Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:32]([O:34][CH3:35])=[O:33])([CH2:30][CH3:31])[CH2:28][CH3:29])/[C:9]1=[O:36])=O)(C)(C)C.[F:37][C:38]1[CH:39]=[CH:40][C:41]([CH3:53])=[C:42]([CH:44]=[N:45][C:46]([O:48][Si](C)(C)C)=[CH2:47])[CH:43]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:36])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([CH2:28][CH3:29])([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH3:31])[CH2:47][C:46](=[O:48])[NH:45][CH:44]3[C:42]3[CH:43]=[C:38]([F:37])[CH:39]=[CH:40][C:41]=3[CH3:53])[C:11]2=[CH:12][CH:13]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21)C(=O)OC
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OC
Temperature: 60 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
A mixture of E/Z-3-[5-chloro-2-(1-methoxycarbonyl-1-ethyl-propoxy)-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (7.6 g, 15 mmol) and 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (60 mmol) prepared in Example 4 in toluene (60 mL) was heated at 60° C. for 3 h, and concentrated in vacuo. To the residue was added DCM (50 mL) and TFA (20 mL), and the resulting solution was stirred at room temperature for 3 h, then concentrated in vacuo, partitioned between ethyl acetate and diluted aqueous NaOH solution. The organic layer was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography to give the title compound as white solid (2.2 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:29](=[O:30])[C:28]4[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 4-methoxy-benzoyl chloride (0.51 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, the product was isolated by filtration, washed with MeCN (10 mL) and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methoxy-benzamide as a white solid (0.99 g, 79% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.58 min (97.92%); mp: 215-217° C.; 1H NMR (DMSO-d6) δ 1.94-2.20 (m, 1H, CHH), 2.39-2.70 (m, 2H, CHH, CHH), 2.78-3.04 (m, 1H, CHH), 3.82 (s, 3H, CH3), 4.63 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.7 Hz, 1H, CH), 7.02 (d, J=8.9 Hz, 2H, Ar), 7.76-7.97 (m, 5H, Ar), 9.08 (t. J=5.9 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.55, 48.99, 55.37, 113.60, 121.91, 123.53, 126.11, 129.11, 129.74, 131.59, 133.40, 147.87, 161.75, 165.91, 167.00, 167.15, 169.82, 172.73; LCMS: MH=422; Anal Calcd for C22H19N3O6: C, 62.70; H, 4.54; N, 9.97. Found: C, 62.40; H, 4.46; N, 10.12.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:23]=[N:22][N:21]([CH:24]4[CH2:28][CH:27]([OH:29])[CH:26]=[CH:25]4)[C:13]=3[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(Cl)(=[O:38])C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:23]=[N:22][N:21]([CH:24]4[CH2:25][CH2:26][CH:27]([OH:29])[CH:28]4[OH:38])[C:13]=3[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3C=CC(O)C3)c2n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CCC(O)C3O)c2n1
Reaction time: 3 h

Procedure:
To a solution of the product of step d) (0.78 g), pyridine (0.43 ml) and 4-dimethylaminopyridine (1 mg) in dichloromethane (15 ml) was added acetyl chloride (0.16 ml). The solution was stirred for 3 hours and then concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate:hexane 1:1 as eluant) to afford the sub-title compound (0.75 g).
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:5][C:6]2[C:7](=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=2[CH3:12])[N:8]=1)[CH3:2].[H-].[Na+].[Cl:19][C:20]([Cl:41])([Cl:40])[C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=2)[N:22]=1.O>CN(C=O)C>[CH2:1]([S:3][C:4]1[N:8]([CH2:38][C:35]2[CH:36]=[CH:37][C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:23]3[N:22]=[C:21]([C:20]([Cl:40])([Cl:19])[Cl:41])[O:25][N:24]=3)=[CH:33][CH:34]=2)[C:7]2=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCSc1nc2c(C(=O)OC)sc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc2c(C)sc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2noc(C(Cl)(Cl)Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooling solution of methyl 2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate (3 g) in DMF (20 ml) was added sodium hydride (60%, oil) (0.56 g), and the mixture was stirred for 10 minutes. To the ice-cooling mixture was added [2'-(5-trichloromethyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl bromide (6.1 g), and the mixture was stirred for two hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel to afford the title compound as a pale yellow syrupy product (4.15 g, 58%).
Reaction SMILES: C1(/C=[CH:8]/[C:9]2[CH:14]=[N:13][C:12]3=[N:15][S:16][N:17]=[C:11]3[CH:10]=2)C=CC=CC=1.C[N+]1([O-])CC[O:22]CC1.O.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O.CC(C)=O>[N:17]1[S:16][N:15]=[C:12]2[C:11]=1[CH:10]=[C:9]([CH:8]=[O:22])[CH:14]=[N:13]2
Reactant: C[N+]1([O-])CCOCC1
Reactant: C(=C/c1cnc2nsnc2c1)\c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1cnc2nsnc2c1
Reaction time: 20 h

Procedure:
To 6-[(E)-2-phenylethenyl][1,2,5]thiadiazolo[3,4-b]pyridine (0.88 g, 3.68 mmol) was added acetone (30 ml), N-methyl-morpholine-N-oxide, 50 wt. % in water (1.525 ml, 7.35 mmol) and then osmium tetroxide in water (0.225 ml, 0.037 mmol). The reaction was then stirred for 20 hours. To the pale brown solution was added sodium periodate (3.15 g, 14.71 mmol) and stirring continued for 45 mins. The solvent was reduced by rotary evaporation and the remainder partitioned between chloroform and water. The aqueous was further extracted with chloroform and the combined organic extracts passed through a hydrophobic frit and concentrated to give brown/black solid (0.6 g). A portion of this material (0.575 g) was purified by chromatography on silica eluting with 20% EtOAc in cyclohexane to a pale yellow solid (160 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:30]=[CH:29][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:30]=[CH:29][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[N:16][C:12]=3[CH:11]=2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CNc3ccc(F)cc3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc([N+](=O)[O-])cc3)c3ccc(F)cc3)ccc2[nH]1
Temperature: 40 °C
Yield: 93.4 %

Procedure:
The product from Example 99B (0.65 g, 1.58 mmol), 1-(bromomethyl)-4-nitrobenzene (0.479 g, 2.22 mmol), and potassium carbonate (0.547 g, 3.96 mmol) were combined in dimethyl formamide (15 mL) and heated at 40° C. for 3 hours then diluted with water and filtered. The product was purified by combi-flash 24 g silica column, eluting with 0-5% methanol in dichloromethane to give 0.805 g (93%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[C:12](I)=[CH:11][N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[C:29]([O:33][C:34](=[O:52])[N:35]([C:45]1[CH:46]=[N:47][C:48]([Cl:51])=[CH:49][CH:50]=1)[C:36]1[CH:41]=[CH:40][C:39]([CH:42]=[O:43])=[C:38]([F:44])[N:37]=1)([CH3:32])([CH3:31])[CH3:30].O>O1CCCC1>[C:29]([O:33][C:34](=[O:52])[N:35]([C:45]1[CH:46]=[N:47][C:48]([Cl:51])=[CH:49][CH:50]=1)[C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:12]2[C:5]3[C:4]([CH:1]4[CH2:2][CH2:3]4)=[N:9][CH:8]=[N:7][C:6]=3[N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[CH:11]=2)[OH:43])=[C:38]([F:44])[N:37]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)nc1)c1ccc(C=O)c(F)n1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2c(C3CC3)ncnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2ccc(N(C(=O)OC(C)(C)C)c3ccc(Cl)nc3)nc2F)c2c(C3CC3)ncnc21
Temperature: -5 °C
Yield: 55.4 %

Procedure:
To 4-cyclopropyl-5-iodo-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (19, 0.72 g, 1.64 mmol) in 6.0 mL of tetrahydrofuran at −40° C. under nitrogen, isopropylmagnesium chloride (0.82 mL, 2.01 M in tetrahydrofuran, 1.65 mmol) is added slowly. The reaction is allowed to warm to −5° C. in 75 minutes, then cooled to −45° C. and (6-chloro-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (80, 0.48 g, 1.38 mmol) in 5.0 mL is added. The reaction is allowed to warm to room temperature in 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (81, 0.51 g). MS (ESI) [M+H+]+=667.2).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[C:7](Cl)[N:6]=1)=[O:4].[Br:16][C:17]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[C:7]([O:25][C:22]2[CH:23]=[CH:24][C:17]([Br:16])=[C:18]([CH:19]=[O:20])[CH:21]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(Cl)nc1C(=O)OC
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(Br)c(C=O)c2)nc1C(=O)OC
Temperature: 80 °C
Yield: 16.6 %

Procedure:
To a solution of 6-chloro-pyridine-2,3-dicarboxylic acid dimethyl ester (18, 4.0 g, 17.42 mmols) and 2-bromo-5-hydroxy-benzaldehyde (3.5 g, 17.42 mmol) in DMF (30 mL) was added cesium carbonate (11.35 g, 34.84 mmols). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure, diluted with EtOAc (100 mL), washed with water (2×25 mL) and brine (50 mL) solution. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give crude product which was purified by column chromatography (Silica gel 20% EtOAc in hexane) to yield title compound 19 (1.14 g, 15%) as a light yellow oil. 1H NMR 400 MHz (DMSO-d6) δ: 10.18 (s, 1H), 8.38 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.55-7.52 (m, 1H), 7.36 (d, J=8.6 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H); MS (ES) m/z: 394 (M+1)+, 396 (M+3)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH3:16])[C:10]([CH3:18])([CH3:17])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH2:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:17])[CH3:18])[CH3:16]
Reactant: [H][H]
Reactant: CCNC1CCN(Cc2ccccc2)CC1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCNC1CCNCC1(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.4 g) and 1-benzyl-4-ethylamino-3,3-dimethylpiperidine (1.3 g, 5.3 mmol) in methanol (10 ml) was stirred in hydrogen atmosphere (1 atm.) at ambient temperature for 15 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-ethylamino-3,3-dimethylpiperidine. Yield 0.8 g (97%), C9H20N2, m/z 157 (M+1), PMR (CDCl3): 0.9 (s, 3H), 1.06 (s, 3H), 1.18-1.38 (m, 5H), 1.85 (bs, 2H, D2O exchangeable), 1.64-2.8 (m, 6H), 2.94 (m, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CO)NCc1ccccc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccc(C(N)=O)cn1)NCc1ccccc1

Procedure:
Reaction of 47 g of 2-benzylamino-2-methyl-1-propanol, 13.3 g of sodium hydride dispersion and 23.5 g of 6-chloronicotinic acid amide in 300 ml of dimethylformamide analogously to Example 1(a) gives 6-(2-benzylamino-2,2-dimethyl-ethoxy)-nicotinic acid amide of melting point 125°-126° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])=[O:31])[CH:24]=[CH:23]2>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:36]2[CH2:35][CH2:34][N:33]([S:30]([C:25]3[CH:24]=[CH:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([Cl:19])[CH:21]=4)[CH:26]=3)(=[O:32])=[O:31])[CH2:38][CH2:37]2)=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1

Procedure:
In a similar manner to Referential Example 12 except for the use of (1-tert-butoxycarbonylpiperidin-4-yl)acetic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [CH2:1](B(O)O)[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[C:15]1[CH:33]=[CH:32][C:18]2[N:19]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[C:28]([O:30][CH3:31])=[O:29])[O:21][C:17]=2[CH:16]=1.O1CCCC1>C1(C)C=CC=CC=1>[CH2:1]([C:15]1[CH:33]=[CH:32][C:18]2[N:19]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]3[C:28]([O:30][CH3:31])=[O:29])[O:21][C:17]=2[CH:16]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CB(O)O
Reactant: COC(=O)[C@@H]1CCCCN1c1nc2ccc(Br)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCCCN1c1nc2ccc(CC(C)C)cc2o1
Temperature: 80 °C
Yield: 13.6 %

Procedure:
Isobutyl boronic acid (475 mg), potassium carbonate (644 mg) and tetrakis triphenylphosphine palladium (269 mg) were added sequentially to a solution of methyl (2S)-1-(6-bromo-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (790 mg) [see Preparation 40] in toluene:tetrahydrofuran, 60:40 by volume, (20 ml) under nitrogen. The reaction mixture was then heated to 80° C. for 20 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between water and dichloromethane. The organic layer was separated and washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 80:20, by volume, hexane:ethyl acetate to afford methyl (2S)-1-(6-isobutyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (100 mg) as an oil.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([C:7]1[S:33][C:10]2[N:11]=[C:12]([NH2:32])[N:13]=[C:14]([C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH:23](OCC)OCC)[C:18]([Cl:30])=[CH:17][C:16]=3[Cl:31])[C:9]=2[CH:8]=1)=[O:6])[CH3:3].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCl>[CH2:2]([NH:4][C:5]([C:7]1[S:33][C:10]2[N:11]=[C:12]([NH2:32])[N:13]=[C:14]([C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH2:23][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:18]([Cl:30])=[CH:17][C:16]=3[Cl:31])[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCNC(=O)c1cc2c(-c3cc(OCC(OCC)OCC)c(Cl)cc3Cl)nc(N)nc2s1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1cc2c(-c3cc(OCCN4CCOCC4)c(Cl)cc3Cl)nc(N)nc2s1
Reaction time: 18 h

Procedure:
Hydrochloric acid was added to a solution of 2-Amino-4-(2,4-dichloro-5-(2,2-diethoxyethoxy)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in THF and the solution stirred for ˜18 hrs. Morpholine was added and the solution stirred, sodium triacetoxyborohydride was added and the resulting suspension stirred for ˜18 hrs. Dichloromethane was added and the mixture washed with aqueous ammonia (0.880), water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a pale yellow solid. The crude product was purified by chromatography on silica eluting with mixtures of ethyl acetate and hexane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].CO.[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH3:19]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CNS(=O)(=O)c1ccc(OC)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.04 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester, 2.2 mmol methanol and 2.34 mmol triphenylphosphine in 10 ml THF was added 2.24 mmol di-tert-butyl azodicarboxylate and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:16]1(C)C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCOCC>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([O:14][CH3:15])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[F:1]
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a round bottom flask, 2-fluoro-5-methoxy-4-nitro-benzoic acid (2.84 g, 0.0132 mol;), toluene (25 mL, 0.23 mol), methanol (5 mL, 0.1 mol;) were added. 2.00 M of trimethylsilyldiazomethane in ether (7.92 mL) was added drop wise at 5° C. The reaction was stirred at room temperature for 2 hours. The solvent was removed under vacuum to afford a yellow solid. The solid was triturated with 10% Et2O and hexane to give 2-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester as an off white solid (2.84, 93%). 1H-NMR (DMSO-D6, 400 MHz): δ 8.06 (d, 1H), 7.70 (d, 1H). 4.14 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25](Cl)=[O:26].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH2:12][NH:13][C:25]([C:17]2[O:16][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH:18]=2)=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)(C)CN)cc1OC
Reactant: O=C(Cl)c1cc2ccccc2o1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)(C)CNC(=O)c2cc3ccccc3o2)cc1OC
Reaction time: 15 h
Yield: 86.3 %

Procedure:
2-(3,4-Dimethoxy-phenyl)-2-methyl-propylamine (106 mg, 0.506 mmol) and benzofuran-2-carbonyl chloride (90.7 mg, 0.502 mmol) were dissolved in 2 mL of 1,4-dioxane containing triethylamine (139 μL, 1.00 mmol). The reaction mixture was stirred for 15 hours, evaporated to dryness, redissolved in dichloromethane, and extracted with 1M hydrochloric acid, 1M sodium hydroxide, and a saturated aqueous solution of sodium chloride. The organic layer dried over sodium sulfate and evaporated to dryness. The crude product was then purified by column chromatography on silica gel using a gradient of 1-30% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (153 mg, 0.433 mmol, 86.3%). ESI-MS m/z calc. 353.2, found 354.2 (M+1)+. Retention time of 2.99 minutes. 1H NMR (400 MHz, CD3CN) δ 1.38 (s, 6H), 3.60 (s, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 6.85-7.06 (m, 4H), 7.31-7.39 (m, 2H), 7.46 (t, J=8.4 Hz, 1H), 7.52-7.56 (m, 1H), 7.72 (d, J=8.2 Hz, 1H).
Reaction SMILES: [Br-].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[CH:17][O:16][N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1.[Br:20][CH2:21]C(NC1C=C(C)ON=1)=O>>[Br-:20].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[C:17]([CH3:21])[O:16][N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Reactant: Cc1cc(NC(=O)CBr)no1
Agent: [Br-]
Product: Cc1cc(NC(=O)C[N+]23CCC(CC2)[C@@H](O)C3)no1

Procedure:
This compound is prepared analogously to (R)-3-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide [Intermediate A] by substituting 2-bromo-N-isoxazol-3-yl-acetamide (in step Aii) with 2-bromo-N-(5-methyl-isoxazol-3-yl)-acetamide.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:31][C:32]([F:44])([F:43])[C:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([OH:36])[C:34]#[CH:35]>>[C:26]([O:25][C@@H:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:35]#[C:34][C:33]([OH:36])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:32]([F:43])([F:44])[F:31])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Reactant: C#CC(O)(c1ccccc1)C(F)(F)F
Product: Cc1cc2ccc(C#CC(O)(c3ccccc3)C(F)(F)F)cc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-(4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-ynyl)naphthalen-2-yl)acetic acid was prepared by the method in Example 8 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate and 1,1,1-trifluoro-2-phenylbut-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.74 (m, 3H), 7.67 (s, 1H), 7.55 (m, 4H), 7.46 (m, 2H), 7.39 (m, 2H), 7.33 (m, 1H), 5.07 (s, 1H), 2.66 (s, 3H), 0.94 (s, 9H). LCMS-ESI+ (m/z): [M-OH]+ calcd for C31H32ClF3O3: 563.2. found: 563.1.