Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28][CH3:29])(=O)[CH2:2][CH2:3][CH3:4].[OH2:30].[O-]Cl.[Na+]>C(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCCSC)cccc2c1Nc1ccccc1Cl
Reactant: O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCCc1cnc2c(OCCCS(C)=O)cccc2c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
3-butyryl-4-(2-chlorophenylamino)-8-(3-methylthiopropoxy)quinoline (0.31 g, 0.72 mmol) was dissolved in methylene chloride (10 ml), 5 ml water was added and then a solution of 1.5 ml (1.09 mmol) of 5% NaOCl in 10 ml methylene chloride was added. The mixture was stirred for 4 h at room temperature. The organic phase was separated and evaporated. Chromatography with methylene chloride:methanol 95:5 as the eluent gave 0.104g (32%) of the title compound.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:28][C:21]3=[N:22][CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(C(F)(F)F)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COc1cnc2[nH]c(C(CC3CCCC3)c3ccc(C(F)(F)F)cc3)cc2c1
Temperature: 50 °C
Yield: 42 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-trifluoromethyl-phenyl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (191 mg, 0.49 mmol) and 10% palladium on activated carbon (50 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-trifluoromethyl-phenyl)-ethyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (80 mg, 41.9%) as a white solid: LC/MS m/e calcd for C22H23F3N2O [M+H]+ 389.54, observed 389.3; 1H NMR (400 MHz, CD3OD) δ ppm 7.84 (d, J=2.5 Hz, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.6 Hz, 3H), 6.31 (s, 1H), 4.25 (t, J=8.0 Hz, 1H), 3.86 (s, 3H), 2.22-2.30 (m, 1H), 2.05-2.13 (m, 1H), 1.60-1.87 (m, 6H), 1.44-1.57 (m, 2H), 1.17-1.29 (m, 2H).
Reaction SMILES: [OH-].[Na+].O.NN.[Br:6][C:7]1[CH:8]=[C:9]([Cl:17])[C:10]([OH:16])=[C:11]([C:13](=O)[CH3:14])[CH:12]=1>C(O)COCCOCCO>[Br:6][C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([OH:16])=[C:9]([Cl:17])[CH:8]=1
Reactant: CC(=O)c1cc(Br)cc(Cl)c1O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CCc1cc(Br)cc(Cl)c1O
Temperature: 160 °C
Yield: 82.8 %

Procedure:
Sodium hydroxide (1.2 g, 30 mmol) and hydrazine monohydrate (1.75 mL, 36 mmol) were added to a solution of 5′-bromo-3′-chloro-2′-hydroxyacetophenone (3 g, 12 mmol) dissolved in triethylene glycol (15 mL). The reaction mixture was heated to 160° C. for 72 hours and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound (2.34 g, 83%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.6 Hz, 3H), 2.65 (q, J=7.6 Hz, 2H), 5.55 (s, 1H), 7.17 (s, 1H), 7.31 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[C:11]1([CH:17]2[O:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:19]2[CH2:20][CH2:21][O:22][CH:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:18]2)=[CH:4][CH:3]=1
Reactant: c1ccc(C2CNCCO2)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCOC(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
429 mg of 4-Bromobenzaldehyde was dissolved in 6 mL of THF and 386 mg of the HCl salt of 2-Phenylmorpholine (Array) and 1.15 g of MP-BH(OAc)3 (2.77 mmol/g) was added. The reaction was agitated on an orbital shaker overnight at room temperature. The reaction was filtered and the resin washed several times with dichloromethane. The filtrate was concentrated and purified by flash chromatography. Yield: 281 mg.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:17][C:18]([F:26])(S(F)(=O)=O)C(O)=O.O>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:18]([F:26])[F:17])=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: OCc1ccc(Br)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: FC(F)OCc1ccc(Br)cc1
Temperature: 45 °C
Yield: 37.1 %

Procedure:
To a solution of 4-bromobenzyl alcohol (5.6 g) in acetonitrile (15 ml), sodium sulfate (0.28 g) was added. While warmed to 45° C., 2,2-difluoro-2-(fluorosulfonyl)acetic acid (1.78 g) was slowly dropwise added, and the mixture was heated and refluxed at 45° C. for 4 hours. The reaction solution was poured into water, the mixture was extracted with diethyl ether and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo and the residue obtained was purified with silica gel column chromatography (hexane:ethyl acetate=19:1 to 17:3) to afford the above-identified compound (0.88 g).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:30][CH2:29]2)[CH:25]=[CH:24][C:23]=1[NH2:39]>C(O)C>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([NH:39][C:23]3[CH:24]=[CH:25][C:26]([N:28]4[CH2:33][CH2:32][CH:31]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:30][CH2:29]4)=[CH:27][C:22]=3[O:21][CH3:20])[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: COc1cc(N2CCC(N3CCCC3)CC2)ccc1N
Agent: Cl
Solvent: CCO
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(N4CCC(N5CCCC5)CC4)cc3OC)nc2N1C(C)C
Temperature: 100 °C
Reaction time: 3 h

Procedure:
50 mg (0.186 mmol) (R)-2-chloro-7-ethyl-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one are dissolved in 0.5 ml of ethanol and 1 ml distilled water, combined with 136 μl of a 33% aqueous hydrochloric acid and 56 mg (0.203 mmol) 2-methoxy-4-(4-pyrrolidin-1-yl-piperidin-1-yl)-phenylamine (method 1) and stirred for 3 h at 100° C.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:15][C:16]3[C:21]([Cl:22])=[CH:20][C:19]([CH:23]([OH:25])[CH3:24])=[CH:18][C:17]=3[Cl:26])[C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1>CN(C=O)C.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>[Cl:26][C:17]1[CH:18]=[C:19]([CH:23]([OH:25])[CH3:24])[CH:20]=[C:21]([Cl:22])[C:16]=1[NH:15][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2]([C:39]3[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=3)[CH:28]=[CH:27][C:5]=2[N:6]=1
Reactant: CC(O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: CN(C)C=O
Product: CC(O)c1cc(Cl)c(Nc2nc3ccc(-c4cnn(C)c4)cc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 9-bromo-5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}benzo[c]-2,6-naphthyridin-1(2H)-one (Examples 94 and 95, Step 3) (300 mg, 0.63 mmol) in DMF (3 mL) were added sodium carbonate (0.3 mL, 2 M) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.00 mmol), followed by tetrakis(triphenylphosphine)palladium (0) (145 mg, 0.13 mmol). The solution was degassed by bubbling nitrogen gas for 5 min. The reaction vessel was sealed and heated to 80° C. overnight. The reaction mixture was extracted with 3:1 (CHCl3/iPrOH) and water. The organic layers were combined and dried with MgSO4, filtered, and concentrated under reduced pressure. Purification with column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) afforded 5-{[2,6-dichloro-4-(1-hydroxyethyl)phenyl]amino}-9-(1-methyl-1H-pyrazol-4-yl)benzo[c]-2,6-naphthyridin-1(2H)-one as racemates. The enantiomers were separated using a Chiralpak AD 10 mm×250 mm column with 40% iPrOH/60% Heptane with a flow rate of 10 ml/min in a 25 min run. The first enantiomer has a retention time of 8.47 min and the second enantiomer has a retention time of 11.68 min.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[C:4]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.P(Cl)(Cl)([Cl:22])=O.C(N(C(C)C)CC)(C)C>ClCCCl>[Cl:22][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]cnc2cc(F)cc(OC3CCOCC3)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 80 °C

Procedure:
A mixture of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (1 g), phosphoryl chloride (4 ml), diisopropylethylamine (1.5 ml) and 1,2-dichloroethane (15 ml) was stirred and heated to 80° C. for 3 hours. The mixture was evaporated to give 4-chloro-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][N:10]3[C:14](=[O:24])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:17]=[C:9]23)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.O.CCOC(C)=O>[CH2:31]([NH:39][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][N:10]3[C:14](=[O:24])[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:17]=[C:9]23)[CH:3]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1cc(Cl)ncn1
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccc2)cc2n1CCCN2c1cc(NCCc2ccccc2)ncn1

Procedure:
To a stirred mixture of 1-(6-chloro-pyrimidin-4-yl)-8-phenyl -1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one (0.158 mg, 0.47 mmol) and excess of K2CO3 in DMF (3 mL) was added phenethylamine (0.15 mL, 1.2 mmol). The overall reaction vessel was irradiated under microwave conditions at 150° C. for 10 min. After diluted with water and EtOAc, the organic layer was taken and the aqueous layer was extracted with EtOAc. The overall organic layers were washed with water, brine, and dried (Na2SO4). Filtration followed by evaporation gave the crude residue, which was washed with EtOAc/ether to provide the title compound as a light yellow solid. MS m/e 424 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([N:9]1[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10]1)[CH2:2]2.I.CS[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[NH:23]>C(O)C>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([N:9]1[C:17]3[C:12](=[CH:13][C:14]([NH:18][C:22]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[NH:23])=[CH:15][CH:16]=3)[CH:11]=[CH:10]1)[CH2:2]2
Reactant: Nc1ccc2c(ccn2C2CN3CCC2CC3)c1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2c(ccn2C2CN3CCC2CC3)c1)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.4 %

Procedure:
Compound 70 (60 mg, 0.249 mmol) is charged to a small, argon purged flask fitted with a magnetic stir bar. Anhydrous ethanol (5 mL) and thiophene-2-carboximidothioic acid methyl ester hydroiodide (124 mg, 0.435 mmol) are added to the flask and the reaction was stirred under argon at ambient temperature for 18 hours, at which time the solvent was evaporated and the residue was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95 to 7.5:92.5) then a second time on silica gel (methanol:CH2Cl2, 1:9 to 2 M NH3 in methanol:CH2Cl2, 1:9) to yield a yellow solid, 71 (30 mg, 34.4%). 1H NMR (DMSO-d6) δ 1.27-1.53 (2×m, 2H), 1.60-1.69 (m, 1H), 1.79-1.96 (2×m, 2H), 2.69-2.87 (m, 3H), 3.03-3.13 (m, 1H), 3.19-3.30 (m, 1H), 3.34-3.44 (m, 1H), 4.57-4.68 (m, 1H), 6.28 (brs, 2H), 6.39 (d, 1H, J=3.1 Hz), 6.70 (dd, 1H, J=8.4, 1.6 Hz), 7.00 (d, 1H, J=1.2 Hz), 7.09 (dd, 1H, J=4.9, 3.9 Hz), 7.39 (d, 1H, J=8.6 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.67 (d, 1H, J=3.2 Hz), 7.71 (d, 1H, J=3.5 Hz); ESI-MS (m/z, %): 351 (M+1, 60%), 176 (M++doubly charged, 100%); ESI-HRMS calculated for C20H23N4S (MH+): 351.1637, observed: 351.1639.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)[CH:25]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+]>>[CH3:31][S:28]([C:26]1[CH:27]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[C:10]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])[CH:23]=[C:24]([C:32]2[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:36][CH:37]=2)[CH:25]=1)(=[O:30])=[O:29]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(S(C)(=O)=O)cc3)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc(-c2cc(OCCCCCCc3cccc(OCCCC(=O)O)c3CCC(=O)O)cc(S(C)(=O)=O)c2)cc1
Yield: 58.9 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[3-[6-(5,4′-bis-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (67 mg, 0.09 mmol) and 1.0 N aqueous sodium hydroxide (0.9 mL) to afford 4-[3-[6-(5,4′-bis-methanesulfonyl-biphenyl-3-yloxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (35 mg, 57%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C33H40O10S2 (M+Na)+ 683.1955, found 683.1954.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:12][N:13]=1.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:38])[CH3:37])[C:31]=1[N:39]=[C:40]=[O:41])([CH3:29])[CH3:28]>C(#N)C>[CH3:29][CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([CH3:37])[CH3:38])[C:31]=1[NH:39][C:40]([NH:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[N:12][N:13]=1)=[O:41])[CH3:28]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCCCc1nnc(N)o1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCc1nnc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)o1
Reaction time: 18 h

Procedure:
Triethylamine (1.67 g, 0.017 mol) was added to a solution of the compound prepared in Step 2 above (4.0 g, 0.015 mol) in acetonitrile (200 mL) and the mixture refluxed for 30 minutes or until solution becomes homogeneous. 2,6-Diisopropylphenyl isocyanate (3.71 g, 0.018 mol) was then added and reflux continued for 18 hours. The mixture was allowed to cool, concentrated, diluted with water (20 mL), filtered, and the solid columned on silica gel, eluting with 20% ethyl acetate in hexanes (loaded in chloroform) to give 0.54 g of a solid; m.p 114°-116.5° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@H:38]([C@H:49]([OH:51])[CH3:50])[C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].[O:62]=[C:63]1[CH:67]=[CH:66][C:65](=[O:68])[N:64]1[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][C:74]([NH:76][NH2:77])=[O:75]>>[O:68]=[C:65]1[CH:66]=[CH:67][C:63](=[O:62])[N:64]1[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][C:74]([NH:76][NH:77][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:61])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:24]([O:55][CH3:56])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:53][CH3:54])[C@@H:34]([CH3:52])[C:35]([NH:37][C@@H:38]([C@H:49]([OH:51])[CH3:50])[C:39]([NH:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:10])[CH3:11])=[O:75]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)NCc1ccccc1)[C@@H](C)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(=O)NCc1ccccc1)[C@@H](C)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
This compound was prepared in analogy to the synthesis described in Intermediate 157 from N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3R)-1-(benzylamino)-3-hydroxy-1-oxobutan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and commercially available 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[F:1])[CH:9]=2)=[O:26])=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(Br)cc2)cc1-c1c(F)cnn1C
Yield: 60 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-bromophenylisocyanate, in a similar manner as described in Example 1.68, providing 27 mg (60% yield) of Compound 85: LCMS m/z (%)=421 (M+H81Br, 100), 419 (M+H79Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.24 (s, 1H), 8.13 (s, 1H), 7.63 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.48 (d, J=2.8 Hz, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.38 (d, JH,F=4.4 Hz, 1H), 7.13 (d, J=9.2 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −177.39 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:21][CH2:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2nc3c(C)cc(OC)cc3s2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3c(CBr)cc(OC)cc3s2)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
4-Methyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (0.53 g, 1.87 mmol), N-bromosuccinimide (0.33 g, 1.87 mmol) and benzoyl peroxide (9 mg) were suspended in carbon tetrachloride (6 mL) and refluxed for 3.5 h, then cooled to room temperature. Solvent was evaporated and the mixture was purified by chromatography to give 4-bromomethyl-6-methoxy-2-(4-methoxy-phenyl)-benzothiazole (0.47 g, 70% yield) as a white solid. Mass spec: MH+=364.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=[O:17].C(=O)([O-])O.[Na+]>C(OCC)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]([C:4]2[S:3][CH:2]=[N:6][CH:5]=2)[OH:17])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Brc1nccs1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: OC(c1ccc(Cl)c(Cl)c1)c1cncs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Bromothiazole (5 g) in dry diethyl ether (20 ml) was added dropwise to a stirred solution of n-butyllithium (1.6M in hexanes, 21 ml) in diethyl ether (20 ml) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, trimethylsilylchlorlde (3.9 ml) was added and the mixture was allowed to warm to 0° C. The mixture was then cooled to -70° C. and further n-butyllithium (21 ml) was added. The mixture was warmed to 0° C. and after 30 minutes was cooled again to -70° C. and 3,4-dichlorobenzaldehyde (5.8 g) in diethyl ether (40 ml) was added. The mixture was then allowed to warm to room temperature and after 30 minutes saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with dichloromethane and the material thus obtained was purified by chromatography on silica gel to give the title compound. The hydrochloride salt was prepared. M.p. 167°-170° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:13][C:14]1[CH:19]=[N:18][C:17](Br)=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>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.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:17]3[N:18]=[CH:19][C:14]([NH2:13])=[N:15][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1cnc(-c2ccc3[nH]ccc3c2)cn1
Temperature: 90 °C
Yield: 41.2 %

Procedure:
Nitrogen was bubbled through a solution of 5-indolylboronic acid (340 mg, 2.11 mmol), 2-amino-5-bromopyrazine (245 mg, 1.41 mmol), sodium carbonate (493 mg, 4.65 mmol), dimethoxyethane (12 mL), and water (4 mL) for 15 min. After this time, the solution was treated with dichlorobis(triphenylphosphine)palladium(II) (98 mg, 0.14 mmol), and the resulting reaction mixture was heated at 90° C. for 2 d. The reaction was then poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 35/65 hexanes/ethyl acetate) afforded 5-(1H-indol-5-yl)-pyrazin-2-ylamine (122 mg, 41%) as a brown solid: EI-HRMS m/e calcd for C2H10N4 (M+) 210.0905, found 210.0901.