Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.[CH3:28][N:29]=[C:30]=[S:31]>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:30]([NH:29][CH3:28])=[S:31])=[CH:5][CH:6]=4)[C:19]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Reactant: CN=C=S
Solvent: C1CCOC1
Solvent: O
Product: CNC(=S)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
A mixture of 150 mg (0.391 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate (see Step 77.5), 31.4 mg (0.429 mmol) of methyl isothiocyanate and 5 ml of THF is stirred at 20° C. for 15 hours. Concentration to a volume of about 1 ml, addition of 5 ml of diethyl ether to the concentrate and filtration yield 4-(3-chloro-phenylamino)-3-[4-(methylamino-thiocarbonylamino-methyl)phenylamino]-1H-pyrazolo[3,4-d]pyrimidine having a water content of 1.22%; m.p. 216-218° C. (decomp.), ESI-MS: (M−H)−=437.
Reaction SMILES: [CH:1]([O:3]CCCC)=[CH2:2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].Br[C:44]1[CH:45]=[C:46]2[C:55](=[C:56]3[C:61]=1[CH:60]=[CH:59][CH:58]=[N:57]3)[NH:54][S:53](=[O:63])(=[O:62])[C:52]1[C:47]2=[CH:48][CH:49]=[CH:50][CH:51]=1>C1COCC1.Cl.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C.O>[O:62]=[S:53]1(=[O:63])[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]2[C:55](=[C:56]3[C:61](=[C:44]([C:1](=[O:3])[CH3:2])[CH:45]=2)[CH:60]=[CH:59][CH:58]=[N:57]3)[NH:54]1
Reactant: C=COCCCC
Reactant: O=S1(=O)Nc2c(cc(Br)c3cccnc23)-c2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1cc2c(c3ncccc13)NS(=O)(=O)c1ccccc1-2
Temperature: 90 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
A solution of DMF/H2O (4:1) was de-gassed for 15 min. DMF/H2O (4:1, 6 ml) and 1-vinyloxy-butane (0.59 ml, 4.53 mmol) were added to a mixture of Pd(OAc)2 (6 mg, 26 μmol), 1,3-bis(diphenylphosphino)propane (24 mg, 57 K2CO3 (150 mg, 1.01 mmol), 12-bromo-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 545 (370 mg, 0.91 mmol), under nitrogen. The mixture was heated at 90° C. for 2.5 h in the microwave. After cooling, the reaction was diluted with THF (2 ml) and 1M HCl (2 ml) and the mixture was stirred for 18 h. The mixture was further diluted with EtOAc (10 ml) and washed with water (10 ml, ×3). The precipitate formed during work-up was collected by filtration of the organic and aqueous phases and was found to be the title compound (140 mg, 40%). The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was triturated from MeOH to give the title compound (90 mg, 24%) which was used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[CH2:27][C:26]3[C:21](=[C:22]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:34])[CH2:15][C:16](O)=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C(N1C=CN=C1)([N:38]1C=CN=C1)=O.[OH-].[NH4+].O>O1CCCC1>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[C:20](=[O:34])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:27]2)[CH2:15][C:16](=[O:17])[NH2:38])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid (400 mg, 0.81 mmol) in tetrahydrofurane was added carbonyldiimidazole (200 mg, 1.21 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added ammonium hydroxide (0.12 ml, 1.6 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile:water=45:55) to give cyclopropanecarboxylic acid {2-[1-(3,4-bis-difluoromethoxy-phenyl)-2-carbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (230 mg, 46%): mp, 198-200° C.; 1H NMR (DMSO-d6): δ 0.87 (d, J=5 Hz, 4H, cyclopropyl ring CH2CH2), 1.74-1.79 (m, 1H, cyclopropyl ring CH), 2.99 (d, J=7.5 Hz, 2H, CH2CONH2), 4.29 (d, J=18 Hz, 1H, CHHN), 4.61 (d, J=18 Hz, 1H, CHHN), 5.69-5.75 (m, 1H, CHN), 6.97 (broad, 1H, NHH), 7.19 (t, JH-F=75 Hz, 1H, OCF2H), 7.22 (t, JH-F=75 Hz, 1H, OCF2H), 7.34-7.37 (m, 3H, Ar), 7.47-7.58 (m, 2H, NHH+1Ar), 8.23 (d, J=8 Hz, 1H, Ar), 10.51 (s, 1H, NHCO); 13C NMR (CDCl3): 8.26, 15.95, 38.10, 47.37, 51.89, 112.77, 112.90, 116.90, 117.03, 117.40, 117.70, 117.99, 120.57, 121.03, 121.16, 121.74, 125.72, 133.38, 137.51, 138.81, 141.60, 141.65, 141.70, 142.15, 142.20, 142.25, 142.79, 168.74, 171.37, 172.24; Anal. Calcd. for C23H21F4N3O5: C, 55.76; H, 4.27; N, 8.48; Found: C, 55.98; H, 4.00; N, 8.46.
Reaction SMILES: [C:1]1(=[O:14])[O:13][C@@H:6]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].N1C=CN=C1.CN(C=O)C.[C:25]([Si:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:28])([CH3:27])[CH3:26]>C(OCC)(=O)C.O>[Si:29]([O:12][CH2:11][C@@H:9]([OH:10])[C@@H:7]([OH:8])[C@@H:6]1[O:13][C:1](=[O:14])[C@H:2]([OH:3])[C@@H:4]1[OH:5])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1O[C@@H]([C@H](O)[C@H](O)CO)[C@@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC[C@@H](O)[C@@H](O)[C@@H]1OC(=O)[C@H](O)[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 55 %

Procedure:
D-glycero-D-gulo-Heptono-1,4-lactone (6) (10 g, 48.08 mmol) and imidazole (4.98 g, 1.5 equiv) were added to dry DMF (25 ml) and the mixture stirred at 0° C. under nitrogen. tert-Butylchlorodiphenylsilane (13.74 ml, 1.1 equiv) was added slowly, after which the reaction mixture was allowed to warm up to room temperature over three hours. After 22 hours, t.l.c. (eluant ethyl acetate) indicated that the mixture contained the desired monosilyl derivative (Rf 0.65) and a smaller amount of another carbohydrate derivative (Rf 0.9). The crude reaction mixture was shaken with water (50 ml), causing a white precipitate to form. Ethyl acetate (90 ml) was added and the layers separated after shaking. The aqueous layer was back-extracted with more ethyl acetate (25 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (4×25 ml) and dried (magnesium sulphate). Evaporation of the solvent followed by dry column chromatography (eluant hexane:ethyl acetate, 2:1, increasing the eluant polarity with each fraction), yielding 7 -O-tert-butyldiphenylsilyl-D-glycero-D-gulo-heptono-1,4-lactone (7) (11.02 g, 55%) as a white solid, m.p. 54°-57° C. (Found: C, 61.58; H, 6.86%. C23H30O7Si requires: C, 61.87; H, 6.77%); [α]d20 -10.56° (c, 0.99 in CHCl3); vmax (CHCl3) 3410 (broad, OH) and 1790 cm-1 (γ-lactone); and 2,7-di-O-tert-butyldiphenylsilyl-D-glycero-D-gulo-heptono-1,4-lactone (8) (5.94 g, 18%) as a colorless, viscous oil [α]D20 -4.08° (c, 1.20 in CHCl3); vmax (CHCl3) 3440 (broad, OH) and 1790 cm-1 (γ-lactone).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:49])([CH3:48])[C:10]([NH:12][C@H:13]([CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)[C:14]([NH:16][C:17]1[N:18]=[C:19]([CH:22]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[C:23]([O:25]CC)=[O:24])[NH:20][CH:21]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O1CCOCC1>O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:49])([CH3:48])[C:10]([NH:12][C@H:13]([CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)[C:14]([NH:16][C:17]1[N:18]=[C:19]([CH:22]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[C:23]([OH:25])=[O:24])[NH:20][CH:21]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(c1ccc2ccccc2c1)c1nc(NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)c[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)Nc1c[nH]c(C(C(=O)O)c2ccc3ccccc3c2)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution consisting of ethyl 2-[4-((2R)-2-(2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino)-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)acetate (1.52 grams, 2.28 mmol), lithium hydroxide (0.11 grams, 4.56 mmol), dioxane (10 mL), and water (10 mL) was stirred at ambient temperature until complete as determined by hplc (30 minutes). The reaction mixture was concentrated to dryness and the residue was dissolved in water (20 mL). The aqueous solution was adjusted to a pH of 3 using a 10% sodium bisulfate solution and extracted with ethyl acetate (3×25 mL). The organic layers were combined, dried using sodium sulfate, filtered, and concentrated to give 1.34 grams (92%) of 2-[4-((2R)-2-(2-[(tert-butoxy)carbonylamino]-2-methyl propanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)acetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[C:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=1)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[C:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[C:23]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:22]=[CH:21][CH:20]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1
Reactant: N#Cc1ccc(B(O)O)cc1
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
A mixture of 4-cyanobenzeneboronic acid (14.7 g, 0.10 mol), 3-bromo-phenyl-carbamic acid tert-butyl ester (27.2 g, 0.10 mol), Pd(Ph3P)4 (11.6 g, 0.01 mol) and K2CO3 (21 g, 0.15 mol) in DMF/H2O (1:1, 350 mL) was stirred under argon at 80° C. overnight. The DMF was evaporated under reduced pressure, and the residue was dissolved in EtOAc (200 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatography (petroleum ether/EtOAc 50:1) on silica gel to give (4′-cyano-biphenyl-3-yl)-carbamic acid tert-butyl ester (17 g, 59%). 1H NMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.85 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.32-7.48 (m, 3H), 1.47 (s, 9H).
Reaction SMILES: C1(N2C(=O)C3=CNC4C=CC(N5CCNCC5)=NC=4C3=N2)C=CC=CC=1.F[C:28]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]=[C:32]3[C:38](=[O:47])[N:39]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)[N:40]=[C:31]3[C:30]=2[N:29]=1.[CH3:48][CH:49]1[CH2:54][NH:53][CH2:52][CH2:51][NH:50]1.N1CCNCC1>>[CH3:48][CH:49]1[NH:50][CH2:51][CH2:52][N:53]([C:28]2[CH:37]=[CH:36][C:35]3[NH:34][CH:33]=[C:32]4[C:38](=[O:47])[N:39]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)[N:40]=[C:31]4[C:30]=3[N:29]=2)[CH2:54]1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccn1
Reactant: CC1CNCCN1
Agent: C1CNCCN1
Agent: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: CC1CN(c2ccc3[nH]cc4c(=O)n(-c5ccccn5)nc-4c3n2)CCN1

Procedure:
The title compound was prepared following the procedure described for 6a using 5b and 2-methylpiperazine instead of 5a and piperazine respectively. 1H-NMR (DMSO-d6) δ (ppm): 1.07 (3H, d, J=6.87 Hz), 2.78 (3H, m), 3.00 (2H, m), 4.31 (2H, m), 7.14 (2H, m), 7.83 (2H, m), 8.22 (1H, dt, J=7.96, 7.64 Hz), 8.49 (2H, m). m/z 362.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C=O)C>[CH2:24]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:23]=[CH2:22]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Reaction time: 14 h
Yield: 100.8 %

Procedure:
To a mixture of dimethyl 5-hydroxy-isophthalate (10 g, 47.577 mmol), Cs2CO3 (31 g, 95.2mmol) in DMF was added allyl bromide (4.83 mL, 57.1 mmol) drop-wise. After stirring the mixture for 14 hours, the reaction was treated with water, extracted with EtOAc (2×). The combined organic extract was dried over sodium sulfate, filtered and evaporated to provide the desired product as white solid (12 g, 100% yield). The crude product was used without further purification. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.94 (s, 6 H) 4.56-4.71 (m, 2 H) 5.33 (dd, J=10.46, 1.41 Hz, 1 H) 5.39-5.53 (m, 1 H) 5.96-6.17 (m, 1 H) 7.76 (d, J=1.32 Hz, 2 H) 8.28 (t, J=1.41 Hz, 1 H); LC-MS: (ESI)+m/z=251.00 (M+1)+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27](O)=[O:28])[CH:5]=1)[CH2:2][CH3:3].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.CN(C=O)C.[NH2:68][C@H:69]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=1[Cl:81])[CH2:70][C:71]([OH:73])=[O:72].Cl>>[Cl:81][C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][C:75]=1[CH2:74][C@@H:69]([NH:68][C:27]([C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=1)=[O:28])[CH2:70][C:71]([OH:73])=[O:72]
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2Cl)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 5-propyl-1-{6-[2-(1H-tetrazol-5-yl)phenyl]pyridin-3-ylmethyl}-1H-pyrazole-3-carboxylic acid (20 mg, 0.05 mmol), HATU (19.5 mg, 0.0514 mmol) and DIPEA (44.7 uL, 257 μmol) in DMF (1.59 mL, 20.5 mmol) was stirred to pre-activate the acid. After 30 minutes, (R)-3-amino-4-(2-chlorophenyl)butanoic acid.HCl (12.8 mg, 0.0514 mmol)) was added. The resulting solution was stirred overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (20.5 mg; 100% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C30H29ClN8O3, 585.21; found 585.4.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C)C=O>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCBr
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1ccc2c(Br)cccc21
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a mixture of sodium hydride (2.54 g, 66.3 mmol, 60% dispersion in mineral oil) in anhydrous N,N-dimethylformamide (50.0 mL) was added 4-bromoindole (10.0 g, 51.0 mmol) at 0° C. The reaction mixture was stirred for 0.5 h followed by the addition of 1-bromopentane (9.25 g, 61.2 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 6 h and quenched with brine solution (20.0 mL). The reaction mixture was diluted with water (100 mL) and extracted with ether (3×200 mL). The combined organic layers was washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with hexane (100%) to give the title compound (13.3 g, 98%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.30-7.27 (m, 2H), 7.14 (t, 1H), 6.88 (t, 1H), 6.55 (d, 1H), 4.08 (t, 2H), 1.87-1.77 (m, 2H), 1.39-1.22 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 136.3, 129.2, 128.4, 122.2, 122.1, 114.9, 108.7, 101.3, 46.8, 29.9, 29.1, 22.3, 13.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.Cl[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].O>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:10]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:9]1[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Cc4ccccc4)cn(C(=O)OC(C)(C)C)c23)CC1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Cc4ccccc4)c(C(=O)OCc4ccccc4)n(C(=O)OC(C)(C)C)c23)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
A solution of 3-benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester (200 mg, 0.41 mmol) in THF (10 ml) was cooled to −78° C., and t-BuLi (1 ml, 1.7 M in pentane) was added. After stirring at −78° C. for 20 minutes, 0.15 ml of benzyl chloroformate was added and the reaction was allowed to warm up to room temperature for 30 minutes. Water was slowly added, followed by EtOAc. The organic layer was separated and washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and the resulting residue was purified by flash chromatography to give 3-benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester as a yellow solid (100 mg, 39%). MS: (M+H)+ 626.4.
Reaction SMILES: [OH:1][C:2]1[C:3]([Br:13])=[C:4]([C:8]([Br:12])=[CH:9][C:10]=1[Br:11])[C:5]([NH2:7])=[O:6].[Na].Br[CH2:16][C:17]([O:19][CH2:20]C)=[O:18]>CO>[CH3:20][O:19][C:17](=[O:18])[CH2:16][O:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([Br:12])=[C:4]([C:5](=[O:6])[NH2:7])[C:3]=1[Br:13]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1c(Br)cc(Br)c(O)c1Br
Agent: [Na]
Solvent: CO
Product: COC(=O)COc1c(Br)cc(Br)c(C(N)=O)c1Br
Yield: 87.8 %

Procedure:
35.5 g (95 mmol) of 3-hydroxy-2,4,6-tribromobenzamide is suspended in 150 ml of methanol and dissolved by adding 2.18 g (95 mmol) of sodium. The mixture is combined with 17.5 g (104 mmol) of ethyl bromoacetate and maintained under reflux for three hours. After several hours of agitation, the crystallized product is vacuum-filtered, washed with a small amount of ice-cold methanol, and dried at b 60° C., thus obtaining 37.2 g (88% of theory) of 3-carbamoyl-2,4,6tribromophenoxyacetic acid methyl ester, mp 231°-233° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([S:19][C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:37]=[O:38].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.ClCCl.CCCCCC>[CH3:8][C:6]1[C:5]([CH:9]([S:19][C:20]2[CH:21]=[N:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=2)[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:4][N:3]=[C:2]([CH:37]=[O:38])[CH:7]=1
Reactant: Cc1cc(Br)ncc1C(Sc1ccc(C(F)(F)F)nc1)c1c(F)ccc(F)c1F
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C=O)ncc1C(Sc1ccc(C(F)(F)F)nc1)c1c(F)ccc(F)c1F
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of 2-bromo-4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]thio](2,3,6-trifluorophenyl)methyl]pyridine (4.76 g, 9.65 mmol) in toluene (100 ml), a hexane solution of n-butyllithium (1.58 M, 6.72 ml, 10.6 mmol) was added in an argon atmosphere at −78° C. The reaction mixture was stirred for 30 minutes at −40° C., and then cooled again to −78° C., and N,N-dimethylformamide (0.897 ml, 11.6 mmol) was added. After completion of dropwise addition, the reaction mixture was allowed to warm to 0° C., and saturated aqueous ammonium chloride was added thereto at the same temperature. Dichloromethane and water were added to the reaction mixture, and the organic layer was separated. Subsequently, the organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=5:1 was concentrated under reduced pressure, to obtain the title compound (2.52 g, 5.70 mmol, 59%) as a yellow oily substance.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12]1.O>C1COCC1>[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:17]1([OH:20])[CH2:18][CH2:19][C:14]2([O:21][CH2:11][CH2:12][O:13]2)[CH2:15][CH2:16]1
Reactant: c1cscn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2nccs2)CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A solution of n-butyllithium (8.1 mL of 1.6 M solution in hexane, 12.92 mmol) was added to thiazole (1.0 g, 11.75 mmol) in THF (10 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (1.84 g, 11.75 mmol) in THF (10 mL) was added to the lithiated compound solution via syringe and stirred for 3 h at −78° C. Water (5 mL) was added, and the reaction mixture was warmed to room temperature and extracted using EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and chromatographed to yield 2.531 g of 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol in 89% yield. MS (EI) (M+H)+=242.2.