Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:26]=[CH:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH:26](/[C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH:27]\[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C=CCCCC
Reactant: CCCCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: CCCC/C=C/c1nc(N)c2nc(NCCCC)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 0.58 h

Procedure:
The reaction was performed with 2-iodo-8-butylaminoadenosine (10, 380 mg, 0.82 mmol) and (E)-1-borocatechol)-1-hexene (2.46 mmol). The mixture was purified by column chromatography (10% MeOH in CH2Cl2). Yield 42 mg (0.10 mmol, 12%); Rƒ 0.44 (10% MeOH in CH2Cl2); 1H NMR (MeOD-d4) δ 6.94–6.80 (m, 1H, ═CHCH2), 6.28 (d, 1H, J=15.42 Hz, ═CH), 6.02 (d, 1H, J=7.62 Hz, H-1′), 4.81–4.69 (m, 1H, H-2′), 4.31–4.20 (m, 1H, H-3′), 4.20–4.05 (m, 1H, H-4′), 3.87–3.70 (m, 2H, H-5′), 3.35–3.23 (m, 2H, NHCH2), 2.29–2.05 (m, 2H, ═CHCH2), 1.72–1.20 (m, 8H, 2×CH2CH2), 1.00–0.83 (m, 6H, 2×CH3); MS m/z 422 (M+H)+; HPLC, System A: 20–100% CH3CN in H2O in 35 min., retention time=8.53 min.; System B: 30–100% CH3OH in H2O in 40 min., retention time=20.47 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[F:23][C:24]([F:28])([F:27])[CH2:25]O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:25][C:24]([F:28])([F:27])[F:23])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OCC(F)(F)F
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: FC(F)(F)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIk was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 2,2,2-trifluoroethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH:8](O)/[CH:9]=[CH:10]/[C:11]1[C:21]([CH3:23])([CH3:22])[CH2:20][C:14]2([S:19][CH2:18][CH2:17][CH2:16][S:15]2)[CH2:13][C:12]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([CH3:31])[CH:25]=1)[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.ClC(OCC)=O>C(Cl)Cl.CCOCC>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:12]2[CH2:13][C:14]3([CH2:20][C:21]([CH3:23])([CH3:22])[C:11]=2/[CH:10]=[CH:9]/[C@@H:8]2[O:5][C:4](=[O:6])[CH2:3][C@@H:2]([OH:1])[CH2:7]2)[S:19][CH2:18][CH2:17][CH2:16][S:15]3)=[CH:25][C:26]=1[CH3:31]
Reactant: Cc1cc(C2=C(/C=C/C(O)CC(O)CC(=O)O)C(C)(C)CC3(C2)SCCCS3)ccc1F
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(C2=C(/C=C/[C@H]3C[C@H](O)CC(=O)O3)C(C)(C)CC3(C2)SCCCS3)ccc1F
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
To a 0°-5° C. solution of 12 (0.90 gm, 1.87 mmol) and triethylamine (315 μL, 2.25 mmol) in 10 mL CH2Cl2 was added dropwise ethyl chloroformate (185 μL 1.87 mmol). The mixture was stirred for 30 min, diluted with ether, washed with H2O saturated NaHCO3 and brine and dried (MgSO4). Removal of the volatiles in vacuo and purification of the residue by SiO2 using 3:2 hexanes:EtOAc as eluent provided 0.61 g of the product. mp 136°-138° C. Anal. C25H31FO3S2 : Theory C: 64.91; H: 6.75. Found C: 65.31; H: 6.82.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C(=O)Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1ccc(F)cc1

Procedure:
Prepared according to general Procedure B using ethyl 3-(4-fluorophenylamino)-2-methyl-3-oxopropanoate (20.0 g, 84 mmol) and NaOH (4.3 g, 81.5 mmol) in THF (50 mL). After purification 3-(4-fluorophenylamino)-2-methyl-3-oxopropanoic acid was obtained as a white solid. Mass Spectrum (ESI) m/e=212.2 (M+1).
Reaction SMILES: C(N1C=C(C2SC(C(OCC)=O)=C(C)N=2)N=N1)C1C=CC=CC=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[CH:34]=[C:33]([C:35]3[S:36][C:37]([C:41]([O:43]CC)=[O:42])=[C:38]([CH3:40])[N:39]=3)[N:32]=[N:31]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]2[CH:34]=[C:33]([C:35]3[S:36][C:37]([C:41]([OH:43])=[O:42])=[C:38]([CH3:40])[N:39]=3)[N:32]=[N:31]2)=[CH:46][CH:47]=1
Reactant: CCOC(=O)c1sc(-c2cn(Cc3ccc(F)cc3)nn2)nc1C
Agent: CCOC(=O)c1sc(-c2cn(Cc3ccccc3)nn2)nc1C
Product: Cc1nc(-c2cn(Cc3ccc(F)cc3)nn2)sc1C(=O)O
Yield: 98 %

Procedure:
Following the procedure as described in Example 3, making variations as necessary to replace ethyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 98% yield: MS (ES−) m/z 317.2 (M−1).
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:11][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:11][O:9][C:8]([C:2]1([NH2:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: NC1(C(=O)O)CCCCC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1(N)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.5 %

Procedure:
In a round-bottomed flask 1-amino-1-cyclohexanecarboxylic acid (1.00 g, 7.0 mmol) was suspended in dichloromethane (26 mL) and MeOH (13 mL). (Trimethylsilyl)diazomethane (2.0 M in hexanes, 6.0 mL, 12.0 mmol) was added dropwise and the reaction mixture gradually became homogeneous as it was stirred at room temperature overnight. The reaction mixture was quenched with a small portion of acetic acid and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated aqueous Na2CO3. The aqueous layer was extracted with dichloromethane and the combined organics were dried over Na2SO4 and concentrated to afford 1.15 g of 1-amino-1-cyclohexanecarboxylic acid methyl ester as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C:15]([OH:17])=O)=[CH:12][N:11]=[C:10]1[S:18][CH2:19][CH2:20][CH3:21].OC1CC(=O)NC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:46][O:47][C:48](=[O:58])[C@H:49]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH2:50].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH3:46][O:47][C:48](=[O:58])[C@H:49]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:50][C:15]([CH2:14][C:13]1[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]([S:18][CH2:19][CH2:20][CH3:21])=[N:11][CH:12]=1)=[O:17]
Reactant: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CC(O)C(=O)N1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCSc1ncc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
A solution of 2-[1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl]acetic acid (0.52 g, 1.6 mmol) in tetrahydrofuran (20 mL) was stirred with N hydroxysuccinimide (0.203 g, 1.76 mmol) and dicyclohexylcarbodiimide (0.33 g, 0.16 mmol) for 30 minutes. Then L-phenylalanine methyl ester hydrochloride (0.449 g, 2.08 mmol) and triethylamine (0.21 g, 2.08 mmol) were added and the suspension was stirred at ambient temperature for 18 hours. The mixture was diluted with ethyl acetate, filtered and the concentrated filtrate was flash chromatographed over silica gel with 3:2 ethyl acetate/hexane to give 0.58 g (74%) of N-[{1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl}methylcarbonyl]-L-phenylalanine methyl ester as an oil.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[CH2:15][CH2:14][N:13]([C@@H:16]([C:48]([CH3:51])([CH3:50])[CH3:49])[C:17]([NH:19][C@@H:20]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:21]([OH:40])[CH2:22][N:23]([S:28]([C:31]3[CH:36]=[CH:35][C:34](/[CH:37]=[N:38]/[OH:39])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:18])[C:12]2=[O:52])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[CH2:41]([C@H:20]([NH:19][C:17](=[O:18])[C@@H:16]([N:13]1[CH2:14][CH2:15][N:11]([CH2:10][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([OH:3])[CH3:2])[N:9]=2)[C:12]1=[O:52])[C:48]([CH3:50])([CH3:51])[CH3:49])[C@H:21]([OH:40])[CH2:22][N:23]([S:28]([C:31]1[CH:32]=[CH:33][C:34](/[CH:37]=[N:38]/[OH:39])=[CH:35][CH:36]=1)(=[O:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(=O)c1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CN(CC(C)C)S(=O)(=O)c3ccc(/C=N/O)cc3)C(C)(C)C)C2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C(C)O)n2)C1=O)C(C)(C)C)S(=O)(=O)c1ccc(/C=N/O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of the product of Example 288A (86 mg) in methanol (1.5 mL) was treated with NaBH4 (8.8 mg, 2 equivalents) at 0° C. The mixture was stirred for 1 h at 25° C. and quenched by adding acetone (0.2 mL). The solvents were evaporated, and the residue was purified using 7% methanol/dichloromethane to give 83 mg (96%) of the title compound.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:3]=1.[C:33]1(B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:33]1([C:2]2[N:6]([S:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)[CH:11]=3)(=[O:8])=[O:9])[CH:5]=[C:4]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH:3]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccc(OC3CCCCO3)c2)c1)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OC3CCCCO3)c2)c1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 10 h

Procedure:
tert-Butyl ((5-bromo-1-((3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 7b (770 mg, 1.5 mmol), 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (394 mg, 1.4 mmol, prepared by a known method disclosed in “Journal of the American Chemical Society, 2002, 124(27), 8001-8006”), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (53 mg, 0.07 mmol) and potassium carbonate (401 mg, 2.9 mmol) were successively added to 15 mL of a mixed solvent of ethylene glycol dimethyl ether and water (V/V=3:1), then the reaction solution was heated up to 100° C. and stirred for 10 h. 15 mL of water were added, and the reaction solution was extracted with ethyl acetate (50 mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system C to obtain the title product tert-butyl ((5-(cyclohex-1-en-1-yl)-1-((3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 7c (554 mg, a light yellow oil) in 72% yield.
Reaction SMILES: [S:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH:4]([C:11]([O:13]CC)=[O:12])[N:3]=C1.C(OCC)C.[ClH:21]>>[ClH:21].[NH2:3][CH:4]([C:5]1([SH:1])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C1N=CSC12CCOCC2
Agent: Cl
Solvent: CCOCC
Product: NC(C(=O)O)C1(S)CCOCC1
Yield: 80.5 %

Procedure:
53 g (0.25 mole) of ethyl alpha-formamido-2,3,5,6-tetrahydro-4H-pyran-Δ4,α -acetate and 14.5 g of phosphorous pentasulfide (P4S10) are suspended in 300 ml of anhydrous benzene. After boiling under reflux for 4 hours with stirring, the benzene solution is decanted off from insoluble material, treated with active carbon and filtered over "Hyflo-cel". After evaporating off the solvent, a brownish oil remains behind which distils at 130-135° C/0.5 mm Hg. In this way, there are obtained 30 g (yield 52% of theory) of ethyl 8-oxa-1-thia-3-azaspiro[4,5]-dec-2-ene-4carboxylate which is used without further purification for the continuation of the synthesis. I.1.c. alpha-Amino-4-mercapto-2,3,5,6-tetrahydro-4H-pyran-4acetic acid (formula III: n=m=2, X=0) 2 g (0.0087 mole) of ethyl 8-oxa-1-thia-3-azaspiro[4.5]-dec-2-ene-4-carboxylate are dissolved in 100 ml of 6 N hydrochloric acid. The reaction mixture is refluxed for 3 hours and is then concentrated in vacuo in a rotary evaporator. The gummy residue obtained is triturated 3 times with 50 ml of benzene, which are evaporated off under reduced pressure in order to eliminate remaining traces of water and hydrochloric acid. The residue is taken up in 100 ml of water and the solution is treated with "Norite" and then lyophilized. Trituration of the lyophilisate with dry diethyl ether gives 1.6 g of alpha-amino-4-mercapto-2,3,5,6-tetrahydro-4 H-pyran-4-acetic acid hydrochloride (yield: 80.5% of theory). The product gives a single spot in thin layer chromatography on silica (eluent: butanol, acetic acid, water: 4:1:1, Rf:0.35); M.P. 196-197° C (decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[CH:4][C:3]=2[CH:6]=1
Reactant: ClCc1ccncc1
Reactant: O=Cc1cc(C(F)(F)F)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3)cc2c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
A mixture of 1.0 g of 2-hydroxy-5-(trifluoromethyl)benzaldehyde, 0.86 g of 4-(chloromethyl)pyridine hydrochloride, 2.54 g of potassium carbonate and 20 ml of DMF was stirred at 80° C. for 2 hours and subsequently at 150° C. for 3 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.91 g of 4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 3”).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[C:4]([Br:12])[C:3]=1[OH:13].CC(C)([O-])C.[K+].[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][C:26]=1[CH:27]([CH3:29])[CH3:28]>CN(C)C(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[C:4]([Br:12])[C:3]=1[O:13][C:24]1[N:23]=[N:22][C:21]([Cl:20])=[C:26]([CH:27]([CH3:29])[CH3:28])[CH:25]=1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: OCCCc1cc(Br)c(O)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)c1cc(Oc2c(Br)cc(CCCO)cc2Br)nnc1Cl
Temperature: 100 °C
Reaction time: 24 h
Yield: 24.7 %

Procedure:
A mixture of 2,6-dibromo-4-(3-hydroxy-propyl)-phenol (20) (5.0 g, 16.3 mmol) in N,N-dimethyl acetamide (8 mL) was treated with potassium tert-butoxide (1.74 g, 15.48 mmol) under nitrogen at room temperature. The suspension was heated to 100° C. for 15 min and turned brown in color. 3,6-Dichloro-4-isopropyl pyridazine (7) (2.47 g, 12.9 mmol) was added to the suspension and the reaction was stirred at 140° C. for 24 h. The reaction was cooled to room temperature, diluted with water (180 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined and were washed with a 1N aqueous sodium hydroxide solution (1×150 mL), followed by a saturated aqueous sodium chloride solution (1×150 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (Biotage 40M) eluted with 15% ethyl acetate in hexanes, followed by 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes. The desired fractions were collected and concentrated under vacuum. The resulting solid was slurried in cold acetonitrile and filtered. The solid was then diluted with a 1:1 mixture of isopropyl acetate:methyl tert-butyl ether (20 mL). The mixture was heated to reflux and then cooled to room temperature. The solvent was decanted. The solid was slurried in heptane, filtered and dried under high vacuum overnight. The filtrate was concentrated. The resulting solid was then diluted with a 1:1 mixture of isopropyl acetate:methyl tert-butyl ether (20 mL). The mixture was heated to reflux and then cooled to room temperature. The solvent was decanted and the solid was slurried in heptane and filtered to afford a second crop of solid which was dried under high vacuum overnight. The solids were combined to afford 3-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-propan-1-ol (21) (1.48 g, 20%) as a white solid; LRMS for C16H17Br2ClN2O2 (M+H) m/z=465. Molecular Weight=464.5871; Exact Mass=461.9345
Reaction SMILES: [C:1]1([N:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:8]([O:10][C:11](=[O:41])[C:12]2[CH:17]=[CH:16][C:15](CC3C4C(=CC=C(NC(=O)CC5CCCC5)C=4)N(CC)C=3)=[C:14]([O:39][CH3:40])[CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:48]1([O:53][C:54]([NH:56][C:57]2[CH:65]=[C:64]3[C:60]([CH:61]=[N:62][N:63]3[CH2:66]C3C=CC(C(O)=O)=CC=3OC)=[CH:59][CH:58]=2)=[O:55])[CH2:52][CH2:51][CH2:50][CH2:49]1>>[C:1]1([N:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:8]([O:10][C:11](=[O:41])[C:12]2[CH:17]=[CH:16][C:15]([CH2:66][N:63]3[C:64]4[C:60](=[CH:59][CH:58]=[C:57]([NH:56][C:54]([O:53][CH:48]5[CH2:52][CH2:51][CH2:50][CH2:49]5)=[O:55])[CH:65]=4)[CH:61]=[N:62]3)=[C:14]([O:39][CH3:40])[CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(=O)O)ccc1Cn1ncc2ccc(NC(=O)OC3CCCC3)cc21
Reactant: CCn1cc(Cc2ccc(C(=O)OC(=O)N(c3ccccc3)c3ccccc3)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Product: COc1cc(C(=O)OC(=O)N(c2ccccc2)c2ccccc2)ccc1Cn1ncc2ccc(NC(=O)OC3CCCC3)cc21
Yield: 96 %

Procedure:
Using a procedure similar to part (f) of Example 4, but using 4-[6-(cyclopentyloxycarbonyl)aminoindazol-1-ylmethyl]-3-methoxybenzoic acid (N) instead of acid (J), there was obtained 4-[6-(cyclopentyloxycarbonyl)aminoindazol-1-ylmethyl]-3-methoxybenzoic N,N-diphenylcarbamic anhydride (K) as a pink solid (2.14 g, 96%); partial NMR: (80 MHz, DMSO-d6): 3.86(s, 3H, OCH3), 5.49(s, 2H, ArCH2N), 7.42(s, 10H, NArH), 9.69(s, 1H, CONH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH2:24]([N:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH3:25]>>[CH2:24]([N:26]([CH2:30][CH3:31])[C:27]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:28])[CH3:25]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC

Procedure:
1,1-Diethyl-3-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.97 mmol) and diethylcarbamoyl chloride (134 μl, 1.06 mmol). The title compound was obtained as yellow powder (85 mg, 21%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]1([C:15](=[C:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:40])[C:25]([C:27]3[C:35]4[C:30](=[C:31]([O:38][CH3:39])[N:32]=[CH:33][C:34]=4[O:36][CH3:37])[NH:29][CH:28]=3)=[O:26])[CH2:20][CH2:19]2)[C:16]#[CH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:41](=[O:43])=[O:42]>C1COCC1>[C:9]1([C:15](=[C:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:40])[C:25]([C:27]3[C:35]4[C:30](=[C:31]([O:38][CH3:39])[N:32]=[CH:33][C:34]=4[O:36][CH3:37])[NH:29][CH:28]=3)=[O:26])[CH2:22][CH2:23]2)[C:16]#[C:17][C:41]([OH:43])=[O:42])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C=O
Reactant: C#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(OC)ncc(OC)c23)CC1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(C#CC(=O)O)c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a solution of LDA [prepared from iPr2NH (0.15 mL, 1.070 mmol) and n-BuLi (0.52 mL, 0.936 mmol)] in THF (3 mL) at −78° C. under Ar was added 1-[4-(1-phenyl-1-ethynyl-methylene)-piperidin-1-yl]-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione (0.160 g, 0.373 mmol). The solution was allowed to stir for 30 min and then a large excess of powdered dry ice was added directly into the flask. The mixture was allowed to warm to room temperature overnight and was then quenched with 10% aqueous HCl. The mixture was extracted with EtOAc (×3) and the combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to afford the title compound as a colorless solid (0.026 g, 15%):
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([C:8]2[CH:36]=[CH:35][C:11]([O:12][C:13]3[N:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[N:27]=5)[CH2:22][CH2:21]4)[C:14]=3[CH3:34])=[CH:10][CH:9]=2)[CH2:4][O:3]1>CC(C)=O>[CH:31]([C:28]1[N:27]=[C:26]([N:23]2[CH2:22][CH2:21][CH:20]([O:19][C:15]3[N:16]=[CH:17][N:18]=[C:13]([O:12][C:11]4[CH:10]=[CH:9][C:8]([CH:5]([CH2:4][OH:3])[CH2:6][OH:7])=[CH:36][CH:35]=4)[C:14]=3[CH3:34])[CH2:25][CH2:24]2)[O:30][N:29]=1)([CH3:33])[CH3:32]
Reactant: Cc1c(Oc2ccc(C3COC(C)(C)OC3)cc2)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Solvent: CC(C)=O
Product: Cc1c(Oc2ccc(C(CO)CO)cc2)ncnc1OC1CCN(c2nc(C(C)C)no2)CC1
Temperature: 27 °C
Reaction time: 2 h
Yield: 8.1 %

Procedure:
To a solution of 5-(4-(6-(4-(2,2-dimethyl-1,3-dioxan-5-yl)phenoxy)-5-methylpyrimidin-4-yloxy)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole (500 mg, 0.0095 moles) in acetone (10 ml) conc. HCl (3 ml) was added portion-wise and reaction mixture was stirred for 2 hours at 27° C. The reaction mixture was concentrated and residue was dissolved in ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield 360 mg product as white solid.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O-]S([O-])(=O)=O.[Mg+2].[C:22]([C:26]1C=C(O)C(=[CH:31][CH:32]=1)O)(C)([CH3:24])[CH3:23].II>CC(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][C:22]([CH3:24])([CH3:23])[CH:26]=[C:32]2[CH3:31])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Agent: II
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC1=CC(C)(C)Nc2ccc(NC(=O)OC(C)(C)C)cc21

Procedure:
A mixture of N-Boc-1,4-phenylenediamine (75 g), MgSO4 (216 g), 4-tert-butylcatechol (1.8 g) and iodine (4.7 g) in anhydrous acetone (600 ml) was refluxed for 20 h. The MgSO4 was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on a short plug of silicagel using heptane/ethyl acetate=8/2 (v/v) as the eluent to give the product as a brown oil.