Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[CH2:14][CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([O:25][C:23]([NH:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([N:13]([CH2:14][CH3:15])[C:4]2[C:5]([CH3:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=3)[CH:3]=2)[CH2:17][CH2:18]1)=[O:24])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(O)cc2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (10 g, 21.3 mmol, see, e.g., WO2012142504 (Attorney Docket No. 41478-507001WO)) and (4-hydroxyphenyl)boronic acid (3.5 g, 25.3 mmol) in a mixture of dioxane (225 mL) and water (75 mL), Na2CO3 (8.01 g, 75.5 mmol) was added and the solution was purged with argon for 30 min. Then Pd(PPh3)4 (2.4 g, 2.07 mmol) was added and argon was purged again for another 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was dried over sodium sulfate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (8.9 g, 87% yield).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][O:6][C:7](=[O:39])[NH:8][CH2:9][CH:10]1[S:15][CH:14]([C:16]2[O:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]2=[C:22]3[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]3=[C:24]([C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)[N:12]2[CH2:11]1>C1COCC1>[Cl:21][C:18]1[O:17][C:16]([CH:14]2[C:13]3=[C:22]4[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]4=[C:24]([C:25]4[S:26][CH:27]=[C:28]([CH3:30])[N:29]=4)[N:12]3[CH2:11][CH:10]([CH2:9][N:8]3[CH2:4][CH2:5][O:6][C:7]3=[O:39])[S:15]2)=[CH:20][CH:19]=1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CNC(=O)OCCCl)SC3c2ccc(Cl)o2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN2CCOC2=O)SC3c2ccc(Cl)o2)n1
Temperature: 25 °C

Procedure:
Sodium hydride (60% wt in mineral oil, 6.69 mg, 0.167 mmol) was added to a solution of 2-chloroethyl((10-(5-chlorofuran-2-yl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-2,4-dioxo-2,3,4,7,8,10-hexahydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazin-8-yl)methyl)carbamate (48.9 mg, 0.084 mmol) in THF (4 mL). The mixture was heated at reflux for 18 hours. A further portion of sodium hydride (60% wt in mineral oil, 33.4 mg, 0.836 mmol) was added and the mixture heated at reflux for a further 2 days. The mixture was cooled to room temperature, quenched with water (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic extracts were washed with brine, passed through a hydrophobic frit and evaporated under vacuum. Purification by mass-directed HPLC under the following conditions afforded the title compound as a mixture of diastereomers.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[S:9][CH:10]=1)C.[BH4-].[Na+]>CCO>[C:15]([O:14][C:12](=[O:13])[NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][CH2:4][OH:3])[N:7]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nc(CCO)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
To a solution of (2-tert-Butoxycarbonylamino-thiazol-4-yl)-acetic acid ethyl ester (4 g, 13.9 mmol) in EtOH (50 ml), NaBH4 (1.59 g, 41.9 mmol) was added at 0° C. and stirred at r.t. for 18 h. Solvent was removed under reduced pressure and extracted in Ethyl acetate (150 ml) washed with brine (2×30 ml) dried over Na2SO4. After evaporation, the residue was purified by preparative chromatography (1:3 EtOAc:Hexanes) to give [4-(2-Hydroxy-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (2.2 g, 65%). 1H NMR (400 MHz, CDCl3): 1.): 1.53 (s, 9H), 2.87 (t, J=5.2 2H), 3.90 (t, J=5.2 Hz, 2H), 6.55 (s, 1H). MS (EI) m/z: 245 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:32]2[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[N:8]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C(C)(C)C
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C(C)(C)C
Yield: 81.5 %

Procedure:
A solution of 1-tert-butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (521 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (501 mg), tetrakis(triphenylphosphine)palladium(0) (170 mg) and 2M aqueous sodium carbonate solution (3.69 mL) in DME (40 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (433 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([Cl:20])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1

Procedure:
This compound was prepared by chlorination of 3,5-di-t-butylbenzoic acid with thionyl chloride using standard procedures to give 3,5-di-t-butylbenzoyl chloride. 3.26 g (12.9 mmol) of the chloride was then reacted with 1.95 g (16.8 mmol) of N,N-diethylethylenediamine in dry chloroform. The reaction mixture was concentrated by evaporation of chloroform and treated with sodium bicarbonate in a mixture of ethanol and water. Following extraction with chloroform, the combined chloroform extracts were dried and concentrated, upon which the amide began to crystallize. Without further purification, the amide was reduced with lithium aluminum hydride in THF using standard procedures. After quenching and filtration of the reaction mixture, the filtrate was dried and concentrated then distilled under reduced pressure to yield 2.00 g (49%) of the diamine.(bp 105-108°, 10 v). Purity by GC>99%.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([N:38]2[C:34](=[O:44])[C:35]3[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:37]2=[O:39])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](O)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (±)-trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (1.1 g, 5.08 mmol) (from Example 10a supra), triphenylphosphine (3.2 g, 12.20 mmol) (Aldrich) and phthalimide (1.8 g, 12.20 mmol) (Aldrich) in anhydrous tetrahydrofuran (45 mL) was cooled to 0° C. To this was added dropwise diethyl azodicarboxylate (2.1 mL, 2.3 g, 12.20 mmol) (Aldrich) and the resulting solution was allowed to slowly warm to room temperature. After stirring overnight the reaction mixture was partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated and the residue was purified by chromatography on a silica gel column using a 0–35% ethyl acetate in hexanes gradient to give (±)-cis-2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl]-isoindole-1,3-dione as a white solid. (Yield 1.52 g, 87%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:10]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CN)cc1

Procedure:
Intermediate (2d) (5.6 g) was dissolved into 20 mL 30% TFA:DCM and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to yield the title compound as an oil in a quantitative yield. MS m/z: [M+H+] calcd for C17H21ClN4O4S 413.1; found 413.3.
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl:9][C:10]1[C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:18][CH2:17]2)=[CH:14][C:13]([CH:26]([F:28])[F:27])=[CH:12][C:11]=1[N:29](CC1C=CC(OC)=CC=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:9][C:10]1[C:15]([N:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:25][O:24][CH2:23]3)[CH2:20][CH2:21]2)=[CH:14][C:13]([CH:26]([F:28])[F:27])=[CH:12][C:11]=1[NH2:29]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C(F)F)cc(N3CCN(C4COC4)CC3)c2Cl)cc1
Solvent: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C(F)F)cc(N2CCN(C3COC3)CC2)c1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
Anisole (633 μl, 5.80 mmol) was added to a solution of tert-butyl (2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (312 mg, 0.58 mmol) in DCE (3 mL), followed by the addition 2.8 mL of TFA. The reaction was stirred at 60° C. for 3 h. The residue was partitioned between CH2Cl2 and sat. NaHCO3, and extracted into CH2Cl2 (3×). The solution was dried over Na2SO4 and concentrated. The residue was dissolved in MeOH and loaded onto a 5 g Strata SCX ion exchange cartridge, washing with MeOH. The desired product was eluted with 7 N NH3—CH3OH. After concentration, 163.4 mg of 2-chloro-5-(difluoromethyl)-3-(4-(oxetan-3-yl)piperazin-1-yl)aniline was obtained.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:13]=[CH:14]/[CH3:15])[C:6]=1[C:7]#[N:8])([O-])=O>CCO.[Fe]>[NH2:2][C:5]1[CH:12]=[CH:11][CH:10]=[C:9](/[CH:13]=[CH:14]/[CH3:15])[C:6]=1[C:7]#[N:8]
Reactant: C/C=C/c1cccc([N+](=O)[O-])c1C#N
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: C/C=C/c1cccc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
Concentrated HCl (34.5 mL) was added slowly to a solution of (E)-2-nitro-6-(prop-1-enyl)benzonitrile (Example 2c) (0.98 g, 5.21 mmol) in EtOH (63.5 mL) at room temperature. Then, the obtained mixture was treated with iron powder (2.91 g, 52.08 mmol), added in small portions at the same temperature. The mixture was stirred at room temperature for 15 min. and then heated at reflux for 30 min. The mixture was cooled to room temperature, EtOH was evaporated and the pH was adjusted to pH˜10 with aqueous solution of NaOH (2.0M). The basified mixture was extracted with EtOAc (4×100 mL) and the combined extract was dried with anhydrous MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient hexanes to hexanes/EtOAc (8:2), to afford 0.67 g (81%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.16-7.23 (m, 1H), 6.78 (d, J=7.2 Hz, 1H), 6.59-6.64 (m, 1H), 6.35-6.53 (m, 2H), 5.92 (broad s, 2H), 1.83-1.89 (m, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:32]=1)[CH3:2].C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C>[ClH:39].[ClH:39].[CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([CH2:18][CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:32]=1)[CH3:2]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCNCC1)C2=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
Compound 23 (1.99 g, 4.48 mmol) obtained in Example 23 was dissolved in ethyl acetate (20 mL), and the mixture was stirred at 60° C. for 4 hours after adding 4 mol/L hydrogen chloride-ethyl acetate (20 mL) at room temperature. Back at room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate (50 mL) was added to the resulting residue, and the mixture was stirred overnight at room temperature. The precipitated solid was filtered off, and dried to give the title compound (Compound 24) (1.72 g, 92%) as a yellow solid.
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[O:8][C:7]1=[O:16])([O:3][CH3:4])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:21]=[C:22]([F:25])[C:23]=1F.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][C:23]3[C:22]([F:25])=[CH:21][C:20]([C:26]([F:27])([F:29])[F:28])=[CH:19][C:18]=3[Cl:17])[CH:13]=[CH:14][C:9]=2[O:8][C:7]1=[O:16])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)Cn1c(=O)oc2ccc(O)cc21
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)Cn1c(=O)oc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Temperature: 75 °C

Procedure:
A mixture of 1.37 grams (0.006 mole) of 3-carbomethoxymethyl-5-hydroxybenzoxazolone, 1.52 grams (0.007 mole) of 3-chloro-4,5-difluorobenzotrifluoride, 1.26 grams (0.009 mole) of potassium carbonate and 25 milliliters of dimethylsulfoxide was stirred in a water bath maintained at 75° C. until HPLC analysis indicated substantially complete consumption of starting material. The mixture was then poured into 100 milliliters of water, cooled in an ice bath and extracted twice with methylene chloride. The organic extracts were further extracted with three portions of water, dried over anhydrous magnesium sulfate and evaporated at reduced pressure. The oily residue was taken up in hexane, solidified, filtered and recrystallized from methanol affording 0.67 gram of material confirmed by NMR analysis as the desired product.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[OH:29][CH2:30][CH:31]([N:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[C:34]1=[O:51])[CH3:32]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[C:34](=[O:51])[N:33]([CH:31]([CH3:32])[CH2:30][OH:29])[CH2:41]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CC(CO)N1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C(C)CO)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-(2-hydroxy-1-methylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=481.1.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]\[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH:20](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][C:13]3[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:21]\[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCC/C=C/B(O)O
Reactant: Cc1cnc(CNc2ccc3ncc(Br)n3n2)cn1
Product: CCCC/C=C/c1cnc2ccc(NCc3cnc(C)cn3)nn12
Yield: 40 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2 providing the title compound (20 mg, 40%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 8.55 (s, 1H), 8.48 (s, 1H), 7.60 (d, J=9.5 Hz, 1H), 7.39 (s, 1H), 6.75 (d, J=9.5 Hz, 1H), 6.51-6.40 (m, 2H), 4.67 (s, 2H), 2.52 (s, 3H), 2.20-2.15 (m, 2H), 1.42-1.34 (m, 4H), 0.94 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 154.8, 153.4, 153.1, 144.9, 143.4, 137.9, 133.2, 129.3, 128.6, 126.0, 116.6, 113.1, 45.9, 34.4, 32.8, 23.4, 20.9, 14.3; HPLC tR=14.6 min (Luna), 98.1%; ES-MS: (M+H)=323 m/z.
Reaction SMILES: [O:1]=[C:2]1[N:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C@H:4]2[C:13]3[C:18]([CH2:19][C@@H:3]12)=[CH:17][CH:16]=[CH:15][CH:14]=3.[CH3:20][NH:21][CH3:22].C1COCC1>>[CH3:20][N:21]([CH3:22])[C:2]([C@@H:3]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@@H:4]1[NH:5][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:1]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2Cc3ccccc3[C@@H]21
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1Cc2ccccc2[C@@H]1NC(=O)OC(C)(C)C
Yield: 91 %

Procedure:
To tert-butyl rel-(2aR,7bR)-2-oxo-2,2a,3,7b-tetrahydro-1H-indeno[1,2-b]azete-1-carboxylate (200 mg, 0.77 mmol) was added 2.00 M dimethylamine in THF (1.90 mL, 3.80 mmol) in the sealed tube, and the mixture was microwaved at 120° C. for 30 minutes. The reaction mixture was concentrated under vacuum, and then the residue was washed with small amount of hexane to give the title compound (226 mg, 91%) as a white solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:14]([O-])=O)[CH2:6]1)(=[O:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.C(OC(=O)C)C.[Fe]>[C:1]([O:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1Cc2cccc([N+](=O)[O-])c2C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)OC1Cc2cccc(N)c2C1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-nitro-2,3-dihydro-1H-inden-2-yl acetate (100 mg, 0.45 mmol) and ammonium chloride (100 mg) in ethanol (6 ml) and water (3 ml) was added iron powder (300 mg) portionwise at room temperature. The mixture was stirred at 90° C. for 1 hour, and after cooled to room temperature, the mixture was diluted with ethylacetate. The mixture was filtered through a pad of celite, and the filtrate was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 4-amino-2,3-dihydro-1H-inden-2-yl acetate.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH2:10]O[Si](OCC)(OCC)CCCN.[C:23]([CH2:25][C:26]([O:28]CC)=O)#[N:24]>CN(C)C=O>[C:2]1([CH:1]=[C:25]([C:26](=[O:28])[CH2:9][CH3:10])[C:23]#[N:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC#N
Solvent: CN(C)C=O
Product: CCC(=O)C(C#N)=Cc1ccccc1
Reaction time: 1.5 h
Yield: 98 %

Procedure:
Benzaldehyde (2 mmol, 0.2 ml) and 0.05 g of LDH/APTES were stirred in 5 ml of dimethylformamide for 5 min. Then the active methylene compound i.e. ethyl cyanoacetate (2 mmol, 0.226 ml) was added and stirring was continued till 90 min at 27° C. The catalyst was filtered and the product was extracted with ethyl acetate, dried over anhydrous sodium sulfate. The final product (FIG. 2) was confirmed by Gas chromatography to afford the product (3-phenyl-2-propanoyl-prop-2-ene-nitrile) in 98% yield.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:34][CH2:35][CH2:36][OH:37].[Br:38][C:39]1[O:43][C:42]([C:44]([OH:46])=O)=[CH:41][CH:40]=1>ClCCl>[Br:38][C:39]1[O:43][C:42]([C:44]([NH:34][CH2:35][CH2:36][OH:37])=[O:46])=[CH:41][CH:40]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCO)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.66 g, 1.7 mmol), N,N-diisopropylethylamine (0.82 mL, 4.7 mmol) and 2-aminoethanol (0.14 mL, 2.4 mmol) were added to a solution of 5-bromo-2-furoic acid (0.30 g, 1.6 mmol) in dichloromethane (15 mL), and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, water (5 mL) was added thereto. The whole was extracted with ethyl acetate (10 mL), and the organic layer was washed with brine (5 mL) and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to give the title reference compound (0.18 g) as a colorless solid (yield 49%).
Reaction SMILES: [ClH:1].[C:2]1([CH2:14][NH2:15])[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH:3]=1.[H][H]>CO.[Pd]>[ClH:1].[CH:2]1([CH2:14][NH2:15])[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3]1
Reactant: NCC1=Cc2cccc3cccc1c23
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC1Cc2cccc3cccc1c23
Yield: 83 %

Procedure:
The N-[(1-acenaphthylenyl)methyl]amine hydrochloride, A as prepared in Example A above (1.8 g, 8.3 mmol) was dissolved in methanol (100 ml) and 5% Pd/C (0.2 g) added. The mixture was stirred at room temperature, under 51 psi of hydrogen, for 2.5 hours (hydrogen uptake: AP=6.8 psi, calculated 7.1). The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was treated with ether (150 ml) and filtered to collect precipitate. The solid was dried at 45° C., in vacuo, overnight, to give 1.5 g (83%) of a white N-[(1,2-dihydro-1-acenaphthylenyl)methyl]amine hydrochloride salt, mp>250° C. Anal (C13H13N.HCl.0.15H2O), calc: C=71.20, H=6.48, N=6.30, Cl=15.54; found: C=70.14, H=6.51; N=6.42; Cl=16.11.