Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21][N:22]=[N+]=[N-])[CH:18]=[CH:17][N:16]4[C:25]=3[CH3:26])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H][H]>[Pd].CO>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([CH2:21][NH2:22])[CH:18]=[CH:17][N:16]4[C:25]=3[CH3:26])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: [H][H]
Reactant: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CN=[N+]=[N-])ccn12
Agent: [Pd]
Solvent: CO
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(CN)ccn12
Yield: 44.3 %

Procedure:
10% Palladium on carbon (0.3 g) was added to a solution of 2-amino-6-[2-(7-azidomethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (1.0 g) in methanol (100 ml) and the mixture was subjected to catalytic reduction at ambient temperature under atmospheric pressure of hydrogen gas. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by alumina column chromatography eluting with a solution of chloroform and methanol (4:1, V/V). The fractions containing object compound was evaporated to give 2-amino-6-[2-(7-aminomethyl-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.41 g).
Reaction SMILES: O.[NH:2]1[C:10](=[O:11])[C:8](=[O:9])[C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.Cl>C(O)C>[OH:9][C:8]1([C:14]2[N:13]([CH3:12])[CH:17]=[CH:16][CH:15]=2)[C:6](=[O:7])[NH:5][C:3](=[O:4])[NH:2][C:10]1=[O:11]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Cn1cccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cn1cccc1C1(O)C(=O)NC(=O)NC1=O
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Alloxan hydrate (3.2 g., 0.02 mole) was dissolved in 50 ml. of ethanol by warming. 1-Methylpyrrole (1.6 g., 0.02 mole) was added and the mixture warmed for 5 minutes on a steam bath, while perfusing with hydrogen chloride. After standing at room temperature for 0.5 hour, the reaction mixture was evaporated to dryness and the residue triturated with water to yield title product as a solid [2.9 g.; m/e 223; Rf 0.5 (1:1 ethyl acetate:hexane/5% acetic acid)].
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)C.C(OC(=O)C1C=CC(NC2N=C(C3C=NC=CC=3)C=CN=2)=CC=1)C>>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:24])=[O:3])=[CH:10][CH:9]=2)[N:17]=1
Reactant: CCOC(=O)c1ccc(Nc2nccc(Nc3nccs3)n2)cc1
Agent: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: O=C(O)c1ccc(Nc2nccc(Nc3nccs3)n2)cc1

Procedure:
4-[4-(thiazol-2-ylamino)-pyrimidin-2-ylamino]-benzoic acid ethyl ester prepared in Preparation 16 was used instead of 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester according to the similar procedure to Preparation 19 to give the titled compound as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]>>[F:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[F:1])[CH:9]=2)=[O:27])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C=Nc1ccc(F)c(F)c1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1c(F)cnn1C
Yield: 63 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3,4-difluorophenylisocyanate, in a similar manner as described in Example 1.69, providing 27 mg (63% yield) of Compound 32: LCMS m/z (%)=377 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.28 (s, 1H), 8.12 (s, 1H), 7.74 (ddd, J1=13.5 Hz, J2=7.3 Hz, J3=2.5 Hz, 1H), 7.63 (ddd, J1=8.8 Hz, J2=2.8 Hz, 1H), 7.47 (d, J=2.8 Hz, 1H), 7.38 (d, JH,F=4.4 Hz, 1H), 7.16 (m, 3H), 3.84 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −138.89 (m, 1F), −148.38 (m, 1F), −177.40 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].Br[C:27]1[C:28]([CH3:42])=[C:29]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:30]=[CH:31][CH:32]=1.[CH3:43][C:44]([Si:47]([CH3:60])([CH3:59])[O:48][CH2:49][C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][CH:55]=1)([CH3:46])[CH3:45]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:46][C:44]([Si:47]([CH3:60])([CH3:59])[O:48][CH2:49][C:50]1[CH:51]=[C:52]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:28]=2[CH3:42])[CH:53]=[CH:54][CH:55]=1)([CH3:43])[CH3:45]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(B(O)O)c1
Reactant: Cc1c(Br)cccc1CNC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(CNC(=O)OC(C)(C)C)cccc1-c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
Pd(OAc)2 (25.8 mg, 0.115 mmol), PPh3 (120.6 mg, 0.46 mmol), K2CO3 (794.0 mg, 5.75 mmol) and 1,1-dimethylethyl [(3-bromo-2-methylphenyl)methyl]carbamate (1.15 g, 3.85 mmol) were suspended in anhydrous 1,4-dioxane (20 mL) under nitrogen. After the mixture was heated to 60° C. for 30 min, [3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]boronic acid (2.04 g, 4.62 mmol) was added. Then the mixture was stirred overnight at 100° C. After cooled to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (20 mL), and then the solution was washed with water (7 mL), brine (7 mL), and, dried over anhydrous Na2SO4. After silica column chromatography, eluted with PE:EA=30:1, 1.1 g of the product was obtained, as a colorless liquid. (Yield: 65%). 1H NMR (400 MHz, CDCl3): 0.10 (s, 6 H), 0.94 (s, 9 H), 1.47 (s, 9 H), 2.19 (s, 3 H), 4.38 (d, J=5.2 Hz, 2 H), 4.76 (br, 1 H), 4.78 (s, 2 H), 7.14-7.39 (m, 7 H). 13C NMR (100 MHz, CDCl3): δ −5.2, 16.1, 18.4, 25.9, 28.4, 43.4, 64.9, 79.4, 124.6, 125.6, 127.0, 127.9, 129.3, 133.7, 136.9, 141.2, 141.9, 143.0, 155.7; HPLC: retention time: 4.987 min; purity: 98.9% (HPLC).
Reaction SMILES: [Si](O[C@@H]1[C@@H](CO[Si](C(C)(C)C)(C)C)O[C@@H](N2C3N=CN=C(OC4C=CC([N+]([O-])=O)=CC=4)C=3N=C2)C1)(C(C)(C)C)(C)C.N1(O[C:52]2[C:53]3[N:54]=[CH:55][N:56]([C:87]=3[N:88]=[CH:89][N:90]=2)[C@@H:57]2[O:86][C@H:76]([CH2:77][O:78][Si:79]([C:82]([CH3:85])([CH3:84])[CH3:83])([CH3:81])[CH3:80])[C@@H:67]([O:68][Si:69]([C:72]([CH3:75])([CH3:74])[CH3:73])([CH3:71])[CH3:70])[C@H:58]2[O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].[OH:97][C:98]1[CH:99]=[CH:100][CH:101]=[C:102]2[C:107]=1[N:106]=[CH:105][CH:104]=[CH:103]2>COCCOC>[N:106]1[C:107]2[C:102](=[CH:101][CH:100]=[CH:99][C:98]=2[O:97][C:52]2[C:53]3[N:54]=[CH:55][N:56]([C:87]=3[N:88]=[CH:89][N:90]=2)[C@@H:57]2[O:86][C@H:76]([CH2:77][O:78][Si:79]([C:82]([CH3:85])([CH3:84])[CH3:83])([CH3:81])[CH3:80])[C@@H:67]([O:68][Si:69]([C:72]([CH3:73])([CH3:74])[CH3:75])([CH3:70])[CH3:71])[C@H:58]2[O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:61])[CH3:62])[CH:103]=[CH:104][CH:105]=1
Reactant: Oc1cccc2cccnc12
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccc([N+](=O)[O-])cc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4cccc5cccnc45)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 72.4 %

Procedure:
As described for the synthesis of 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-(4-nitrophenyl)-2′-deoxyinosine, this quinolinyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)inosine (27) (71.8 mg, 0.099 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and 8-hydroxyquinoline (16.0 mg, 0.110 mmol) in dry DME (1.0 mL) at 85° C. for 1 h. Chromatographic purification (SiO2, elution with 50% EtOAc in hexanes) afforded 52.9 mg (72% yield) of the title compound as a white foam. Rf (50% EtOAc in hexanes)=0.58. 1H NMR (500 MHz, CDCl3): δ 8.74 (m, 1H, Ar—H), 8.48 (s, 1H, Ar—H), 8.33 (s, 1H, Ar—H), 8.20 (m, 1H, Ar—H), 7.79 (d, 1H, Ar—H, J=8.3), 7.67-7.60 (m, 2H, Ar—H), 7.39 (dd, 1H, Ar—H, J=8.5, 4.2), 6.13 (d, 1H, H-1′, J=4.4), 4.63 (t, 1H, H-2′, J=4.4), 4.37 (t, 1H, H-3′, J=4.1), 4.17 (m, 1H, H-4′), 4.07 (dd, 1H, H-5′, J=11.2, 3.4), 3.83 (dd, 1H, H-5′, J=11.2, 2.4), 0.97, 0.94, 0.84 (3S, 27H, tert-Bu), 0.17, 0.15, 0.12, 0.11, 0.0, −0.11 (6 s, 18H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 161.0, 152.9, 151.9, 150.2, 149.1, 141.9, 141.5, 135.9, 129.7, 126.4, 125.9, 122.0, 121.6, 121.5, 88.7, 85.1, 76.2, 71.5, 62.3, 26.1, 25.8, 25.7, 18.6, 18.1, 17.9, −4.3, −4.7, −4.73, −4.9, −5.3, −5.4. FAB HRMS calcd for C37H60N5O5Si3 (M++H) 738.3902. found 738.3885.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[C:15]([O:16][CH3:17])=[C:14]([O:18][CH2:19][CH3:20])[C:13]([C:21](=[O:23])[CH3:22])=[C:12]([O:24][CH3:25])[C:10]=3[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C>[Pd]>[N:1]1([CH:7]2[CH2:11][C:10]3[C:12]([O:24][CH3:25])=[C:13]([C:21](=[O:23])[CH3:22])[C:14]([O:18][CH2:19][CH3:20])=[C:15]([O:16][CH3:17])[C:9]=3[O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1c(C(C)=O)c(OC)c2cc(N3CCCCC3)oc2c1OC
Agent: [Pd]
Product: CCOc1c(OC)c2c(c(OC)c1C(C)=O)CC(N1CCCCC1)O2

Procedure:
A solution of 100g. of piperidino-6-ethoxy-5-acetyl-4,7-dimethoxybenzofuran in 600ml of 96° alcohol is hydrogenated in the presence of 11g. of palladium on 5% charcoal, under a pressure of 5 kg and at a temperature between 65° and 70° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:12])[CH2:10][CH3:11].[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:10]([CH3:11])[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:13])([F:14])[F:1])=[O:12]
Reactant: CCC(=O)c1ccccc1C(F)(F)F
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)C(=O)c1ccccc1C(F)(F)F
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a solution of 2′-trifluoromethyl-propiophenone (10 g, 48 mmol) in carbon tetrachloride (50 ml) was added a solution of bromine (2.72 mL, 52.8 mmol) in carbon tetrachloride (20 mL) dropwise. After the addition was complete, stirring was continued for another 2 h. The solution was washed with satd NaHCO3 and water, dried (anhyd Na2SO4) and concentrated under reduced pressure to give 2-bromo-1-(2-trifluoromethyl-phenyl)-propan-1-one as an oil (12.8 g, 95%), which was used in the next step without purification. 1H-NMR (CDCl3): δ 7.73 (m, 2H), 7.58-7.67 (m, 2H), 4.96 (q, 1H), 1.90 (d, 3H). To a solution of 2′-trifluoromethyl-propiophenone (10 g, 48 mmol) in carbon tetrachloride (50 ml) was added a solution of bromine (2.72 mL, 52.8 mmol) in carbon tetrachloride (20 m To a suspension of NaH (60%, 2.88 g, 72 mmol) in anhyd THF (200 mL) was added methyl cyanoacetate (4.5 mL, 50 mmol). After this mixture was stirred for 3 h at 20° C., a solution of 2-bromo-1-(2-trifluoromethyl-phenyl)-propan-1-one (13.5 g, 48 mmol) was added and the mixture was stirred overnight at 20° C. The mixture was quenched with water and the organic layer was separated. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried (anhyd Na2SO4) and concentrated under reduced pressure to afford the title compound as an oil (13.3 g, 93%), which was used in the next step without purification. MS (ES): 300 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13](O)=[O:14])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C(=O)C2C=CC=CC=2N=N1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)=[O:14])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)O)cc1-c1ccccc1
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C(=O)Nc2ccccn2)cc1-c1ccccc1

Procedure:
To a solution of the resultant acid from Example 60A (1.0 equivalent) in DMF is added 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (1.5 equivalents) followed by 2-aminopyridine (1.0 equivalent) and 1-(3-dimehtylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 equivalents). When judged complete by TLC analysis, the reaction is taken up in ethyl acetate which is washed by 1N HCl and saturated brine, and then is dried and evaporated. The crude reaction mixture is purified by column chromatography to afford the title product.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([O:26]CC)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)[N:4]=1)[CH3:2].[OH-].[Li+].Cl.[Cl-].[Li+]>C1COCC1.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=2)[N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1ccn2c(C(=O)Nc3cccc4c3c(CC)nn4Cc3cccc(C)n3)cnc2c1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carboxylate (430 mg, 0.891 mmol) (Example 23) in THF/water (6 mL/1 mL) was added lithium hydroxide (21.3 mg, 0.89 mmol). The mixture was heated at 70° C. with stirring in a sealed tube for 2 hours. The mixture was allowed to cool and hydrogen chloride (0.45 mL, 4M in dioxane) was added. The solvent was removed under reduced pressure to give a mixture of the product and lithium chloride (410 mg) which was carried on directly to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24]C(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([OH:24])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(Cc2nccs2)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C(=O)O)N1CC[C@H](N(Cc2nccs2)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
A solution of tert-butyl (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](1,3-thiazol-2-ylmethyl)amino]-2-oxopyrrolidin-1-yl}propanoate (0.03 g) in DCM (1 ml) was treated with trifluoroacetic acid (1 ml) and stirred at room temperature for 1 h. The solution was then concentrated under reduced pressure to give the title compound (0.019 g) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COc1cc(C)cc(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)cc(CBr)c1

Procedure:
A refluxing solution of 3,5-dimethylanisole (13 g), azoisobutyronitrile (1.6 g) and N-bromosuccinimide (17 g) in carbon tetrachloride (100 ml) was irradiated with light for 6 h. The solution was filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica gel (eluting with 0-5% ethyl acetate--petroleum ether bp=60°-80° C.) to yield 3-bromomethyl-5-methylanisole.
Reaction SMILES: C(OP(C#N)(=O)OCC)C.[NH2:11][C:12]1[N:13]=[CH:14][C:15]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]3[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[N:16][C:17]=1[C:18]([NH:20][NH2:21])=[O:19].[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH:52]1[C:57]1[CH:65]=[CH:64][C:60]([C:61](O)=O)=[CH:59][CH:58]=1)=[O:50])([CH3:47])([CH3:46])[CH3:45].CCN(CC)CC>CN(C=O)C.O.C(OCC)(=O)C>[NH2:11][C:12]1[C:17]([C:18]2[O:19][C:61]([C:60]3[CH:59]=[CH:58][C:57]([CH:52]4[CH2:53][O:54][CH2:55][CH2:56][N:51]4[C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:50])=[CH:65][CH:64]=3)=[N:21][N:20]=2)=[N:16][C:15]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]3[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(-c3cnc(N)c(C(=O)NN)n3)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CCOCC1c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(-c3cnc(N)c(-c4nnc(-c5ccc(C6COCCN6C(=O)OC(C)(C)C)cc5)o4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.6 %

Procedure:
diethylcyanophosphonate (41.07 mg, 37.64 μL, 0.2518 mmol) was added to a solution of tert-butyl 3-[4-[5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate (100 mg, 0.2098 mmol), 4-(4-tert-butoxycarbonylmorpholin-3-yl)benzoic acid (64.48 mg, 0.2098 mmol) and Et3N (25.48 mg, 35.10 μL, 0.2518 mmol) in DMF (1.500 mL) and the resulting solution stirred at ambient temperature for 20 minutes. A further portion of diethylcyanophosphonate (68.44 mg, 62.73 μL, 0.4196 mmol) and Et3N (42.46 mg, 58.48 μL, 0.4196 mmol) were added and the reaction mixture stirred at 55° C. for 20 hours. Further portions of Et3N (42.46 mg, 58.48 μL, 0.4196 mmol) and diethylcyanophosphonate (68.44 mg, 62.73 μL, 0.4196 mmol) were added and the reaction mixture stirred at 55° C. for a further 3 hours. Further portions of Et3N (42.46 mg, 58.48 μL, 0.4196 mmol) and diethylcyanophosphonate (68.44 mg, 62.73 μL, 0.4196 mmol) were added and the reaction mixture stirred at 55° C. for a further 4.5 hours. The reaction mixture was cooled to ambient temperature and diluted with water and ethyl acetate and the layers separated. The aqueous layer was extracted further with ethyl acetate (×2) and the combined organic extracts were washed with water (×2), brine (×2), dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 24 g column, eluting with 0 to 80% EtOAc/Petroleum Ether, loaded in DCM) to give the sub-title product as a yellow solid (81 mg, 51% Yield). LC/MS m/z 748.1 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].[F:11][C:12]([F:16])([F:15])CI.[F-].[Cs+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][C:12]([F:16])([F:15])[F:11]
Reactant: FC(F)(F)CI
Reactant: Oc1cc(F)c(F)cc1Br
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(Br)c(OC(F)(F)F)cc1F
Temperature: 120 °C
Yield: 52.4 %

Procedure:
A mixture of 2-bromo-4,5-difluoro-phenol (1.0 g, 4.8 mmol), 1,1,1-trifluoro-2-iodo-ethane (706 mg, 7.2 mmol) and CsF (882 mg, 5.8 mmol) in DMSO (20 mL) was heated at 120° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (10:1) to give the title compound (697 mg, 50%). 1H NMR (500 MHz, CDCl3) δ ppm 4.36 (q, J=7.93 Hz, 2H) 6.85 (dd, J=10.98, 7.02 Hz, 1H) 7.43 (t, J=8.85 Hz, 1H).
Reaction SMILES: [Cu][C:2]#[N:3].[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:29]=[C:28]3I)=[O:24])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[C:4]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([S:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:29]=[C:28]3[C:2]#[N:3])=[O:24])([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)C1
Reactant: N#C[Cu]
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3c(c2)c(C#N)cn3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
Copper(I) cyanide (76 mg, 0.852 mmol) was added to a 25 mL round bottom flask charged with 3-(1-benzenesulfonyl-3-iodo-1H-indole-5-carbonyl)-3-benzyl-pyrrolidine-1-carboxylic acid tert-butyl ester (143 mg, 0.213 mmol), followed by 1,1′-bis(diphenylphosphino)ferrocene (24 mg, 0.043 mmol) and tris(dibenzylideneacetone) dipalladium(0) (10 mg, 0.011 mmol). 1,4-Dioxane (1.5 mL) was then added and the mixture was heated to reflux under nitrogen atmosphere for one hour. The reaction mixture was cooled to room temperature and filtered through a celite pad. The filter cake was rinsed with EtOAc and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (30% of EtOAc in hexane) to give 115 mg (95% yield) of 3-(1-benzenesulfonyl-3-cyano-1H-indole-5-carbonyl)-3-benzyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow foam.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([OH:18])[CH:6]=[CH:7][C:8]=2[CH3:17])[C:3]1=[O:19].[CH2:20](Br)[CH:21]=[CH:22][CH3:23].[OH-].[K+]>CC(C)=O>[CH3:1][CH:2]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([O:18][CH2:20][CH:21]=[CH:22][CH3:23])[CH:6]=[CH:7][C:8]=2[CH3:17])[C:3]1=[O:19]
Reactant: Cc1ccc(O)c2c1C(c1ccccc1)C(C)C2=O
Reactant: CC=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC=CCOc1ccc(C)c2c1C(=O)C(C)C2c1ccccc1

Procedure:
A solution of 19.0 g of 2,3-dihydro-2,4-dimethyl-3-phenyl-7-hydroxy-1H-inden-1-one, 13.98 of crotyl bromide and 5.47 g of potassium hydroxide in 200 ml of acetone was heated and refluxed under stirring condition. After the reaction was completed, the reaction mixture was concentrated and extracted with ethyl acetate, then the extract was washed with water and with an aqueous solution saturated with sodium chloride, then dried. The extract was concentrated by removing the solvent under a reduced pressure, then recrystallized from methanol to obtain 11.8 g of 2,3-dihydro-2,4-dimethyl-3-phenyl-7-crotyloxy-1H-inden-1-one as in the form of cis-trans mixture. Colorless stick-like crystals. Melting point: 138.5°-139.5° C.