Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Br.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ccc(Cl)c(CBr)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3cc(Cl)ccc3Cl)c2c1

Procedure:
The titled compound (17 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2,5-dichlorobenzyl bromide according to the method of the process (7) of Example 4.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]23[NH:41][CH2:40][CH2:39][N:24]2[C:25](=[O:38])[C:26]2[N:27]([N:29]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:31]=2)[CH2:28]3)=[CH:19][CH:18]=1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1.O>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]23[N:41]([C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][CH:5]=4)=[O:9])[CH2:40][CH2:39][N:24]2[C:25](=[O:38])[C:26]2[N:27]([N:29]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:31]=2)[CH2:28]3)=[CH:21][CH:22]=1
Reactant: Cc1nocc1C(=O)O
Reactant: O=C1c2cc(-c3ccccn3)nn2CC2(c3ccc(Cl)cc3)NCCN12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3cc(-c4ccccn4)nn3CC12c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
To generate the acid chloride: to a chilled suspension of 3-methylisoxazole-4-carboxylic acid (231 mg, 1.8 mmol) in dry CH2Cl2 (3.0 mL) was added oxalyl chloride (0.31 mL, 3.7 mmol) followed by DMF (1 drop). The suspension was stirred at 0° C. for 5 minutes and then at room temperature for 1 hour. The resulting solution was concentrated in vacuo at ambient temperature to yield an oil, dried by stirring under nitrogen. 10a-(4-chlorophenyl)-7-(pyridin-2-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]pyrazin-5-one (111 mg, 0.3 mmol) in pyridine (3.5 mL) was added to a mixture of the acid chloride (generated as above, 1.8 mmol) in pyridine (2 mL) at 0° C. and stirred at 0° C. to room temperature for 1 hour. LCMS after this time indicated the reaction was complete. The suspension was then diluted with water (15 mL) and extracted with CH2Cl2 (3×10 mL). The extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo to yield a yellow residue. The material was purified by trituration with EtOAc/hexanes (9:1) to give 10a-(4-chlorophenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-(pyridin-2-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]pyrazin-5-one (63) as a beige solid (70 mg, yield 49%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].C[C:16]1[C:24](C)(C)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:27][C:28]([OH:30])=[O:29])[CH:22]=2)[N:17]=1.[Br-:31].[Na+].C(OCC)(=O)C>S1(CCCC1)(=O)=O>[Br-:31].[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][N+:17]1[C:18]2[C:23](=[CH:22][C:21]([CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=2)[CH2:24][CH:16]=1)([O-:3])=[O:2]
Reactant: CC1=Nc2ccc(CC(=O)O)cc2C1(C)C
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Agent: [Br-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc2c(c1)CC=[N+]2Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 54 %

Procedure:
3,5-Dinitrobenzyl chloride (12.46 g, 57.5 mmol) was added to a solution of 2,3,3-trimethyl-3H-indol-5-yl-acetic acid (2.5 g, 11.5 mmol) with sodium bromide (5.92 g, 57.5 mmol) in sulfolan (10 ml). The reaction was heated at 100° C. for 20 hrs, then cooled to room temperature. The crude reaction mixture was added dropwise to an excess of ethyl acetate and the dark brown solid was filtered OFF and dissolved in dimethylsulfoxide before purification by reverse phase chromatography. The product was isolated as beige solid (54% yield). 1H NMR (d6-DMSO): δH: 8.75 (s, 1H), 8.45 (s, 2H), 7.15 (s, 1H), 6.95 (d, 1H), 6.70 (d, 2H), 5.10 (s, 2H), 3.95 (s, 2H), 3.45 (s, 3H), 1.40 (s, 6H). MALDI-TOF, m/z=398 (M+=398 for C20H20N3O6).
Reaction SMILES: Cl.[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH2:12])[CH2:9]2.[CH:13]1([C:18]([CH:20]2C(=O)OC(C)(C)[O:22][C:21]2=O)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[CH:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH:12][C:21](=[O:22])[CH2:20][C:18]([CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19])[CH2:9]2
Reactant: CC1(C)OC(=O)C(C(=O)C2CCCC2)C(=O)O1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(CC(=O)C1CCCC1)NC1C2CC3CC(C2)CC1C3
Temperature: 110 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
2-Adamantanamine hydrochloride (1.641 g, 8.74 mmol) was added to 5-(cyclopentanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate#77), (2.1 g, 8.74 mmol) and N-Ethyldiisopropylamine (1.512 mL, 8.74 mmol) in toluene (30 mL). The resulting suspension was stirred at 110° C. for 2 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with 2M HCl (20 mL), and water (2×50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford N-(2-adamantyl)-3-cyclopentyl-3-oxo-propanamide (1.030 g, 40.7%) as a brown oil which crystallised on standing.
Reaction SMILES: CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.N1C2C(=CC=CC=2)CC1.FC(F)(F)C(O)=O.[N:50]1[N:51]([CH2:58][C:59]([CH3:62])([OH:61])[CH3:60])[CH:52]=[C:53]2[CH2:57][NH:56][CH2:55][C:54]=12.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:71]([N:74]1[C:82]2[C:77](=[N:78][C:79](I)=[C:80]([Cl:83])[CH:81]=2)[N:76]=[C:75]1[O:85][C@@H:86]1[CH2:90][O:89][C@@H:88]2[C@H:91]([O:94][Si:95]([C:98]([CH3:101])([CH3:100])[CH3:99])([CH3:97])[CH3:96])[CH2:92][O:93][C@H:87]12)[CH:72]=[CH2:73]>O1CCOCC1>[Si:95]([O:94][C@H:91]1[C@H:88]2[O:89][CH2:90][C@@H:86]([O:85][C:75]3[N:74]([CH2:71][CH:72]=[CH2:73])[C:82]4[C:77]([N:76]=3)=[N:78][C:79]([N:56]3[CH2:57][C:53]5[C:54](=[N:50][N:51]([CH2:58][C:59]([CH3:62])([OH:61])[CH3:60])[CH:52]=5)[CH2:55]3)=[C:80]([Cl:83])[CH:81]=4)[C@H:87]2[O:93][CH2:92]1)([C:98]([CH3:100])([CH3:101])[CH3:99])([CH3:96])[CH3:97]
Reactant: CC(C)(O)Cn1cc2c(n1)CNC2
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(I)c(Cl)cc21
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(N3Cc4cn(CC(C)(C)O)nc4C3)c(Cl)cc21
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of Ruphos indoline precatalyst (12.6 mg, 0.017 mmol, Strem), 1-(5,6-dihydro-4H-pyrrolo[3,4-c]pyrazol-2-yl)-2-methyl-propan-2-ol 2,2,2-trifluoroacetic acid (102 mg, 0.346 mmol), potassium phosphate tribasic (184 mg, 0.865 mmol) and [(3R,3aR,6R,6aS)-3-(1-allyl-6-chloro-5-iodo-imidazo[4,5-b]pyridin-2-yl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (100 mg, 0.173 mmol) in dioxane (1.0 ml) was degassed (3×) and placed under nitrogen before being heated to 110° C. After 18 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc (30 ml), washed with water (20 ml), brine (10 mL), dried over MgSO4, filtered, and evaporated under reduced pressure to give an oil. The oil was purified on preparative silica plates (1×1000 u developed and eluted with EtOAc) to give the title compound. LC-MS: calculated for C30H43ClN6O5Si 630.28 observed m/e: 631.27 (M+H)+ (Rt 1.36/2 min)
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: C#CC(O)CC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (28.5 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 3 supra) using (Ph3P)2PdCl2 (9.5 mg) and CuI (2.6 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give rac-(Z)-1,3-dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 17 mg, 39%).
Reaction SMILES: [H-].[Na+].[O:3]1[C:8]2[CH:9]=[CH:10][C:11](CC3C=C([C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@@H](COC(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)O4)C=CC=3CC)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.C(Br)C1C=CC=CC=1>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: CCc1ccc([C@@H]2O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Agent: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 2.2 g, 54.64 mmol) in DMF (40 ml), was added a solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol (8.0 g, 12.14 mmol) in DMF (10 ml) at 0° C. After stirring for 4 h at room temperature, reaction mixture was cooled to 0° C. and added TBAI (0.45 g, 1.21 mmol) followed by benzyl bromide (5.1 ml, 42.50 mmol). Then it was allowed to attain room temperature and stirred for overnight. Reaction mixture was poured into ice cold water and extracted with ethyl acetate (2×80 ml). Combined organic layers were washed with water (100 ml), brine (100 ml), dried over sodium sulfate, concentrated and purified by silica gel column chromatography to give 8.5 g of 6-[2-ethyl-5-(2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-trityloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-2,3-dihydro-benzo[1,4]dioxine as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=3)[N:23]=[CH:22][N:21]=2)=[N:15]1>CN(C)C=O>[CH3:13][N:14]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][C:2]4[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=4)[CH:28]=3)[N:23]=[CH:22][N:21]=2)=[N:15]1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc([N+](=O)[O-])nc4)cc23)n1
Temperature: 60 °C
Reaction time: 14 h
Yield: 76 %

Procedure:
5-Bromo-2-nitropyridine (460 mg, 2.3 mmol) and sodium hydride (120 mg, 3.1 mmol) were added to an N,N-dimethylformamide suspension (10 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (500 mg, 2.1 mmol), and stirred at 60° C. for 14 hours. The reaction solution was cooled to room temperature, the precipitate was collected by filtration, washed with water. The obtained precipitate was dried, then purified by silica gel column chromatography (chloroform:methanol=96:4) to obtain N-(1-methyl-1H-pyrazol-3-yl)-6-[(6-nitropyridin-3-yl)oxy]quinazoline-4-amine (580 mg, yield: 77%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]3[C:22]([C:23]([CH3:29])([CH3:28])[C:24]([F:27])([F:26])[F:25])=[CH:21][N:20]=[C:13]3[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.Cl.Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]2=[O:47])[CH2:34][CH2:33]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]3[C:22]([C:23]([CH3:28])([CH3:29])[C:24]([F:25])([F:27])[F:26])=[CH:21][N:20]=[C:13]3[C@H:14]([CH2:16][C:17]([N:32]3[CH2:33][CH2:34][CH:35]([N:38]4[C:46]5[C:41](=[N:42][CH:43]=[CH:44][CH:45]=5)[NH:40][C:39]4=[O:47])[CH2:36][CH2:37]3)=[O:18])[CH2:15][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: CC(C)(c1cnc2n1Cc1c(cc(Cl)c3[nH]ncc13)C[C@H]2CC(=O)O)C(F)(F)F
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(c1cnc2n1Cc1c(cc(Cl)c3[nH]ncc13)C[C@H]2CC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [(7S)-4-chloro-10-(2,2,2-trifluoro-1,1-dimethylethyl)-3,6,7,12-tetrahydroimidazo[1′,2′:1,7]azepino[3,4-e]indazol-7-yl]acetic acid (100 mg, 0.275 mmol), 1-Piperidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride [Bergey et al. WO 2006/044504], HOBT (43 mg, 0.28 mmol), EDC (54 mg, 0.28 mmol) and N,N-diisopropylethylamine (48 uL, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:34])[CH:6]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[CH:21]=[CH:20][N:19]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]1=[O:33])[NH:7]C(OC(C)(C)C)=O)[CH:2]=[CH2:3].C(OC(=O)C(CCN1C(=O)C2=CC=CC=C2C1=O)NC(OC(C)(C)C)=O)C=C.[CH3:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([S:71](Cl)(=[O:73])=[O:72])=[CH:67][CH:66]=1>>[CH2:1]([O:4][C:5](=[O:34])[CH:6]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[CH:21]=[CH:20][N:19]([CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:18]1=[O:33])[NH:7][S:71]([C:68]1[CH:67]=[CH:66][C:65]([O:64][CH3:63])=[CH:70][CH:69]=1)(=[O:73])=[O:72])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(CCn1c(=O)ccn(COCc2ccccc2)c1=O)NC(=O)OC(C)(C)C
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Product: C=CCOC(=O)C(CCn1c(=O)ccn(COCc2ccccc2)c1=O)NS(=O)(=O)c1ccc(OC)cc1
Yield: 93 %

Procedure:
In a similar manner to the procedures described in Example 1(2)-a and b, reactions were carried out using (±)-2-[2-(1-benzyloxymethylpyrimidin-2,4-dione-3-yl)ethyl]-N-(tert-butoxycarbonyl)glycine allyl ester, the product of (1) above, instead of (±)-N-(tert-butoxycarbonyl)-2-(2-phthalimidoethyl)glycine allyl ester and using 4-methoxybenzenesulfonyl chloride instead of 4-phenoxybenzenesulfonyl chloride to afford the desired compound (yield 93%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[CH:6]2[O:11][CH3:12].[CH3:14][O:15][CH:16]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:25])[C:19]=2[CH2:18][CH:17]1[CH3:26].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1N(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C1(C)C=CC=CC=1>[CH3:12][O:11][CH:6]1[C:7]2[C:3](=[C:2]([O:25][C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:19]=3[CH2:18][CH:17]([CH3:26])[CH:16]4[O:15][CH3:14])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH:5]1[CH3:13]
Reactant: COC1c2cccc(Br)c2CC1C
Reactant: COC1c2cccc(O)c2CC1C
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC1c2cccc(Oc3cccc4c3CC(C)C4OC)c2CC1C
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To a mixture of 14.6 g (60.5 mmol) of 4-bromo-1-methoxy-2-methylindane, 10.8 g (60.5 mmol) of 1-methoxy-2-methyl-4-indanol, 38.5 g (181 mmol) K3PO4, and 200 ml of toluene, a mixture of 696 mg (1.21 mmol) Pd(dba)2 and 825 mg (2.42 mmol) of 2-di(tert-butyl)phosphino-2′-(N,N-dimethylamino)biphenyl was added under an argon atmosphere. This mixture was stirred for 14 hours at 100° C. Then, 300 ml of water was added. The organic layer was separated, and the aqueous layer was extracted with 3×100 ml of CH2Cl2. The combined extract was washed with 2×100 ml of water, dried over K2CO3, and evaporated to dryness. The analytically pure product was obtained using flash chromatography on Silica Gel 60 (40-63 μm, d 50 mm, 1 400 mm, eluant:hexanes-dichloromethane=1:1, vol.). Yield 12.4 g (61%). On the evidence of NMR spectra, the product consists of a mixture of isomers.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][N:3]=[N:2]1.[CH3:15][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>ClCCl.CO.CCCCCC>[CH3:15][N:3]1[N:2]=[N:1][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:4]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCc1nnn[nH]1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: Cn1nnc(CNC(=O)OC(C)(C)C)n1

Procedure:
To a stirred solution of Intermediate 36 (1.0 g) in dichloromethane (35 ml) and methanol (10 ml) at 22° C. under nitrogen was added dropwise 10% trimethylsilyldiazomethane in hexane (12.0 ml). The mixture was stirred for 2 h at 22° C. before acetic acid (2 ml) was added dropwise and the solvents were evaporated in vacuo. The crude residue was purified by Biotage flash column chromatography on silica gel (90 g cartridge), eluting with 10% cyclohexane in ether. The fractions for the first eluting isomer were combined and the solvents evaporated in vacuo to give the title compound as pale yellow crystals (0.487 g).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1([OH:22])[CH2:10][CH2:9][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].[CH3:29]I>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][C:5]1([O:22][CH3:29])[CH2:6][CH2:7][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CI
Reactant: CCOC(=O)c1ccc(N2CCC(O)(Cc3ccccc3F)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(Cc3ccccc3F)(OC)CC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 1C (17.89 g, 50.1 mmol) in THF (150 mL) and HMPA (33 mL) was treated with NaH (4.0 g of a 60% dispersion, 100 mmol) at 0° C., stirred for 30 minutes, treated with CH3I (20 mL, 321 mmol), and stirred overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4Cl. The organic layer was washed with water (2×), dried (MgSO4), and filtered. Filtration of the concentrate provided the desired product which was used without further purification. MS (ESI) m/e 372 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[N:13]1([C:9]2[CH2:8][CH2:7][C:6]3[C:11]([CH:10]=2)=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNC1
Reactant: O=C1CCc2cccc(Br)c2C1
Product: C1=C(N2CCCC2)CCc2ccccc21

Procedure:
When R2 in the compounds of Formula I is methyl, the methyl-substituted 8-bromo-2-tetralone can be prepared from the corresponding unsubstituted 8-bromo-2-tetralone. The 8-bromo-2-tetralone first is treated with pyrrolidine to produce the corresponding 1,2-dihydro-3-pyrrolidinyl-naphthalene. The latter, upon treatment with methyl iodide and acid hydrolysis, gives the desired 8-bromo-1-methyl-2-tetralone.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[CH:12]/[N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:10][C:5]=2[CH2:4][O:3]1.[CH2:26](Cl)Cl>CC([O-])=O.CC([O-])=O.[Pd+2]>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]3[CH2:26][CH:12]3[N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(/C=C/c2ccc3c(c2)COC3=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCN(C2CC2c2ccc3c(c2)COC3=O)CC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4-[(E)-2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethenyl]piperazine-1-carboxylate (1.1 g, 3 mmol) in 30 mL of DCM was added Pd(OAc)2 (100 mg) and was cooled by ice/water. 50 mL of newly prepared CH2N2 solution was added dropwise. The reaction was warmed to room temperature and stirred over night. The solid was filtered off, and the filtrate was evaporated at reduced pressure to get crude product, which was purified via prep-HPLC to afford tert-butyl 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)cyclopropyl]piperazine-1-carboxylate.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl-].[Na+].O>[CH:22]1(/[CH:21]=[C:20](/[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)\[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.6 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (200 mg, 0.38 mmol) and tetrabutylammonium fluoride in tetrahydrofuran (1 M, 7.6 mL, 7.6 mmol) was stirred for 12 h at room temperature. The mixture was poured into brine (15 mL), extracted with ethyl acetate (2×50 mL), washed with a saturated aqueous ammonium chloride solution (3×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give 2-[(E)-2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (147 mg, 100%) as a solid which was used in the next step without purification: LC/MS m/e calcd for C21H21FN2O2S [M+H]+ 385.48, observed 385.2; 1H NMR (400 MHz, MeOD) δ ppm 8.04 (d, J=8.3 Hz, 3H), 7.51-7.56 (m, 3H), 6.45 (d, J=10.1 Hz, 1H), 5.77 (s, 1H), 3.32 (br. s., 1H), 3.16-3.20 (m, 3H), 2.37-2.44 (m, 1H), 1.72-1.82 (m, 4H), 1.45-1.57 (m, 4H).