Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#C)[C:5]2[O:9][C:8]([CH2:10][C:11]3[CH:16]=[C:15](C(C)(C)C)[C:14](O)=[C:13](C(C)(C)C)[CH:12]=3)=[N:7][C:6]=2[CH:26]=1.BrC1C=CC=C[N:31]=1>C(N(CC)CC)C.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>[N:31]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:11]#[C:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][CH:2]=[CH:26][C:6]=2[N:7]=1
Reactant: Brc1ccccn1
Reactant: C#Cc1cc(Cl)cc2nc(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#Cc1nc2ccccc2o1)c1ccccn1
Temperature: 90 °C
Yield: 224 %

Procedure:
A suspension of 5-chloro-2-(3,5-di-t-butyl-4-hydroxy-benzyl)-7-ethynyl-benzoxazole (2.38 g, 6.0 mmol), 2-bromo-pyridine (0.66 ml, 98%, 6.6 mmol), bis(triphenylphosphine)palladium(II) dichloride (21.1 mg, 30 μmol) and copper (I) iodide (1.2 mg, 6 μmol) in triethylamine (12 ml) was heated at 90° C., under argon, for 1.5 hours. The triethylamine was removed in-vacuo and the residue dissolved in ether (100 ml). The organics were washed with water (50 ml), 1 N HCl (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), dried (Na2SO4) and evaporated in-vacuo to give 2.96 g (104.2%) of crude pyridylethynylbenzoxazole. The crude benzoxazole was purified by column chromatography (SiO2; dichloromethane), and the product crystallized from methanol and suspended in hot water. The resulting crystals were collected, washed, and dried to give 1.49 g (52.5%) of the title compound (mp 138-9° C.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>>[CH3:23][N:24]([CH2:25][C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: CNCC(=O)N1CCOCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CN(CC(=O)N1CCOCC1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 2-(methylamino)-1-morpholinoethanone to give 225. MS: (ESI+)=454.1
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([NH:11][O:12][CH3:13])=[O:10])=[CH:4][C:3]=1[NH:14][C:15]1[C:20]2=[C:21]([CH:27]([CH3:29])[CH3:28])[C:22]([C:24]([OH:26])=O)=[CH:23][N:19]2[N:18]=[CH:17][N:16]=1.C(N(CC)CC)C.C1(P([N:51]=[N+:52]=[N-:53])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9](=[O:10])[NH:11][O:12][CH3:13])=[CH:4][C:3]=1[NH:14][C:15]1[C:20]2=[C:21]([CH:27]([CH3:28])[CH3:29])[C:22]([C:24]([N:51]=[N+:52]=[N-:53])=[O:26])=[CH:23][N:19]2[N:18]=[CH:17][N:16]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CONC(=O)c1cc(Nc2ncnn3cc(C(=O)O)c(C(C)C)c23)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CONC(=O)c1cc(Nc2ncnn3cc(C(=O)N=[N+]=[N-])c(C(C)C)c23)c(F)cc1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of Example 22 (1.11 g, 2.74 mmol) in dioxane (25 mL) was added triethylamine (0.57 mL, 4.1 mmol) followed by diphenylphosphoryl azide (0.77 mL, 3.57 mmol) and the resulting mixture was stirred at 40° C. After 1 h, the mixture was concentrated and the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to afford acyl azide, 4-(2,4-difluoro-5-methoxycarbamoyl-phenylamino)-5-isopropyl-pyrrolo[2, 1-f][1,2,4]triazine-6-carbonyl azide (0.95 g, 81%) as pale yellow foam.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCO>[CH2:16]([S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[NH:3][CH:2]=[N:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: c1ccc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol), benzyl bromide (0.178 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH:21]1[CH2:23][CH:22]1[C:24]([O:26]CC)=[O:25])=[CH:15]2.[OH-].[Na+].Cl.[CH3:32]O>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C@@H:21]1[CH2:32][C@H:23]1[CH2:22][C:24]([OH:26])=[O:25])=[CH:15]2
Reactant: CCOC(=O)C1CC1c1cc2cc(OCCCNc3ccccn3)ccc2[nH]1
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C[C@@H]1C[C@H]1c1cc2cc(OCCCNc3ccccn3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Ethyl 2-{5-[3-(2-pyridylamino)propoxy]indolyl}cyclopropanecarboxylate (0.38 g, 1.056 mmol), as prepared in the preceding step, was dissolved in 7.5 mL of methanol. A solution of NaOH (0.13 g, 3.18 mmol) in water (2.5 mL) was added and the reaction was stirred at ambient temperature overnight. The base was then neutralized with an aqueous solution of HCl (3.18 mmol), and the solvent was evaporated under vacuum. The crude product was chromatographed on silica gel to obtain the title compound (200 mg, 57%). 1H NMR (400 MHz, CDCl3) 5 1.66 (m, 2H), 2.00 (m, 1H), 2.16 (m, 2H), 3.58 (m, 2H), 3.72 (m, 1H), 4.12 (t, 2H, J=5.8 Hz), 6.31 (dd, 1H, J=0.7, 3.2 Hz), 6.77 (m, 1H,), 6.85 (dd, 1H, J=2.3, 8.8 Hz), 6.97 (d, 1H, J=9.0 Hz), 7.06 (d, 1H, J=2.3 Hz), 7.13 (d, 1H, J=3.2 Hz), 7.33 (d, 1H, J=8.8 Hz), 7.77 (m, 2H). Mass spectrum (LCMS, ESI pos.) Calcd. for C21H23N3O3 352.2 (M+H); Found: 352.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[CH:27]=O)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[CH2:27][N:32]3[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]3)[N:20]=2)[N:10]=[N:9]1
Reactant: OC1CCNC1
Reactant: O=Cc1cccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)c1
Product: OC1CCN(Cc2cccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)c2)C1

Procedure:
The title compound was prepared following the procedure described for Example 94, starting from 3-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (100 mg; 0.24 mmol) and 3-pyrrolidinol (32.7 mg; 0.48 mmol) to give Example 134 as an off-white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.97 (1H, s), 7.96-7.84 (2H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.6 Hz), 7.59-7.49 (4H, m), 4.74 (1H, d, J=4.4 Hz), 4.29-4.21 (1H, m), 3.75-3.63 (2H, m), 2.75 (1H, dd, J=9.6, 6.2 Hz), 2.63 (1H, q, J=7.8 Hz), 2.51-2.45 (1H, m), 2.36 (1H, dd, J=9.6, 3.8 Hz), 2.10-1.99 (1H, m), 1.64-1.55 (1H, m). LC/MS (Method C): 484 (M+H)+. HPLC (Method E) Rt 2.13 min (Purity: 97.8%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH:13][CH:14]([CH2:17][OH:18])[CH2:15][NH2:16].[H][H]>O.CO.[Ni]>[OH:13][CH:14]([CH2:17][OH:18])[CH2:15][NH:16][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: [H][H]
Reactant: NCC(O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Solvent: CO
Solvent: O
Product: OCC(O)CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 2 h

Procedure:
A solution of 19.6 gm (0.2 mol) of D-glucose (containing 0.1 mol of H2O) and 18.2 gm (0.2 mol) of 2,3-dihydroxypropylamine in 400 ml of water and 350 ml of methanol was, after the addition of 18 gm of Raney nickel, hydrogenated for 2 hours at 50° C. in an autoclave having stirring means, and then for 3 hours at 70° C., both at a hydrogen pressure of about 180 kg/cm. After the catalyst had been filtered off and the solvent removed by distillation under reduced pressure, the residue was recrystallized from water/2-propanol and digested with cold 2-propanol. 36.5 gm (72% of theory) of colorless, crystalline N-(2,3-dihydroxypropyl)-glucamine with a melting point of 133° to 134° C. was obtained.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].CS(O[CH2:18][CH2:19][C@H:20]1[C@@H:27]2[C@@H:23]([O:24][C:25]([CH3:29])([CH3:28])[O:26]2)[O:22][C@@H:21]1[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)(=O)=O.C(OCC)(=O)C.O>CN(C)C=O>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][C@H:21]3[O:22][C@@H:23]4[O:24][C:25]([CH3:28])([CH3:29])[O:26][C@@H:27]4[C@@H:20]3[CH2:19][CH2:18][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[CH:37][CH:36]=2)=[CH:39][CH:40]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC1(C)O[C@H]2O[C@H](CCc3ccc(-c4ccc(Cl)cc4)cc3)[C@@H](CCOS(C)(=O)=O)[C@H]2O1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)O[C@H]2O[C@H](CCc3ccc(-c4ccc(Cl)cc4)cc3)[C@@H](CCN3C(=O)c4ccccc4C3=O)[C@H]2O1
Temperature: 50 °C

Procedure:
Potassium phthalimide (0.051 g) was added in one portion to a stirred solution of the compound obtained from step j above (0.12 g) in dimethylformamide (5 mL) at room temperature under a nitrogen atmosphere. The resulting solution was heated at 50° C. for about 14 hours and then cooled to room temperature. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous sodium sulphate. The organic phase was evaporated to dryness under reduced pressure. The residue thus obtained was purified by column chromatography using 30% ethyl acetate in hexane as eluant to furnish the title compound (0.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].Br[CH:37]([CH2:39][CH3:40])[CH3:38]>>[CH3:38][CH:37]([O:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:39][CH3:40]
Reactant: CCC(C)Br
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1O
Product: CCC(C)Oc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1OC

Procedure:
prepared by reaction of 2-[1-(3-hydroxy-4-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 2-bromo-butane
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12](Cl)=[O:13])[CH2:9][CH3:10]>N1C=CC=CC=1>[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([OH:4])=[O:13])[CH2:9][CH3:10].[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([OH:4])=[O:13])[CH2:9][CH3:10].[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[O:13])[CH2:9][CH3:10]
Reactant: OCCNCCO
Reactant: CCCC(CCC)C(=O)Cl
Solvent: c1ccncc1
Product: CCCC(CCC)C(=O)N(CCO)CCO
Product: CCCC(CCC)C(=O)O

Procedure:
Into a perfectly clean and dry flask were introduced 105.1 g (1 mol) of rectified diethanolamine and 1600 ml of anhydrous pyridine. While stirring, 507.4 g (3.12 mols) of di-n-propylacetyl chloride were added in 30 to 45 minutes, care being taken to maintain the temperature below +30° C. The reaction medium was then stirred at room-temperature for 48 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[C:13]([O-])([O-])=O.[K+].[K+].C([O:22][CH2:23][CH3:24])(=O)C>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[CH2:13][C:23](=[O:22])[CH3:24]
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CC1(O)C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Fluoroisatin 32 (10 mmol, Lancaster, order no. 14553) was dissolved in acetone 46 (50 ml), K2CO3 (138 mg, 1 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The course of the reaction was monitored by TLC (eluent: ethyl acetate). To work up the product the acetone was completely distilled off in vacuo. The residue was dissolved in ethyl acetate, and the solution was filtered over silica gel with ethyl acetate. The filtrate was concentrated to 20 ml, and hexane was added until precipitation started. To complete the precipitation, the solution was cooled to approx. 10° C. in a refrigerator overnight. The product which precipitated was filtered out with suction and dried in vacuo. The resulting crude product was recrystallized from ethyl acetate/hexane (1:4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].Br[CH:18]([CH2:24]Br)[C:19]([O:21][CH2:22]C)=[O:20]>CC(C)=O.CO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[O:10][CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:24][NH:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(O)c(N)c1
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)C1CNc2cc(C#N)ccc2O1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
3-Amino-4-hydroxy-benzonitrile (180 mg, 1.34 mmol) was dissolved in acetone (1.4 mL). To the solution was added K2CO3 (555 mg, 4.02 mmol) and ethyl 2,3-dibromopropanoate (380 mg, 1.46 mmol). The mixture was heated to reflux for 16 h. After cooling to room temperature the reaction mixture was filtered and concentrated in vacuo to give an oil. The oil was dissolved in methanol and was purified by silica gel chromatography (0-10% dichloromethane/hexanes) to afford methyl 6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (148 mg, 0.68 mmol). The methyl ester was isolated as methanol was used for loading the compound on silica resulting in transesterification. 1H NMR (400.0 MHz, DMSO-d6) δ 6.98 (dd, J=2.0, 8.2 Hz, 1H), 6.93-6.90 (m, 2H), 6.34 (s, 1H), 5.13 (t, J=3.3 Hz, 1H), 3.66 (s, 3H), 3.50-3.41 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]([CH2:14][C:15]2[CH:23]=[C:22]([CH3:24])[C:21]3[C:17](=[CH:18][N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:20]=3)[CH:16]=2)[CH2:10][C:11]([OH:13])=O)[CH:4]=1)[CH3:2].N1([C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[NH:42][C:41](=[O:49])[N:40]=2)CCCCC1.C(N(CC)CC)C.CCOP(ON1N=[N:75][C:70]2C=[CH:72][CH:73]=[CH:74][C:69]=2C1=O)(OCC)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]([CH2:14][C:15]2[CH:23]=[C:22]([CH3:24])[C:21]3[C:17](=[CH:18][N:19]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:20]=3)[CH:16]=2)[CH2:10][C:11]([N:75]2[CH2:72][CH2:73][CH:74]([N:40]3[CH2:39][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:42][C:41]3=[O:49])[CH2:69][CH2:70]2)=[O:13])[CH:4]=1)[CH3:2]
Reactant: CCc1ccnc(C(CC(=O)O)Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)c1
Reactant: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Reactant: O=c1nc(N2CCCCC2)c2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1ccnc(C(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of (±)-3-(4-ethylpyridin-2-yl)-4-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)butanoic acid (0.166 mmol, 1.0 equiv) in methylene chloride (3 mL) was added 3,4-dihydro-3-(4-piperidinyl-2(1H)-quinazolinone (46 mg, 0.199 mmol, 1.2 equiv). Triethylamine (70 μL) was then added followed by 3-(diethoxyphosphoryloxy)-1,2,3-benzotriain-4(3H)-one (DEPBT, 60 mg, 0.199 mmol 1.2 equiv) under nitrogen. The resulted cloudy yellow solution was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and quenched with 0.5 N sodium hydroxide solution. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (10% methanol in methylene chloride) to afford the desired product (72 mg, 65% for two steps): (ESI) 667 (MH)+.
Reaction SMILES: C(S)CCS.[CH2:6]([O:8][P:9]([CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])([CH:11]([N:24]=[N+]=[N-])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[CH3:7].C(N(CC)CC)C>CO>[CH2:6]([O:8][P:9]([CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])([CH:11]([NH2:24])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])=[O:10])[CH3:7]
Reactant: CCOP(=O)(COC(=O)CCC(C)C)C(CCCCNC(=O)OC(C)(C)C)N=[N+]=[N-]
Agent: SCCCS
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOP(=O)(COC(=O)CCC(C)C)C(N)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.04 ml of 1,3-propanedithiol were added dropwise to a stirred solution of 3.65 g of benzyl 2(R or S)-[[(RS)-(ethoxy)[1-(RS)-azido-5-tert.butoxycarbonylaminopentyl]phosphinyl]methyl]-4-methylvalerate and 2.83 ml of triethylamine in 80 ml of methanol. The mixture was stirred at room temperature overnight, the solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel using 4% methanol/dichloromethane for the elution to give 3.25 g of benzyl 2(R or S)-[[(RS)-(ethoxy)[1-(RS)-amino-5-tert.butoxy carbonylaminopentyl]phosphinyl]methyl]-4-methylvalerate as an off-white foam; nmr (CDCl3): 7.36 (s,5H); 5.2-5.08 (m,2H); 4.6 (brs,1H); 4.2-3.98 (m,2H); 3.17-3.08 (m,2H); 3.0-2.76 (m,2H); 2.4-2.13 (m,1H): 2.0-1.25 (m,25H); 0.98-0.86 (m,6H); MS: 513 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>CCO>[C:2]1([C:1]2[N:20]=[N:19][C:15]([OH:17])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=23)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1cccnc1C(=O)O
Solvent: CCO
Solvent: O
Product: Oc1nnc(-c2ccccc2)c2cccnc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 3-benzoylpicolinic acid (0.272 g, 0.120 mmol) and hydrazine hydrate (0.17 mL, 0.37 mmol) in EtOH (3.3 mL) was stirred at 80° C. overnight, concentrated, diluted with saturated aqueous NaHCO3, extracted with CH2Cl2, dried (Na2SO4), and concentrated to give the title compound as a white solid (0.28 g, 0.12 mmol). 1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.10 (dd, 1H), 8.09 (dd, 1H), 7.88 (dd, 1H), 7.54-7.63 (m, 5H).
Reaction SMILES: [CH:1]1([CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][CH:16]=3)[CH:8]=2)[F:6])[CH2:3][CH2:2]1.CS(C)=[O:27].[OH2:29]>CC#N.CC#N.Cl[Pd]Cl>[CH:1]1([CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([C:13](=[O:27])[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][CH:16]=3)=[O:29])[CH:10]=[CH:11][CH:12]=2)[F:6])[CH2:3][CH2:2]1
Reactant: FC(=CC1CC1)c1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reactant: O
Reactant: CS(C)=O
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: O=C(C(=O)c1cccc(C(F)=CC2CC2)c1)c1ccc(OC(F)F)cc1
Temperature: 145 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(2-cyclopropyl-1-fluorovinyl)-3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene (0.1 g, 0.3 mmol) and DMSO (1 mL) was degassed with argon for 5 minutes. Then, bis(acetonitrile)dichloropalladium (II) (7.8 mg, 0.03 mmol) was added and the mixture was stirred at 145° C. for 8 hours. Then, the mixture was poured into water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by ICSO (hexane/EtOAc 4/1) gave 1-[3-(2-cyclopropyl-1-fluorovinyl)phenyl]-2-[4-(difluoromethoxy)phenyl]ethane-1,2-dione 1:1 Z/E isomers (78 mg); MS m/e (M)+ 360.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:3]1[C:4]2[N:8]=[N:7][NH:6][C:5]=2[CH:9]=[CH:10][C:2]=1[Cl:1])([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc2[nH]nnc2c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)ccc2[nH]nnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
5-Chloro-1H-benzotriazole (3.08 g, 20 mmol) was dissolved in conc. sulphuric acid (40 ml) and cooled to 0° C. on an ice bath. Nitric acid (40 ml, excess) was added drop wise to the cooled solution over a period of 20 minutes. Stirring was continued for 1 hour at 0° C. and then at 60° C. for an additional 1 hour, by which time TLC (A) indicated the conversion of starting material. The solution was cooled to room temperature and poured over ice to precipitate a white solid. The solid was collected by filtration and washed with copious amounts of water until neutral to afford [22] in 83% yield. Rf (A) 0.49 δH(400 MHz; DMSO-d6) 7.75 (1H, d, J8.8, BT) 8.38 (1H, br s, BT); m/z (EI−HR) 197.99383 [(M) calc. for C6H3N4O235Cl 197.99445] and 199.99345 [(M) calc. for C6H3N4O237Cl 199.99150].
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13]C(C(O)=O)[S:15][CH2:16]2)=[CH:11][CH:10]=1.CN(C=O)C>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH:1]([C:2]([Cl:4])=[O:3])[S:15][CH2:16]2)=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2c(c1)CSC(C(=O)O)C2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CSC(C(=O)Cl)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2.0 M solution of oxalyl chloride (3.57 mL, 7.14 mmol) in CH2Cl2 was added under N2 to a solution of 7-methoxy-isothiochroman-3-carboxylic acid (0.80 g, 3.57 mmol) and a drop of DMF in CH2Cl2 (100 mL). The solution was allowed to stir at room temperature for 3 h and was concentrated under reduced pressure to provide 7-methoxy-isothiochroman-3-carbonyl chloride as a tan oil. The acid halide was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](C)=[C:6](O)[CH:7]=1.[NH3:10].[OH2:11]>[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH:2]1[C:3](=[N:10][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:4]=[CH:5][C:6](=[O:11])[CH:7]=1
Reactant: Cc1ccc(N)cc1O
Reactant: N
Reactant: O
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Product: Nc1ccc(N=C2C=CC(=O)C=C2)cc1

Procedure:
0.02 mole (2.46 g) 5-amino 2-methyl phenol and 0.02 mole (2.85 g) chloroparaphenylene diamine are dissolved in 200 cc water to which have been added 50 cc ammonia 22° Be. To this mixture there is added, little by little with agitation, 0.04 mole (13.16 g) potassium ferricyanide. The reaction mass is then filtered on a suction filter and a yield of 5 g of said indoaniline is obtained. After recrystallization in a pyridine and water mixture, the said indoaniline recovered melts at 120°.