Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([OH:16])=O)[C:5]2=[CH:4][N:3]=1.CN(C(ON1N=[N:38][C:33]2[CH:34]=CC=N[C:32]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C(N)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([NH:38][CH:33]([CH3:34])[CH3:32])=[O:16])[C:5]2=[CH:4][N:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc(C(=O)O)cc1-c1nn(C)c2nc(N)ncc12
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CC(C)N
Product: COc1ccc(C(=O)NC(C)C)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(6-Amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-4-methoxy-benzoic acid (Example 94) (0.075 g, 0.25 mmol) is dissolved in DMF (5 ml), HATU (0.095 g, 0.25 mmol) is then added followed by N-Methylmorpholine (0.110 ml, 1.0 mmol) and isopropylamine (0.022 ml, 0.25 mmol) and the reaction mixture is stirred at room temperature for 15 hours. The solvent is removed in vacuo and the residue is diluted with water (3 ml) and left to stand for 3 hours. The resulting solid precipitate is collected by filtration, washed with a further 5 ml of water and dried under vacuum to afford the title compound.
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([F:35])[C:28]=1[C:36]1[N:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[CH:38][C:37]=1[F:45]>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:42](=[O:43])[C:40]2[CH:39]=[CH:38][C:37]([F:45])=[C:36]([C:28]3[C:29]([F:35])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=3[F:26])[N:41]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Product: COc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)ccc2F)c(F)c1
Yield: 26 %

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinic acid (see WO2010/56576) gave 187 as a white solid (22 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 8.31 (dd, J=8.6, 4.0 Hz, 1H), 8.21 (s, 1H), 7.71-7.63 (m, 1H), 6.64 (d, J=10.1 Hz, 2H), 4.84-4.73 (m, 2H), 4.07-3.89 (m, 3H), 3.87 (s, 3H), 3.77 (s, 3H), 3.41 (dd, J=23.1, 9.5 Hz, 1H), 2.67 (br s, 1H), 2.15-2.08 (m, 1H), 2.08-1.94 (m, 1H), 1.95-1.84 (m, 1H), 1.85-1.73 (m, 1H). LCMS (ES+) m/z 494 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[F:12][C:13]1[C:14](B(O)O)=[CH:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:14]2[C:13]([F:12])=[CH:18][N:17]=[C:16]([O:19][CH3:20])[CH:15]=2)=[N:3][CH:4]=1
Reactant: COc1cc(B(O)O)c(F)cn1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ncc(Br)cc2[N+](=O)[O-])c(F)cn1
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A mixture of 2,5-dibromo-3-nitropyridine, commercially available from Matrix Scientific (0.72 g, 2.55 mmol), 5-fluoro-2-methoxypyridin-4-ylboronic acid, commercially available from Asymchem (0.39 g, 2.34 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (90 mg, 0.13 mmol), and 1.0M sodium carbonate (3.5 mL, 7.0 mmol) in 1,4-dioxane (10 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt then treated with water. After extracting twice with EtOAc, the organic layer was combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the yellowish brown residue was treated with MeOH and placed on the rotoevaporator (without vac.) in a 45° C. water bath. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as 5-bromo-5′-fluoro-2′-methoxy-3-nitro-2,4′-bipyridine. 1H NMR (500 MHz, CDCl3) δ ppm 9.01 (1H, d, J=2.0 Hz), 8.56 (1H, d, J=2.0 Hz), 8.06 (1H, d, J=1.2 Hz), 7.02 (1H, d, J=4.6 Hz), 4.04 (3H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(N(CC)CC)C.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>CN(C=O)C>[C:21]([O:20][C:18](=[O:17])[NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(O)c1
Temperature: 25 °C
Yield: 22.1 %

Procedure:
3-hydroxybenzylamine (Apin, 1.0 g, 8.1 mmole) was dissolved in DMF(25 ml). Triethylamine (0.33 ml, 2.4 mmole) and (BOC)2O (1.8 g, 8.1 mmole) were added, the mixture stirred over night at room temperature under argon atmosphere. The reaction was concentrated, chromatographed on silica gel (0 to 20% EtOAc/hexanes) to give the titled compound (400 mg, 22%). MH+223.0
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)C1C=CC=CC=1.C(O)(=O)CC(O)=O.S(Cl)([Cl:29])=O>N1C=CC=CC=1.N1CCCCC1>[C:1]([Cl:29])(=[O:11])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Solvent: O=Cc1ccccc1
Product: O=C(Cl)C=Cc1ccccc1

Procedure:
A cinnamic acid is first prepared by reacting a benzaldehyde with malonic acid in pyridine and piperidine. The cinnamic acid is then reacted with thionyl chloride to produce a cinnamoyl chloride derivative. The HE-CelCN is finally synthesized by reacting HE-cellulose with the cinnamoyl chloride derivative in an inert solvent (such as chloroform, nitrobenzene, chlorobenzene, or the like). The reaction mixture is diluted with methanol, filtered, dried in a vacuum, and milled by a vibrating mill, whereupon the CelCN is obtained.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([C:7]1[C:8]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1)=O.CO>C1COCC1.CCOC(C)=O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([C:8]2[C:7]([CH2:5][OH:4])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1cccnc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ncccc2CO)CC1
Temperature: 2.5 °C
Reaction time: 2.5 h
Yield: 44.1 %

Procedure:
NaBH4 (0.6 g, 15.8 mmol, 5 eq.) was added to a solution of 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-3,1′-dicarboxylic acid 1′-t-butyl ester 3-methyl ester (1.0 g, 3.1 mmol, 1.0 eq.) in THF (40 mL), under nitrogen. This mixture was cooled to 0-5° C. and MeOH (8 mL) was added dropwise. The resulting solution was stirred for 2.5 hours at room temperature. The solution was diluted with EtOAc (50 mL), then washed with saturated NH4Cl (1×100 mL) and saturated aqueous NaCl (2×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:5) to yield 3-hydroxymethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4]-bipyridinyl-1′-carboxylic acid t-butyl ester (0.4 g) as a white solid. MS m/z: [M+H]+ calcd for C16H25N2O3, 293. found 293.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2]>C(O)(C)(C)C>[C:1]([O:5][O:6][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OO
Solvent: CC(C)(C)O
Product: CC(C)(C)OOC(C)(C)C

Procedure:
in a dehydration step, dehydrating the mixture of tertiary butanol and tertiary butyl hydroperoxide to produce di-tertiary butyl peroxide,
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N:12]([C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:26])=[CH2:25])[CH:19]=1)([CH3:17])[CH3:16])=[C:13]=[O:14].C(N(CC)CC)C>C1COCC1>[CH2:25]=[C:24]([C:20]1[CH:19]=[C:18]([C:15]([NH:12][C:13]([NH:11][C@@H:5]2[CH:6]3[CH2:9][CH2:10][N:3]([CH2:8][CH2:7]3)[CH2:4]2)=[O:14])([CH3:17])[CH3:16])[CH:23]=[CH:22][CH:21]=1)[CH3:26]
Reactant: N[C@H]1CN2CCC1CC2
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)c1cccc(C(C)(C)NC(=O)N[C@H]2CN3CCC2CC3)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
To a solution of (R)-quinuclidin-3-amine dihydrochloride (120 mg, 0.603 mmol) and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (119 mg, 0.597 mmol) in THF (3 mL) was added triethylamine (168 uL, 1.21 mmol). The reaction mixture was stirred at room temperature for 18 h and then quenched with brine. The mixture was extracted with CHCl3 and the organic layer was dried (Na2SO4) and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding urea (163 mg, 50%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.62 (t, J=1.6 Hz, 1H), 7.44 (dt, J=1.9, 7.0 Hz, 1H), 7.41-7.33 (m, 2H), 5.35 (br s, 1H), 5.11 (p, J=1.4 Hz, 1H), 4.84 (s, 1H), 4.21 (d, J=7.5 Hz, 1H), 3.70-3.61 (m, 1H), 3.13 (ddd, J=2.3, 9.3, 14.2 Hz, 1H), 2.71-2.54 (m, 3H), 2.30-2.22 (m, 1H), 2.15 (dd, J=0.8, 1.4, 3H), 2.05-1.96 (m, 1H), 1.65 (s, 3H), 1.64 (s, 3H), 1.65-1.60 (m, 1H) 1.54-1.45 (m, 2H), 1.22-1.12 (m, 1H), 0.95-0.80 (m, 1H) ppm. 13C NMR (400 MHz, CDCl3) δ 157.4, 148.5, 143.8, 141.3, 128.4, 124.4, 123.8, 122.2, 112.6, 55.2, 53.4, 46.2, 46.1, 44.5, 30.5, 30.4, 25.0, 22.2, 17.7, 8.9 ppm. Purity: 97.5% UPLCMS (210 nm); retention time 0.83 min; (M+1) 328.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:36])[C:15](=[O:35])[CH:16]([O:18][C:19]2[N:24]=[C:23]([CH3:25])[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:21]([CH3:34])[N:20]=2)[CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][Si]([N-][Si](C)(C)C)(C)C.[K+].CI.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:36])[C:15](=[O:35])[CH:16]([O:18][C:19]2[N:24]=[C:23]([CH3:25])[C:22]([N:26]([CH3:37])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[C:21]([CH3:34])[N:20]=2)[CH3:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1nc(OC(C)C(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1nc(OC(C)C(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1N(C)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a tetrahydrofuran (1 mL) solution of Compound 56 (72 mg), potassium bis(trimethylsilyl)amide (0.5M toluene solution: 273 μL) was added at −78° C. The mixture was stirred at −78° C. for 30 min and methyl iodide (9 μL) was added portionwise. The mixture was then stirred overnight as it was allowed to be slowly warmed to room temperature (20 to 30° C.). Subsequently, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted twice with chloroform. The organic layer was concentrated under reduced pressure and the resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (ethyl acetate:hexane=1:19 to 1:1) to give 7.7 mg (10% yield) of tert-butyl 2-(1-((l-benzylpiperidine-4-yl)(methyl)amino)-1-oxopropane-2-yloxy)-4,6-dimethylpyrimidine-5-yl(methyl)carbamate. 2.6 mg (42% yield) of the title compound was synthesized from tert-butyl 2-(1-((1-benzylpiperidine-4-yl)(methyl)-amino)-1-oxopropane-2-yloxy)-4,6-dimethylpyrimidine-5-yl(methyl)-carbamate in the same manner as in Example 71.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20]CC)=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:36]3[CH:37]=[CH:38][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=3)=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]1[C:18]([OH:20])=[O:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(Nc2ccc3c(c2)c(-c2ccccc2)c(C(=O)O)n3Cc2ccccc2)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate and 4-tert-butylbenzeneboronic acid according to the procedure of Example 1 Step 3 as a pale green solid: 1H NMR (DMSO-d6) δ 1.22 (s, 9 H), 5.81 (s, 2 H), 6.87 (d, J=6.7 Hz, 2 H), 7.10-7.50 (m, 15 H), 12.85 (br s, 1 H); MS (ESI) m/z 475 (MH+); MS (ESI) m/z 473 ([M-H]−); Anal. calcd. for C32H30N2O2.0.5H2O: C, 79.78; H, 6.46; N, 6.02. Found: C, 79.42; H, 6.28; N, 6.01.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[CH:14]=[CH:15]/[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18](C2CCCCO2)[N:17]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>CO>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](/[CH:15]=[CH:14]/[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:17]1
Reactant: C(=C/c1nn(C2CCCCO2)c2ccccc12)\c1ccccc1Nc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1Nc1ccccn1
Yield: 2.7 %

Procedure:
A solution of (E)-3-{2-[2-(2-pyridylamino)phenyl]vinyl}-1-(tetrahydropyran-2-yl)-1H-indazole (49 mg, 1.2 mmol) obtained in Step 2 and trifluoroacetic acid (1.0 mL) in methanol (0.50 mL) was stirred at room temperature for 18 hours. A 2 mol/L aqueous sodium hydroxide solution was added to neutralize the mixture and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=97/3) to obtain Compound 164 (10 mg, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I-].C[N+:15](C)(C)N.CCC([O-])(C)C.[Na+]>CS(C)=O>[NH2:15][C:9]1[C:2]([OH:1])=[C:3]([CH:6]=[CH:7][C:8]=1[N+:10]([O-:12])=[O:11])[C:4]#[N:5]
Reactant: C[N+](C)(C)N
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: CCC(C)(C)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc([N+](=O)[O-])c(N)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 2-hydroxy-4-nitro-benzonitrile [1.0 g, 6.1 mmol, prepared as described in Yasubiro Imakura et. al. Chem. Pharm. Bull. 40 (7), 1691-1696 (1992)] in DMSO (60 mL) was added trimethylhydrazinium iodide (1.23 g, 6.09 mmol), followed by sodium tert-pentoxide (2.01 g, 6.09 mmol). The mixture was stirred at rt overnight, and then partitioned between 10% HCl and ether. The separated ether layer was washed with H2O, brine, dried (Na2SO4), and concentrated under reduced pressure to furnish the title compound (0.78 g) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][S:30]([CH3:29])(=[O:32])=[O:31])[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(Cc2cccc([N+](=O)[O-])c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(Cc2cccc(NS(C)(=O)=O)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
A mixture of ethyl N-tert-butoxycarbonyl-4-(3-nitrobenzyl)-piperidine-4-carboxylate (0.85 g, 2.17 mmol; Example 69, Step A) and 5% palladium on charcoal (0.06 g) in ethanol (100 mL) was hydrogenated at room temp. at 50 psi overnight. The resultant mixture was filtered through a plug of Celite, and the filtrate was concentrated under vacuum. The residue was dissolved in pyridine (5 mL), treated with methanesulfonyl chloride (0.24 mL, 3.2 mmol), and heated at 60° C. for 3 h. The product mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with 2% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:9](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH2:27][CH2:28][NH:29][CH3:30]>>[CH3:25][N:26]([CH2:27][CH2:28][NH:29][CH3:30])[C:2]1[N:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:9](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CNCCNC
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Product: CC/C(=C(/c1ccc(O)cc1)c1ccc(N(C)CCNC)nc1)c1ccccc1

Procedure:
Following the same procedure as described in example 39, step D, (E)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (100 mg, 1.0 eq, made from example 2) was reacted with N,N′-dimethylethane-1,2-diamine (262 mg, 10.0 eq) to give the desired product. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=2.4 z, 1H), 7.06-7.14 (m, 6H), 6.69 (d, J=8.8 Hz, 2H), 6.49 (d, J=8.8 Hz, 1H), 6.43 (d, J=8.8 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H), 3.08 (s, 3H), 2.88 (t, J=6.4 Hz, 2H), 2.53 (q, J=7.6 Hz, 2H), 2.48 (s, 3H), 0.95 (t, J=7.6 Hz, 3H); m/z=388[M+1]+.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH3:9])[CH:3]1[O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P([N:65]=[N+:66]=[N-:67])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:65]([CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH3:9])[CH:3]1[O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[N+:66]=[N-:67]
Reactant: COC1CCCC(O)C1O[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1CCCC(N=[N+]=[N-])C1O[Si](C)(C)C(C)(C)C

Procedure:
To a solution of racemic [1-Hydroxy-3-methoxy-2-cyclohexanoxy]tert-butyl-dimethylsilane, 51f, (2.5 g; 9.6 mmol) in 60 mL of dry THF at room temperature was added, triphenylphosphine (5.0 g; 19.2 mmol), DIAD (3.9 g; 19.2 mmol) and diphenylphosphoryl azide (5.3 g; 19.2 mmol) and the reaction mixture was stirred at room temperature for 60 h. The solvent was concentrated in vacuo and the resultant oil was purified by silica gel chromatography (10% Et2O-Hexane to ether gradient) to afford 2.57 g of the desired product 51g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:22])[C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Clc1ccc(-c2nc3cccnc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2ncccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
Under nitrogen atmosphere, the 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine (5.0 g, 0.022 mole) was added to a suspension of sodium hydride (0.96 g of 60% in oil, 0.024 mole, washed once with hexanes) in dimethylformamide (100 ml). The mixture was heated at 70°-85° C. for 1.5 hr before adding the α-bromoacetophenone (4.38 g, 0.022 mole) at room temperature. The reaction mixture was stirred at room temperature overnight, then poured into water. The precipitate was collected by filtration, washed with water, and dried under high vacuum. A sample was dissolved in isopropyl alcohol, then concentrated to initiate crystallization. The crystals were collected by filtration, washed with isopropyl alcohol, and dried under high vacuum at 70° C. over a weekend to give 1.5 g (20%) of title compound, mp. 262°-263° C.
Reaction SMILES: B.CSC.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]2[O:17][CH2:16][C:15](=O)[N:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]2)[CH:9]=[CH:10][CH:11]=1.CO.Cl>O1CCCC1>[ClH:5].[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]2[O:17][CH2:16][CH2:15][N:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)N1CC(c2cccc(Cl)c2)OCC1=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: CC(C)(C)N1CCOC(c2cccc(Cl)c2)C1
Yield: 117.2 %

Procedure:
Borane-methyl sulphide (0.5 ml) was added dropwise, under nitrogen, to a stirred solution of 2-[3-chlorophenyl]-4-[1,1-dimethylethyl]-5-oxo-morpholine (0.85g) in dry tetrahydrofuran (40 ml). The mixture was heated under reflux for 2 h., cooled, treated with methanol (5 ml) and heated for 1 hr. The resulting solution was cooled, treated with hydrogen chloride and evaporated to give 2-[3-chlorophenyl]-4-[1,1-dimethylethyl]morpholine hydrochloride as a white solid (0.54g), m.p. 223-8° C. (ethyl acetate).
Reaction SMILES: C(=O)(O)[O-].[Na+].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:19][CH2:18][CH2:17][O:16]2)=[CH:11][CH:10]=1)([O-])=O>CCO.[Pt](=O)=O>[O:16]1[CH2:17][CH2:18][O:19][CH:15]1[C:12]1[CH:13]=[CH:14][C:9]([NH2:6])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(C2OCCO2)cc1
Agent: O=[Pt]=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(C2OCCO2)cc1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a mixture of platinum dioxide (227 mg, 1.00 mmol) and sodium bicarbonate (420 mg, 5.00 mmol) under dry nitrogen was added a solution of 2-(4-nitrophenyl)-1,3-dioxolane (976 mg, 5.00 mmol) in EtOH (30.0 mL). The reaction mixture was bubbled with hydrogen for 15 min and then stirred under a hydrogen atmosphere (balloon) for 2 h. The reaction mixture was then filtered through a pad of Celite washing with MeOH. The filtrate was concentrated under reduced pressure to give the title compound (0.80 g, 96% yield).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([OH:32])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1.CO.[OH-].[Li+].Cl>CCOC(C)=O.O>[OH:32][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)[C:3]([OH:33])=[O:2]
Reactant: COC(=O)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 12 h
Yield: 97.8 %

Procedure:
To a solution of hydroxy-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-acetic acid methyl ester (0.312 g, 0.684 mmol) in mixed solvent (14 mL, MeOH: H2O=3:1) at rt was added lithium hydroxide (LiOH) (0.098 g, 4.10 mmol). After stirring for 12 hours, the reaction mixture was diluted with EtOAc and acidified with aqueous 3N HCl. The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid (0.296 g, 98%).