Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:14][O:15][C:16]1[C:21](B(O)O)=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH3:14][O:15][C:16]1[C:21]([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Nc1nc(-c2cccc(Br)c2)c[nH]1
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1cccc(-c2c[nH]c(N)n2)c1

Procedure:
In a similar manner to Example 33, Step 1, the Suzuki coupling reaction of the bromide from Step 1 of Example 37 (111 mg, 0.41 mmol) and (2-methoxy-pyridin-3-yl)-boronic acid (125 mg, 0.817 mmol) afforded the 4-[3-(2-methoxy-pyridin-3-yl)-phenyl]-1H-imidazol-2-ylamine, after passing through an SPE ion-exchange plug, as a colorless glass (37.5 mg, 34.4% yield). LC/MS (m/z 267.0 (M+H)+); HPLC Rt: 2.2 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([I:13])=[C:7]([CH2:9][C:10](O)=[O:11])[CH:8]=1)[CH3:2].CN(C=O)C.S(Cl)([Cl:21])=O>C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([I:13])=[C:7]([CH2:9][C:10]([Cl:21])=[O:11])[CH:8]=1)[CH3:2]
Reactant: CCc1ccc(I)c(CC(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(I)c(CC(=O)Cl)c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
5-Ethyl-2-iodophenylacetic acid is dissolved in methylene chloride (400 ml) and DMF (1 ml) is added. Thionyl chloride (21 ml, 300 mmol) is then added dropwise over 20 minutes. The mixture is heated to reflux and heating continued for 3.5 hours when the mixture is cooled and ice-water (400 ml) and methylene chloride (300 ml) are added. The layers are separated, the organic layer is washed with a sodium bicarbonate solution, saturated brine, dried (magnesium sulfate), and evaporated under reduced pressure to yield 5-ethyl-2-iodophenylacetyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[O:23][C:22]([CH3:28])([CH3:27])[C:18]1([CH2:21][O:20][CH2:19]1)[C:5]12[CH2:9][O:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:6]1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[CH:3]=[C:4]3[C:24](=[CH:25][CH:26]=2)[O:23][C:22]([CH3:28])([CH3:27])[C:18]2([CH2:21][O:20][CH2:19]2)[C:5]23[CH2:9][O:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[N:6]2)=[O:37])=[N:34][CH:35]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(N)ccc1OC(C)(C)C21COC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1OC(C)(C)C21COC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A mixture of tert-butyl (6′-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)carbamate (878 mg, 2.25 mmol), 5-chloro-2-pyridinecarboxylic acid (476 mg, 2.93 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (562 mg, 2.93 mmol), 1-hydroxybenzotriazole (396 mg, 2.93 mmol), N,N-diisopropylethylamine (0.502 mL, 2.93 mmol) and CH2Cl2 (8.78 mL) was stirred for 1.5 hours at ambient temperature. After concentration of the reaction mixture at reduced pressure, the residue was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 90%) to give tert-butyl (6′-{[(5-chloropyridin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)carbamate (976 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(Cl)c1ccccc1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)c1ccccc1
Yield: 55 %

Procedure:
Using the general method of Example 47, benzoyl chloride (56 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.11 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]benzamide as a white solid. Analysis: Calculated for C24H28N6O+¼H2O: %C, 68.47; %H, 6.82; %N, 19.96: Found: %C, 68.24; %H, 6.76; %N, 19.90.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:13]1([CH2:19][CH2:20][OH:21])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[OH:21][CH2:20][CH2:19][N:13]1[CH2:18][CH2:17][N:16]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:10])[CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: OCCN1CCNCC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCN(CCO)CC1

Procedure:
Using 4-nitro-benzoic acid (320 mg) instead of 3-nitro-benzoic acid, and 2-piperazin-1-yl-ethanol (282 μl) instead of 1-ethyl-piperazine, in the same manner as Step A in Example 1-D-101, the desired compound was obtained as a crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[CH2:7][NH:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH:30]=[CH:29][N:28]=[N:27]1>[Cu]>[CH3:9][NH:8][CH2:7][C:6]1[CH:10]=[C:2]([N:27]2[N:28]=[CH:29][CH:30]=[N:26]2)[CH:3]=[CH:4][C:5]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1
Reactant: c1c[nH]nn1
Reactant: CNCc1cc(Br)ccc1Oc1ccc(SC)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNCc1cc(-n2nccn2)ccc1Oc1ccc(SC)cc1
Temperature: 160 °C

Procedure:
The bromide of Example 23 (2.0 g, 6 mmol) was mixed with copper powder (378 mg, 6 mmol) 1,2,3-triazole (ca. 5 g, excess), and potassium carbonate (828 mg, 6 mmol) were heated together at 160° C. for 48 h. After cooling to room temperature the reaction mixture was partitioned between sodium hydroxide (3 M) and ethyl acetate. The organic layer was separated and washed with sodium hydroxide (3 M) (3 x), water, and brine, before being dried (MgSO4) and evaporated. The resulting residue was purified by flash chromatography [SiO2; DCM/ MeOH/ 880 NH3 (97.5:2.5:0.25)] to afford, separately, the 1-substitiuted triazole derivative compound of Example 181 and the 2-substituted isomer compound of Example 182. The hydrochloride salt of each was precipitated by treatment with ethereal hydrochloric acid (1 M solution, excess).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:12][C:13]1[S:16][N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([F:2])=[CH:4][CH:5]=2)[N:8]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-fluorobenzamidine hydrochloride (0.385 g) in DCM (5 mL) was added perchloromethyl mercaptan (0.219 mL). The resulting mixture was cooled to 0° C., treated with 6 N NaOH (2 mL) and stirred for 30 min. The resulting mixture was diluted with water (10 mL) and extracted with DCM (20 mL). The organic layer was dried (MgSO4) and concentrated. Chromatography of the residue (0-20% EtOAc-hexanes) gave the title compound as a yellow-orange solid (0.43 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]23[CH2:22][CH2:21][C:18]([CH2:23][CH2:24][OH:25])([CH2:19][CH2:20]2)[CH2:17][O:16]3)[CH:5]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:7]=1.[OH-].[Na+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C1(C)C=CC=CC=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].O>[F:1][C:2]1[CH:3]=[C:4]([C:15]23[CH2:20][CH2:19][C:18]([CH2:23][CH2:24][O:25][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([CH2:21][CH2:22]2)[CH2:17][O:16]3)[CH:5]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:7]=1
Reactant: OCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of 2-(1-(3-fluoro-5-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl) ethanol (350 mg, 1.00 mmol) in toluene (1 mL) was added Bu4NCl.H2O (89 mg, 0.300 mmol). The reaction mixture was cooled to 0° C. after which aqueous 35% NaOH (10 mL) and tert-butyl bromoacetate (295 μL, 1.99 mmol) were successively added. The reaction was stirred at rt for 18 h. The organic layer was separated, washed with H2O (5×15 mL) and brine (15 mL) until the pH=7, and then was concentrated in vacuo. The residual crude oil was purified by flash chromatography (SiO2) using a gradient from 0% to 30% EtOAc/hexane (10 min) to give the title compound (400 mg, 0.861 mmol, 86% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ: 6.86 (t, J=1.7 Hz, 1H), 6.77-6.72 (m, 1H), 6.67 (d, J=10.5 Hz, 1H), 5.39 (s, 1H), 3.94 (s, 2H), 3.87 (s, 3H), 3.57 (t, J=6.9 Hz, 3H), 2.04-1.95 (m, 5H), 1.84 (d, J=5.0 Hz, 2H), 1.77-1.57 (m, 7H), 1.55-1.50 (m, 11H); 19F NMR (471 MHz, CDCl3) δ: −112.2 (s, 1F).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[OH-].[Na+].Cl.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[CH:34]=[CH:33][C:32](Br)=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2>CN(C=O)C.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]>[N:15]12[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]1)[C@@H:17]([NH:23][C:24]([C:26]1[O:27][C:28]3[CH:34]=[CH:33][C:32]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=4)=[CH:31][C:29]=3[CH:30]=1)=[O:25])[CH2:16]2
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(-c3ccc(CO)cc3)ccc2o1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
110 mg (0.73 mmol) of 4-(hydroxymethyl)phenylboronic acid and 1.46 ml of 1N sodium hydroxide solution are added to a mixture of 170 mg (0.49 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-bromo-1-benzofuran-2-carboxamide (Example 3A) and 35 mg (0.05 mmol) of PdCl2(dppf) in 2 ml of DMF. The reaction mixture is heated at 85° C. overnight. The solvent is removed under reduced pressure. Addition of a mixture of 1N sodium hydroxide solution and ethyl acetate to the residue is followed by extraction of the aqueous phase once more with ethyl acetate. The combined organic phases are washed twice with each of 1N sodium hydroxide solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated in a rotary evaporator under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with DMF, again with methanol, with dichloromethane, again with methanol, with water and finally with methanol again. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. 148 mg (80% of theory) of the title compound are isolated.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:35])[C@H:5]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:6][C:7](=[O:26])[C@H:8]([CH2:24][OH:25])[NH:9][C:10](=[O:23])[C@H:11]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[NH2:12].[CH2:36]([O:43][C:44]([NH:46][C@H:47]([C:53](O)=[O:54])[CH2:48][CH2:49][C:50](=[O:52])[NH2:51])=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH3:2][O:3][C:4](=[O:35])[C@H:5]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[NH:6][C:7](=[O:26])[C@H:8]([CH2:24][OH:25])[NH:9][C:10](=[O:23])[C@H:11]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[NH:12][C:53](=[O:54])[C@H:47]([CH2:48][CH2:49][C:50](=[O:52])[NH2:51])[NH:46][C:44]([O:43][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:45]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A mixture of the product from (c) above, 1.4 g. of Nα -benzyloxycarbonyl-L-glutamine, 670 mg. of 1-hydroxybenztriazole and 50 ml. of dimethylformamide is stirred and cooled to -10° C., and 0.7 ml. of triethylamine is added. After 15 minutes, it is treated with 1.2 g. of dicyclohexylcarbodiimide and stirred a few hours at -10° C., then at room temperature for two days and finally let stand an additional three days. The solution is filtered and the filtrate evaporated at 50° C. under reduced pressure. The residue is precipitated from methanol with water and then crystallized from methanol three times; m.p. 245°-248° C.; [α]D25 -4.4° (c 1, DMF); ultraviolet in methanol, λmax 290 E11 75.7; λmax 280 E11 100.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:19])[CH:17]=[CH2:18])[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28]([NH2:30])=[O:29].CO.C(Cl)Cl>CC1C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]1[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=[C:2]([NH:24][C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:28]([NH2:30])=[O:29])[N:7]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: Cc1ccc(C(N)=O)cc1N
Reactant: C=CC(=O)Nc1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)Nc1ccccc1Nc1nc(Nc2cc(C(N)=O)ccc2C)ncc1C(F)(F)F
Temperature: 95 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To a solution of Intermediate 1 (1 g, 2.923 mmol) in 0.04 M PTSA solution in 1,4-Dioxane (20 mL) was added 3-amino-4-methylbenzamide (526 mg, 3.5076 mmol), and the mixture was stirred at 95° C. for 16 h. TLC showed completion of starting material. (TLC system: 10% Methanol/DCM, (Rf): 0.6). The reaction mixture was directly absorbed on silica gel and purified by column chromatography using 4% methanol/DCM as eluents. The resulting off-white solid was stirred in a mixture of DCM:EtOAc:Diethyl Ether (10 mL:10 mL:30 mL) for 10 min, then filtered and dried under vacuum to obtain 596 mg of the desired compound (44%). 1HNMR (400 MHz, DMSO-d6) δ 2.15 (s, 3H), 5.78-5.81 (dd, 1H, J=1.9, 10.0 Hz), 6.26-6.31 (dd, 1H, J=2.0, 17.0 Hz), 6.40-6.46 (dd, 1H, J=10.0, 16.9 Hz), 7.02-7.09 (m, 2H), 7.13-7.15 (d, 1H, J=7.5 Hz), 7.19-7.21 (dd, 1H, J=7.9 Hz), 7.32 (br s, 1H), 7.57-7.59 (dd, 1H, J=1.6, 7.6 Hz), 7.66-7.68 (d, 1H, J=8 Hz), 7.88-7.91 (d, 2H, J=11.4 Hz), 8.21 (s, 1H), 8.27 (s, 1H), 9.12 (br s, 1H) 10.3 (s, 1H). MS: m/z 457.3 (ES+, M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl.Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)O)cc23)ccn1
Temperature: 23 °C
Reaction time: 0.83 h
Yield: 85.2 %

Procedure:
The synthetic intermediate from Step 1 (392 mg, 0.791 mmol), dichloromethane (2 ml), and trifluoroacetic acid (2 ml) were combined in an open vial. Triethylsilane (1.011 ml, 6.33 mmol) was then added, and the resulting mixture was stirred at a temperature of 23° C. for 50 minutes. The reaction mixture was then diluted with dichloromethane, and 2N HCl was added drop-wise until the pH of the mixture was between 4 and 5. This resulting precipitate was collected via filtration and rinsed with water, methanol and dichloromethane to afford 3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxylic acid (220 mg, 0.674 mmol, 85% yield) as a green solid. The crude product was progressed to the next step without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([OH:17])[C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=[O:5])=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][N:2]([CH3:25])[S:3]([N:6]1[CH:10]=[C:9]([CH:11]([OH:17])[C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[CH:7]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)n1cc(C(O)c2cccs2)nc1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cnc(C(O)c2cccs2)c1
Reaction time: 3 h

Procedure:
2-(tert-butyl-dimethyl-silanyl)-4-(hydroxy-thiophen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (Intermediate-E1) (2.5 g, 6.2 mmol) in THF (60 mL) was treated with tetrabutylammonium fluoride (TBAF) (6.9 mL of a 1M soln) at 0° C. for 1 h and at rt for 3 h. The reaction mixture was subjected to an aqueous work-up and the product was purified by chromatography on silica gel with EtOAc to give 4-(hydroxy-thiophen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide as a white solid, 1.43 g. 4-(Hydroxy-thiophen-2-yl-methyl)-imidazole-1-sulfonic acid dimethylamide (0.5 g, 1.74 mmol) in dichloromethane (25 mL) was reacted with trifluoroacetic acid (4.3 mL, 56 mmol) and triethylsilane (TES) (2.2 mL, 14 mmol) at rt for 18 h. The mixture was quenched with water and solid NaHCO3. This material was subjected to an aqueous work-up and the residue was purified by chromatography on silica gel with 50% EtOAc: hexane to yield 4-thiophen-2-ylmethyl-imidazole-1-sulfonic acid dimethylamide (Intermediate-E2) 0.44 g.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][S:30]([CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1([CH3:42])[CH3:41])(=[O:32])=[O:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:41][C:36]1([CH3:42])[N:35]([CH2:34][CH2:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH2:40][CH2:39][N:38]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:37]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC1(C)CNCCN1CCS(C)(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CCS(C)(=O)=O)C(C)(C)C3)n(C)c2n1
Reaction time: 64 h

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (80 mg, 0.21 mmol), 1-(2-methanesulfonylethyl)-2,2-dimethylpiperazine (56 mg, 0.25 mmol) and 4 Å powdered molecular sieves (100 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (90 mg, 0.42 mmol). The reaction mixture was stirred for 64 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 330 as a white solid (70 mg, 58%). LCMS (Method G): RT 6.62 min [M+H]+ 582.3. 1H NMR (CDCl3, 400 MHz): δ 8.12-8.07 (m, 1 H); 7.74-7.70 (m, 1 H); 7.29-7.25 (m, 2 H); 4.35 (m, 4 H); 3.91-3.83 (m, 7 H); 3.69 (s, 2 H); 3.11 (m, 2 H); 3.06 (s, 3 H); 2.95 (s, 3 H); 2.63 (m, 2 H); 2.54 (m, 2 H); 2.30 (s, 2 H); 1.78 (m, 2 H) and 1.10 (s, 6 H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH2:11])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)Cc1cccc(Br)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#CCc1cccc(Br)c1
Reaction time: 0.17 h

Procedure:
2-(3-Bromophenyl)acetamide (10.0 g, 46.73 mmol) (example 1) in dry 1,4-dioxane (100 mL) was cooled to 0° C. Triethylamine (18.91 g, 187.92 mmol) was added and the reaction mixture was stirred for about 10 minutes. Trifluoroacetic anhydride (39.26 g, 186.92 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for about 12 hours. The reaction mixture was poured into cold water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulphate, filtered and the solvent evaporated under vacuum. An oily residue was obtained which was purified by column chromatography over silica gel using ethyl acetate and hexane (1:49) to afford the title compound as light yellow colored oil. Yield: 8.4 g.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][SiH:18]([CH3:24])[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21].C[SiH2]C1C=CC=CC=1>CCCCCC>[C:1]1([CH:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:9][CH2:10][Si:18]([CH3:24])([CH3:17])[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[SiH](C)O[Si](C)(C)C
Reactant: C=CCC(c1ccccc1)c1ccccc1
Agent: C[SiH2]c1ccccc1
Solvent: CCCCCC
Product: C[Si](C)(C)O[Si](C)(C)CCCC(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
4,4-Diphenyl-1-butene (compound 1, 0.40 mmol) and pentamethyl disiloxane (0.6 mmol) were dissolved in hexane (2.0 ml), added with poly (methylphenylsilane)-supported platinum (200 mg, 5.5 mol %) prepared in Example 10A and stirred at 20° C. for 2 hr. The filtrate was washed with hexane after separation from catalyst, concentrated, and purified by silica gel column chromatography using hexane as an eluting solvent. (4,4-Diphenylbutyl) pentamethyl disiloxane was obtained as oil without color (140 mg (98%)) and 1,1-diphenyl butane was obtained (2 mg (yield 2%)).