Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:13]([CH:15]([CH2:26][CH3:27])[CH2:16][C:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:14]>N1C=CC=CC=1>[CH2:13]([CH:15]([CH2:26][CH3:27])[CH2:16][C:17]1([C:23]([NH:1][C:2]2[C:3]([S:12][C:23]([C:17]3([CH2:16][CH:15]([CH2:26][CH3:27])[CH2:13][CH3:14])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:24])=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:14]
Reactant: CCC(CC)CC1(C(=O)Cl)CCCCC1
Reactant: Nc1cc2ccccc2cc1S
Solvent: c1ccncc1
Product: CCC(CC)CC1(C(=O)Nc2cc3ccccc3cc2SC(=O)C2(CC(CC)CC)CCCCC2)CCCCC1
Temperature: 60 °C

Procedure:
To a solution of 3-amino-naphthalene-2-thiol in pyridine are added two mol equivalents of 1-(2-ethyl-butyl)-cyclohexanecarbonyl chloride at room temperature. After completion of the addition, the reaction mixture is heated to 60° C. for 2 hours. The pyridine is then removed under reduced pressure, water is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with sat. NaHCO3-solution, diluted hydrochloric acid and brine, dried (Na2SO4) and concentrated to obtain crude 1-(2-ethyl-butyl)-cyclohexanecarbothioic acid S-(3-{[1-(2-ethyl-butyl)-cyclohexanecarbonyl]-amino}-naphthalen-2-yl)ester.
Reaction SMILES: CN(C)C(=O)C.[I-].[CH3:8][N+:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:21])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1.CC(C)([O-])C.[K+]>O>[CH3:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:21])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH2:10]1
Reactant: COc1cc2c(cc1O)C=[N+](C)CC2
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2c(cc1O)CN(C)CC2
Reaction time: 0.08 h

Procedure:
2,3',4'-Trimethoxy-5-methyl-4-nitrodiphenyl ether (2e) (6.38 g) was added to N,N-dimethyl acetamide (125 ml) under nitrogen, stirred for 5 min., and treated with 2 -methyl-6-methoxy-7-hydroxy-3,4-dihydroisoquinolinium iodide (1) (7.65 g). Potassium t-butoxide (4.39 g) was then added in small portions over 15 min. The reaction mixture was stirred under nitrogen at room temperature for 7 hours, diluted with cold water (600 ml), stirred for 10-15 min. and refrigerated overnight. The supernatant aqueous layer was decanted from the solid which was collected and washed with 1:1 methanol-ether (20 ml) followed by ether (100 ml) and sucked dry (9.40 g, 92%), to yield 1-[2'-nitro-4'-methoxy-5'-(3", 4"-dimethoxy)phenoxybenzyl]-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (3e), mp 169°-171°. An analytical sample was crystallized from chloroform-methanol: mp 173°-174°; nmr δ 2.40 (3H, NCH3), 3.85, 3.88, 3.92, and 3.98 (each 3H, 4 OCH3), 6.37-7.60 (7H, ArH).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([N:7]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:6].O>C(O)(=O)C>[N+:1]([C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:5][CH3:6])[C:19]3[C:14]([C:13]=2[CH:12]=1)=[CH:15][CH:16]=[CH:17][CH:18]=3)([O-:4])=[O:2]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCn1c2ccccc2c2cc([N+](=O)[O-])ccc21
Temperature: 40 °C
Yield: 70.9 %

Procedure:
A solution of 7.3 g of 70% nitric acid (81.1 mmol) in 50 ml acetic acid was added dropwise to a cooled (19°-21° C) acetic acid (200 ml) solution of 15.0 g of N-ethylcarbazole (76.9 mmol). The green reaction solution was then heated on a water bath at 40° C for 2 hours. Upon cooling, addition to 400 ml of water gave a light green precipitate wgich was filtered and air dried. Recrystallization from acetone/methanol gave 13.1 g (71% yield) of 3-nitro-N-ethylcarbazole, mp 118.5°-20° C; the sulfur content (X-ray) was found to be <20 ppm, so that the sulfur in N-ethylcarbazole must be in the elemental or organic (no inorganic) form, most likely the latter, and is easily oxidized to a water soluble form.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[NH:15][C:14]1=[S:26])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O.[CH2:29](O)C.[OH-].[NH4+].IC>O>[CH3:1][C:2]([CH3:27])([CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:15]=[C:14]1[S:26][CH3:29])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CCO
Reactant: CC(C)(CNC(=O)OC(C)(C)C)Cn1c(=S)[nH]c2cnc3ccccc3c21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nc2cnc3ccccc3c2n1CC(C)(C)CNC(=O)OC(C)(C)C

Procedure:
A suspension of tert-butyl 2,2-dimethyl-3-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (7.78 g, 20.1 mmol) and 100 mL of 1:1 water/ethanol was treated with 20 mL of concentrated ammonium hydroxide and iodomethane (1.50 mL, 24.2 mmol). Two hours later an additional 50 mL of H2O was added, and the precipitate was filtered and rinsed with ether. When the ether was added, the funnel became clogged, so the precipitate was transferred into a flask with the aid of methanol and CH2Cl2. The solvents were removed under reduced pressure to give a light yellow solid. The filtrate was then concentrated under reduced pressure to ˜150 mL of mostly water. Organic material was extracted from this solution using CH2Cl2 (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, combined with the precipitated material, and concentrated under reduced pressure to give tert-butyl 2,2-dimethyl-3-[2-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (7.81 g) as a light yellow solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([Si:9]([CH3:12])([CH3:11])Cl)([CH3:8])([CH3:7])[CH3:6].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:5]([Si:9]([CH3:12])([CH3:11])[O:2][CH2:1][CH2:3][NH2:4])([CH3:8])([CH3:7])[CH3:6]
Reactant: NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethanolamine (0.5 mL, 8.1 mmol), tert-butyldimethylchlorosilane (1.42 g, 8.9 mmol), Et3N (1.25 mL, 8.9 mmol) and DMAP (51 mg, 0.41 mmol) in DCM (25 mL) is stirred at RT for 18 h. The reaction mixture is quenched by H2O, DCM is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a colorless oil; ES-MS: M+=176.2; 1HNMR (CDCl3) 3.95-3.85 (m, 2H), 3.15-3.10 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H), NH2 is missing.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 21 h
Yield: 97.3 %

Procedure:
A mixture of 4-(pyridin-2-ylmethoxy)-benzaldehyde (29 g, 136 mmol) described in Manufacturing Example 203-1-1, nitromethane (36.6 mL, 680 mmol), ammonium acetate (21 g, 272 mmol), and acetic acid (300 mL) was stirred for 21 hours at 100° C. This mixture was cooled to room temperature and concentrated under a reduced pressure. The residue was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (33.9 g, 97%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].FC(F)(F)C([N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]2[C:15]3[CH:16]=[C:17]([O:22]S(C(F)(F)F)(=O)=O)[CH:18]=[CH:19][C:20]=3[CH2:21][C@H:10]12)=O>S(=O)(=O)(O)O>[N+:1]([C:18]1[C:17]([OH:22])=[CH:16][C:15]2[C@@H:11]3[C@@H:10]([NH:9][CH2:14][CH2:13][CH2:12]3)[CH2:21][C:20]=2[CH:19]=1)([O-:4])=[O:2]
Reactant: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2c(cc1O)[C@H]1CCCN[C@H]1C2
Reaction time: 1 h

Procedure:
A ca. 10° C.-cold mixture of nitric acid (65%, 0.36 mL) and sulfuric acid (96%, 0.55 mL) is added dropwise to a solution of trifluoro-methanesulfonic acid cis-1-(2,2,2-trifluoro-acetyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (2.00 g) in sulfuric acid (96%, 12 mL) chilled in an ice bath. The solution is stirred in the cooling bath for 1 h and poured then onto crushed ice. The precipitate formed is separated by filtration and taken up in methanol (10 mL). The resulting solution is treated with saturated aqueous K2CO3 solution (alternatively NaOH is used) until the trifluoromethylsulfonyl and trifluoroacetyl group are cleaved off (TLC or HPLC). Water is then added and the resulting mixture is extracted with ethyl acetate. The combined extract is concentrated to give the crude title compound that is used without further purification. Yield: 1.10 g (crude); LC (method 1): tR=1.44 min; Mass spectrum (ESI+): m/z=235 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15]N(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.[C:21]([NH2:29])(=[NH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na].[O-]CC>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:28]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2nc(-c3ccccc3)ncc2C1
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step B, 509 mg, 2.0 mmol), benzamidine hydrochloride hydrate (470 mg, 3.0 mmol), and sodium, ethoxide (1 M in ethanol, 6.0 mL, 6.0 mmol) in absolute ethanol (4 mL) was heated to reflux for about 3 d, cooled to room temperature, and concentrated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (Biotagq Flash 40S™, 10→15% ethyl acetate/hexanes) to give 304 mg (49%) of the title compound of Example 101, Step C as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.52 (s, 1H), 8.40-8.38 (c, 2H), 7.50-7.44 (c, 3H), 4.62 (s, 2H), 3.78 (t, 2H) 3.02 (t, 2H), 1.50 (s, 9H); MS (APCI) 312 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[B:11]([OH:13])[OH:12].[CH2:14](O)[CH2:15][CH2:16]O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[B:11]1[O:13][CH2:16][CH2:15][CH2:14][O:12]1
Reactant: OB(O)c1ccc2c(c1F)OCO2
Reactant: OCCCO
Solvent: Cc1ccccc1
Product: Fc1c(B2OCCCO2)ccc2c1OCO2
Yield: 93.4 %

Procedure:
2-Fluoro-3,4-methylenedioxyphenylboronic acid (1.4 g, 7.6 mmol) was slurried in toluene and propane-1,3-diol (0.6 g, 7.9 mmol) and the mixture heated under reflux for 0.5 hour. The mixture was cooled, filtered through glass wool and concentrated to give 2-(2-fluoro-3,4-methylenedioxyphenyl)-[1,3,2]-dioxaborinane (1.6 g, 7.1 mmol): 1H NMR (DMSO-d6): δ 7.12 (dd, 1H, J=7.8, 5.7 Hz), 6.75 (d, 1H), 6.09 (s, 2H), 4.06 (t, 4H), 1.98 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Temperature: 130 °C
Yield: 95.1 %

Procedure:
To a solution of 2-chloro-6-(trifluoromethyl)pyridine (1.5 g, 8.26 mmol) and 4-hydroxybenzaldehyde (1.009 g, 8.26 mmol) in DMF (18 mL), was added K2CO3 (1.713 g, 12.39 mmol). The mixture was heated at 130° C. for 5 h, and then transferred to a sealed tube and heated with a microwave condition at 135° C. for 3 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (2.10 g) as a brown oil. LCMS: rt=3.25 min, [M+H+]=268
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([F:39])=[C:37]([OH:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:46]=[CH:45][C:44]([C:47]2[CH:48]=[N:49][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:51][CH:52]=2)=[CH:43][N:42]=1.[F:62][C@@H:63]([CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:64]O>C1COCC1>[F:32][C:33]1[C:38]([F:39])=[C:37]([O:40][CH2:64][C@@H:63]([F:62])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH:36]=[CH:35][C:34]=1[C:41]1[N:46]=[CH:45][C:44]([C:47]2[CH:48]=[N:49][C:50]([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:51][CH:52]=2)=[CH:43][N:42]=1
Reactant: CCCCCCCC[C@H](F)CO
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OC[C@@H](F)CCCCCCCC)c(F)c3F)nc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
3.2 mmol of diethyl azodicarboxylate are added dropwise at 0° C. to 3.2 mmol of triphenylphosphine in 20 ml of THF, and the mixture is stirred at room temperature for a further 20 minutes. 2.4 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine and 2.4 mmol of 2-(S)-fluorodecanol are then added, and the reaction mixture is allowed to stand overnight. After the solvent has been removed in vacuo, the crude product is chromatographed on silica gel 60 using dichloromethane/ethyl acetate 20:1 (v/v) as eluent and is recrystallized from acetonitrile, giving 1.2 g (86%) of colorless crystals, X 97 SC * 150.5 SA 161.5 I.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Br[CH:39]([CH2:41][CH3:42])[CH3:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH:39]([CH2:41][CH3:42])[CH3:40])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: CCC(C)Br
Product: CCC(C)Oc1cc2c(cc1OC)CCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-bromo-butane
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:25]>CCOCC>[ClH:25].[ClH:25].[C:1]1([C:7]2[O:11][N:10]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc(-c3ccccc3)n2)CC1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(-c2nc(N3CCNCC3)no2)cc1
Yield: 93 %

Procedure:
A solution of tert-butyl 4-(5-phenyl-1,2,4-oxadiazol-3-yl)piperazine-1-carboxylate (5 g) in a 2M solution of HCl in ether (100 mL) was stirred at RT for 6 hours. The solvent was removed under vacuum to afford 4.3 g (93%) of the title compound as a solid. TLC-Chloroform/methanol (8/2): Rf=0.2. HPLC purity: 97%.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1.C(N(CC)CC)C.CS([Cl:32])(=O)=O>ClCCl>[Cl:32][CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CO)cs2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(1,1-dimethylethyl) 4-(4-hydroxymethyl-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 1, Step B) (0.83 g, 2.8 mmol) and triethylamine (836 μL, 6.0 mmol) in dichloromethane (3 mL) was cooled to 0° C., and a solution of methanesulfonyl chloride (235 μL, 3.0 mmol) in dichloromethane (2 mL) was added dropwise. The reaction mixture was warmed to ambient temperature, stirred for 2 h, diluted with dichloromethane, washed with 1 N aqueous hydrochloric acid and brine, and dried (MgSO4). The organic layers were concentrated under reduced pressure and purified by silica gel chromatography using 25-50% ethyl acetate in hexanes as eluant to give 0.20 g of the title compound as a white solid.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:11]1[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][NH:8][CH2:9][CH:10]12
Reactant: c1ccc(CN2CC3CCCNC3C2)cc1
Agent: [Pd]
Solvent: CO
Product: C1CNC2CNCC2C1

Procedure:
69 g (0.32 mol) of 6-benzyl-octahydropyrrolo[3,4-b]pyridine are hydrogenated in 450 ml of methanol over 7 g of palladium-on-active charcoal (5% strength) at 90° C./90 bar in the course of 3 hours. The catalyst is then filtered off, the filtrate is concentrated and the residue is distilled. 33.8 g (84.% of theory) of a colorless solid having a melting point of 65°-67° C. and a boiling point of 78° C./9 mbar are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[NH:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:10])=[N:3]1.[Na].O>C(O)C>[CH3:1][C:2]1([CH3:11])[NH:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([CH3:10])[NH:3]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1CC(C)(C)NC(C)(C)N1
Temperature: 25 °C

Procedure:
A sample of 27.4 grams 2,2,4,4,6-pentamethyl-2,3,4,5-tetrahydropyrimidine was dissolved in 50 grams of ethanol. To the ethanolic solution was added 6.9 grams of sodium metal at such a rate that a temperature of 70°-80° C. was maintained. After the addition was completed, the mixture was heated for one hour at 85°-95° C. The mixture was allowed to cool to room temperature and water added to the mixture. The organic layer was extracted with toluene, the toluene extract washed with water, dried, and the toluene removed, yielding 2,2,4,4,6-pentamethyl-hexahydroprimidine.
Reaction SMILES: C(O[C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)C.[CH2:32]([CH2:34][NH2:35])[OH:33].C([O-])([O-])=O.[K+].[K+]>CCO>[OH:33][CH2:32][CH2:34][NH:35][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)cc1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(NCCO)c1ccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)cc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
4-[3-(3-Pyrazol-1-yl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-benzoic acid ethyl ester (Ex. 1.11) (1 eq, 0.086 mmol, 35 mg) and ethanol amine (10 eq, 0.86 mmol, 0.05 ml) are dissolved in EtOH (2 ml) and K2CO3 (1.5 eq, 0.128 mmol, 17.7 mg) is added. The reaction mixture is stirred for 5 h at 55° C. The solvent is removed in vacuo and the reaction is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-(2-hydroxy-ethyl)-4-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-a]-pyridin-7-yl]-benzamide as a white solid; [M+H]+=424
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH2:6][CH2:5][C:4]1=[O:64])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH2:6][CH2:5][C:4]1=[O:64])[CH3:2]
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.7 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (115 mg) (STEP 31A) in acetonitrile (2.5 ml) was added a solution of 2% HF in aqueous acetonitrile (40 μl), and the mixture was stirred at room temperature. After 4 hours, the solution was diluted with ethyl acetate and quenched with saturated sodium bicarbonate. The layers were separated, and the organic layer was washed with brine and dried over magnesium sulfate. Purification of the concentrate-by flash chromatography on silica gel (ethyl acetate:hexane (1:2)) gave the title compound (42 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.Cl.[CH:31]1([CH2:34][NH:35][CH:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH2:38])[CH2:33][CH2:32]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:31]1([CH2:34][N:35]([CH:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:37]=[CH2:38])[C:13](=[O:15])[CH:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:16][CH:17]=[CH2:18])[CH2:33][CH2:32]1
Reactant: C=CC(NCC1CC1)c1ccccc1
Reactant: C=CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CCC(C(=O)N(CC1CC1)C(C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: -20 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pent-4-enoic acid (4b) (166 mg) in DCM (1 mL) at −20° C. under N2 was added a mixture of EDAC.HCl (156 mg) and DMAP (3 mg) in DCM (1 mL) portionwise. This mixture stirred for ten min. before N-(cyclopropylmethyl)-1-phenylprop-2-en-1-amine (4a) (127 mg) in DCM (0.5 mL) was added dropwise. The reaction mixture was stirred for 1 h at −20° C. and 3 h at RT, then diluted with DCM (50 mL) and washed with 0.2 N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified via flash chromatography (5% then 10% EtOAc/hexanes) to give the desired product (214 mg, 76%). 1H NMR (300 MHz) The NMR of this compound in both CDCl3 and DMSO-d6 (with elavated temperatures) was complex, thus limiting interpretation. MS APCI, m/z=415 (M+1). LC/MS 2.86 min., Method A.