Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:14])[C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1.[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[Cl:13][C:11]1[C:10]([CH3:14])=[CH:9][C:7]2[NH:8][C:4]([S:3][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[N:5][C:6]=2[CH:12]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Cc1cc2[nH]c(S)nc2cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2[nH]c(Sc3ccc(C=O)o3)nc2cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
Aldehyde intermediate preparation: A mixture of sodium hydride (60% dispersion in mineral oil, 0.338 g, 8.46 mmol) and 2-mercapto-5-chloro-6-methyl-1H-benzimidazole (1.05 g, 5.29 mmol) in 35 ml of tetrahydrofuran is stirred at room temperature for 2 hours. 5-nitro-2-furaldehyde (0.746 g, 5.29 mmol) in 7 ml of tetrahydrofuran is then added dropwise over a 15 minute period and the mixture is stirred for 16 hours at room temperature. The reaction mixture is then concentrated under reduced pressure and dissolved in 100 ml ethyl acetate and washed with water (2×30 ml). The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is triturated in diisopropylether and pentane and dried under vacuum to yield 854 mg of 5-(5-chloro-6-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde. Yield=55%. Analytical LC/MS (method B): retention time=3.64 min, m/z=272.97 (1Cl, positive ion mode).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1.[ClH:30].O1CCOCC1>CO>[F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1.[ClH:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4cccc(F)n4)ccnc3[nH]2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Fc1cccc(-c2ccnc3[nH]c(C4=CCNCC4)cc23)n1

Procedure:
A mixture of Example 309E (4.0 g, 10.14 mmol) and 4M HCl in dioxane (25.4 ml, 101 mmol) in methanol (10 mL) was stirred at room temperature for 4 hours. The mixture was concentrated and the solid was washed with ethyl acetate and vacuum dried to provide the title compound as an HCl salt. 1H NMR (400 MHz, DMSO-d6) δ 2.81 (s, 2H), 3.33 (s, 2H), 3.83 (s, 2H), 6.62 (s, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.30 (dd, J=7.9, 2.6 Hz, 1H), 7.68 (d, J=5.2 Hz, 1H), 8.08-8.25 (m, 2H), 8.37 (d, J=5.2 Hz, 1H), 9.46 (s, 2H), 12.44 (s, 1H). MS (ESI+) m/z 295.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[S:16][C:17]([C:20](O)=[O:21])=[CH:18][N:19]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].[Li].Cl.[CH:31]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:31]1([CH2:34][CH2:35][NH:36][C:20]([C:17]2[S:16][C:15]([N:13]3[CH2:14][C:9]4[CH2:8][N:7]([C:5](=[O:6])[C:4]5[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=5[C:2]([F:28])([F:1])[F:27])[CH2:11][C:10]=4[CH2:12]3)=[N:19][CH:18]=2)=[O:21])[CH2:33][CH2:32]1
Reactant: NCCC1CC1
Reactant: O=C(O)c1cnc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(NCCC1CC1)c1cnc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)s1

Procedure:
2-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]thiazole-5-carboxylic acid, lithium salt (88 mg, 0.212 mmol), 2-cyclopropylethylamine hydrochloride (38.7 mg, 0.318 mmol), triethylamine (126 μl, 0.92 mmol) and HATU (128 mg, 0.37 mmol) were stirred at room temperature for 2 h. The solvent was evaporated off and the residue was purified by preparative HPLC (PR18, acetonitrile/water, 0.1% TFA). Yield: 6 mg (6%), M+H+: 477.19.
Reaction SMILES: [F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4].[CH2:13](O)[CH3:14].C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:1][C:2]([F:12])([CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:13][CH3:14])=[O:4]
Reactant: CC(C)CC(O)C(F)(F)C(=O)O
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(F)(F)C(O)CC(C)C
Yield: 84.9 %

Procedure:
To a mixture of 25.0 g of Intermediate 1 (Example 1), 20 g of ethanol and 200 g of benzene was added 0.15 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated for 20 hours while water of reaction was sequentially removed out of the system. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried, and concentrated, obtaining 24.5 g (yield 85%) of crude ethyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][NH:20][C:21]4([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]=O>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:19][N:20]([CH3:33])[C:21]4([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CCOCC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CCOCC1

Procedure:
4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]tetrahydro-2H-pyran-4-carboxylic acid was coupled with paraformaldehyde using an analogous method to that described for the equivalent step in Example 11 to give 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]tetrahydro-2H-pyran-4-carboxylic acid; 1H NMR Spectrum: (DMSO-d6) 1.70-1.89 (m, 2H), 2.05-2.19 (m, 2H), 2.20 (s, 3H), 3.10-3.60 (m, 2H+ H2O), 3.70 (s, 2H), 3.88 (m, 2H), 3.93 (s, 3H), 7.18 (s, 1H), 7.28 (m, 1H), 7.40-7.60 (m, 2H), 8.30 (s, 1H), 8.41 (s, 1H), 9.76 (brs, 1H). Mass Spectrum: (M+H)+ 475.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19].[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Br)[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:1][C:2]2[CH:22]=[CH:21][CH:20]=[C:4]([CH2:5][O:6][C:7]3[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=3[CH2:17][CH2:18][CH3:19])[CH:3]=2)[CH:27]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CCCc1c(OCc2cccc(N)c2)ccc(C(C)=O)c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCc1c(OCc2cccc(Nc3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Temperature: 100 °C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
Combine 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (500 mg, 1.67 mmol), 3-bromo-benzoic acid methyl ester (326 mg, 1.52 mmol) and cesium carbonate (693 mg, 2.13 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add BINAP [rac-2,2′-Bis(diphenyl-phosphino)-1,1′-binaphthyl] (142 mg, 0.228 mmol), and palladium acetate (34 mg, 0.152 mmol). Purge reaction vessel with argon. Heat to 100° C. After 18 hours, cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by flash chromatography eluting with ethyl acetate:hexanes to yield the title compound as a white solid (280 mg, 43%): 1H NMR (DMSO-d6) δ 0.81 (t, 3H), 1.46 (sextet, 2H), 2.57 (m, 5H), 3.82 (s, 3H), 5.23 (s, 2H), 6.71 (d, 1H), 6.95 (d, 1H), 7.01 (d, 1H), 7.19 (m, 1H), 7.28-7.41 (m, 4H), 7.65 (m, 1H), 7.81 (d, 1H), 8.49 (bs, 1H), 12.84 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:19]3[N:20]=[CH:21][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C:19]3[N:20]=[CH:21][NH:22][CH:23]=3)([OH:18])[CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(O)(c1ccc(-c2ccc(F)cc2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)C(O)(c1ccc(-c2ccc(F)cc2)cc1)c1c[nH]cn1
Yield: 76.5 %

Procedure:
A solution (75 ml) of 1-(4′-fluoro[1,1′-biphenyl]-4-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (3.12 g) and pyridine hydrochloride (1.11 g) in methanol was stirred at 60° C. for 3.5 h. The solvent was evaporated from the reaction mixture under reduced pressure and the residue was diluted with ethyl acetate. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by column chomatography (eluent, hexane:ethyl acetate=2:1→1:5) and recrystallized from ethyl acetate-hexane to give the title compound (1.34 g) as colorless needle crystals.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[CH2:19][CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O.CO.O>[CH:20]([CH2:19][N:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13](=[O:15])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2)=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCC=Cc1ccccc1
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: O=c1c2ccccc2n(CC=Cc2ccccc2)c2ccccc12
Temperature: 45 °C
Reaction time: 5 h

Procedure:
15 g of 9(10H)acridone (manufactured by Wako Pure Chemical Industries, Ltd.) and 3.4 g of sodium hydroxide (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved in 84 g of dimethyl sulfoxide (manufactured by Wako Pure Chemical Industries, Ltd.), and the solution was heated to 45° C. 17.6 parts of CMS-P (manufactured by Seimi Chemical Co., Ltd.; chloromethylstyrene) was added dropwise to the solution, and the mixture was subjected to heating and stirring for further 5 hours at 50° C. This reaction liquid was poured under stirring into a mixed solution of 30 g of distilled water and 30 g of methanol (manufactured by Wako Pure Chemical Industries, Ltd.), and the resulting precipitate was separated by filtration and washed with 300 g of a solution prepared by mixing equal amounts by weight of distilled water and methanol. The resulting solids were dried under reduced pressure, and thus 17.5 g of 10-[(styrenyl)methyl]-9-acridanone was obtained as pale yellow solids. 175 g of N-methylpyrrolidone (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 17.5 g of 10-[(styrenyl)methyl]-9-acridanone and 60.9 g of thioglycerol (manufactured by Sigma-Aldrich Co.), and the mixture was heated to 65° C. and stirred for 30 minutes under a nitrogen atmosphere. Subsequently, 0.14 g of V-65 (trade name, manufactured by Wako Pure Chemical Industries, Ltd.; 2,2′-azobis(2,4-dimethylvaleronitrile) was added thereto, and the mixture was stirred for 2 hours. 500 g of a mixed solvent of water/methanol (mixture at a weight ratio of 1:1) was added to the reaction solution, and the crystals crystallized out therefrom were separated by filtration and were washed using 100 g of methanol. The obtained solids were dried under reduced pressure, and 22.0 g of M-1 was obtained as pale yellow solids.
Reaction SMILES: [F:1][C:2]1[C:21]([C:22](OC)=[O:23])=[C:20]([F:26])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[Li+].[OH-].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[N-:52]=[N+:53]=[N-:54].[Na+]>C1COCC1.O>[N:52]([C:22]([C:21]1[C:2]([F:1])=[C:3]([CH:18]=[CH:19][C:20]=1[F:26])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]1)=[O:23])=[N+:53]=[N-:54]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1c(F)ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c(C(=O)N=[N+]=[N-])c2F)CC1
Reaction time: 8 h
Yield: 122.4 %

Procedure:
To a room temperature solution of tert-butyl 4-(2,4-difluoro-3-(methoxycarbonyl) benzyl)piperazine-1-carboxylate (2.0 g, 5.4 mmol, 1.0 equiv) in THF (5.0 mL) was added a solution of LiOH (249 mg, 5.94 mmol, 1.1 equiv) in water (5 mL). The resulting mixture was stirred overnight. The resulting lithium carboxylate salt was concentrated in vacuo and used in the next step without purification. The lithium salt was suspended in dioxane (50 mL), and N-hydroxysuccinimide (652 mg, 5.67 mmol, 1.05 equiv) and DCC (1.28 g, 6.21 mmol, 1.15 equiv) were added as solids. After the reaction mixture was stirred for 2 days, it was charged with sodium azide (340 mg, 5.4 mmol, 1.0 equiv) and then stirred overnight. The resulting solid was filtered and washed with DCM. The organic layer was passed through a plug of silica gel and concentrated in vacuo to provide tert-butyl 4-(3-(azidocarbonyl)-2,4-difluorobenzyl)piperazine-1-carboxylate (2.52 g crude) which was taken on to the next step without purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[N:19]=2)[CH:15]=[CH:14][S:13]3)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:57][C@@H:58]2[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]2)(=O)=O)=CC=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:63][C:60]1([CH3:64])[O:59][C@H:58]([CH2:57][N:27]2[CH2:28][CH2:29][CH2:30][C@@H:25]([NH:24][C:20]3[N:19]=[C:18]([C:17]4[N:16]5[C:12]([S:13][CH:14]=[CH:15]5)=[N:11][C:10]=4[C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=4)[CH:23]=[CH:22][N:21]=3)[CH2:26]2)[CH2:62][O:61]1
Reactant: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(C[C@@H]4COC(C)(C)O4)C3)n2)c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 63.4 %

Procedure:
The 4-[6-(3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[(3R)-piperidin-3-yl]-pyrimidin-2-amine hydrochloride (310 mg, 0.7 mmol) was dissolved in DMF (15 ml) and was treated successively with Hunig's base (240 uL, 1.4 mmol), potassium carbonate (192 mg, 0.7 mmol) and terabutylammonium iodide (26 mg, 0.07 mmol). The mixture was heated to 130° C. and the [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methyl-benzenesulfonate (0.2 g, 0.7 mmol) was added in three portions. The mixture was kept at 130° C. for 5 hours, at which point no more starting material appears by HPLC. The volatiles were removed in vacuo and the residue was taken up in ether (100 ml). The organic phase was washed with water (2×20 ml) and with an aqueous sodium chloride solution (20 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo, giving a yellow oil. The product was purified by flash chromatography (5:4:0.5 hexanes/EtOAc, MeOH), affording the title compound as an off-white solid (231 mg, 64%). M.p.=73-75° C. 400 MHz 1H NMR (DMSO-d6) δ: 8.71 (br. s, 1H), 8.07 (d, J=5.1 Hz, 1H), 7.42 (d, J=4.4 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.19-7.11 (m, 2H), 7.04-6.92 (m, 2H), 6.36 (d, J=5.1 Hz, 1H), 4.19 (quintet, J=6.2 Hz, 1H), 3.99 (dd, J=8.1, 6.2 Hz, 1H), 3.96-3.87 (m, 1H), 3.77 (s, 3H), 3.52 (t, J=7.5 Hz, 1H), 3.15 (s, 2H), 3.05 (d, J=9.9 Hz, 1H), 2.69 (d, J=10.3 Hz, 1H), 2.15 (t, J=9.4 Hz, 1H), 2.04 (t, J=9.5 Hz, 1H), 1.90-1.82 (m, 1H), 1.75-1.65 (m, 1H), 1.59-1.48 (m, 1H), 1.40-1.25 (m, 1H), 1.29 (s, 3H), 1.21 (s, 3H). LCMS: 521 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH2:10].[C:20]1([N:26]2[C:30](=[O:31])[CH:29]=[CH:28][C:27]2=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[C:20]1([N:26]2[C:30](=[O:31])[CH:29]3[CH:28]([CH2:10][CH:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C:11]4[NH:12][C:13]5[C:18]([C:19]=43)=[CH:17][CH:16]=[CH:15][CH:14]=5)[C:27]2=[O:32])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=C(c1cc2ccccc2[nH]1)c1ccc(Cl)cc1Cl
Reactant: O=C1C=CC(=O)N1c1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1C2CC(c3ccc(Cl)cc3Cl)c3[nH]c4ccccc4c3C2C(=O)N1c1ccccc1
Yield: 50 %

Procedure:
7 ml of xylene was added to a mixture of 1.5 g of 2-[1-(2,4-dichlorophenyl)vinyl]indole and 1.0 g of N-phenylmaleimide. The resulting mixture was refluxed for 1 hour. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 1.2 g (yield: 50%) of N-phenyl-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydro-carbazole-3,4-dicarboximide as colorless crystal.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[N:5]2.CN(C)C=O.S(Cl)([Cl:22])=O>ClCCl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([Cl:22])=[O:14])[CH:6]=[N:5]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc2cc(I)ccc2n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc2cc(I)ccc2n1
Temperature: 25 °C

Procedure:
To a solution of compound 23 (200 mg, 0.67 mmol) in dry dichloromethane (10 mL), under argon and at 0° C., was added dropwise dry N,N-dimethylformamide (100 μL) and thionyl chloride (200 μL, 2.74 mmol). The reaction mixture was stirred at reflux for 3 h. After cooling to room temperature, the solvent was removed under reduced pressure to afford crude 6-iodoquinoxaline-2-carbonyl chloride. This was suspended in dry tetrahydrofuran (10 mL) and were successively added, under argon, p-nitrophenol (93 mg, 0.67 mmol) and dropwise a solution of triethylamine (95 μL, 0.68 mmol) in dry tetrahydrofuran (5 mL). The solution was stirred at 50° C. for 18 h. After cooling to room temperature, dichloromethane (30 mL) was added and the resulting solution was washed with a 5% aqueous sodium carbonate solution (20 mL). The aqueous layer was extracted with dichloromethane (5×15 mL) and the organic layers were combined, dried on magnesium sulfate and evaporated under reduced pressure. The resulting precipitate was triturated with ether (5 mL) and collected by filtration to afford ester 24 (225 mg, 0.53 mmol) as a beige solid. Yield 80%; mp 228-230° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, 2H, J=7 Hz), 8.09 (d, 1H, J=9 Hz), 8.30 (dd, 1H, J=2, 9 Hz), 8.41 (d, 2H, J=7 Hz), 8.72 (d, 1H, J=2 Hz), 9.60 (s, 1H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:17])[C@@H:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH3:11])[CH3:10])[C@H:4]([C:18]2[NH:19][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([C:33]3[CH:38]=[CH:37][C:36]([C:39]5[NH:43][C:42]([C@@H:44]6[CH2:48][CH2:47][CH2:46][N:45]6C(OC(C)(C)C)=O)=[N:41][CH:40]=5)=[CH:35][CH:34]=3)[CH:27]=[CH:26]4)=[CH:21][N:22]=2)[CH2:3]1.Cl.[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([OH:65])=O)=[O:60].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO>[OH:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:17])[C@@H:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH3:11])[CH3:10])[C@H:4]([C:18]2[NH:19][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([C:33]3[CH:38]=[CH:37][C:36]([C:39]5[NH:43][C:42]([C@@H:44]6[CH2:48][CH2:47][CH2:46][N:45]6[C:63](=[O:65])[C@H:62]([NH:61][C:59](=[O:60])[O:58][CH3:57])[C:66]6[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=6)=[N:41][CH:40]=5)=[CH:35][CH:34]=3)[CH:27]=[CH:26]4)=[CH:21][N:22]=2)[CH2:3]1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 22.5 %

Procedure:
To (S)-tert-butyl 2-(5-(4-(6-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (61 mg, 0.082 mmol) in MeOH (2.5 mL) was added HCl (4M in dioxane, 0.5 mL). The solution stirred o/n, and the solvent was removed. The intermediate was dissolved in DMF (2 mL). (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (19 mg, 0.09 mmol), COMU (39 mg, 0.082 mmol), and DIPEA (0.07 mL, 0.41 mmol) were added sequentially. The solution was stirred o/n and the mixture was purified by HPLC to yield product (15.5 mg). LCMS-ESI+: calc'd for C47H50N8O7: 838.95 (M+); Found: 839.29 (M+H+).
Reaction SMILES: CI.CN([CH:6]=[O:7])C.[Br:8][C:9]1[C:18]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Br:8][C:9]1[C:18]([O:19][S:20]([C:23]([F:26])([F:24])[F:25])(=[O:21])=[O:22])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[O:7][CH3:6]
Reactant: COC(=O)c1cc(O)c(Br)c(OS(=O)(=O)C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cc(OC)c(Br)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 1-liter egg plant-type flask, methyl iodide (6.67 mL, 105 mmol) was added to a DMF (200 mL) solution of methyl 4-bromo-3-hydroxy-5-{[(trifluoromethyl)sulfonyl]oxy}benzoate (19.9 g) and potassium carbonate (14.5 g, 105 mmol), and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline water, dried with sodium sulfate, filtered, and concentrated to obtain a crude product. This was purified through silica gel column chromatography (Biotage [SiO2, 40+M]) with a hexane/ethyl acetate developer system to obtain the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[NH:4][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COc1cc(Br)c(N)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(Br)c(NC(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
4.40 g (18.6 mmol) 2-Bromo-5-chloro-4-methoxy-aniline and 3.1 ml (22.0 mmol) triethylamine were dissolved in 50 ml THF. 1.42 ml (20.0 mmol) acetylchloride were added dropwise at room temperature. The reaction mixture was stirred at room temperature for additional 2 hours, saturated NaHCO3 solution was added and the mixture was extracted with ethyl acetate. Removal of the solvent and crystallisation with ether gave 3.6 g (12.9 mmol, 69%) of the title compound.