Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([NH:13]C(=O)OCC2C=CC=CC=2)=[CH:4][N:3]=1>[Pd].CO>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]([NH2:13])=[CH:4][N:3]=1
Reactant: Cc1ncc(NC(=O)OCc2ccccc2)n1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1ncc(N)n1-c1ccccc1

Procedure:
To a mixture of benzyl N-(2-methyl-3-phenyl-imidazol-4-yl)carbamate (510 mg, 1.659 mmol) and Pd on C, wet, Degussa (176.6 mg, 0.1659 mmol) was added methanol (10 mL). The reaction was hydrogenated (balloon pressure) for 2 h before the catalyst was filtered off and the filtrate concentrated in vacuo yielding 2-methyl-1-phenyl-1H-imidazol-5-amine as a yellow oil that is immediately used in next step without further purification. MS (ES+) 174.4.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[O:18][CH:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16][CH2:15]4)[CH2:7][CH2:6]2)[O:4]CC1.Cl>O1CCCC1.C(OCC)(=O)C>[C:22]1([CH:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH:8]4[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]4)[CH:13]=3)[O:18]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(C2CCc3cc(OC4CCC5(CC4)OCCO5)ccc3O2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
430 mg of 6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-2-phenyl-chroman were dissolved at room temperature in 5 ml of tetrahydrofuran. 5 ml of 10% aqueous hydrochloric acid were added and stirring at room temperature was continued for 16 h. The reaction mixture was diluted with ethyl acetate and the organic layer washed with saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried with sodium sulfate and filtered, and the volatile components removed under reduced pressure. 357 mg of the title compound were obtained as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:24][CH:23]=1
Reactant: CC1CCCCN1CCN
Reactant: O=C(O)c1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1CCCCN1CCNC(=O)c1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of DCM containing 4-(2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid (Intermediate 7, 1 eq.) was stirred at room temperature, DMAP (1.1 equivalent) and 2-(2-methylpiperidin-1-yl)ethanamine (1 eq.) were added. The reaction mixture was then cooled down to 0° C. and EDC (1.1 eq.) was added portion-wise. After stirring for 1 hour at 0° C., the reaction mixture was allowed to warm to room temperature. The reaction was monitored by TLC and LC/MS. Usually after 12 hours stirring at RT, the reaction mixture was hydrolyzed, washed with sodium carbonate solution (10%), dried over MgSO4, and evaporated in vacuo to give a crude product. Flash chromatography on silica gel, eluting with 60% EtOAc in hexane gave, after evaporation, the expected product N-[2-(2-methylpiperidin-1-yl)ethyl]-4-(2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide (1) as a beige solid, in 80% yield (96% purity by HPLC). MS(ESI+): 442.7; MS(ESI−): 440.5.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[Cl:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:39])[CH3:38])[C:29](OC)=O>C1COCC1>[Cl:25][C:26]1[CH:27]=[C:28]([C:29]2[O:1][N:2]=[C:3]([C:4]3[C:14]4[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10][CH2:9][C:8]=4[CH:7]=[CH:6][CH:5]=3)[N:22]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH:37]([CH3:38])[CH3:39]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=N)NO)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)CC4)no2)cc1Cl

Procedure:
1,1-dimethylethyl 6-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 15) (170 mg, 0.557 mmol) was dissolved in THF (30 ml) and stirred with sodium hydride (24.49 mg, 0.612 mmol) under argon at room temperature for 30 minutes. Then methyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (may be prepared as described in WO2005058848) (191 mg, 0.835 mmol) was added and the reaction heated at reflux temperature for 1.5 hours. The cooled reaction was evaporated and partitioned between DCM (100 ml) and water (100 ml). The water layer was washed with DCM (50 ml) and the combined DCM layers dried (hydrophobic frit) and evaporated. The title compound was isolated by silica chromatography (eluting with DCM). 1,1-dimethylethyl 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (260 mg, 0.537 mmol, 96% yield) was isolated as an off-white foam. δH (400 MHz, CDCl3) 8.22 (1H, s), 8.05 (1H d), 7.68 (1H, d), 7.30-7.24 (2H, m), 7.06 (1H, d), 4.72 (1H, sept), 3.65-3.55 (4H, m), 3.35-3.25 (2H, m), 2.95-3.05 (2H, m); 1.45 (6H, d), 1.43 (9H, s); MS (ES) C26H3035ClN3O4 requires 483; found 484 [M+H]+.
Reaction SMILES: C[C@@H](N)[C@@H](O)C1C=CC=CC=1.B#B.O1CCCC1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[C:28](/[N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)\[C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].Cl>ClCCCl>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[C:28](/[N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)\[CH:29]([OH:34])[C:30]([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: B#B
Agent: C[C@@H](N)[C@@H](O)c1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Reaction time: 24 h
Yield: 99.4 %

Procedure:
In a nitrogen atmosphere, a solution of 0.272 g of (+)-norephedrine in 4 ml of 1,2-dichloroethane was added dropwise at -78° C. to a mixture comprising 1.8 ml of a 0.500M diborane-tetrahydrofuran solution and 2 ml of 1,2-dichloroethane, and the temperature of the resulting mixture was raised from -78° C. to room temperature over about 2 hours. Thereafter, to this solution was added dropwise at room temperature a solution of 0.39 g of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=99.9/0.1) in 4 ml of 1,2-dichloroethane, and stirring was carried out for 24 hours. Thereafter, 6 ml of 2M hydrochloric acid was added to the reaction solution, followed by stirring for about 2 hours. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified on a column packed with 2 g of silica gel using a chloroform solvent and then concentrated under reduced pressure to obtain 0.39 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol as a crude crystal. The conversion was 98.6%, and the composition of the product obtained was: E-form alcohol, 98.6% and Z-form alcohol, 1.4%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][C:6]=1[F:19])[CH3:2].[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.O1CCCC1.C(OCC)C.[Cu]I.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>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:7][C:6]=1[F:19])[CH3:2]
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1F
Temperature: 70 °C
Yield: 94.6 %

Procedure:
A solution of ethyl-2-fluoro-4-trifluoromethylsulfonyloxy-benzoate (Intermediate 6, 1.82 g, 6 mmol) in triethyl amine (12 mL) and anhydrous tetrahydrofuran (30 mL) was treated with copper(I)iodide (0.12 g, 0.6 mmol) and sparged with argon. Dichlorobis(triphenylphosphine)palladium(II) (0.43 g, 0.6 mmol) was added followed by (trimethylsilyl)acetylene (3.6 mL, 24 mmol) and the resulting reaction mixture was heated at 70° C. overnight. It was then cooled to ambient temperature, diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated in vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as an orange oil (1.5 g, quantitative).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.O.[NH2:23][NH2:24]>O1CCOCC1>[NH:23]([C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1)[NH2:24]
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1nnc(NN)nc1N1CCc2ccccc2CC1

Procedure:
In analogy to the procedure as described in example 4 the 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4] triazine-6-carbonitrile was reacted with hydrazine hydrate in dioxane at 140° C. during 3 hours to give 3-hydrazino-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a yellow amorphous powder; MS: 282 (M+H)+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH:24]2[O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]3[O:49][CH2:48][CH2:47][N:46]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:45]=3[CH:55]=2)=[CH:19][CH:18]=1.O[C:57]1[CH:58]=[C:59]([CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH:60]=[CH:61][CH:62]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:67]([O:66][C:64]([CH2:63][C:59]1[CH:58]=[C:57]([CH:62]=[CH:61][CH:60]=1)[O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:25][CH:24]2[O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]3[O:49][CH2:48][CH2:47][N:46]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:45]=3[CH:55]=2)=[CH:21][CH:22]=1)=[O:65])[CH3:68]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(OCc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3OCc3ccc4c(c3)N(CCCOC)CCO4)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.1122 g of diisopropyl azodicarboxylate is added dropwise to a solution of 0.246 g of benzyl 4-(4-hydroxymethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270c), 0.1061 g of ethyl (3-hydroxyphenyl)acetate, 0.1396 g of triphenylphosphine and 5 ml of tetrahydrofuran. The solution is stirred at room temperature for 1 hour and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.28 (1:1 EtOAc-heptane); Rt=5.91.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([F:35])([F:34])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CC(F)(F)F
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (11 mg, 35%), MS (ISP) m/z=442.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3,3,3-trifluoropropanoic acid.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:10][C:9]=1[C:19]([O:21]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:10][C:9]=1[C:19]([NH2:2])=[O:21])[CH3:5]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N=NN(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1cc(-c2ccccc2)sc1C(N)=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 8 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (80 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]-5-phenylthiophene-2-carboxylate (2.2 g) in THF (15 mL) for 5 min followed by catalytic amount of PEG-400 and the mixture was stirred at rt for 36 h. The solution was poured into ice cooled water and extracted with chloroform. The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (94:6) as eluents to give the product. The crude product was recrystallized from chloroform-hexane to give the product as a yellow color solid (170 mg, 8%), mp 220-222° C. IR (neat) νmax, 3343, 2922, 2855, 1642, 1595, 1221, 1023, 880, 841 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.30 (1H, br s), 7.64-7.66 (2H, m), 7.53 (1H, s), 7.30-7.41 (3H, m), 6.34 (1H, br s), 3.59 (3H, s), 3.20 (3H, s); 13C NMR (100 MHz, CDCl3): δ 164.7, 151.1, 146.7, 133.9, 128.9, 128.5, 125.8, 125.4, 114.7, 43.6, 36.5; LC-MS (positive ion mode): m/z 297 (M+Na)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](N)[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]=[CH2:13])([O-:3])=[O:2].ClC1C=CC([C:20]([OH:22])=[O:21])=CC=1[N+]([O-])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]=[CH2:13])[C:20]([OH:22])=[O:21])([O-:3])=[O:2]
Reactant: C=CCNc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: C=CCNc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
Synthesis and working up as for compound 1, but with 4-chloro-3-nitrobenzoic acid instead of 4-fluoro-3-nitroaminobenzene. Yellow crystals, melting point 195°-200° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][N:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:15][C:13]2[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[N:11]3[N:12]=2)=[O:22])=[CH:19][N:18]=1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc(Cl)nc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and 6-chloronicotinoyl chloride (65 mg, 0.60 mmol; 2.0 eq.) as a white powder (47.7 mg, 47%). HPLC, Rt: 3.00 min. (purity 98.6%). LC/MS, M+(ESI): 340.2, M−(ESI): 338.2.
Reaction SMILES: [C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=[C:11]([OH:15])[C:12]([OH:14])=O)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:40][C@H:41]([C:49]([NH2:51])=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=[C:11]([OH:15])[C:12]([NH:40][C@H:41]([C:49](=[O:50])[NH2:51])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)c1ocnc1C=C(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ocnc1C=C(O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O

Procedure:
To a solution of compound 3 (2.6 g, 12.3 mmol) in DMF was added HOBt.H2O (2.26 g, 14.76 mmol), EDC.HCl (2.80 g, 14.76 mmol), HCl.H-Phe-NH2 (3.16 g, 14.76 mmol), triethylamine (1.72 mL, 12.3 mmol) sequentially at 0° C. and the mixture was stirred for 14 h at room temperature. After the solvent was removed in vacuo, the residue was dissolved in AcOEt and washed with 5% citric acid, 5% NaHCO3 and saturated NaCl for three times, respectively. Then, the organic layer was dried over Na2SO4 and evaporated in vacuo. The resultant crude product was purified by silica-gel column chromatography (CHCl3:MeOH=100:1 to 10:1) to obtain the desired compound 4; yield 1.9 g (43.4%); m.p. 49-53° C.; 1H NMR (300 MHz, CDCl3) δ 11.04 (s, 1H), 7.82 (s, 1H), 7.34-7.22 (m, 5H), 6.24 (s, 1H), 5.96 (br s, 1H), 5.45 (br s, 1H), 4.78-4.71 (m, 1H), 3.24-3.11 (m, 2H), 1.38 (s, 9H); HRMS (EI): m/z 357.1689 (M+) (calced for C19H23N3O4: 357.1688).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][S:29]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2B2OC(C)(C)C(C)(C)O2)[CH2:33]1)(=[O:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+].O.O1CCCC1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][S:29]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([CH:18]5[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:20][CH2:19]5)=[CH:14][CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH2:33]1)(=[O:31])=[O:30]
Reactant: NC(=O)CN1CCC(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: CC1(C)OB(c2cccc3c2CN(S(C)(=O)=O)C3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cccc(-c3ccc4cnc(Nc5ccc(C6CCN(CC(N)=O)CC6)cc5)nn34)c2C1
Temperature: 25 °C
Yield: 1.9 %

Procedure:
2-{4-[4-(7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)-phenyl]-piperidin-1-yl}-acetamide (150 mg, 0.00035 mol), 2-Methanesulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindole (169.4 mg, 0.0005241 mol), 0.9 M of Sodium carbonate in water (0.23 mL, 0.00021 mol), Tetrakis(triphenylphosphine)palladium (O) (0.040 g, 0.000035 mol) and Tetrahydrofuran (2 mL, 0.03 mol) were heated at 80° C. overnight. The reaction was cooled to RT, dissolved partially in DCM and filtered. The filtrate was placed onto a 40 gm column eluting with DCM to 5% MeOH/DCM. Dissolved in DMSO, filtered and placed onto the Gilson. Most pure fractions were free based and worked up to give 2-(4-{4-[7-(2-Methanesulfonyl-2,3-dihydro-1H-isoindol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide as a yellow solid (3.7 mg, 1.9%). MP 244-247° C. LCMS (E/I+) 546 (M+H). NMR 1H (DMSO-d6)-9.45 (s, 1H), 9.01 (s, 1H), 7.97 (d, 1H, J=7.77 Hz), 7.62 (d, 2H, J=8.60 Hz), 7.56 (t, 1H, J=7.68 Hz), 7.44 (d, 1H, J=7.54 Hz), 7.20 (s, 1H), 7.12 (s, 1H), 7.10 (d, 1H, J=8.51 Hz), 7.06 (d, 1H, J=4.63 Hz), 6.98 (d, 1H, J=4.80 Hz), 4.74 (s, 4H), 2.91-2.92 (m, 4H), 2.86-2.89 (m, 3H), 2.38-2.42 (m, 1H), 2.10-2.20 (m, 2H), 1.65-1.74 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:8].[C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)([OH:26])=[O:25].[BH4-].[Na+]>C(O)(=O)C>[C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:14][C:9]([C:7]([NH:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][CH2:30][C:29]3[CH:28]=[C:27]([CH:34]=[CH:33][CH:32]=3)[C:24]([OH:26])=[O:25])[CH:23]=[CH:22][CH:21]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: Nc1cccc(CNC(=O)c2ccc(-c3ccccc3)cc2)c1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1cccc(CNc2cccc(CNC(=O)c3ccc(-c4ccccc4)cc3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
N-(3-aminobenzyl)-1,1′-biphenyl-4-carboxamide (20 mg, 0.07 mmol) was dissolved in acetic acid (0.5 ml). 3-Carboxybenzaldehyde (14 mg, 0.09 mmol) was added and then sodium borohydride (11 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 2 hours and evaporated to dryness. DCM was added into the residue. The mixture was loaded on a column (ISOLUTE® SI, 500 mg/3 ml). It was eluted with DCM, MeOH/DCM (0.5:99.5) and then MeOH/DCM (1:99). The product fractions were combined and the solvent was removed, Re-chromatography of the residue on a column (ISOLUTE® SI, 1 g/6 ml) using DCM, MeOH/DCM (0.5:99.5) and then MeOH/DCM (1:99) as eluant gave 9 mg the desired product, yield 31%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:23]([N:26]([P:30](N(C(C)C)C(C)C)[O:31][CH2:32][CH2:33][C:34]#[N:35])[CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24]>ClCCl>[CH:23]([N:26]([P:30]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:10])[O:31][CH2:32][CH2:33][C:34]#[N:35])[CH:27]([CH3:28])[CH3:29])([CH3:24])[CH3:25]
Reactant: COC(=O)CCCCCO
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: COC(=O)CCCCCOP(OCCC#N)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.786 g (5.37 mmole) of methyl-6-hydroxyhexanoate and 0.48 g (2.8 mmole) of diisopropylammonium tetrazolide in 25 ml of dichloromethane were added dropwise 1.62 g (5.37 mmole) of bis(diisopropyl amino)-2-cyanoethyoxyphosphine (Aldrich). The resulting solution was stirred at 25° C. for 2 hours and extracted with phosphate buffer at pH 7. Drying over magnesium sulfate and fast chromatography on silica gel (40% ethylacetate-hexanes, trace triethylamine) yielded the diisopropylamino-5-(carbomethoxy)pentyloxy-2-cyanoethoxy phosphine linking group as a colorless oil (1.30 g: 70%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([OH:10])=[C:8]([C:11]3[NH:16][C:15]4[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=4[S:13](=[O:22])(=[O:21])[N:12]=3)[C:7](=[O:23])[N:6]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5]=2[N:31]=1.N(OC(C)(C)C)=O>CN(C=O)C>[CH2:24]([N:6]1[C:7](=[O:23])[C:8]([C:11]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[S:13](=[O:21])(=[O:22])[N:12]=2)=[C:9]([OH:10])[C:4]2[S:3][CH:2]=[N:31][C:5]1=2)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1nc2c(s1)c(O)c(C1=NS(=O)(=O)c3ccccc3N1)c(=O)n2Cc1ccccc1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2scnc2n1Cc1ccccc1
Yield: 54 %

Procedure:
The product of Example 147 (0.0085 g, 0.019 mmol) was reacted with tert-butyl nitrite (5 □L, 0.037 mmol) in DMF (0.3 mL) at 60° C. for 1 hour. The reaction was cooled, and the crude mixture was purified by column chromatography with silica gel eluting with hexane and ethyl acetate (1:1) to give the title compound as a yellow solid (0.0045 g, 54%). MS (ESI) m/z 437 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 5.53 (s, 2 H), 7.25 (m, 1 H), 7.31 (m, 4 H), 7.43 (m, 2 H), 7.66 (m, 1 H), 7.80 (d, J=8.46 Hz, 1 H), 9.48 (s, 1 H), 14.56 (br s, 1 H).