Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15](O)=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:13]=[N:12][C:11]=3[N:10]([CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:15]1[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:13][N:12]=[C:11]2[N:10]([CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]=12
Reactant: Oc1c(-c2ccccc2)nnc2c1c(-c1ccc(F)cc1)nn2CCN1CCOCC1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc(-c2nn(CCN3CCOCC3)c3nnc(-c4ccccc4)c(Cl)c23)cc1

Procedure:
3-(4-fluorophenyl)-1-(2-morpholinoethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-4-ol (27.8 mg, 0.07 mmol) was heated to 80° C. in POCl3 (0.5 ml) for 2.75 h the solvent was removed in vacuo and the crude purified by preparative HPLC to give Compound 78 as an orange solid (10.7 mg).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]([NH:20][C@H:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[N:7][C:8]3[C:9]([C:15]#[C:16][CH:17]4[CH2:19][CH2:18]4)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH:17]1([C:16]#[C:15][C:9]2[C:8]3[N:7]=[C:6]([NH:20][C@H:21]([CH3:26])[C:22]([CH3:25])([CH3:23])[CH3:24])[C:5]4[CH:27]=[CH:28][CH:2]=[CH:3][C:4]=4[C:13]=3[C:12](=[O:14])[NH:11][CH:10]=2)[CH2:19][CH2:18]1
Reactant: C[C@@H](Nc1nc2c(C#CC3CC3)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Nc1nc2c(C#CC3CC3)c[nH]c(=O)c2c2ccccc12)C(C)(C)C
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 9-bromo-4-(cyclopropylethynyl)-6-{[(1R)-1,2,2-trimethylpropyl]amino}benzo[c]-1,6-naphthyridin-1(2H)-one (104 mg, 0.237 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (92 mg, 0.474 mmol) and 1,1′-bis(dipheylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (38.7 mg, 0.047 mmol) was added DMF (2.4 mL) and the mixture was stirred under an argon atmosphere for five minutes. Sodium carbonate (2N) (0.237 mL, 0.474 mmol) was added, and the mixture was further degassed with argon. The reaction was then heated to 130° C. for 35 minutes using microwave irradiation, then quenched with the dropwise addition to a dilute aqueous NaHCO3 solution. The crude product mixture was filtered and purified via silica gel chromatography using 0.5-10% CH3OH in CH2Cl2 as eluent to afford the title compound 4-(cyclopropylethynyl)-6-{[(1R)-1,2,2-trimethylpropyl]amino}benzo[c]-1,6-naphthyridin-1(2H)-one. LRMS (APCI) calc'd (C23H25N3O) [M+H]+, 360.2; found 360.2. 1H NMR (500 MHz, DMSO-d6) δ 11.33 (d, 1H), 9.80 (d, 1H), 8.51 (d, 1H), 7.75 (t, 1H), 7.58 (t, 1H), 7.49 (d, 2H), 4.88 (m, 1H), 1.54 (m, 1H), 1.21 (d, 3H), 0.98 (s, 9H), 0.87 (m, 2H), 0.70 (m, 2H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:30])([CH3:29])[O:24][C:23]=4[CH:31]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:29])([CH3:30])[O:24][C:23]=4[CH:31]=3)[C:40]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:41])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Reactant: O=C(Cl)C1CCCCC1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)C3CCCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The titled compound was prepared following the procedure M using 7-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and cyclohexanecarbonyl chloride as an orange oil (52%). 1H NMR (CDCl3, 300 MHz) δ 7.92 (d, J=8.3 Hz, 1H), 7.41 (m, 4H), 7.14 (m, 4H), 6.77 (m, 0.5H), 6.75 (m, 0.5H), 6.57 (m, 1H), 4.87 (s, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.2 (m, 1H), 1.71 (s, 6H), 1.69-1.52 (m, 8H), 1.39-0.97 (m, 6H), 0.91 (t, J=7.3 Hz, 3H). M+ (ESI): 550.1. HPLC, Rt: 6.35 min (Purity: 97.5%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[C:11]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Yield: 57.9 %

Procedure:
According to the literature procedure (J. Am. Chem. Soc. 189 (1957)), trans-4-hydroxy-L-proline (5.12 g, 0.039 mot) was treated with benzyl chloroformate (8.5 mL, 0.06 mol) to provide the title compound (6.0 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3[C:13](=[O:23])[N:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[S:15](=[O:17])(=[O:16])[C:6]=3[C:5]=2[CH:4]=1.C[O-].[Na+]>C1(C)C=CC=CC=1.C(O)(C)(C)C>[OH:23][C:13]1[C:7]2[N:8]([CH3:12])[C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:6]=2[S:15](=[O:17])(=[O:16])[NH:14][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CN1C(=O)c2c(c3cc(OC)ccc3n2C)S1(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(O)c2c(c3cc(OC)ccc3n2C)S(=O)(=O)N1
Yield: 58.5 %

Procedure:
35.1 gm (0.104 mol) of methyl 3,4-dihydro-7-methoxy-4-methyl-3-oxo-2H-isothiazolo[4,5-b]indole-2-acetate 1,1-dioxide were reacted analogous to Example 18(e) with sodium methylate in toluene/tert. butanol to form 20.6 gm (59% of theory) of methyl 2,5-dihydro-4-hydroxy-8-methoxy-5-methyl-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide; M.p.: 225°-226° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[F:8].Cl[SiH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([SiH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C@H:20]3[CH2:21][CH2:22][C@H:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25]3)[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCCC[C@H]1CC[C@H](CCC2CC[SiH](Cl)CC2)CC1
Reactant: Fc1ccc([Mg]Br)cc1F
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCC2CC[SiH](c3ccc(F)c(F)c3)CC2)CC1

Procedure:
A 15 ml THF solution of 1.0M 3,4-difluorophenylmagnesium bromide (15 mmol) was dripped into a mixed solution of 2.5 g (7.9 mmol) of 1-chloro-4-(2-(trans-4-n-pentylcyclohexyl) ethyl)-1-silacyclohexane and 50 ml of THF.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[H-].[Na+].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1>C1COCC1>[CH2:17]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCCCCOCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,6-hexan-diol in dry THF at 0° C., NaH (1.1 equiv) was added. After stirring for 30 min, BnBr (1 equiv) was added slowly dropwise using a syringe and stirred for additional 3 h. After completion of the reaction (monitored by TLC), it was quenched with ice and the organic layer was extracted using ether and washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuum and concentrated. The crude was purified by chromatographic technique (EtOAc:pet ether=20:80). 1H NMR (CDCl3, 200 MHz) δ 7.3-7.4 (5H, m), 4.5 (s, 2H), 3.6 (t, 2H), 3.4 (t, 2H), 1.8 (br s, 1H), 1.6 (m, 4H), 1.4 (m, 4H); 13C NMR (CDCl3, 50 MHz): 138.56, 128.34, 127.62, 127.50, 72.87, 70.29, 62.63, 32.67, 29.73, 26.03, 25.62
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[N-:38]=[N+:39]=[N-:40].[Na+]>CCO.[Cu]I>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([N:38]=[N+:39]=[N-:40])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(Br)ccc2F)COC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(N=[N+]=[N-])ccc2F)COC1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
A mixture of [5-(5-bromo-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (5.0 g, 12.91 mmol) in EtOH (50 ml) was homogenized in an ultrasound bath for 10 min. To this suspension was added water (22 ml), cyclohexane dimethyldiamine (0.611 ml, 0.551 g, 3.87 mmol), sodium ascorbate (0.512 g, 2.58 mmol), sodium azide (3.36 g, 51.6 mmol) and CuI (0.492 g, 2.58 mmol). The reaction mixture was degassed with Ar and heated for 1 h at 70° C., then cooled to rt, filtered through silica gel and concentrated. The resulting title compound was purified by FC (cyclohexane:EtOAc 100.0 to 80:20).
Reaction SMILES: [ClH:1].Cl.[CH:3]1[CH:12]=[CH:11][C:10]2[CH2:13][CH2:14][CH2:15][N:8]3[C:9]=2[C:4]=1[C@H:5]1[CH2:18][NH:17][CH2:16][C@H:6]1[CH2:7]3.[CH2:19](Br)[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl.CCOCC>O1CCOCC1.C(OCC)(=O)C>[ClH:1].[ClH:1].[CH2:19]([N:17]1[CH2:18][C@H:5]2[C@H:6]([CH2:7][N:8]3[CH2:15][CH2:14][CH2:13][C:10]4[CH:11]=[CH:12][CH:3]=[C:4]2[C:9]3=4)[CH2:16]1)[CH2:20][CH2:21][CH3:22]
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CCC2
Reactant: CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCCCN1C[C@H]2CN3CCCc4cccc(c43)[C@H]2C1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of (±)-cis-5,6,8,8a,9,10,11,11a-octahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline free base from EXAMPLE 11 (124 mg, 0.58 mmol) in 5 mL of 1,4-dioxane was added n-butylbromide (79 mg, 0.58 mmol), potassium carbonate (160 mg, 1.16 mmol) and potassium iodide (10 mg, 0.06 mmol) The mixture was stirred at 90° C. for 24 h. The reaction was then cooled, diluted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, basified with sat'd aq Na2CO3 and extracted twice with ethyl acetate. The organics were washed with brine, dried (Na2SO4) and concentrated to a free base. The residue was taken up in about 4:1 ether/ethanol and then there was added 2M HCl in ether (1.0 mL, 2.0 mmol). The resulting solid was filtered, washed twice with ether and dried in vacuo to afford the title compound of EXAMPLE 104 as an off-white powder. 1H NMR (dmso-D6) δ: 6.90-6.78 (m, 2H), 6.62-6.55 (m, 1H), 4.00-3.93 (m, 1H), 3.85-3.77 (m, 1H), 3.65-3.59 (m, 1H), 3.50-3.35 (m, 2H), 3.15-2.95 (m, 4H), 2.92-2.75 (m, 3H), 2.73-2.63 (m, 2H), 1.95-1.85 (m, 2H), 1.65-1.55 (m, 2H), 1.33-1.22 (m, 2H), 0.91-0.83 (m, 3H). LRMS. (ES)+: 271.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.[S:21]1[CH2:25][CH2:24][S:23][CH:22]1[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:33][CH:34]=[C:35]([C:37]([NH:39][NH2:40])=[O:38])[N:36]=2)=[CH:28][CH:27]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17]([NH:40][NH:39][C:37]([C:35]3[N:36]=[C:32]([C:29]4[CH:28]=[CH:27][C:26]([CH:22]5[S:21][CH2:25][CH2:24][S:23]5)=[CH:31][CH:30]=4)[S:33][CH:34]=3)=[O:38])(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1csc(-c2ccc(C3SCCS3)cc2)n1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(NCc1ccc(S(=O)(=O)NNC(=O)c2csc(-c3ccc(C4SCCS4)cc3)n2)s1)c1ccc(Cl)cc1
Yield: 80 %

Procedure:
A solution of sulfonyl chloride 1b (1.0 equivalents), 2-[4-(1,3-Dithiolan-2-yl)phenyl]-1,3-thiazole-4-carbohydrazide (1.1 equivalents), and pyridine (1.2-2 equivalents) in CHCl3 is heated to reflux for 2 h. Filtration over SiO2 (CH3CN) and evaporation yielded 80% of the desired sulfonyl hydrazide 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH3:12])[NH:7][CH2:6][CH2:5]2.B(O)O>>[CH3:12][CH:8]1[C:9]2[C:4](=[CH:3][C:2]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][CH:4]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][NH:7]1
Reactant: CC1NCCc2cc(Br)ccc21
Agent: OBO
Product: CC1NCCc2cc(-c3cccnc3)ccc21

Procedure:
In close analogy to the procedure described above, 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: ClC1C=CC(S(O[CH2:12][C@@H:13]2[O:19][C@@H:18]3[N:15]([C:16](=[O:20])[CH2:17]3)[CH2:14]2)(=O)=O)=CC=1.[N-:21]=[N+:22]=[N-:23].[Na+].CN(C=O)C>C(OCC)(=O)C>[N:21]([CH2:12][C@H:13]1[O:19][C@@H:18]2[N:15]([C:16](=[O:20])[CH2:17]2)[CH2:14]1)=[N+:22]=[N-:23]
Reactant: O=C1C[C@@H]2O[C@@H](COS(=O)(=O)c3ccc(Cl)cc3)CN12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@@H]1CN2C(=O)C[C@@H]2O1
Temperature: 65 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of (3R,5S)-3-(4-chlorobenzenesulfonyl)oxymethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one (400 mg, 1.26 mmol), sodium azide (212 mg, 3.8 mmol) and DMF (5 ml) was stirred at 65° C. for 2 hrs. The resulting mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (2:1) as eluent and 210 mg of (3S,5S)-3-azidomethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one was obtained.
Reaction SMILES: N1C=CN=C1.[CH2:6]([N:13]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].O>CN(C)C=O>[CH2:6]([N:13]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCC1CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.7 %

Procedure:
Imidazole (30.0 g) was added to a solution of 1-benzyl-3-hydroxymethylpyrrolidine (43.45 g) and t-butyldimethylsilyl chloride (48.5 g) in dimethylformamide(150 ml) under ice-cooling. The mixture was stirred at the same temperature for 2 hours and at ambient temperature for 15 hours. The mixture was poured into water (600 ml), extracted twice with ethyl acetate (200 ml and 100 ml), dried over magnesium sulfate and evaporated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (500 g) and eluted with a mixture of methanol and dichloromethane (5:95 V/V) to give 1-benzyl-3-t-butyldimethylsilyloxymethylpyrrolidine (60.15 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1)[CH3:2].CN(C=O)C.C1C(=O)N([Br:37])C(=O)C1>C(#N)C>[Br:37][C:12]1[C:7]2[NH:6][N:5]=[C:4]([NH:3][CH2:1][CH3:2])[C:8]=2[CH:9]=[N:10][C:11]=1[NH:13][C:14]([NH:16][C@@H:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:18])=[O:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCNc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNc1n[nH]c2c(Br)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-1-(3-(Ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 2; 316 mg, 0.974 mmol) was dissolved in acetonitrile (10 mL) and DMF (2 mL) then NBS (225 mg, 1.266 mmol) was added. The reaction was stirred at room temperature overnight. The solvents were concentrated in vacuo and the residue was purified by flash chromatography (2-10% MeOH/DCM) to give (R)-1-(7-bromo-3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C12H19BrN6O [M+1]+ 403. found 403.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][CH:17]3[CH:12]([CH2:13][CH:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[NH:16]3)[CH2:11]2)=[CH:5][CH:4]=1.[BH4-].[Li+].Cl>C1COCC1>[OH:22][CH2:21][CH:14]1[CH2:13][CH:12]2[CH:17]([CH2:18][CH2:19][CH:10]([CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:11]2)[NH:16][C:15]1=[O:20]
Reactant: CCOC(=O)C1CC2CC(Cc3ccc(OC)cc3)CCC2NC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CC2CCC3NC(=O)C(CO)CC3C2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a manner analogous to Example 6, but using THF solvent instead of CH2Cl2, ethyl 3,4,4a,5,6,7,8,8a-octahydro-6-((4-methoxyphenyl)methyl)quinolin-2[1H]-one-3-carboxylate was prepared as a 60:40 w/w mixture of (±)-(3RS,4aSR,6RS,8aRS) to (±)-(3SR,4aSR,6RS,8aRS) isomers). This product was suspended in THF (20 ml) at 0° C. and an ice cold solution of 1M lithium borohydride in THF (13.1 ml) was added. The mixture was left to stir 51/2 hours at 0° C. and then was added to methanolic hydrogen chloride (120 ml). The acidic solution was left to stand 18 hours and was then evaporated. The residue was dissolved in chloroform and washed with saturated sodium carbonate solution, water and then brine. The organic solution was dried (MgSO4), evaporated and the residual oil was left to stir in hexane containing a small quantity of ethyl acetate for 3 days. The resin obtained was purified by repeated chromatography on a 4 mm "Chromatotron" plate. The early running fractions were combined to give 0.2 g of the title compound. This was recrystallised from ethyl acetate mp 205°-209° C.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:35]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH:44]2[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]2)[CH2:40][CH2:39]1)[CH2:36][CH3:37]>C1COCC1>[CH2:35]([C@H:38]1[CH2:43][CH2:42][C@H:41]([CH:44]2[CH2:49][CH2:48][C:47](=[CH:9][CH2:8][CH:3]3[O:2][CH2:7][CH2:6][CH2:5][O:4]3)[CH2:46][CH2:45]2)[CH2:40][CH2:39]1)[CH2:36][CH3:37]
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C2CCC(=CCC3OCCCO3)CC2)CC1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A mixture of 531 g (1170 mmol) of 2-(1,3-dioxane-2-yl)ethyltriphenylphosphonium bromide and 4.0 l of THF was cooled to −30° C. under a nitrogen gas stream with a refrigeration medium. To this mixture, 121 g (1080 mmol) of t-BuOK was added, followed by stirring for 1 hour. Furthermore, 1 l of a THF solution containing 200 g (899 mmol) of 4-(trans-4-propylcyclohexyl)cyclohexanone was added dropwise to the mixture, while the temperature was maintained at −30° C. or less. After the dropping, the reaction temperature was slowly raised to room temperature, and the solution was further stirred for 5 hours. Next, the reaction solution was filtered through Celite, and the solvent was then distilled off under reduced pressure. The resulting residue was purified through silica gel column chromatography (a developing solvent: a mixed solvent of toluene/ethyl acetate=9/1 (v/v)) to obtain 277 g of crude 2-(2-(4-(trans-4-propylcyclohexyl)cyclohexylidene)ethyl)-1,3-dioxane.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:7][C:8]2[O:12][C:11]([CH2:14][CH2:15]/[CH:16]=[C:17](/[C:19](OCC)=[O:20])\[CH3:18])([CH3:13])[CH2:10][C:9]=2[C:24]=1[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:3])[CH3:2].O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:7][C:8]2[O:12][C:11]([CH2:14][CH2:15]/[CH:16]=[C:17](\[CH3:18])/[CH2:19][OH:20])([CH3:13])[CH2:10][C:9]=2[C:24]=1[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(C)=C/CCC1(C)Cc2c(cc(C(C)(C)C)c(OC(C)=O)c2C(C)(C)C)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CC/C=C(\C)CO)O2
Reaction time: 1 h
Yield: 32.6 %

Procedure:
5-Acetoxy-4,6-di-tert-butyl-2-(4-ethoxycarbonyl-4-methyl-3(E)-butenyl)-2-methyl-2,3-dihydrobenzofuran (13.2 g) was dissolved in benzene (250 ml) and a tetrahydrofuran solution (60 ml) of 1M diisobutylaluminum hydride was added dropwise to the solution under cooling with ice. After stirring the mixture for 1 h, a saturated aqueous solution of ammonium chloride was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (33% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2-(5-hydroxy-4-methyl-3(E)-pentenyl)-2-methyl-2,3-dihydrobenzofuran [3.9 g (yield, 33%)] as a colorless oil. In addition, 4,6-di-tert-butyl-5-hydroxy-2-(5-hydroxy-4-methyl-3(E)-pentenyl)-2-methyl-2,3-dihydrobenzofuran [4.2 g (yield, 39%)] was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][CH2:38][CH:37]1[C:41]1[NH:42][C:43]([C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[C:48]([C:61]([O:63][CH3:64])=[O:62])[CH:47]=2)=[CH:44][N:45]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)(O)[O-].[Na+]>O.CCOC(C)=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>[CH3:28][O:27][C:25]([C:20]1[C:21]([C:49]2[C:48]([C:61]([O:63][CH3:64])=[O:62])=[CH:47][C:46]([C:43]3[NH:42][C:41]([CH:37]4[CH2:38][CH2:39][CH2:40][N:36]4[C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])=[N:45][CH:44]=3)=[CH:51][CH:50]=2)=[CH:22][CH:23]=[C:18]([C:15]2[NH:14][C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:17][CH:16]=2)[CH:19]=1)=[O:26]
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1Br
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: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1-c1ccc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)cc1C(=O)OC
Temperature: 80 °C
Yield: 34.8 %

Procedure:
To the solution of 2-[5-(4-bromo-3-methoxycarbonyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (158 mg, 0.35 mmol) and 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (166 mg, 0.33 mmol) in 1,2-dimethoxyether (3 ml) and water (1 ml) was added sodium bicarbonate (91 mg, 1.1 mmol), followed by Pd(PPh3)4 (15 mg) and PdCl2(dppf)CH2Cl2 (15 mg). The mixture was heated at 80° C. for 7 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (EtOAc) gave 4,4′-Bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-2,2′-dicarboxylic acid dimethyl ester (85 mg). m/z: 741.0 (M+H)+, 370.9 (M+2H)+/2.