Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[N:9]=1.CC1C=CC(S(O[CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=O)=O)=CC=1.O>CCCCCC.O1CCCC1>[CH:36]1([CH2:35][CH:15]([C:10]2[N:9]=[C:8]([O:7][CH3:6])[C:13]([CH3:14])=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][C:19]([S:22][CH3:23])=[CH:20][CH:21]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reactant: COc1nc(Cc2ccc(SC)cc2)ccc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1nc(C(CC2CCCC2)c2ccc(SC)cc2)ccc1C
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.46 M n-butyllithium in hexane (1.11 mL) was added to a solution of 2-methoxy-3-methyl-6-[4-(methylsulfanyl)benzyl]pyridine obtained in Reference Example 2-1 (400 mg) in tetrahydrofuran (5 mL) in the presence of an argon gas at −78° C., and the mixture was stirred at −35° C. for 30 minutes. The reaction solution was cooled again to −78° C. and a solution of cyclopentylmethyl 4-methylbenzenesulfonate (549 mg) in tetrahydrofuran (3 mL) was added, after which the mixture was stirred at −78° C. to 0° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=19:1) to give 6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethyl}-2-methoxy-3-methylpyridine as a colorless amorphous (220 mg, 42%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)[CH:10]=[C:9]1[C:27]1[C:28]2[S:41][C:40]([CH2:42][OH:43])=[CH:39][C:29]=2[N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)[CH:10]=[C:9]1[C:27]1[C:28]2[S:41][C:40]([CH2:42][O:43][S:52]([CH3:51])(=[O:54])=[O:53])=[CH:39][C:29]=2[N:30]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[N:31]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCN4CCCCC4)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCN4CCCCC4)cc3n2C(=O)OC(C)(C)C)c2sc(COS(C)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-indole-1-carboxylic acid tert-butyl ester [1.21 g, 1.98 mmol, Intermediate (78)] in dichloromethane (25 mL) at 0° C. was added triethylamine (0.29 mL, 2.28 mmol) and methane sulfonyl chloride (0.34 mL, 4.40 mmol). The mixture was stirred at 0° C. for 30 minutes then at room temperature for 4 hours. It was diluted with dichloromethane then washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed through silica gel (dichloromethane/methanol, 90/10 as eluant) to produce 2-(1-tert-butoxycarbonyl-5-methanesulfonyloxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-indole-1-carboxylic acid tert-butyl ester [0.85 g, 62%, Intermediate (79)] as a yellow foam. LC/MS: 689.3 (M+H), RT=2.58 minutes.
Reaction SMILES: C(O[C:4](OCC)([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])C.[Br:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:24]=1[NH2:25].C(O)(=O)C>>[Br:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:24]=1[N:25]=[C:4]([CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCC(CCC(=O)OCC)(OCC)OCC
Reactant: Nc1c(F)cccc1Br
Solvent: CC(=O)O
Product: CCOC(=O)CCC(CCC(=O)OCC)=Nc1c(F)cccc1Br
Temperature: 145 °C

Procedure:
To the ketal of Step 1 (8.46 kg, 24.31 mol), were charged 2-bromo-6-fluoroaniline (2.509 L, 22.10 mol) and acetic acid (0.253 L, 4.42 mol) under nitrogen. The mixture was heated to 145° C. and ethanol was removed by distillation. The product was used in the next reaction.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)[C@H:3]([OH:27])[CH2:4][N:5]([CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22][C:23]#[N:24])[S:6]([C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1)(=[O:8])=[O:7].[O:43]1[CH2:47][CH2:46][C@H:45]([O:48][C:49](ON2C(=O)CCC2=O)=[O:50])[CH2:44]1.C(NC(C)C)(C)C.C(#N)C>>[O:13]1[C:12]2[CH:16]=[CH:17][C:9]([S:6]([N:5]([CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:4][C@@H:3]([OH:27])[C@@H:2]([NH:1][C:49](=[O:50])[O:48][C@H:45]3[CH2:46][CH2:47][O:43][CH2:44]3)[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:34]=3)(=[O:8])=[O:7])=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: CC(C)(CCCC#N)CN(C[C@@H](O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: CC(C)(CCCC#N)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@H]1CCOC1)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
N-{(2R,3S)-3-Amino-4-[4-(benzyloxy)phenyl]-2-hydroxybutyl}-N-(5-cyano-2,2-dimethylpentyl)-1,3-benzodioxole-5-sulfonamide was treated with 1-({[(3S)-tetrahydro-3-furanyloxy]carbonyl}oxy)-2,5-pyrrolidinedione/diisopropylamine/acetonitrile as previously described to provide the title product as a solid foam. 1H NMR (DMSO-d6): δ 0.88 (3H, s), 0.90 (3H, s), 1.3 (2H, dd), 1.5-1.6 (2H, m), 1.7-1.8 (1H, m), 2.0-2.2 (1H, m), 2.37 (1H, t), 2.4 (2H, t), 2.75-2.85 (3H, m), 2.9 (1H, dd), 3.30-3.45 (3H, m), 3.55 (1H, dd), 3.65 (1H, dd), 3.7 (2H, dd), 4.9 (1H, s), 4.98 (1H, d), 5.0 (2H, s), 6.15 (2H, s), 6.8 (2H, d), 7.0 (2H, d), 7.06 (2H, d), 7.24 (1H, s), 7.25-7.42 (6H, m); MS: 708 (MH+);
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:26]([F:27])=[CH:25][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:19][CH2:18][CH:17]([C:20]([O:22]CC)=[O:21])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:28])=[CH:3][CH:2]=1.O([Si](C)(C)C)[K]>C1COCC1.CCOC(C)=O>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:26]([F:27])=[CH:25][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:28])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)C1
Agent: C[Si](C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 3-{[5-(biphenyl-4-yl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclopentanecarboxylate (0.039 g, 0.084 mmol) was dissolved in 1 mL of THF and treated with KOTMS (0.032 g, 0.253 mmol). The reaction mixture was stirred overnight at ambient temperature, and then diluted with EtOAc and washed with 2 N HCl. The layers were separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound as a white solid. LCMS: calculated for C25H20F2N2O3 434.43, observed m/e 434.9 (M+H)+ (Rt 2.24/4 min). 1H NMR (500 MHz, d6-DMSO): δ7.77 (d, 2H), 7.73 (d, 2H), 7.56-7.46 (m, 4H), 7.39 (m, 111), 7.14 (d, 1H), 5.50 (m, 1H), 2.95 (m, 1H), 2.20-1.80 (m, 6H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:15]O>S(=O)(=O)(O)O.CCOC(C)=O>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([O:10][CH3:15])=[O:9])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Yield: 95 %

Procedure:
3-(Aminosulfonyl)-4-chlorobenzoic acid (943 mg, 4.0 mmol) was heated at 70° C. in CH3OH (10 mL) with 3 drops of concentrated sulfuric acid for 34 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water, brine, and dried (Na2SO4). The solvent was evaporated to afford the product (950 mg, 95%) as a white solid. MS (ES+) m/z 250 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](OC)=[O:4].C(N(CC)CC)C.[NH2:16][CH2:17][C:18]([OH:20])=[O:19].Cl>CO.C(OCC)(=O)C>[F:8][C:2]([F:1])([F:7])[C:3]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:4]
Reactant: NCC(=O)O
Reactant: COC(=O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)CNC(=O)C(F)(F)F
Reaction time: 18 h
Yield: 86.9 %

Procedure:
Methyl trifluoroacetate (804 μL, 7.99 mmoles) and triethylamine (928 μL, 6.66 mmoles) were added to a suspension of glycine (500 mg, 6.66 mmoles) in methanol (2.5 mL). After the mixture was stirred vigorously for 18 h, 1 N HCl was added dropwise until the a pH of 2 was obtained. The reaction was added to ethyl acetate (30 mL) was washed with 1 N HCl (2×10 mL), dried over MgSO4, and concentrated in vacuo to yield the amide as a white solid (991 mg, 5.79 mmoles, 87%). LRMS: (CI+) calcd for C4H4NO3F3 (M+NH4): 189. found: 189. 1H NMR: spectrum is consistent with the predicted structure.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[CH2:9][CH2:8]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](COS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)[C@H]1CC[C@@H](CN=[N+]=[N-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of crude butyl cis-4-{[(methylsulfonyl)oxy]methyl}-cyclohexane carboxylate (35.3 g, 117 mmol) in dimethylformamide (146 ml) was added sodium azide (30.4 g, 468 mmol, 4 equiv.). The mixture was stirred under nitrogen at 80° C. for eight hours. Approximately one-half of the dimethylformamide was distilled off (80° C. oil bath, 3.5 mm). The residue was diluted with water (750 ml) and extracted with ether (3×250 ml). The combined extract was washed with water (2×100 ml) and brine (100 ml), dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure to give crude butyl cis-4-(azidomethyl)cyclohexanecarboxylate (26.80 g, 98%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[CH2:12][C:13]3[C:18]([C:3]1=2)=[CH:17][CH:16]=[CH:15][C:14]=3[Li].[Cl-:20].[Cl-].[Cl-].[Cl-].[Zr+4:24]>C(OCC)C>[Cl-:20].[Cl-:20].[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([CH3:11])=[CH:6][C:5]=2[C:4]2[CH2:12][C:13]3[C:18]([C:3]1=2)=[CH:17][CH:16]=[CH:15][C:14]=3[Zr+2:24][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH2:12][C:4]1[C:5]3[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][C:10]=3[N:2]([CH3:1])[C:3]=12
Reactant: [Li]c1cccc2c1Cc1c-2n(C)c2ccc(C)cc12
Reactant: [Zr+4]
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1ccc2c(c1)c1c(n2C)-c2cccc([Zr+2]c3cccc4c3Cc3c-4n(C)c4ccc(C)cc34)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under the nitrogen protection, 0.24 gram (0.001 mole) of 5,8-dimethyl-5,10-dihydroindeno[1,2-b]indolyllithium is dissolved in 20 mL of diethylether. The solution is slowly added to zirconium tetrachloride (0.12 gram, 0.0005 mole) slurry in 20 mL of diethylether. The mixture is stirred at 25° C. for two hours, filtered, washed with diethylether and dried under vacuum, yielding 0.23 gram of Catalyst III.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]1[C:26](=[O:27])[CH:25]=[C:24]([CH3:28])[O:23][C:22]=1[C:29]([OH:31])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C=O>[CH:32]1([NH:38][C:29]([C:22]2[O:23][C:24]([CH3:28])=[CH:25][C:26](=[O:27])[C:21]=2[O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:31])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCCCC1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCCCC2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
1,1′-carbonyldiimidazole (1.99 g, 12.30 mmol) was added to a solution of the 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (2.0 g, 7.69 mmol) in dimethylformamide (DMF, 18 ml) at room temperature. The resulting solution was heated at 40°-50° C. for 3 hrs. A light yellow solution was observed. Cyclohexylamine (1.23 ml, 10.76 mmol) was then added. The resulting mixture was stirred at room temperature for overnight. The DMF was removed under reduced pressure to give light yellow oil as a crude product, which was purified by flash column chromatography (elution gradient: from 1:1 ethyl acetate/hexane to 10% methanol in ethyl acetate) to yield the titled compound (1.60 g, yield 61%) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:11]N1C(=O)CCC1=O>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(Cl)Cl
Product: Brc1cnc2[nH]cc(I)c2c1
Temperature: 95 °C
Reaction time: 8 h
Yield: 320.9 %

Procedure:
A mixture of 5-Bromo-1H-pyrrolo[2,3-b]pyridine (50 g, 252.5 mmol) and N-iodosuccinimide (13.6 g, 60.6 mmol) in dichloroethane (200 ml) was stirred at 95° C. overnight. The reaction was allowed to cool to room temperature and saturated Na2H2SO4 (200 ml) was added. The mixture was then extracted with ethyl acetate (400 ml×2). The combined organic layers were dried with Na2SO4, concentrated. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (62.8 g, 77% yield).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([C@H:13]3[CH2:15][C@H:14]3[C:16](O)=[O:17])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:22][NH2:23]>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]3[CH:13]4[CH:14]([C:16](=[O:17])[NH:22][N:23]=3)[CH2:15]4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)[C@H]1C[C@H]1C(=O)O
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1NN=C(c2ccc(C3CCCCC3)cc2)C2CC12
Yield: 92.5 %

Procedure:
8.0 g (29.4 millimoles) of cis-2-(p-cyclohexylbenzoyl)-cyclopropanecarboxylic acid, 1.6 g (32.0 millimoles) of hydrazine hydrate and 100 ml of ethanol are refluxed for 8 hours. The product is filtered off at 0° C. and dried under reduced pressure at 50° C. 7.3 g (93% of theory) of 2-(p-cyclohexylphenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as almost colorless crystals, of melting point 211°-212° C. after recrystallization from isopropanol.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].Cl[C:15]1[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[C:32]([O:31][C:29]([N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][O:21][C:18]2[CH:19]=[N:20][C:15]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([C:3](=[O:4])[NH:2][CH3:1])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:16][CH:17]=2)[CH2:24][CH2:25]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Reactant: CNC(=O)c1ccc2[nH]ccc2c1
Product: CNC(=O)c1ccc2c(ccn2-c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using N-methyl-1H-indole-5-carboxamide (intermediate-14) and tert-butyl 4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (intermediate-29).
Reaction SMILES: [CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[N:4]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[N:4]=1
Reactant: [H][H]
Reactant: COc1nn(-c2ccc([N+](=O)[O-])cc2)c(=O)o1
Agent: [Pd]
Solvent: CO
Product: COc1nn(-c2ccc(N)cc2)c(=O)o1

Procedure:
A mixture consisting of 1.4 g of 5-methoxy-3-(4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one, 0.5 g of Pd/C and 20ml of methanol was hydrogenated under atmospheric pressure at room temperature until the calculated amount of hydrogen had been taken up. The catalyst was then filtered off, and the solution was concentrated in vacuo. The remaining semisolid residue was stirred with isopropanol and filtered off with suction.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[Li].N.[CH2:12](Br)[CH:13]=[CH2:14]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([CH2:14][CH:13]=[CH2:12])[CH2:3]1
Reactant: C=CCBr
Reactant: CC1(C)C=CC(=O)CC1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC1CC(C)(C)CCC1=O
Temperature: -33 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
A solution of 4,4-dimethyl-2-cyclohexen-1-one (500 mg) in dry tetrahydrofuran (2 ml) was added to a well stirred solution of lithium (141 mg) in liquid ammonia (5 ml). The mixture was stirred at -33° C. for 1 hr. And then, to this solution allyl bromide (2.4 g) was added, and stirred for 30 min. The reaction was quenched by addition of methanol, and the ammonia was allowed to evaporate. The residue was diluted with water, and extracted with diethyl ether. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue with silica gel column chromatography (using n-hexane:ethyl acetate=30:1 as an eluent) gave 4,4-dimethyl-2-(2-propenyl)cyclohexanone (345 mg, 52% yield) as a colorless oil. (b) To a solution of lithium tri-tert-butoxyaluminohydride (460 mg) in dry tetrahydrofuran (3.5 ml) there was added a solution of 4,4-dimethyl-2-(2-propenyl)cyclohexanone (250 mg) at 0° C., and the mixture was stirred at room temperature for 2 hrs. The reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by silica gel column chromatography (using n-hexane: ethyl acetate=20:1 as an eluent) gave (1R*,2R*)-4,4-dimethyl-2-(2-propenyl)cyclohexanol (185 mg, 73% yield) as a colorless oil; EI-MS: m/z 168 (M+); 1H-NMR (CDCl3)d: 0.90 (3H,s), 0.93 (3H, s), 1.2~1.8 (7H,m), 1.95 (1H,m), 2.46 (1H,m), 3.23 (1H,dt,J=5 & 11 Hz), 5.02 (1H,br.d,J=10 Hz), 5.06 (1H,br.d,J=17 Hz), 5.85 (1H,m).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26](O)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]3[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]3)[CH:40]=2)[CH:36]=[CH:37][CH:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:29][CH3:30])=[C:10]([CH2:19][NH:20][C:21]([C:23]3([C:26]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH:46]6[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C1(C(=O)NCc2cccc(-c3cccc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropanecarboxylic acid (100 mg, 0.241 mmol), 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperidinecarboxylate (70.9 mg, 0.241 mmol), HBTU (110 mg, 0.289 mmol) and Et3N (0.101 mL, 0.722 mmol) in DCM (3 mL) was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give the crude residue. It was then purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were dried under GeneVac and then combined to give the intermediate 1,1-dimethylethyl 4-[(3′-{[({1-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]cyclopropyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperidinecarboxylate. It was then dissolved in 2 mL of 25% TFA in DCM and stirred at room temperature for 3 h. The crude products were purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and washed with 1 N NaOH and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-{[3′-(4-piperidinylmethyl)-3-biphenylyl]methyl}-1,1-cyclopropanedicarboxamide as a solid (32 mg, 19.6%). LC-MS m/z 678 (M+H)+, 0.79 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[CH:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][CH:18]([F:27])[O:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.CCN(CC)CC.C(#N)C>CCOC(C)=O.[Cu]I.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>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH:18]([F:27])[F:17])=[CH:21][CH:22]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 60 °C
Yield: 99.9 %

Procedure:
A mixture of (3-ethynyl-phenyl)-carbamic acid tert-butyl ester (14.7 g, 67.7 mmol), 1-difluoromethoxy-4-iodo-benzene (18.2 g, 67.7 mmol), NEt3 (47 mL, 338 mmol), acetonitrile (225 mL), CuI (1.29 g, 6.77 mmol), and Pd(PPh3)2Cl2 (2.85 g, 4.05 mmol) was heated to 60° C. for 1 h. The reaction was diluted with EtOAc/Hex (1:10) and then passed through a pad of silica gel and concentrated and purified with chromatography using hexanes/ethyl acetate (10:1) as the eluting solvents gave the title compound (24.3 g, 100%), characterized by NMR and mass spectral analyses.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][C:9](Cl)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=[O:15])C>>[N:1]1([C:6]2[CH:7]=[CH:8][C:9](=[O:15])[NH:10][N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1ccc(-n2ccnc2)nn1
Reactant: CC(=O)O
Product: O=c1ccc(-n2ccnc2)n[nH]1
Yield: 55 %

Procedure:
9.93 g (0.055 mole) of 6-(1-imidazolyl)-3-chloropyridazine [prepared according to J. Med. Chem. 24, 59 (1981)] are boiled with 7.7 g (0.0781 mole) of fused potassium acetate in 114 ml of acetic acid under reflux for 10 hours and then evaporated to dryness under reduced pressure. The residue is taken up in 200 ml of chloroform, the precipitate is filtered off, washed 4 times with water, then with ether and diisopropyl ether and dried to give 4.9 g (55% yield) of the aimed product, m. p. 239°-240° C.