Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:17]3([CH2:21][O:20][C:19]([N:22](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18]3)[C:13]3([CH2:16][O:15][CH2:14]3)[C:9]3([CH2:12][CH2:11][CH2:10]3)[O:8][C:5]2=[CH:6][CH:7]=1.[CH3:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[N:42][CH:43]=1.C([O-])([O-])=O.[Na+].[Na+].C>O1CCOCC1.O.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>[CH3:37][C:38]1[CH:39]=[C:40]([C:2]2[CH:3]=[C:4]3[C:17]4([CH2:21][O:20][C:19]([NH2:22])=[N:18]4)[C:13]4([CH2:14][O:15][CH2:16]4)[C:9]4([CH2:12][CH2:11][CH2:10]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:41]=[N:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC1(CCC1)C21COC1
Reactant: Cc1cncc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cncc(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)C2(CCC2)O3)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A mixture of di-tert-butyl (6′-bromotrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl)imidodicarbonate (300 mg, 0.531 mmol), 5-methylpyridine-3-boronic acid (145 mg, 1.06 mmol), bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.053 mmol) and Na2CO3 (169 mg, 1.59 mmol) in dioxane-H2O (4:1, 6.0 mL) was stirred for 1 hour at 100° C. To the mixture was added charcoal and the mixture was stirred for 10 minutes at 50° C. The mixture was filtered through celite pad (eluted with EtOAc) and the filtrate was washed with H2O and brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. To the residue were added toluene (3.0 mL) and silica gel (neutral; 900 mg), and the mixture was stirred for 3 hours at 120° C. After concentration of the reaction mixture at reduced pressure, the residue was purified with column chromatography on silica gel (CHCl3-EtOH, a linear gradient of EtOH from 0 to 20%) to afford 6′-(5-methylpyridin-3-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (151 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][C:21](OCC)=[O:22])[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1.[BH4-].[Li+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][CH2:21][OH:22])[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1c(Nc2ccc(Cl)cc2Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CCO)c12
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
To a solution of ethyl {4-chloro-2-[(2,4-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}acetate (99 mg, 0.211 mmol) in tetrahydrofuran (1.5 mL) was added lithium tetrahydroborate (14 mg, 0.634 mmol), and the mixture was stirred at 65° C. for 1.5 hr. After cooling, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting solid was washed with n-hexane to give the title compound (86 mg, 0.202 mmol, 96%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[C:20]1([CH2:30][NH2:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:31][CH2:30][C:20]1[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCc1cccc2ccccc12
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cccc2ccccc12
Yield: 80 %

Procedure:
The compound prepared in Example 3 was reacted with 1-naphthalenmethyl-amine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 80%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20].[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:12]([C:6]1[C:7]([CH3:11])=[N:8][N:9]([CH3:10])[C:5]=1[O:4][CH2:3][CH2:2][N:23]([CH3:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: Cc1nn(C)c(OCCBr)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: CNc1ccccc1
Product: Cc1nn(C)c(OCCN(C)c2ccccc2)c1C(=O)c1ccc(Cl)cc1Cl

Procedure:
A mixture of 1.1 g of 5-(2-bromoethoxy)-4-(2,4-dichlorobenzoyl)-1,3-dimethylpyrazole and 6 ml of N-methylaniline was heated at 110° to 120° C. for 3 hours with stirring. Excess N-methylaniline was distilled off under reduced pressure. The residue was then purified by silica gel chromatography (eluent, benzene:ethyl acetate at 10:1) to give 0.71 g of the desired product, Compound 2, having a refractive index nD24 1.5975 (yield 60.5%).
Reaction SMILES: [CH:1]([C@H:4]1[N:9]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:22]3[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([C:33](OC)=[O:34])=[CH:25][C:23]=3[N:24]=[C:5]12)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:1]([C@H:4]1[N:9]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([F:21])([F:19])[F:20])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:22]3[CH:28]=[C:27]([S:29]([CH3:32])(=[O:30])=[O:31])[C:26]([CH2:33][OH:34])=[CH:25][C:23]=3[N:24]=[C:5]12)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(F)(F)F)c(OC)n1)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(N2CCn3c(nc4cc(CO)c(S(C)(=O)=O)cc43)[C@H]2C(C)C)ncc1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
To a solution of (R)-methyl 1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (15 mg, 0.028 mmol) in CH2Cl2 (2 mL) was added DIBAL H (1M in toluene, 0.1 mL, 0.1 mmol) at −78° C. The mixture was stirred at −78° C. for 2 h and warmed to rt for 6 h. Sat. NH4Cl solution (1 mL) was added and the mixture was filtered. The filtrate was concentrated under vacuum. Water (5 mL) and EtOAc (5 mL) were added to the mixture. The aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-(1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol (3.50 mg, 24.6% yield) as a white solid. Analytical chiral HPLC: tR=6.598 min in 15 min chromatography, 94.60% ee (Method: OD-H—3—5—40—2.35 ML). LC-MS MS (ESI) m/z 500.1 [M+H]+. 1H NMR (CDCl3 300 MHz): δ 8.31 (s, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 6.02-5.98 (m, 1H), 5.43-5.38 (m, 1H), 5.04-4.98 (m, 2H), 4.32-4.28 (m, 1H), 4.16 (dt, J=5.1 and 12.0 Hz, 1H), 4.01 (s, 3H), 3.77-3.68 (m, 1H), 3.21 (s, 3H), 3.11-3.06 (m, 1H), 2.50-2.47 (m, 1H), 1.30 (d, J=6.6 Hz, 3H), 1.07 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH2:12][CH2:13][CH2:14][C:15]#[N:16])[C:6]=2[CH:17]=1.[Br-].[C:19](CCCC[Zn+])#N>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH:12]([CH3:19])[CH2:13][CH2:14][C:15]#[N:16])[C:6]=2[CH:17]=1
Reactant: N#CCCCc1cc(=O)oc2ccc(Cl)cc12
Reactant: N#CCCCC[Zn+]
Agent: [Br-]
Product: CC(CCC#N)c1cc(=O)oc2ccc(Cl)cc12

Procedure:
Is prepared via the method used for 4-(6-Chloro-2-oxo-2H-1-benzopyran-4-yl)-butyronitrile except 4-cyanobutylzinc bromide is used instead of 3-cyanopropylzinc bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[OH:10])=[CH:5][N:4]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1)=[O:10]
Reactant: COc1ccc(C(O)c2ccccn2)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)c2ccccn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 0.83 g of α-(2-methoxypyridin-5-yl)-2-pyridinemethanol in 20 ml of an acetone was added 1.70 g of activated manganese dioxide, followed by vigorously stirring at room temperature for 30 minutes. The resulting precipitates were filtered off and washed with acetone. Then, the filtrate was concentrated, to give 0.80 g of the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:28])[NH:12][C:13](=[O:27])[C:14]=2[C:15]2[CH:16]=[C:17]3[C:22]4=[C:23]([CH2:25][CH2:26][N:21]4[CH2:20][CH2:19][CH2:18]3)[CH:24]=2)=[CH:2]1>ClCCl.[O-2].[O-2].[Mn+4]>[CH:25]1[C:23]2=[C:22]3[C:17](=[CH:16][C:15]([C:14]4[C:13](=[O:27])[NH:12][C:11](=[O:28])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:24]2)[CH2:18][CH2:19][CH2:20][N:21]3[CH:26]=1
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1cc2c3c(c1)CCN3CCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C1NC(=O)C(c2c[nH]c3ccccc23)=C1c1cc2c3c(ccn3CCC2)c1
Reaction time: 1 h

Procedure:
A solution of 3-(1H-indol-3-yl)-4-(1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-pyrrole-2,5-dione (90 mg) in dichloromethane (10 ml) at room temperature was treated with manganese dioxide (300 mg; ca. 85%, 5 μm, activated) and stirred for 1 hour. The reaction mixture was filtered through a bed of celite and the filter cake was washed with methanol (15 ml). The filtrate was evaporated to dryness and 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione (88 mg) was used without further purification. 400 MHz 1H NMR (CDCl3) δ: 8.65 (s, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.51 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.07 (m, 2H), 6.70 (t, J=8.0 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H), 6.38 (d, J=3.2 Hz, 1H), 4.13 (m, 2H), 2.79 (t, J=6.4 Hz, 2H), 2.16 (m, 2H); LCMS: 368 [M+H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example B5) (6.81 g, 20 mmol) and pyrrolidine (8.27 mL, 100 mmol) in DMSO (70 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (7.35 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=CC=1>CO.[Pd]>[O:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH2:10][CH:11]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:6]1
Reactant: COc1cccc(C=CC2CCCCC(=O)N2)c1
Agent: [Pd]
Solvent: CO
Product: O=C1CCCCC(CCc2ccoc2)N1

Procedure:
The title material of Example 163 In MeOH is hydrogenated over Pd on carbon in a standard Parr apparatus by the method of Example 35 to generate the title product
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@H:5]([C:7]([O:9]C)=O)[CH2:4][O:3]1.[Cl:12][CH2:13]I.[Li+].CC([N-]C(C)C)C.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Cl:12][CH2:13][C:7]([C@@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:11])[O:6]1)=[O:9]
Reactant: ClCI
Reactant: COC(=O)[C@@H]1COC(C)(C)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](C(=O)CCl)O1
Temperature: -78 °C
Yield: 42 %

Procedure:
To a solution of (S)-methyl 2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.3 g, 8.1 mmol) and chloroiodomethane (4.3 g, 24 mmol) in THF (50 mL) at −78° C. was added a solution of LDA (16.2 mL, 24 mmol) in portions over 10 minutes. The reaction was stirred at −78° C. After addition, the slurry was warmed to ambient temperature. The reaction was poured into EtOAc (200 mL) and the aqueous layer basified using 1 N NaOH. The organics were separated and washed with brine, dried over MgSO4 and concentrated in vacuo. The material was purified by chromatography using DCM as eluent to give (S)-2-chloro-1-(2,2-dimethyl-1,3-dioxolane-4-yl)ethanone (0.60 g, 3.4 mmol, 42% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@@H:7]([OH:8])[C@H:6]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:5]2[CH:19]=[C:20](I)[CH:21]=[CH:22][C:4]=2[O:3]1.[CH3:25][CH:26]([O:28][C:29]1[C:30](=[O:47])[C:31](=[O:46])[C:32]=1[Sn](CCCC)(CCCC)CCCC)[CH3:27]>CN(C=O)C.CC#N.[Cu]Cl>[OH:8][C@H:7]1[C@H:6]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:18])[C:5]2[C:4](=[CH:22][CH:21]=[C:20]([C:32]3[C:31](=[O:46])[C:30](=[O:47])[C:29]=3[O:28][CH:26]([CH3:27])[CH3:25])[CH:19]=2)[O:3][C:2]1([CH3:1])[CH3:24]
Reactant: CC1(C)Oc2ccc(I)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Agent: Cl[Cu]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)Oc1c(-c2ccc3c(c2)[C@@H](N2Cc4ccccc4C2=O)[C@H](O)C(C)(C)O3)c(=O)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.1 %

Procedure:
To a solution of 217 mg (0.50 retool) of trans-2-[2,3-dihydro-2,2-dimethyl-3-hydroxy-6-iodo-4H-1-benzopyran-4-yl]-2,3-dihydro-1H-isoindol-1-one, prepared in Example 2, and 235 mg (0.55 mmol) of 3-(1-methylethoxy)-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione, as prepared by Liebeskind et. al. (J. Org. Chem. 55, 5359 (1990)), in DMF (620 μL) was added 23 mg (0.03 mmol) of trans-benzyl(chloro)bis(trisphenyl-phosphine) palladium (II) and 8.5 mg (0.04 mmol) of copper (I) chloride. After stirring at ambient temperature for 1.5 h, the reaction mixture was dissolved in hot CH3CN (200 mL) and was washed with hexane. The acetonitrile phase was dried over MgSO4 and was concentrated to a solid, which was then dissolved in hot THF/CH2Cl2 and absorbed onto silica gel. Purification by flash chromatography (65% EtOAc/35% hexane) gave 36 mg (16% yield) of the title compound. Additional compound was prepared in a repeat reaction in 52% yield by purifying with a short flash chromatography column using (CH3CN elution). Repeated crystallizations from CH3CN/Et2O/hexane provided an analytically pure sample, mp>250° C.: 1H-NMR (DMSO-d6 ; 400 MHz) δ7.83 (d, 1 H), 7.78 (dd, 1 H), 7.54-7.66 (m , 3 H), 7.38 (s, 1 H), 7.05 (d, 1 H), 5.86 (d, 1 It), 5.32 (br d, 1 H), 5.24 (septet, 1 H), 4.47-4.48 (br d, 1 H), 3.9-4.1 (br, 2 H), 1.51 (s, 3 H), 1.29 (s, 3 H), 1.25 (d, 3 H), and 1.02 ppm (d, 3 H); mass spectrum (DEI) m/e 447,429, 414. Anal. Calcd. for C26H25NO6. 0.5 H2O: C, 68.41; H, 5.74; N, 3.07 Found: C, 68.31; H, 5.56; N, 3.08.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH:3]=[CH:2]1.[Li][C:8]([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([C:1]1[CH:2]=[CH:3][CH2:4][CH:5]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: [Li]C(C)(C)C
Reactant: O=C1C=CCC1
Solvent: C1CCOC1
Product: CC(C)(C)C1=CCC=C1
Temperature: 20 °C
Yield: 20.2 %

Procedure:
2-Cyclopenten-1-one (14.2 mL, 0.17 mol) was added dropwise over about 30 min. at about -78° C. to t-BuLi (340 mmol) in dry THF (450 mL). The reaction was allowed to warm to about 20° C. and then chilled to about -78° C. to quench with NH4Cl (18.2 g). Solvent was removed in vacuo and the residue was partitioned between Et2O (300 mL) and brine (100 mL). The organic phase was washed with brine, dried over MgSO4 (s), filtered and concentrated in vacuo. The residue of crude 1-tert-butylcyclopent-2-en-1-ol (23.8 g) was treated with benzenesulfonic acid (0.24 g) in refluxing Et2O for 1.5 h. Solvent was removed in vacuo and the residue was vacuum distilled (12 mm, ~27-30° C.) to obtain pure 2-tert-butylcyclopentadiene (4.2 g). This diene (1.3 g, 10.7 mmol) was dissolved in xylene (5 mL) along with a crystal of hydroquinone and trans-β-nitrostyrene (1.95 g, 13.1 mmol). The tube was sealed under N2 (g) and heated to about 140° C. for about 10 h. Flash chromatography on silica (30% CH2Cl2 /hexanes) afforded 1.79 g (GC-MS m/z 271) of the nitro derivative which was reduced by dropwise addition of an etheral (10 mL) solution over 20 min. to LiAlH4 (0.5 g) in Et2O (25 mL). The mixture was refluxed for about 5 h. and quenched by serial additions of H2O (0.5 mL), 15% NaOH (0.5 mL) and H2O (1.5 mL), respectively. The mixture was filtered and the filtrate was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 (s), filtered, and concentrated in vacuo. The residue (1.1 g) was dissolved in dry Et2O (6 mL), chilled to about 5° C., and treated dropwise with 1M HCl in Et2O (6 mL) to precipitate the desired amine as its HCl salt (610 mg; LC-MS m/z 242).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([C:20]([O-])=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]([NH:10][C@H:11]([CH2:20][OH:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)[O-])OCc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCc1ccc(Cl)cc1
Yield: 56 %

Procedure:
In 30 ml of tetrahydrofuran was dissolved 1.0 g of methyl (N-(4-chlorobenzyloxycarbonyl)-tyrosinate. To the solution was added dropwise 10 ml of tetrahydrofuran solution containing 4.2 ml of sodium dihydro-bis-(2-methoxyethoxy) aluminate (65% toluene solution) with stirring while cooling with ice. The mixture was stirred at room temperature for one hour. After addition of 200 ml of 3% hydrochloric acid, the reaction mixture was concentrated in vacuo and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was dissolved in chloroform and subjected to column chromatography with 10 g of silicagel to give 509 mg of N-(4-chlorobenzyloxycarbonyl)-tyrosinol: yield 56%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:14]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH2:30]Br)=[CH:25][C:24]=1[S:33][CH3:34])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[C:14]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH2:30][NH:5][C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])=[CH:25][C:24]=1[S:33][CH3:34])(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CSc1cc(C(=O)CBr)ccc1OC(=O)c1ccccc1
Reactant: NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1cc(C(=O)CNC(=O)C(F)(F)F)ccc1OC(=O)c1ccccc1

Procedure:
Add trifluoroacetamide (6.8 g=60 mmol) and potassium carbonate (8.0 g=60 mmol) to a solution of 4'-benzoyloxy-3'-methylthio-2-bromoacetophenone (11.0 g=30 mmol) in 200 ml acetonitrile. Reflux for 16 hours, allow to cool, filter, and concentrate. Dissolve the residue in ethyl acetate, wash with 1.0 N sodium hydroxide, then water. Dry, concentrate and treat the residue with ether to obtain the product as a yellow solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH:32](=O)[CH2:33][CH2:34][CH3:35].CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:32]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCC=O
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCN1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 25 mg (0.061 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 1 mL chloroform was treated with 0.011 mL (0.12 mmol) butyraldehyde and 26 mg (0.12 mmol) NaBH3(CN) before 1 mL methanol was consequently added. The mixture was stirred at ambient temperature for 15 h when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 20 mL DCM, washed with 20 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained. MS (ES+): 468 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][C:13]([CH2:17]O)([CH2:15]O)[CH3:14]>>[Cl:8][C:6]1[CH:5]=[C:4]([B:9]2[O:10][CH2:14][C:13]([CH3:17])([CH3:15])[CH2:12][O:11]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(C)(CO)CO
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CC1(C)COB(c2cc(Cl)cc(Cl)c2)OC1
Yield: 80 %

Procedure:
The title compound (80%, crystals) was prepared from 3,5-dichlorophenylboronic acid and neopentylglycol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:13]=1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:36]1[CH2:41][CH2:40][N:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:45]([S:42]([N:39]1[CH2:38][CH2:37][CH:36]([C:27]2[C:26]3[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=[C:24]([C:12]4[CH:11]=[N:10][CH:9]=[C:8]([CH2:7][NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:13]=4)[CH:25]=3)[NH:29][CH:28]=2)[CH2:41][CH2:40]1)(=[O:44])=[O:43])[CH3:46]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: COCCCNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCCCOC)c4)cc23)CC1
Yield: 83 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [3-(methyloxy)propyl]amine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 22 mg of crude [3-(methyloxy)propyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [3-(methyloxy)propyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 31 mg of the title compound (83%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Cl.[CH3:11][CH2:12][O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15].[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4][N:19]1[CH2:18][CH2:17][N:16]([C:14]([O:13][CH2:12][CH3:11])=[O:15])[CH2:21][CH2:20]1
Reactant: CCOC(=O)N1CCNCC1
Reactant: ClCc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCOC(=O)N1CCN(Cc2c(Cl)cccc2Cl)CC1
Yield: 87.8 %

Procedure:
A mixture of 95.9 g (0.49 moles) of 2,6-dichlorobenzyl chloride, 77.6 g (0.49 moles) of ethyl N-piperazinocarboxylate, 500 ml of isopropyl alcohol and 70 ml of 10N sodium hydroxide was heated at reflux for 18 hours. The solution was evaporated in vacuo and gave a crystalline residue. The residue in 100 ml of water was extracted twice with 200 ml portions of dichloromethane. The combined organic extract was dried over anhydrous sodium sulfate, filtered, evaporated in vacuo and gave an oil. The oil was subjected to Kugelrohr distillation, bp 117° C./0.45 mm of mercury and gave 136.4 g of 4-(2,6-dichlorobenzyl)-1-piperazinecarboxylic acid, ethyl ester as an oil.