minutes and 0.9 mmol 1-iodo-3-methoxypropane [61542-10-7] are added carefully at 0° C. The mixture is stirred at room temperature for 3 hours, then neutralized with acetic acid to pH 7. The mixture is extracted with chloroform (10×) and the organic layer is dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and identified based on its Rf value.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C(O)C>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CN)OC
Reactant: O=Cc1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(CNCc1cccs1)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Thiophene-2-carboxaldehyde (22.4 g, 200 mmol) was dissolved in anhydrous ethanol (200 mL) and treated with 2,2-dimethoxyethanamine (26.6 g, 200 mmol) and para-toluenesulfonic acid hydrate (0.1 g, catalytic) and the mixture heated to reflux for 4 h. The reaction was allowed to cool down to room temperature and sodium borohydride (7.6 g, 200 mmol) was added in small portions to the reaction. Following complete addition, the reaction was stirred at room temperature for 15 min, then at reflux for 2 h. The reaction was allowed to cool down to room temperature and all the volatiles removed in vacuo. The residue was dissolved in ethyl acetate and was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, passed through a pad of silica gel, concentrated and placed on a vacuum line to afford an off-white solid. Yield=40.1 g. MS (M+H)+ 202.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[Cl:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[Cl:11][C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=1[B:17]([OH:20])[OH:18]
Reactant: CC(C)c1ccc(Cl)c(Br)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1ccc(Cl)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-1-chloro-4-isopropylbenzene (0.37 g, 1-59 mmol) in dry THF (5 mL) at −78° C., n-butyl lithium (0.76 mL, 1.90 mmol, 2.5 M) was added. The solution was stirred at −78° C. for 30 min. Trimethyl borate (0.53 mL, 4.76 mmol) was added. The solution was stirred at −78° C. for 2.5 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (3×15 mL). The combined EtOAc layers were dried over Na2SO4. The residue was used without further purification after evaporation of the solvent.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[N+:28]([C:31]1[CH:32]=[C:33]2[C:38](=[O:39])O[C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1)([O-:30])=[O:29]>C(O)(=O)C>[N+:28]([C:31]1[CH:32]=[C:33]2[C:38](=[O:39])[N:1]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([C:21]5[CH:22]=[CH:23][C:24]([N:27]6[C:38](=[O:39])[C:33]7=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:41][CH:40]=[C:34]7[C:35]6=[O:36])=[CH:25][CH:26]=5)[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:15]5[C:20]4=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:6][CH:7]=3)[C:35](=[O:36])[C:34]2=[CH:40][CH:41]=1)([O-:30])=[O:29]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: Nc1ccc(C2(c3ccc(N)cc3)c3ccccc3-c3ccccc32)cc1
Solvent: CC(=O)O
Product: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1c1ccc(C2(c3ccc(N4C(=O)c5ccc([N+](=O)[O-])cc5C4=O)cc3)c3ccccc3-c3ccccc32)cc1
Yield: 73 %

Procedure:
A mixture of 9,9-bis(4-aminophenyl)fluorene (3.5 g, 10 mmol) and 40 ml of acetic acid was stirred and then 4-nitrophthalic anhydride (4.1 g, 21 mmol) was added to the mixture. The resulting mixture was stirred and heated under reflux for 7 hours. After cooling, the beige-colored precipitate was filtered, washed with acetic acid (2×100 ml) and then with water (500 ml). The washed precipitate was recrystallized from dimethyl-fromamide-methanol to provide the title compound as an off-white powder (5.1 g, 73% yield) having a melting point of 360°-363° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1>>[F:23][C:22]([F:25])([F:24])[C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: FC(F)(F)c1cccc(I)c1
Product: COC(=O)CCc1ccc(C#Cc2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (101 mg, 0.54 mmol) and 1-iodo-3-(trifluoromethyl)benzene (0.09 mL, 0.62 mmol) according to the general procedure IC to give 119 mg (67%) of an yellow oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.58 (EtOAc:hexanes, 2:5); 1HNMR (CDCl3) δ 7.77 (s, 1H), 7.68-7.66 (m, 1H), 7.57-7.55 (m, 1H), 7.48-7.43 (m, 3H), 7.21-7.18 (m, 2H), 3.67 (s, 3H), 3.00-2.94 (t, 2H, J=7.8 Hz), 2.67-2.61 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 173.0, 141.4, 134.6, 131.8, 128.8, 128.4, 128.3, 128.3, 124.7, 124.6, 124.6, 124.3, 120.5, 90.8, 87.5, 51.6, 35.3, 30.8; ESI-MS m/z 355.1 (MNa+).
Reaction SMILES: [C:1]1([CH:7]2[C:13]3([CH2:17][CH2:16][C:15](=O)[NH:14]3)[CH:11]3[CH2:12][CH:8]2[CH:9]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].[O-2].[Ca+2]>>[C:1]1([CH:7]2[C:13]3([CH2:17][CH2:16][C:15](=[S:20])[NH:14]3)[CH:11]3[CH2:12][CH:8]2[CH:9]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC2(N1)C1C=CC(C1)C2c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Ca+2]
Agent: [O-2]
Product: S=C1CCC2(N1)C1C=CC(C1)C2c1ccccc1

Procedure:
20 mmoles of 3-phenyl-spiro[bicyclo[2.2.1]-hept-5-ene-2,2'-pyrrolidin]-5'-one, 4 g of phosphorus pentasulfide and 3 g of calcium oxide are stirred at 50°C. for 2 hours and the mixture is filtered hot into a saturated sodium carbonate solution. The residue is substantially disintegrated with concentrated hydrochloric acid, the mixture is diluted with water and the solutions are combined. The mixture is extracted several times by shaking with toluene and the organic phases are separated off, dried and evaporated in vacuo. Recrystallization of the residue from ethyl acetate gives colorless crystals of melting point 204° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:14])([CH3:13])[CH:4](OS(C)(=O)=O)[C:5]([OH:7])=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([SH:25])[N:18]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([O:16][CH3:15])[N:18]=[C:19]([S:25][CH:4]([C:3]([O:2][CH3:1])([CH3:13])[CH3:14])[C:5]([OH:7])=[O:6])[N:20]=1
Reactant: COc1cc(OC)nc(S)n1
Reactant: COC(C)(C)C(OS(C)(=O)=O)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(SC(C(=O)O)C(C)(C)OC)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
That is, after 3-methoxy-3-methyl-2-methylsulfonyloxybutanoic acid (22.6 g, 0.1 mol) and 4,6-dimethoxy-2-mercaptopyrimidine (17.3 g, 0.1 mol) were added to N,N-dimethylformamide (200 ml) and further anhydrous potassium carbonate (13.8 g) was added, the mixture was stirred at 50° C. for 2 hours. The resulting reaction mixture was added to a 1N hydrochloric acid aqueous solution (300 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution and dried over magnesium sulfate, and ethyl acetate was removed under reduced pressure. The crystals obtained were washed with n-hexane to obtain 24.1 g (yield: 80%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([C:19]([OH:21])=O)=[CH:9]2)=[CH:4][CH:3]=1.O=S(Cl)[Cl:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([C:19]([Cl:24])=[O:21])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2ccccc2c1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cn(-c2ccc(F)cc2)c2ccccc2c1=O
Yield: 95.1 %

Procedure:
A mixture of intermediate k 2 g (0.007 moL) and sulfoxide chloride (20 mL) was heated to reflux for 6 h, the excess sulfoxide chloride was evaporated in vacuo to obtain white solid 2 g. Yield: 95.1%.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:24][NH:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[CH3:24][NH:25][S:26](=[O:28])(=[O:27])[NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:16]3)=[CH:18][CH:19]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1
Solvent: c1ccncc1
Product: CNS(=O)(=O)Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 4-(3-morpholin-4-yl-quinoxalin-6-yl)-phenylamine [Intermediate Example 4.1] (100 mg) and pyridine (0.5 mL) was treated with a solution of methylsulfamyl chloride (75 mg, 0.65 mmol) in pyridine (0.6 mL) and stirred at room temperature overnight. The reaction was partitioned between dichloromethane and water, the phases separated and the organic layer concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to give the title compound (30 mg), contaminated by ca. 20% formic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH3:10])[C:8]=1[NH2:9])[CH3:2].[OH-].[K+].Br[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>CS(C)=O>[CH3:10][C:7]1[CH:6]=[C:5]([O:11][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[NH2:9]
Reactant: CCc1cc(O)cc(C)c1N
Reactant: CCOC(=O)CCCCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCOc1cc(C)c(N)c(CC)c1
Temperature: 15 °C
Yield: 71.4 %

Procedure:
500 ml of dimethyl sulfoxide (DMSO) are introduced at room temperature and, while stirring vigorously, 52.1 g (338.6 mmol) of the 3-ethyl-4-amino-5-methylphenol prepared in stage 2 are added in small portions. The mixture is cooled to 15° C. Then 33.5 g (507.9 mmol) of aqueous 85% strength potassium hydroxide solution are added dropwise so that the reaction temperature does not exceed 20° C. Then 82.7 ml (507.9 mmol) of ethyl 5-bromovalerate are added dropwise over the course of 70 minutes, maintaining the reaction temperature at 25° C. After a homogeneous solution has formed it is added to a mixture of 130 ml of 4M hydrochloric acid and ice and stirred well. The aqueous mixture is washed with diethyl ether. The aqueous phase is then made alkaline with 2M NaOH and extracted with diethyl ether, and the ether phase is washed twice with water and then with saturated brine, dried over sodium sulfate and concentrated. 67.5 g of a viscous oil are obtained and purified by vacuum distillation. Yield 31.7 g (33.7% of theory), boiling point 151°-152° C./10-2Torr.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH2:7][OH:8]
Reactant: COc1cc(Br)cc(C=O)c1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(Br)cc(CO)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
10.67 g of 5-bromo-2,3-dimethoxybenzaldehyde was dissolved in 100 ml of tetrahydrofuran and 100 ml of ethanol, and 1 g of sodium borohydride was added, and then the solution was stirred overnight at room temperature. 1 N hydrochloric acid was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 10.27 g of 5-bromo-2,3-dimethoxybenzyl alcohol. 5.326 g of this crude product was dissolved in 50 ml of N,N-dimethylformamide, and 1.8 g of imidazole and 5.9 g of t-butylchlorodiphenylsilane were added thereto, and the solution was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 10.72 g of [(5-bromo-2,3-dimethoxybenzyl)oxy](t-butyl)diphenylsilane.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:20]([NH:28][C:29]1[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:30]=1[C:31]([O:33]C)=[O:32])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:37]2[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[C:29]([NH:28][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:38]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)cc1
Temperature: 90 °C
Reaction time: 11 h
Yield: 7.5 %

Procedure:
56 mg of 4-(acetamido)phenylboronic acid, 55 mg of sodium carbonate and 30 mg of polymer supported bis(acetato)triphenylphosphine palladium(11) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of methyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 11 hours. After the reaction mixture was cooled to room temperature, 19 mg of 4-(acetamido)phenylboronic acid was added and the mixture was stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, 11 mg of sodium carbonate and 30 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added and stirred at 90° C. for 14 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.2 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 1 mL of 1.0 mol/L aqueous sodium hydroxide and 2 mL of ethanol were added to the obtained residue and stirred at room temperature for 1 hour. 0.6 mol/L hydrochloric acid was added, and solid substances were separated by filtration and purified with reversed-phase silica gel column chromatography [eluent; 40-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 5.9 mg of 4-(4-(acetamido)phenyl)-2-(benzamido)benzoic acid as white solid.
Reaction SMILES: C1(C[O:8][C@H:9]2[C@@H:14]([NH:15]CC3C=CC=CC=3)[CH2:13][CH2:12][N:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]2)C=CC=CC=1.[H][H]>[Pd].CO>[NH2:15][C@H:14]1[CH2:13][CH2:12][N:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][C@H:9]1[OH:8]
Reactant: [H][H]
Reactant: CCOC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CC[C@H](N)[C@H](O)C1

Procedure:
A mixture of 170 parts of ethyl cis-3-(phenylmethoxy)-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and 400 parts of methanol was hydrogenated at normal pressure and at 80° C. with 20 parts of palladium-on-charchoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The oily residue was distilled, yielding 75 parts of ethyl cis-4-amino-3-hydroxy-1-piperidinecarboxylate; bp. 175°-185° C. at 0.4 mm. pressure. (intermediate 49).
Reaction SMILES: [Cu][C:2]#N.C[Li].C(OCC)C.Br[CH2:12][C:13]1[C:17]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)=[N:16][N:15]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:14]=1>O1CCCC1>[CH2:12]([C:13]1[C:17]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)=[N:16][N:15]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:14]=1)[CH3:2]
Reactant: N#C[Cu]
Reactant: FC(F)(F)Oc1cccc(Oc2nn(-c3ccc(C(F)(F)F)cc3)nc2CBr)c1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Temperature: 0 °C

Procedure:
To a suspension of copper(I) cyanide (0.037 g, 0.41 mmol) in anhydrous tetrahydrofuran (2 mL) at −78° C. under a nitrogen atmosphere was added a solution of methyllithium in diethyl ether (1.6 M, 0.54 mL, 0.86 mmol). The mixture was stirred at 0° C. until a clear, colorless solution formed, and then the solution was cooled back to −78° C. To the methylcuprate solution was added a solution of 4-(bromomethyl)-5-[3-(trifluoromethoxy)phenoxy]-2-[4-(trifluoromethyl)phenyl)-2H-1,2,3-triazole (i.e. the product of Example 6, Step A, 0.100 g, 0.21 mmol) in anhydrous tetrahydrofuran (4 mL). The mixture was stirred for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and stirred vigorously at 23° C. until the solution turned deep blue in color. The reaction mixture was extracted with ethyl acetate (2×10 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the crude product which was purified by chromatography on silica gel eluting with 0 to 10% ethyl acetate in hexanes to obtain the title compound (0.038 g) as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a stirred and cooled (0° C.) solution of tert-butyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethylcarbamate (C50) (0.10 g, 0.22 mmol) in dichloromethane (1.6 mL) was added trifluoroacetic acid (0.19 mL, 0.25 mmol), and the solution was allowed to warm slowly to ambient temperature and stirred overnight. The reaction mixture was concentrated, taken up in hexanes, and concentrated until a solid was obtained. The solid was dissolved in dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with saturated sodium bicarbonate. The organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a white solid (0.075 g, 97%): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.18-8.07 (m, 2H), 7.83-7.74 (m, 2H), 7.41-7.29 (m, 4H), 3.02 (t, J=6.8 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 1.45-1.29 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −58.04.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:2]([CH:1]=[O:9])[C:3]=1[OH:4])([O-:12])=[O:11]
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=Cc1cccc([N+](=O)[O-])c1O

Procedure:
Salicylaldehyde (10 grams) is dissolved in acetic acid (50 grams) and nitrated with 10 ml. of red fuming nitric acid at 40°-45° C. The mixture is poured over ice and filtered. The solid product is a mixture of 3- and 5- nitrosalicylaldehyde. The isomers are separated by fractional recrystallization in acetic acid or by fractional recrystallization of their sodium salts in warm water, the 5-nitro isomer being less soluble in water than the 3-nitro isomer.