Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[S:17][C:10]2[C:11](=[O:16])[NH:12][CH2:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:6].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][C:5]([C:7]4[S:17][C:10]5[C:11](=[O:16])[NH:12][CH2:13][CH2:14][CH2:15][C:9]=5[CH:8]=4)=[O:6])[CH2:31][CH2:32]3)=[N:25][O:26][C:22]=2[CH:21]=1
Reactant: O=C(CCCCl)c1cc2c(s1)C(=O)NCCC2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(CCCN1CCC(c2noc3cc(F)ccc23)CC1)c1cc2c(s1)C(=O)NCCC2
Temperature: 90 °C
Reaction time: 22 h
Yield: 29.8 %

Procedure:
A mixture of 1.1 g of 2-(4-chlorobutyryl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one, 1.1 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride, 1.68 g of potassium carbonate and 670 mg of potassium iodide in 10 ml of dimethylformamide and 10 ml of toluene was stirred at 90° C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel and recrystallized from ethyl acetate-isopropyl ether to give 0.55 g of 2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one 1/2hydrate, m.p. 186°-187° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[Mg].[CH2:13]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH:20]=[CH:19]1)[CH2:14][CH2:15][CH2:16][CH3:17].Cl>C(OCC)C>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH2:20]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CCCCCC1C=CC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC1=CCC(O)(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
A solution of 8.0 g of 4-trifluoromethylbromobenzene in 30 ml of anhydrous diethyl ether was added dropwise under stirring at 15°-20° C. to 1 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of 4-pentylcyclohexenone was added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 4-(4-trifluoromethylphenyl)-4-hydroxy-l-pentylcyclohexene was obtained as a crude reaction product.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:27])[CH2:6][C@@H:5]1[CH2:28][CH3:29])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:39]([O:42][C:43](Cl)=[O:44])[CH2:40][CH3:41]>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:27][C:43](=[O:44])[O:42][CH2:39][CH2:40][CH3:41])[CH2:6][C@@H:5]1[CH2:28][CH3:29])(=[O:3])[CH3:2]
Reactant: CC[C@H]1C[C@@H](N)c2cc(-c3ccc(CN4CCCCC4)cc3)ccc2N1C(C)=O
Reactant: CCCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCOC(=O)N[C@@H]1C[C@H](CC)N(C(C)=O)c2ccc(-c3ccc(CN4CCCCC4)cc3)cc21
Reaction time: 0.67 h

Procedure:
(cis)-1-Acetyl-2-ethyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 5) (50 mg, 0.128 mmol) was dissolved in dichloromethane (DCM) (2 mL), mixed with DIPEA (0.045 mL, 0.255 mmol) and propylchloroformate (0.019 mL, 0.166 mmol, Aldrich) and stirred under nitrogen. After 40 minutes the reaction was loaded onto a 5 g SCX-column, eluting with MeOH (70 mL) followed by 2M MeOH/NH3 (70 mL). Product-containing fractions were evaporated to dryness to give a colourless solid (38 mg). This was purified on a 12+M Biotage silica column, eluting with 0 to 8% 2M methanolic ammonia in DCM. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (16 mg). LCMS (Method C): Rt=0.83, MH+=478
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20](O)[CH3:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=S(Cl)Cl.[N-:27]=[N+:28]=[N-:29].[Na+].O>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[N:27]([CH:20]([C:18]1[N:19]=[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[C:15]2=[N:16][CH:17]=1)[CH3:21])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)O)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)N=[N+]=[N-])cnc32)cc1
Reaction time: 15 h
Yield: 100.4 %

Procedure:
To a solution of 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanol (0.600 g, 1.89 mmol) in DCM (10 mL) was added SOCl2 (0.690 mL, 9.45 mmol) at ambient temperature. After about 4 h the reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL) was added to the reaction mixture. After gas evolution ceased, the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (10 mL) and sodium azide (0.615 g, 9.45 mmol) was added to the reaction mixture. After about 15 h, EtOAc (50 mL) and water (50 mL) were added to the reaction mixture. The organic layer was separated, concentrated under reduced pressure, and purified by silica gel chromatography eluting with 20-80% EtOAc/heptane to provide 2-(1-azidoethyl)-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (0.65 g, 100%) as a colorless solid: LC/MS (Table 2, Method a) Rt=2.67 min; MS m/z: 343 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([N:14]=[C:15]=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1C(O)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:15]([C:22]2[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:21]=2)=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=O
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=O)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-(2-tert-butylphenoxy)pyridin-3-amine (1a) (80 mg, 0.33 mmol), 1H-benzo[d]imidazole-2-carboxylic acid (54 mg, 0.33 mmol) and BOP (172 mg, 0.39 mmol) in DMF was stirred at rt for 3 days. LC-MS showed only a small amount of the desired product. The reaction was diluted with EtOAc (15 mL), washed with 1 N HCl solution, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and evaporated to give the crude product. Purification of the crude product by reverse phase preparative HPLC provided Example 71 (12 mg) as a yellow solid. LC-MS m/z 387.2 [M+H]+.
Reaction SMILES: CS(O)(=O)=O.[CH2:6]([C:8]1([CH2:20][C:21]([OH:23])=[O:22])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[C:9]1=[O:19])[CH3:7].[CH2:24](O)[CH3:25]>>[CH2:6]([C:8]1([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[C:9]1=[O:19])[CH3:7]
Reactant: CCO
Reactant: CCC1(CC(=O)O)CCc2cc(O)ccc2C1=O
Agent: CS(=O)(=O)O
Product: CCOC(=O)CC1(CC)CCc2cc(O)ccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
Methane sulfonic acid (5 mL) was added to a solution of 4B (5 g, 20.16 mmol) in ethanol (50 mL), and the mixture was stirred at room temperature for 16 h. Ethanol was removed under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated NaCl solution. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under vacuum to afford the title compound (4 g, 72%) as a solid. 1H NMR (300 MHz, CDCl3): δ 7.92 (d, J=8.7 Hz, 1H), 6.86 (bs, 1H), 6.7 (dd, J1=2.4 Hz, J2=8.7 Hz, 1H), 6.61 (d, J=2.1 Hz, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.1-2.9 (m, 2H), 2.77 (dt, J1=16.9 Hz, J2=4.5 Hz, 1H), 2.5-2.35 (m, 2H), 2.02 (dt, J1=13.5 Hz, J2=4.8 Hz, 1H), 1.8-1.58 (m, 2H), 1.2 (t, J=7.2 Hz, 3H), 0.9 (t, J=7.5 Hz, 3H). ESI-MS m/z=275 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=3)=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:23][NH:24][O:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([N:24]([O:25][CH3:26])[CH3:23])=[O:21])=[CH:17][CH:18]=3)=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)Cc2c(COc3ccc(N=C=O)cc3)cccc2O1
Reactant: CNOC
Solvent: Cc1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCc2cccc3c2CC(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
1.8 g of 4-(2,3-dihydro-2,2-dimethyl-4-benzofuranylmethyloxy)phenyl isocyanate was dissolved into 20 ml of toluene, and 2.0 g of N,O-dimethylhydroxylamine dissolved in 5 ml of toluene was slowly added dropwise thereto at room temperature. After the mixture was stirred at room temperature for 2 hours, toluene was distilled off and the residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/4) as a developer to obtain 1.8 g of Compound No. 6 shown in Table 1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:18][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of N-tert-butoxycarbonyl-D-Phenylalaninol (754 mg) and TEA (0.5 ml) in dichloromethane was added methanesulfonyl chloride (0.28 ml) at 0°~5° C. The reaction mixture was stirred at 0°~5° C. for 30 min, quenched with water, and extracted with dichloromethane. The organic layer was washed with 10% citric acid and sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane=1/2 to afford the product (931 mg).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[Cl-].[Na+]>CN(C)C=O>[CH2:11]([O:10][C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CCOC(=O)CCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of ethyl salicylate (10.0 g, 60.2 mmol), 60% sodium hydride (2.41 g, 60.2 mmol) and N,N-dimethylformamide (150 ml) w as stirred at room temperature for about 1 hour, followed by adding dropwise thereto ethyl 4-bromobutyrate (12.9 g, 66.2 mmol). The reaction mixture was stirred at room temperature for 4.5 hours and then at 65-70° C. for 2 hours. The reaction mixture was poured into a cooled 5% aqueous sodium chloride solution and extracted twice with ethyl acetate, and the extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; ethyl acetate:n-hexane=5:95) to obtain 16.4 g of ethyl 4-(2-ethoxycarbonylphenyloxy)butyrate.
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](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][C:43]([CH2:55][OH:56])([O:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=2)[CH2:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:54][C:50]1[CH:49]=[C:48]([CH:53]=[CH:52][CH:51]=1)[O:47][C:43]1([CH2:55][OH:56])[CH2:44][CH2:45][CH2:46][CH:41]([NH:40][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:42]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NC1CCCC(CO)(Oc2cccc(F)c2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(CO)(Oc5cccc(F)c5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.2 mmol, 100 mg), HCl salt of (3-amino-1-(3-fluorophenoxy)cyclohexyl)methanol (0.2 mmol, 55 mg), HATU (0.2 mmol, 76 mg) and DIEA in DMA was stirred at room temperature for overnight. The product, N-(3-(3-fluorophenoxy)-3-(hydroxymethyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])=[N:17][N:18]([CH3:21])[C:19]=1[CH3:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:14][C:15]2[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])=[N:17][N:18]([CH3:21])[C:19]=2[CH3:20])(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Reactant: Cc1c(N)c(CC(C)C)nn1C
Solvent: c1ccncc1
Product: Cc1c(NS(=O)(=O)c2c(Cl)cc(Br)cc2Cl)c(CC(C)C)nn1C
Yield: 12.4 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (0.68 g, 2.1 mmol) and 4-amino-1,5-dimethyl-3-isobutyl-1H-pyrazole (0.35 g, 2.1 mmol) in pyridine (5 ml) according to the method of intermediate 1, to give the title compound as a white solid (120 mg, 0.26 mmol, 12%). δH (D-6 DMSO, 300K) 7.65 (2H, s), 6.54 (1H, s), 3.70 (3H, s), 2.17 (3H, s), 1.96 (2H, d J 7.9 Hz), 1.74 (1H, m), 0.78 (6H, d J 6.6 Hz). m/z (ES+, 70V) 456.0 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][N:28]4[C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCCCN3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCCCC1c1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Reaction time: 16 h
Yield: 9.8 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.22 mmol), N,N-dimethylglycine (27 mg, 0.26 mmol), EDCl (46 mg, 0.24 mmol), HOBt (32 mg, 0.24 mmol), and N,N-diisopropylethylamine (114 μL, 0.65 mmol) in DMF (1.5 mL) was stirred at it for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 11 mg (10%) of the desired product. NMR (400 MHz, CD3OD) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.80 (d, 1 H), 7.55-7.68 (m, 1 H), 7.25-7.42 (m, 5 H), 7.16 (s, 1 H), 6.08 (d, 1 H), 5.65 (s, 2 H), 3.59-4.46 (m, 2 H), 2.99-3.26 (m, 1 H), 2.63-2.85 (m, 1 H), 2.25-2.42 (m, 1 H), 1.97 (s, 6 H), 1.54-1.82 (m, 3 H), 1.29-1.53 (m, 1 H), 1.22 (s, 2 H); ES-MS m/z 509.26 [M+H]+, HPLC RT (min) 2.16.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:8][C:7]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][C:5]=1[C:16]([OH:18])=O)[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:53]=[C:54]([NH2:61])[C:55]4[CH:56]=[N:57][NH:58][C:59]=4[CH:60]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:60]=[C:59]4[C:55]([CH:56]=[N:57][NH:58]4)=[C:54]([NH:61][C:16]([C:5]4[N:6]=[C:7]([CH2:9][N:10]5[CH2:11][CH2:12][O:13][CH2:14][CH2:15]5)[S:8][C:4]=4[CH:2]([CH3:1])[CH3:3])=[O:18])[CH:53]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1
Reactant: CC(C)c1sc(CN2CCOCC2)nc1C(=O)O
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1sc(CN2CCOCC2)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
To a solution of 5-(1-methylethyl)-2-(4-morpholinylmethyl)-1,3-thiazole-4-carboxylic acid (31 mg) in DMF (3 ml) was added HATU (44 mg) and the mixture stirred at 20° C. for 10 min, then 6-(1H-indol-4-yl)-1H-indazol-4-amine (13 mg) and DIPEA (0.037 ml) were added and the mixture allowed to stand for 18 h. The mixture was blown to dryness under a stream of nitrogen and the residue purified by mass directed preparative HPLC (Method A) to give the title compound (8 mg) as a pale brown solid.
Reaction SMILES: C[N:2]([C:19](=[O:45])[C@@H:20]([CH2:35][C:36]1[CH:41]=[C:40]([Br:42])[C:39]([OH:43])=[C:38]([Br:44])[CH:37]=1)[NH:21][C:22]([NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)=[O:23])[C@H:3]([C:16]([OH:18])=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH-].[Li+]>O>[CH3:14][C:12]([CH3:15])([O:11][C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:16]([OH:18])=[O:17])[NH:2][C:19](=[O:45])[C@@H:20]([CH2:35][C:36]1[CH:41]=[C:40]([Br:42])[C:39]([OH:43])=[C:38]([Br:44])[CH:37]=1)[NH:21][C:22]([NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)=[O:23])=[O:10])[CH3:13]
Reactant: COc1cccc(CCNC(=O)N[C@H](Cc2cc(Br)c(O)c(Br)c2)C(=O)N(C)[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(CCNC(=O)N[C@H](Cc2cc(Br)c(O)c(Br)c2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 7.75 g (10.4 mmol) of methyl N6-[(1,1-dimethyl-ethoxy)carbonyl]-N2-[N-[[[2-(3-methoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-L-lysine, 3.5 g (140 mmol) of lithium hydroxide and 150 ml of water was stirred overnight at room temperature. The aqueous phase was washed once with ethyl acetate, acidified by the addition of 1 M aqueous potassium hydrogen sulphate solution and then extracted with ethyl acetate. The organic phase was dried over sodium sulphate and evaporated down in vacuo. 6.9 g (91% of theory) of a yellowish oil were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13]>C(#N)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:12]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[S:13])[S:8][C:4]=2[CH:3]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc2nc(N)sc2c1
Solvent: CC#N
Product: Cc1ccc2nc(NC(=S)n3ccnc3)sc2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
To 6-methylbenzo[d]thiazol-2-amine (1.0 g, 6.2 mmol) in acetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (1.44 g, 8.1 mmol). The reaction was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (40° C.) for 1 hour to yield N-(6-methylbenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (1.06 g, 3.86 mmol, 62% yield) and then used in the next step without any further purification or characterization.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15].[I-:16].[Na+].S(=O)(O)[O-].[Na+]>O.S(=O)(=O)(O)O.CCOCC.CS(C)=O>[I:16][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[OH:15]
Reactant: [I-]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1ccc(I)c(O)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
Add, dropwise, a solution of 20.7 g (300 mmol) of sodium nitrite (NaNO2) in 100 mL of water to a solution of 30.81 g (200 mmol) of 2-amino-5-nitrophenol in a mixture of 500 mL of sulphuric acid at 30 wt. % and 500 mL of DMSO cooled to 5° C., maintaining the temperature at 5° C. After 30 min at 5° C., add dropwise a solution of 90 g (600 mmol) of sodium iodide in 100 mL of water, then bring the reaction mixture up to RT. After stirring for 2 h, distribute the reaction mixture in 2 L of a mixture of ether/aqueous solution at 10 wt. % of sodium bisulphite 1:1. Extract the aqueous phase again with 200 mL of ether, combine the organic phases and wash with 3×1 L of water, then dry over Na2SO4. After concentration under reduced pressure, purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 10% of EtOAc. After concentration under reduced pressure, we obtain 39.8 g of 2-iodo-5-nitrophenol in the form of a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[O:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[S:10][C:11]=1[O:12][CH3:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: COc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylic acid (85 mg, 0.31 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (119 mg, 0.31 mmol) [prepared according to the procedure of Preparation 6] and PyBrop (180 mg, 0.384 mmol) in chloroform (3.5 mL). DIEA (270 μL, 1.54 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (94 mg, 0.14 mmol, 45%): LC-MS (ES) m/z=603 (M+H)+.