Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH2:3][CH2:2]1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:10]3[N:11]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[S:8][CH:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: O=C(O)c1csc(N2CCOCC2)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(N2CCOCC2)n1
Yield: 5.48 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-morpholinothiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-morpholino-1,3-thiazole-4-carboxylic acid (0.454 g, 2.117 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.5 g, 1.764 mmol. The product was purified by Flash-chromatography. Yield 5.48%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 3.38-3.43 (m, 4H), 3.67-3.72 (m, 4H), 4.27-4.45 (m, 3H), 6.95 (d, 1H), 7.40 (s, 1H), 7.83 (d, 1H), 7.92 (dd, 1H), 7.97 (d, 1H), 7.98 (dd, 1H), 8.06 (d, 1H).
Reaction SMILES: C(OC)(=O)CC(OC)=O.C[O-].[Na+].C(Br)CCCCCCCCCCCCCCCCC.CCOCC.[CH3:37][O:38][C:39](=[O:63])[CH:40]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[C:41](OC)=O.[OH-].[K+].C(C(C(O)=O)C(OC)=O)CCCCCCCCCCCCCCCCC.C(NCC)C.C=O.C([O-])(=O)C=C>CO.O>[CH2:45]([C:40](=[CH2:41])[C:39]([O:38][CH3:37])=[O:63])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: CCCCCCCCCCCCCCCCCCC(C(=O)OC)C(=O)OC
Agent: C=CC(=O)[O-]
Agent: C=O
Agent: CCCCCCCCCCCCCCCCCCBr
Solvent: CCNCC
Solvent: CO
Solvent: O
Product: C=C(CCCCCCCCCCCCCCCCCC)C(=O)OC
Reaction time: 8 h
Yield: 69.2 %

Procedure:
After addition of dimethyl malonate (0.50 mole) to a solution of sodium methylate (0.50 mole in 400 ml methanol), octadecyl bromide (0.45 mole) is added dropwise. The reaction mixture was heated gently during the addition and the mixture was refluxed for 10 hours after addition of the halide. At the end of this time, the methanol was distilled off. The residue was cooled and stirred with 500 ml of water. The product, a pasty solid, floated on top of the water, and ether (350 mole) was added to dissolve it. The ether layer was evaporated, and the product was recrystallized from 900 ml of methanol. After recrystallization from methanol and drying in a vacuum oven, a 69.2 percent yield was obtained, m.p. 45°-47° C. The dimethyl-n-octadecylmalonate (0.17 mole), dissolved in 200 ml of methanol, was added to a solution of 11.3g potassium hydroxide (86.1 percent) in 45 ml of methanol. The mixture was stirred for 1.5 days and the potassium salt which separated was filtered. The salt was dissolved in 500 ml of water with stirring. After acidifying with 6N HCl, the solution was stirred for 3 hours to flocculate the precipitate. The product was filtered, washed and dried in a vacuum oven. A 95 percent yield was obtained, m.p. 68°-70° C. Methyl hydrogen octadecylmalonate (0.16 mole), diethyl amine (0.16 mole), and 13g of a 37 percent formaldehyde solution were stirred with heating to initiate the reaction, after which stirring was continued without heating for 6 hours. After standing overnight, impure solid acrylate had settled out. The pasty product layer was washed with hydrochloric acid followed by water until neutral (sodium sulfate was used to break emulsions formed during the washing). The ether layer was dried over anhydrous potassium carbonate. The solution was filtered and evaporated. The compound was crystallized from benzene. A 40 percent yield was obtained, m.p. 48°-50°C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](Cl)=[N:16][N:15]=[CH:14]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)=[N:16][N:15]=[CH:14]2
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2nncc3cc(Br)ccc23)CC1
Yield: 92.7 %

Procedure:
A mixture of the isonipecotamide (71 mg, 554 μmol), 6-bromo-1-chlorophthalazine (Example 1, 90 mg, 370 μmol) and potassium carbonate (51 mg, 370 μmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizes microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 190° C. for about 20 min. at which the starting material was consumed, by TLC, to form product (M+1=335, 337). The mixture was concentrated and purified by column, eluting with a gradient of 2% 2M ammonia in MeOH/DCM to 10% 2M ammonia in MeOH/DCM to give 1-(6-bromophthalazin-1-yl)piperidine-4-carboxamide (0.115g) as a pale yellow solid. Found MS (ES+): 335, 337(M+H)+.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]2[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)=[N:9]1.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(P(=O)(OCC)OCC)#N>C(#N)C.CN(C=O)C.C(Cl)Cl>[N:28]1([CH2:27][CH2:26][NH:25][C:22]([C:19]2[CH:18]=[C:17]([C:10]3[C:11]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:8][N:9]=3)[NH:21][CH:20]=2)=[O:24])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCN1CCOCC1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.073 mL) was added to a mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (100 mg, 0.44 mmol) (from Example 12) and 4-(2-aminoethyl)morpholine (62.8 mg, 1.1 eq.) (Aldrich, Milwaukee, Wis.) in acetonitrile (1 mL) and DMF (1 mL). The mixture was cooled in an ice bath and to it was added diethyl cyanophosphonate (86 mg, 1.2 eq.). The mixture was allowed to warm up slowly to room temperature and stirred for overnight. The reaction was diluted with DCM, washed with NaHCO3 and water, dried and concentrated. The residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]([F:22])([F:21])[F:20])=[N:6][CH:7]=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(N)CN>O1CCOCC1.[Cu]I.CCOC(C)=O>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:30][C:2]2[CH:7]=[N:6][C:5]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=4[N:10]=[C:9]3[C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(Br)cn1
Reactant: NC(=O)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: NCCN
Product: COc1ccc2c(c1)nc(C(F)(F)F)n2-c1cnc(NC(=O)c2ccc(F)cc2)cn1

Procedure:
Into a 50 mL 3-necked round bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-(5-bromo-pyrazin-2-yl)-5-methoxy-2-trifluoromethyl-1H-benzoimidazole (iv) (100 mg, 0.27 mmol) in 1,4-dioxane (30 mL). To this was added 4-fluorobenzamide (80 mg, 0.58 mmol), K3PO4 (250 mg, 1.18 mmol), CuI (10 mg, 0.05 mmol) and ethane-1,2-diamine (EDA) (5 mg, 0.08 mmol). The resulting solution was stirred at reflux overnight. The reaction progress was monitored by TLC (EtOAc/PE=1:2). When the reaction had gone to completion, the mixture was filtered to remove the solid components, then concentrated under vacuum. The residue was dissolved in EtOAc, then washed with water. The organic layer was dried over Na2SO4, then concentrated to yield a crude product.
Reaction SMILES: FC1C=CC(CN)=CC=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1ccccn1
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccccn1
Yield: 43 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 2-(aminomethyl)pyridine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 43% yield: mp 149-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.52-8.46 (m, 2H), 7.72 (t, J=5.7 Hz, 1H), 7.39-7.19 (m, 7H), 4.49 (d, J=5.7 Hz, 2H), 4.40 (s, 2H), 3.97 (t, J=7.5 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.4, 159.1, 157.9, 155.5, 151.5, 149.2, 137.1, 136.7, 129.1, 128.2, 127.9, 122.4, 121.2, 118.2, 47.3, 45.0, 42.4, 42.0, 17.6; MS (ES+) m/z 408.3 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]1([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[C:4]1([C:10](=[N:2][OH:3])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(CC(=O)c2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(CC(=NO)c2ccccc2)c1
Yield: 77.1 %

Procedure:
A solution of hydroxylamine hydrochloride (185.5 g, 2.67 mol) water (0.3 L) was added with stirring to a solution of 1-phenyl-2-(3-methoxyphenyl)ethanone (187 g, 0.89 mol) in 95% ethanol (1.4 L). Then, 0.3 L of 20% NaOH was added, with stirring, to the resulting mixture. The mixture was heated to reflux for 2 hrs, cooled, and the alcohol was evaporated with a water aspirator. The aqueous residue was extracted with ether (3×500 ml). The combined ether extracts were dried over MgSO4 and evaporated to provide a solid residue which was then recrystallized from cyclohexane (1 L) to provide 165.5 g (82%) of 1-phenyl-2-(3-methoxyphenyl)ethanone oxime. An analytical sample, recrystallized from ethylacetate/cyclohexane, had mp. 72°-73° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:24][C@H:25]([CH3:28])[CH2:26][OH:27])=[N:7][C:8]([S:12]([CH2:15][C:16]3C=C[CH:19]=[C:18](F)[C:17]=3F)(=O)=O)=[N:9]2)=[N:4][CH:3]=1.[S:29]1C=CC=C1S.CC(C)([O-])C.[K+]>CS(C)=O.C1COCC1>[NH2:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:24][C@H:25]([CH3:28])[CH2:26][OH:27])=[N:7][C:8]([S:12][CH2:15][C:16]3[S:29][CH:19]=[CH:18][CH:17]=3)=[N:9]2)=[N:4][CH:3]=1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2nc(N)cnc12
Reactant: Sc1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: C[C@H](CO)Nc1nc(SCc2cccs2)nc2nc(N)cnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from Example 10, step (a) (0.18 g) and 2-thienylmercaptan (70 mg) in anhydrous DMSO (3 ml) was treated with potassium t-butoxide solution in THF (1.0 M, 0.44 ml) and stirred at room temperature for 1 hour. The solution was purified directly by preparative reversed phase HPLC on a Waters 19×50 mm Symmetry C8 silica column eluted with 0.1% aqueous ammonium acetate:acetonitrile (70:30) to give an off-white solid that was dried under reduced pressure at 40° (20 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[OH:36][CH:37]1[CH2:40][NH:39][CH2:38]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:39]5[CH2:40][CH:37]([OH:36])[CH2:38]5)=[O:27])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: OC1CNC1
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CC(O)C4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61B starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61B, Step 2) and 3-hydroxyazetidine hydrochloride (Oakwood, Cat. No. 013898). LCMS (M+H)+: m/z=515.2.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:21]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:33])[N:22]=1>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][O:13][C:21]3[N:30]([CH3:31])[C:29](=[O:32])[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]=4[CH3:33])[N:22]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CO)cc1
Reactant: Cc1cccc2nc(Cl)n(C)c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(OCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
To a solution of 4-(4-chlorobenzoyl)benzyl alcohol (1.0 g) in DMF (20 ml) was added 60% sodium hydride (210 mg) and the mixture was stirred at room temperature for 10 minutes. Then, 2-chloro-3,5-dimethyl-4(3H)-quinazolinone (850 mg) was added and the mixture was stirred at room temperature for 1 hour and at 80° C. for 10 minutes. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate: chloroform=4:1:1) to provide the title compound as colorless solid (350 mg).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.C1(C)C=CC=CC=1NN.[O:16]=[CH:17][C@@H:18]([C@H:20]([C@@H:22]([C@@H:24]([CH2:26][OH:27])[OH:25])[OH:23])[OH:21])[OH:19].[O:28]=[CH:29][C:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])=O>O>[C@@H:26]1([O:27][C@H:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])[CH:29]=[O:28])[O:19][C@H:18]([CH2:17][OH:16])[C@@H:20]([OH:21])[C@H:22]([OH:23])[C@H:24]1[OH:25]
Reactant: O=CC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CC(=O)[O-]
Agent: Cc1ccccc1NN
Agent: Cl
Solvent: O
Product: O=C[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C

Procedure:
This oligosaccharide (5 μmol), sodium acetate (10 μmol) and o-tolylhydrazine hydrochloride (30 μmol) were dissolved in 0.15 mL water in a small vial (Pierce reacti-vial, 0.2 mL capacity, with Tuf-bond Teflon-silicone cap seals). The vial was sealed under argon and warmed on a heating block to 70° C. for 6 hours; the solution became yellow over time and gave a yellow crystalline precipitate, which increased upon cooling to room temperature overnight. The water-insoluble material was the cleavage product, glucose o-tolylosazone (D-arabino-hexos-2-ulose o-tolylosazone. The water soluble fraction contained 2-Oβ-D-glucopyranosyl-D-glucose o-tolylhydrazone, and small amounts of D-glucose and the starting oligosaccharide.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[BH4-].[Na+]>CO>[OH:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:1][OH:2]
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
A solution of methyl 3-formyl-4-hydroxybenzoate (19.80 g; 109.90 mmol; 1 eq.) in MeOH (396 mL) was added at 0° C. NaBH4 (6.24 g; 164.85 mmol; 1.50 eq.) in several portions (portions over 20 min). The reaction mixture was stirred at RT for 2 hours. The reaction mixture was concentrated and the residue was suspended in EtOAc (500 mL). The organic layer was washed with a saturated aqueous solution of NH4Cl (2×200 mL), water (200 mL), then brine (200 mL). The aqueous layer contained a lot of the desired compound so it was saturated with NaCl and extracted with EtOAc (4×600 mL). Organics were combined, dried over MgSO4 and concentrated affording the title compound as a beige solid (10.52 g, 52%). LC/MS (Method B): 181.1 (M−H)−.
Reaction SMILES: [CH3:1][Si:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][O:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1OS(C(F)(F)F)(=O)=O)=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].C(=[NH:47])(C1C=CC=CC=1)C1C=CC=CC=1.O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][Si:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][O:5][C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[NH2:47])=[O:7]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOC(=O)c1c(N)ccc2ccccc12
Temperature: 65 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To a solution of 2-trifluoromethanesulfonyloxy-naphthalene-1-carboxylic acid 2-trimethylsilanyl-ethyl ester (4.22 g, 10.0 mmol) in THF (40 mL) were added cesium carbonate (4.58 g, 14.05 mmol), palladium acetate (0.067 g, 0.3 mmol), BINAP (0.28 g, 0.45 mmol) and benzophenone imine (2.0 mL, 12.04 mmol) under an argon atmosphere. The mixture was heated at 65° C. for 16 h. After addition of water the mixture was extracted with EtOAc, washed with brine, dried (Na2SO4) and concentrated to dryness. To the residue were added THF (40 mL), methyl alcohol (10 mL) and 2N HCl (6.6 mL), and the mixture was stirred for 2 h at room temperature. After addition of 10% NaHCO3 the mixture was extracted, dried (Na2SO4) and concentrated to dryness. Purification by chromatography gave 1.8 g of 2-amino-naphthalene-1-carboxylic acid 2-trimethylsilanyl-ethyl ester.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:20]=[CH:19][C:13]([CH2:14][P:15](=[O:18])([OH:17])[OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].N1C=C[CH:24]=[CH:23][CH:22]=1>O1CCCC1>[N+:7]([C:10]1[CH:20]=[CH:19][C:13]([CH2:14][P:15]2(=[O:16])[O:17][CH2:24][CH2:23][CH2:22][O:18]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Reactant: c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CP2(=O)OCCCO2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
Oxalyl chloride (22.09 g) was added dropwise to a mixture of 4-nitrobenzylphosphonic acid (17.99 g), pyridine (13.76 g) and tetrahydrofuran (500 ml) at -78° C. After the mixture was stirred at -78° C. for 30 minutes and then at room temperature for 1.5 hours, the insoluble solid was filtered off. The flitrate was concentrated under reduced pressure, and the residual oily substance was dissolved in tetrahydrofuran (500 ml). To this solution, a solution of 1,3-propanediol (2.58 g) in acetonitrile (30 ml) was added dropwise at -78° C. over a 15-minute period. Then, pyridine (5.62 g) was added dropwise at -78° C. over a 5-minute period, and the mixture was stirred at room temperature for 15 hours. After the insoluble solid was filtered off, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-chloroform-methanol (10:10:1, v/v) to yield 2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinane-2-oxide (5.62 g, 26%), which was then recrystallized from ethanol-hexane to yield colorless needles having a melting point of 144° to 145° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH:10][C:11]2[O:12][C:13]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[N:14][N:15]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:21]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:21]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]([C:8]([NH:10][C:11]3[O:12][C:13]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)=[N:14][N:15]=3)=[O:9])[CH:5]=[N:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cncc(Br)c1
Product: O=C(Nc1nnc(-c2ccco2)o1)c1cncc(-c2ccc(-c3ccccc3)cc2)c1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 5-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-3-pyridinecarboxamide prepared in Reference Example 8 instead of compound Ia-50 and using commercially available 4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[CH:8][CH:9]=[N:10][C:5]2=[C:4]([Cl:11])[N:3]=1.C1C(=O)N([I:19])C(=O)C1>C1COCC1>[I:19][C:8]1[CH:9]=[N:10][C:5]2[C:6]=1[NH:7][C:2]([Cl:1])=[N:3][C:4]=2[Cl:11]
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1nc(Cl)c2nccc-2[nH]1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncc(I)c-2[nH]1
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a solution of 2,4-dichloro pyrrolo[3,2-d]pyrimidine 19 (100 mg, 0.53 mmol) in anhydrous THF (5 mL), NIS (144 mg, 0.64 mmol) was added under N2 atmosphere and stirred for 2 h after which TLC indicated consumption of 19. The solvent was removed in vacuo and the residue dissolved in EtOAc. The organic phase was washed with aq. solution of Na2S2O3 followed by water, brine and then dried over MgSO4. The organic layer was concentrated in vacuo and loaded on silica. The product 20 was purified using column chromatography eluting with 9:1 hexanes/EtOAc to obtain product as off-white solid (90 mg, 54%). Rf 0.55 in 3:1 hexanes/EtOAc. Mp decomposed from 160-230° C. 1H NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 13.19 (s, 1H, NH). 13C NMR (400 MHz, DMSO-d6): δ 58.2, 124.4, 140.9, 143.5, 149.8, 153.5. ESI-MS m/z for calculated [M+H]+ 313.8743. found 313.8740.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[C:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:17]=3)[C:12]3[CH:27]=[C:28]([Cl:31])[CH:29]=[N:30][C:11]2=3)(=O)=O)C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:31][C:28]1[CH:29]=[N:30][C:11]2[NH:10][C:18]3[C:13]([C:12]=2[CH:27]=1)=[CH:14][C:15]([C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:16][CH:17]=3
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(C#Cc3ccccc3)cc2c2cc(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Clc1cnc2[nH]c3ccc(C#Cc4ccccc4)cc3c2c1
Yield: 90 %

Procedure:
To a solution of 9-benzenesulfonyl-3-chloro-6-(2-phenylethynyl)-9H-pyrido[2,3-b]indole (88 mg, 0.20 mmol, 1 equiv.) in anhydrous THF under argon, TBAF 1M in THF (1 ml, 1 mmol, 5 equiv.) is added dropwise. The reaction is carried out at reflux for 4 hours and then evaporated. The crude product (yellow solid) is purified over silica gel chromatography (CH2Cl2/AcOEt 9:1) to afford the product 60 as a white solid (53 mg, 0.18 mmol) in 88% yield. 1H NMR (300 MHz, DMSO d6) δ 12.25 (br s, 1H), 8.77 (d, 1H, J=2.5 Hz), 8.49 (br s, 1H), 8.47 (d, 1H, J=2.5 Hz), 7.67 (dd, 1H, J=1.5, 8.5 Hz), 7.59-7.54 (m, 3H), 7.45-7.42 (m, 3H).