Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:29]([NH:32][NH2:33])(=[O:31])[CH3:30]>C(OCC)(=O)C.ClCCl>[C:29]([NH:32][NH:33][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)(=[O:31])[CH3:30]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(=O)NN
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NNC(=O)c1ccc(C)c([N+](=O)[O-])c1
Yield: 43.9 %

Procedure:
4-Methyl-3-nitrobenzoic acid (3.00 g, 16.5 mmol) was added to dichloromethane (50 ml), triethylamine (3.0 ml, 21.3 mmol) and isobutyl chloroformate (2.80 ml, 21.5 mmol) were added under ice-cooling with stirring, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was ice-cooled again, acetohydrazide (2.45 g, 33.1 mmol) was added with stirring, and the mixture was stirred at room temperature for about 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous citric acid solution, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was washed with diethyl ether and hexane to give the title compound (1.72 g, yield 44%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=2)=[CH:23][C:22]=1[C:39]([F:42])([F:41])[F:40]>CCO.CC(O)=O.[Zn]>[F:1][C:2]([F:43])([F:44])[C:3]1[CH:8]=[C:7]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[CH:23][C:22]=1[C:39]([F:42])([F:41])[F:40]
Reactant: O=C(Nc1ccc(-c2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc2C(F)(F)F)c(C(F)(F)F)c1)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)Nc2ccc(-c3ccc(NC(=O)c4ccc(N)cc4)cc3C(F)(F)F)c(C(F)(F)F)c2)cc1

Procedure:
The prepared precursor, DA167, i.e., N,N′-(2,2′-bis(trifluoromethyl)-[1,1′-biphenyl]-4,4′-diyl)bis(4-nitrobenzamide) (6.18 g, 0.01 mol) is dissolved in the mixture of solvents EtOH/AcOH (100/20 mL) at mild reflux. Zinc (Zn) powder (6.54 g, 0.1 mol) is carefully added in 1 portion, which is extremely exothermic, thus 2 liter (L) high-beaker is recommended to be used. The mixture is immediately bubbled up within several seconds, and then clear colorless solution is formed. The mixture is refluxed for additional 10 minutes or more and filtered hot to remove unreacted zinc. The solution is poured into H2O (300 mL), resulting in white precipitate. Precipitate is filtered and thoroughly washed with H2O (2×300 mL) by suspension-filtration procedure to remove traces of mother liquor and zinc salts. Filtration of solid and drying under vacuum at 90° C. for 12 hours yields white powder of N,N′-(2,2′-bis(trifluoromethyl)-[1,1′-biphenyl]-4,4′-diyl)bis(4-aminobenzamide), DA168 4.1 g (yield 73.5%). 1H NMR 300 MHz of DA168 are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]#[N:25])[CH:3]=3)[O:8][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:10]2)[N:12]=1
Reactant: CN1OC2(CC(C3CCOCC3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(C3CCOCC3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 4.8 %

Procedure:
A mixture of 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 0.131 mmol), 3-cyanophenylboronic acid (40 mg, 0.222 mmol), Cs2CO3 (2 M, 0.5 mL) and Pd(PPh3)2C12 (15 mg) in 1,4-dioxane (3 mL) under Ar was stirred in a microwave reactor at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (2.54 mg, 5%). 1H-NMR (CDCl3): 1.54 (m, 2H), 1.62 (m, 1H), 1.88 (m, 1H), 2.10 (m, 1H), 2.48 (m, 1H), 3.39 (m, 3H), 3.42 (m, 3H), 4.03 (m, 3H), 6.90 (m, 1H), 7.45 (m, 2H), 7.58 (m, 2H), 7.62 (m, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([CH:8]([NH:11][C:12]1[C:13]([N+:27]([O-:29])=[O:28])=[CH:14][C:15]([CH2:24][CH:25]=[O:26])=[C:16]([CH:21]([CH3:23])[CH3:22])[C:17]=1[N+:18]([O-:20])=[O:19])[CH2:9][CH3:10])[CH3:7].[Mn]([O-])(=O)(=O)=[O:31].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH2:6]([CH:8]([NH:11][C:12]1[C:13]([N+:27]([O-:29])=[O:28])=[CH:14][C:15]([CH2:24][C:25]([OH:31])=[O:26])=[C:16]([CH:21]([CH3:22])[CH3:23])[C:17]=1[N+:18]([O-:20])=[O:19])[CH2:9][CH3:10])[CH3:7]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(CC=O)c(C(C)C)c1[N+](=O)[O-]
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(CC(=O)O)c(C(C)C)c1[N+](=O)[O-]
Temperature: 12 °C
Reaction time: 8 h

Procedure:
A mixture of concentrated sulfuric acid (4.25 g) and water (17.3 g) is cooled to about 12° C., and a solution of {5-[(1-ethylpropyl)amino]-4,6-dinitro-o-cumenyl}acetaldehyde (6.5 g; 0.0192 mol) in methylene chloride (40 ml) is added slowly while the temperature of the mixture is maintained at about 12° C. Next, potassium permanganate (3.0 g; 0.0192 mol) is added to small portions. After stirring overnight at room temperature, tlc indicates the presence of some starting material. The mixture is cooled to 15° C., and a second portion of potassium permanganate (3.0 g; 0.0192 mol) added. When tlc indicates the absence of starting material, sodium thiosulfate is added until a clear red solution is obtained. Methylene chloride is added and the layers are separated. The methylene chloride layer is washed, dried over magnesium sulfate, and evaporated to leave a red oil (6.6 g; 97%) which slowly solidifies to a yellow solid. This solid is purified by column chromatography using 90/10 toluene/ethyl acetate to elute the product, melting point 116°-118° C. An analytical sample, recrystallized from pentane, melts at 117.5°-118.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][NH:32][CH3:33]>C1COCC1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:32]([CH3:33])[CH3:31])=[O:29])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CNC
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N(C)C)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and 2.0 M dimethylamine in THF. LCMS (M+H)+=475.0/477.0.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10]([N:12]([C:20]1[S:29][CH2:28][C@H:27]2[C@:22]([C:30]3[S:31][CH:32]=[C:33]([N:35]=[N+]=[N-])[CH:34]=3)([CH2:23][O:24][CH2:25][CH2:26]2)[N:21]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.[Zn]>[C:5]([O:9][C:10]([N:12]([C:20]1[S:29][CH2:28][C@H:27]2[C@@:22]([C:30]3[S:31][CH:32]=[C:33]([NH2:35])[CH:34]=3)([CH2:23][O:24][CH2:25][CH2:26]2)[N:21]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(N=[N+]=[N-])cs3)COCC[C@H]2CS1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(c3cc(N)cs3)COCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
Zinc powder (133 mg) and ammonium formate (320 mg) were added to a solution of (±)-N,N-di(tert-butyloxycarbonyl)-[(4aR*,8aR*)-8a-(4-azidothiophen-2-yl)-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (503 mg) in methanol (76.2 ml). The mixture was stirred at room temperature overnight, and then the solvent was evaporated under reduced pressure at room temperature or lower. Water was added to the residue, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (325 mg).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[OH:18])[CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH:19]1([CH2:25][CH2:26][CH2:27]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O>CN(C)C=O>[O:6]1[C:7]2([CH2:11][CH2:10][N:9]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[O:18][CH2:27][CH2:26][CH2:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:8]2)[O:3][CH2:4][CH2:5]1
Reactant: BrCCCC1CCCCC1
Reactant: O[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C1CCC(CCCO[C@H]2CCCC[C@@H]2N2CCC3(C2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (200 mg, 8.33 mmol) in anhydrous dimethylformamide (20 mL) was added a solution of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)cyclohexanol (1.5 g, 6.6 mmol) in anhydrous dimethylformamide (10 mL). The resulting mixture was stirred at room temperature for 30 min. and then a solution of 3-(cyclohexyl)propyl bromide (1.67 g, 8.15 mmols) in anhydrous dimethylformamide was quickly added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (200 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic extracts were back-washed with brine (50 mL) and the solvent was evaporated in vacuo. The residue was taken up with water (50 mL) and the pH was adjusted to pH 1.0 with 6M HCl aqueous solution. The acidic aqueous solution was extracted with diethyl ether (2×50 mL), then basified to pH 5.0-5.5 with 5M NaOH aqueous solution and extracted with diethyl ether (3×50 mL). The combined organic extracts at pH 5.0-5.5 were concentrated in vacuo to provide the crude title compound suitable for the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[OH:40][CH2:39][C:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[C:4]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:9]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])([CH3:42])[CH3:41]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)CO)c3)c2)n1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-benzeneboronic acid (example G.9) (0.442 g, 1.2 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example H.4) (0.381 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.150 g, 22%). MS (ISP) 499.2 [(M+H)+]; mp 181° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[CH2:16]Cl)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl.[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH2:33].O>CN(C=O)C>[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH:33][CH2:16][C:9]1[CH:10]=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:8]=1[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18]
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1CCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCc1cc(F)c(F)cc1NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
To a solution of (2-chloromethyl-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester) (5.65 g, 20.3 mmol) in DMF (50 mL) was added DIPEA (10.6 mL, 60.9 mmol). The resulting solution was stirred for 5 min, followed by dropwise addition of solution of glycine methyl ester hydrochloride in DMF at 0° C. The reaction mixture was stirred overnight at 50° C. After completion of the reaction as confirmed by TLC, water (60 mL) was added to the reaction mixture and crude compound was extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4. The solvents were removed in vacuo to afford the crude compound which was purified by column chromatography (silica gel: 1.5:8.5 EtOAc:Pet. ether) to obtain pure (2-tert-butoxycarbonylamino-4,5 difluoro-benzylamino)-acetic acid methyl ester (5.37 g, 80%) as thick gel.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17](=[O:19])[N:16]([CH3:20])[C:15]=3[CH:21]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1.Cl.C([O-])(O)=O.[Na+].Br[C:31](C)([CH3:35])[C:32](Br)=O>[OH-].[Na+].O1CCOCC1.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:31]([CH3:35])([CH3:32])[C:17](=[O:19])[N:16]([CH3:20])[C:15]=3[CH:21]=2)=[O:10])=[C:4]([Cl:23])[CH:3]=1
Reactant: CC(C)(Br)C(=O)Br
Reactant: CC(C(=O)c1ccc2oc(=O)n(C)c2c1)c1ccc(Br)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C(=O)c1ccc2c(c1)N(C)C(=O)C(C)(C)O2)c1ccc(Br)cc1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
A mixture of 5-[2-(4-bromo-2-chloro-phenyl)-propionyl]-3-methyl-3H-benzooxazol-2-one (20 mg, Example 116 step 7) in 1N aqueous NaOH (1 ml) and dioxane (1 ml) was heated for 20 min at 100° C. in a microwave oven. Aqueous 1N HCl solution (1.2 ml) was added, followed by NaHCO3 (100 mg) and EtOAc (10 ml). Bromoisobutyryl bromide (20 mg) was added and the mixture was stirred for 1 h. Water (10 ml) was added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was dissolved in DMF (3 ml), and K2CO3 (100 mg) was added. The mixture was heated to 100° C. for 2 h. The mixture was purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (11 mg) as a light yellow oil. MS (m/e)=438.0 [M+H+].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#[N:9])C.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.NOS(O)(=O)=O>O>[NH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CC#N
Agent: NOS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NN1CCc2ccccc21
Reaction time: 0.17 h
Yield: 37 %

Procedure:
In 40 ml of water was dissolved 2.76 g(20 mmol) of potassium carbonate thoroughly, and 10 ml of acetonitrile and 2.24 ml(20 mmol) of indoline were added thereto in this order. After stirring the reaction mixture for 10 min, 2.26 g(20 mmol) of hydroxylamine-O-sulfonic acid was added thereto. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under the reduced pressure. The concentrate was extracted with dichloromethane and treated with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under the reduced pressure, and the resulting concentrate was subjected to chromatography over silica gel using dichloromethane as an eluent. The fractions were concentrated to give 0.99 g of the desired compound(37%).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][S:23]1(=[O:33])=[O:32])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1.O>[O:33]=[S:23]1(=[O:32])[N:22]([CH2:21][CH2:20][CH2:19][OH:18])[CH2:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24]1
Reactant: CC(C)(C)[Si](OCCCN1Cc2ccccc2NS1(=O)=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)Nc2ccccc2CN1CCCO
Temperature: 23 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A solution of 3-(3-{[tert-butyl(diphenyl)silyl]oxy}propyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.44 g, 0.92 mmol) in tetrahydrofuran (4 mL) was treated with tetrabutylammonium fluoride (1.4 mL of a 1 M solution in tetrahydrofuran, 1.4 mmol) and acetic acid (0.16 mL, 2.8 mmol), and stirred at 23° C. for 18 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with dichloromethane (2×50 mL), dried (Na2SO4), and evaporated. Flash chromatography (SiO2, 2.5-100% ethyl acetate/hexanes) provided 3-(2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl)propan-1-ol (0.20 g, 90%) as a colorless oil:
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)[CH:14]=[C:13]([CH3:26])[C:3]=1[O:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[CH2:7]1.C(O)C.[H][H]>[Pt]=O.C(OCC)(=O)C>[NH2:23][C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[C:13]([CH3:26])[C:3]([O:4][CH2:5][CH:6]3[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[CH2:7]3)=[C:2]([CH3:1])[CH:16]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(-c2cccc([N+](=O)[O-])c2)cc(C)c1OCC1CCCN(C)C1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(-c2cccc(N)c2)cc(C)c1OCC1CCCN(C)C1

Procedure:
A mixture of 3-[2,6-dimethyl-4-(3-nitrophenyl)phenoxymethyl]-1-methylpiperdine (785 mg, 2.21 mmol), ethanol (10 mL), and ethyl acetate (5 mL) was hydrogenated overnight with platinum oxide (50 mg) at 1 atmosphere of hydrogen. The reaction was purged with nitrogen and filtered through Celite. The solids were washed with methanol and ethyl acetate. The filtrate and the washings were concentrated to give 3-[4-(3-aminophenyl)-2,6-dimethylphenoxymethyl]-1-methylpiperidine as a yellow oil (735 mg, quantitative).
Reaction SMILES: [CH3:1][N:2](C)CCCN=C=NCC.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:17]=[CH:18][CH:19]=1.OS1C2C=CC=CC=2N=C1.CN.C(O)C>C(Cl)Cl.CN(C)C=O.C(OCC)(=O)C>[CH3:1][NH:2][C:21](=[O:22])[CH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:25])([F:24])[F:12])[CH:15]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN
Agent: O[SH]1C=Nc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (21.6 g (0.11 mol) was added to a solution of 3-(trifluoromethyl)phenylacetic acid (Aldrich 19,335-6, 23.0 g, 0.11 mol) and 1-hydroxybenzothiazole (21.6 g, 0.11 mol) in DCM (50 ml) and N,N-dimethylformamide (50 ml). The reaction mixture was stirred for 20 min at 0° C. A 33% solution of methylamine in ethanol (280 ml, 2.25 mol) was added. The reaction mixture was stirred for 56 hours and successively diluted with ethyl acetate (200 ml). It was washed with a 10% aqueous solution of sodium hydrogensulphate (300 ml). The aqueous phase was extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (300 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using ethyl acetate/heptane 2:1 as eluent, to give 19.8 g of N-methyl-2-(3-trifluoromethylphenyl)acetamide.
Reaction SMILES: [O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N:5]=[C:4]([CH2:15][CH2:16][CH2:17][OH:18])[N:3]=1)[CH2:12][CH2:11][CH2:10]3.CO.CC[O:23]C(C)=O>>[O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N+:5]([O-:23])=[C:4]([CH2:15][CH2:16][CH2:17][OH:18])[N:3]=1)[CH2:12][CH2:11][CH2:10]3
Reactant: CCOC(C)=O
Reactant: [O-][n+]1nc(CCCO)nc2cc3c(cc21)CCC3
Solvent: CO
Product: [O-][n+]1nc(CCCO)[n+]([O-])c2cc3c(cc21)CCC3

Procedure:
H2O2 (70%, 1.6 mL, ca. 33 mmol) was added dropwise to a stirred solution of TFAA (4.6 mL, 33 mmol) in DCM (30 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. The solution was added to a solution of 1-oxide 70 (0.86 g, 3.3 mmol) in DCM (50 mL) at 0° C. and the solution was stirred at 20° C. for 16 h. Dilute aqueous NH3 solution (30 mL) was added and the mixture stirred vigorously for 30 min and then extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give (i) starting material 70 (283 mg, 33%) and (ii) 1,4-dioxide 71 (347 mg, 40%) as a yellow solid: mp (MeOH/EtOAc) 153-155° C.; 1H NMR δ 8.33 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.68 (br dt, J=6.1, 5.7 Hz, 2H, CH2O), 3.33 (t, J=6.9 Hz, 2H, CH2), 3.13-3.20 (m, 4H, H-6, H-8), 3.09 (br t, J=6.1 Hz, 1H, OH), 2.26 (p, J=7.5 Hz, 2H, H-7), 2.10-2.18 (m, 2H, CH2); 13C NMR δ 155.5, 155.0, 150.9, 138.8, 134.0, 115.8, 114.1, 61.2, 33.4, 32.9, 29.6, 26.8, 25.6. Anal. calcd for C13H15N3O3: C, 59.8; H, 5.8; N, 16.1. Found: C, 60.0; H, 5.7; N, 16.1%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.CN(C=O)C.[H-].[Na+].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:11]=[CH:10][N:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccccc1-c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccnc1-c1ccccc1Br
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
2-(2-bromophenyl)-1H-imidazole (WO 9407486; 1.0 g, 4.48 mmol) was dissolved in THF (11 mL) and DMF (11 mL) and cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 197 mg, 4.93 mol) was added and the reaction stirred for 20 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (0.79 mL, 4.93 mmol) was added and the reaction stirred overnight at room temperature. The reaction was quenched with MeOH then partitioned between water and Et2O. The organic layer was dried (MgSO4) and concentrated in vacuo and the residue was purified by flash column chromatography to afford 2-(2-bromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole as an off-white solid (1.5 g).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].Br[CH2:28][C:29]#[N:30]>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:28][C:29]#[N:30])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: N#CCBr
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCC#N)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 and 2-bromoacetonitrile using an analogous procedure to that outlined in the preparation of Compound 205.11-1 NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, J=7.33 Hz, 3H) 3.22 (q, J=7.33 Hz, 3H) 5.14 (s, 2H) 7.31-7.37 (m, 2H) 7.82 (t, J=7.71 Hz, 1H) 7.91 (d, J=7.83 Hz, 1H) 8.09 (d, J=7.83 Hz, 1H) 8.11-8.15 (m, 2H) 8.22 (s, 1H) 14.04 (br. s., 1H) [M+H] calc'd for C22H19N3O3S, 406; found, 406.