Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@@H:17]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)(=[O:16])=[O:15])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31].Cl[Si](C)(C)C>CO>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([S:14]([C@@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)(=[O:15])=[O:16])=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@@H]3CCN(C(=O)OC(C)(C)C)C3)ccc21
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)[C@@H]3CCNC3)ccc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of (R)-tert-butyl 3-(1-(2-(dimethylamino)ethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)pyrrolidine-1-carboxylate (STEP B, 612 mg, 1.24 mmol) in methanol (5 mL) was added chlorotrimethylsilane (749 microL, 6.21 mmol). The mixture was stirred at 50° C. for 3 h. The mixture was concentrated in vacuo. To the residue was added 2 mol/L sodium hydroxide aqueous solution to pH>7 and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with brine and dried over sodium sulfate. The resulting solution was concentrated to give the title compound (453 mg, 93%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]([F:20])[F:19])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(#N)C.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:18]([F:20])[F:19])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: O=C(c1ccc(OCC(F)F)cc1)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: COC(C)(C)C
Solvent: CCOCC
Solvent: CC#N
Product: FC(F)COc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
Under Ar protection, (5-bromo-2-chloro-phenyl)-[4-(2,2-difluoroethoxy)phenyl]methanone 12o (55.7 g, 148.6 mmol) was dissolved in 400 mL acetonitrile, triethyl silane (46.54 g, 401.22 mmol) was added and cooled to 0° C., followed by the slow dropwise addition of boron trifluoride etherate (57 g, 401.22 mmol). Then the reaction mixture was heated to 50° C. and stirred for 16 hours. Thereafter, the reaction mixture was cooled to room temperature before MTBE (200 mL) was added and 300 mL saturated sodium bicarbonate solution were dropwise added, and partitioned. The organic extracts were washed with 200 mL saturated NaCl solution and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography to obtain the title compound 4-bromo-1-chloro-2-[[4-(2,2-difluoroethoxy)phenyl]methyl]benzene 12p (20 g, colourless grease), yield: 20.0%. MS m/z (ESI): 362.0 [M+1].
Reaction SMILES: [ClH:1].[CH:2]1([C:8]2(O)[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:21][CH2:20]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C1COCC1.CO>[ClH:1].[C:2]1(=[C:8]2[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:20][CH2:21][N:22]([C:25]5[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=5)[CH2:23][CH2:24]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(C3CCCCC3)C(C)(C)O4)CC2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=C3CCCCC3)C(C)(C)O4)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
Concentrated hydrochloric acid (0.5 mL) was added to a solution of 1-(3-cyclohexyl-3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine (670 mg, 1.4 mmol) obtained in Example 43 in THF (5 ml) and methanol (5 ml) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was made to basic with 10% aqueous potassium carbonate. The mixture was extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was treated with 4N hydrochloric acid in ethyl acetate solution and the title compound was crystallized from ethanol-diisopropyl ether to obtain 520 mg (yield 75%). mp. 220–222° C.
Reaction SMILES: N1CCCCC1.C1C2C(COC(=O)[NH:23][C@H:24]([C:45]([OH:47])=[O:46])[CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:38][C:39]3[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=3)[CH2:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])C3C(=CC=CC=3)C=2C=CC=1>CN(C=O)C>[NH2:23][C@@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:30][C:31]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])[CH2:38][C:39]1[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=1)[C:45]([OH:47])=[O:46]
Reactant: Cn1ccnc1CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)CC(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Piperidine (0.40 mL) was added to a solution of (S)-1-(9H-fluoren-9-yl)-14,14-dimethyl-10-((1-methyl-1H-imidazol-2-yl)methyl)-3,12-dioxo-2,13-dioxa-4,10-diazapentadecane-5-carboxylic acid (190 mg, 0.33 mmol) in DMF (2.0 mL). The mixture was stirred at room temperature for 2 hrs. The solvent was evaporated under reduce pressure to afford a residue, which was purified by Amberchrom to afford (S)-2-amino-6-((2-tert-butoxy-2-oxoethyl)((1-methyl-1H-imidazol-2-yl)methyl)amino)hexanoic acid (115 mg, 100%). 1H NMR (400 MHz, DMSO) 7.27 (brs, 1H), 7.04 (s, 1H), 6.72 (s, 1H), 3.73 (s, 2H), 3.64 (s, 3H), 3.15 (s, 2H), 3.04 (dd, J=6.8, 5.2 Hz, 1H), 2.47 (t, J=7.2 Hz, 2H), 1.65-1.46 (m, 2H), 1.39 (s, 9H), 1.30-1.21 (m, 4H); MS (ESI), 355 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:20]#[N:21])=[N:4][N:5]([CH2:17][CH2:18][CH3:19])[C:6]=1[CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].Cl.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)CC>[NH2:21][C:20]1[C:3]2=[N:4][N:5]([CH2:17][CH2:18][CH3:19])[C:6]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[C:2]2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1
Reactant: Nc1ccccc1B(O)O
Reactant: CCCn1nc(C#N)c(Br)c1CCNC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCCO
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCNC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 44.7 %

Procedure:
A flask containing a mixture of tert-butyl 2-(4-bromo-3-cyano-1-propyl-1H-pyrazol-5-yl)ethylcarbamate (15.8 g, 44.2 mmol), 2-aminophenylboronic acid hydrochloride (11.5 g, 66.3 mmol), triphenylphosphine (1.04 g, 3.98 mmol), palladium (II) acetate (299 mg, 1.33 mmol), 2 M aqueous sodium carbonate (67 mL, 133 mmol), 1-propanol (77.4 mL), and water (15.5 mL) was heated overnight under a nitrogen atmosphere in a 100° C. oil bath. The reaction was allowed to cool to ambient temperature and water (300 mL) was added. The mixture was extracted with chloroform, dried over magnesium sulfate, filtered, and concentrated to provide an oil that was purified twice by flash chromatography (silica gel, first column: eluted sequentially with 0-10% CMA in chloroform, and then 25% CMA in chloroform; second column: gradient elution with 50-60% ethyl acetate in hexanes) to yield 7.3 g of tert-butyl 2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethylcarbamate as a yellow resin.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[C:24]([F:36])=[CH:23][C:22]=1[NH:37][C:38]([NH:40][C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][C:42]=1[F:51])=[O:39].FC1C=CC(C(F)(F)F)=CC=1NC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=O>>[NH2:11][C:9]1[C:10]2=[C:2]([C:25]3[C:24]([F:36])=[CH:23][C:22]([NH:37][C:38]([NH:40][C:41]4[CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=[CH:43][C:42]=4[F:51])=[O:39])=[C:21]([F:20])[CH:26]=3)[C:3]([CH3:19])=[C:4]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:6]=[CH:7][N:8]=1
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Reactant: CC1(C)OB(c2cc(F)c(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2F)OC1(C)C
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Product: Cc1c(-c2cc(F)c(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2F)c2c(N)ncnn2c1CN1CCOCC1
Yield: 14 %

Procedure:
The title compound was prepared in a manner similar to the procedure described for the preparation of Example 117 Step 4, using the product of step 1, Example 119 (5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine) in place of 5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and Intermediate AAB (1-[2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[2-fluoro-5-(trifluoromethyl)-phenyl]urea) in place of Intermediate AAN (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea) 25 mg (14%) of the desired product was isolated. 1H-NMR (DMSO-d6) δ 9.51-9.45 (m, 2H), 8.63-8.61 (m, 1H), 8.20-8.13 (m, 1H), 7.87 (s, 1H), 7.55-7.48 (m, 1H), 7.45-7.39 (m, 1H), 7.33-7.27 (m, 1H), 3.80 (s, 2H), 3.53-3.50 (m, 4H), 2.41-2.39 (m, 4H), 2.03 (s, 3H); MS [M+H]+=580.1; LCMS RT=2.65.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:29]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C>[C:1]1([N:7]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:29]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccc4)ccc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.45 g (0.84 mMol) of 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide were dissolved in 15 ml of ethanol, mixed with 2 ml of 2N sodium hydroxide solution and stirred for 4 hours at room temperature. Then the mixture was acidified with 3 ml of 2N hydrochloric acid and the solvent was distilled off. The crude product obtained was taken up in 5 ml dichloromethane/ethanol (2:1) and filtered to remove the insoluble sodium chloride. After the distillation of the solvent the desired compound was obtained as a yellow foam. Yield: 0.26 g (67% of theory), Rf value: 0.47 (silica gel; methanol/5% aqueous sodium chloride=6:4) C25H23N5O3S (473.55) Mass spectrum: (M+H)+ =474
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][NH:5][CH:4]=1)#[N:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>O>[C:14]([N:5]1[CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:3]([C:1]#[N:2])=[CH:4]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Solvent: O
Product: CC(=O)n1cc(C#N)c(-c2ccccc2)c1

Procedure:
4 g of 3-cyano-4-phenylpyrrole (Compound No. 8) was added to 20 ml of acetic anhydride and heated for 4 hours in oil-bath of 140°-150° C. After cooling, the resulting reaction mixture was poured into about ten-times volume of cold water to decompose excess acetic anhydride. The resulting precipitate was filtrated, washed with water and dried to obtain 4.5 g of crystal. The crystal was recrystallized from methyl alcohol to obtain 3 g of the desired product.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH:2]=[CH2:3].[CH3:7][NH:8][C:9](=S)[NH:10][NH2:11].C(O)C.NC(NNC(=O)N)=O>P(Cl)(Cl)(Cl)=O>[CH2:1]([NH:4][C:5]1[S:6][C:9]([NH:8][CH3:7])=[N:10][N:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCN=C=S
Reactant: CNC(=S)NN
Agent: NC(=O)NNC(N)=O
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCNc1nnc(NC)s1
Temperature: 2 °C
Yield: 21.4 %

Procedure:
A stirred suspension of allyl isothiocyanate (19.8 g, 0.2 mole) and of 4-methyl-3-thiosemicarbazide (21.0 g, 0.2 mole) in 150 ml denatured ethanol (5% methanol) was refluxed for one hour. The crystalline suspension was briefly chilled, and the 1-allyl-6-methyl-2,5-dithiobiurea was collected and vacuum dried. A stirred solution of this biurea (30.6 g, 0.15 mole) in phosphorous oxychloride (150 ml) was refluxed for 11/2 hours. Unreacted phosphorus oxychloride was removed in vacuo, and the residue carefully partitioned between 1.2 M hydrochloric acid (150 ml) and chloroform (150 ml) while maintaining this mixture at 2° C with ice-bath cooling. The chloroform phase was extracted with another portion of 1.2 M hydrochloric acid (100 ml), and the combined acid layer was carefully made alkaline with conc. ammonium hydroxide. The resultant alkaline suspension was extracted with two portions of chloroform, and the combined chloroform extract was washed with a small portion of distilled water. After drying this chloroform extract over magnesium sulfate, the solvent was removed under reduced pressure to yield a colorless solid. Crystallization of the product from ethyl acetate gave 7.3 g (29 percent) of 2-allylamino-5-methylamino-1,3,4-thiadiazole (a colorless solid). Analysis confirmed the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:4](=[O:16])[CH:3]=1.C1C(=O)N([Cl:24])C(=O)C1>C(Cl)Cl>[Cl:24][C:3]1[C:4](=[O:16])[N:5]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(O)cc(=O)n1Cc1cccnc1
Solvent: ClCCl
Product: Cc1cc(O)c(Cl)c(=O)n1Cc1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 224.1 %

Procedure:
To a suspension of 4-hydroxy-6-methyl-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one (1.016 g, 4.7 mmol) in MeCl2 (10 mL) was added NCS (1.21 g, 1.78 mmol). The reaction mixture stirred at room temperature for 24 hours under nitrogen. The suspension was chilled in an ice bath and filtered. The solid was washed with fresh MeCl2 and dried to afford a yellow solid (1.00 g, 85%) after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.54 (m, 2H), 7.85 (d, 1H, J=1.6 Hz), 7.61 (m, 1H), 6.10 (s, 1H), 5.41 (s, 2H), 2.33 (s, 3H); ES-LRMS (M+H) m/z 251/253.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20](O)[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:52]I>C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][C@H:20]([I:52])[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC[C@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CC[C@@H](I)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
To a solution of 7 (4.33 g, 11.2 mmol) in 250 mL toluene was added triphenylphosphine (5.9 g, 22.4 mmol), imidazole (2.3 g, 33.6 mmol), and iodine (4.26 g, 16.8 mmol) under a nitrogen atmosphere. The reaction mixture was lowered into a preheated heating mantle and refluxed for 1 hour. The reaction mixture was quenched by pouring into 200 mL saturated NaHCO3 solution. Excess triphenylphosphine was destroyed by the addition of iodine until an iodine coloration remained in the organic phase. The organic phase was then washed with 5% sodium thiosulfate solution (2×100 mL) and 2×200 mL water. The product was purified by flash chromatography with 6:1 hexane/ethyl acetate: yield 4.75 g (85%) of a viscous oil; [α]D25 +6.5° (C=1, CHCl3); FAB MS 497 (M+H)+, 439 (M-t-butyl)+ ; 1H NMR (CDCl3) δ 7.89 (m, 4, ArH), 7.4 (m, 6, ArH), 4.15 (m, 1, H-4), 3.85 (m, 2, CH2), 3.7 (s, 3, OCH3), 2.5 (m, 2, CH2), 2.25 (m, 1, H-2), 2.1 (m, 1, H-2), 1.1 (s, 9, t-butyl).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[O:16]=[S:17]1(=[O:23])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:20]2[CH2:21][CH2:22][S:17](=[O:23])(=[O:16])[CH2:18][CH2:19]2)=[O:15])=[CH:4][N:3]=1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: O=S1(=O)CCNCC1
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCS(=O)(=O)CC3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 1,1-dioxidothiomorpholine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[C:25]([O:32][CH3:33])=[CH:26][C:27]([Cl:31])=[C:28]([CH3:30])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>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:31][C:27]1[C:28]([CH3:30])=[CH:29][C:24]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C@@H:3]([CH3:14])[C@H:2]([OH:1])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:6][CH:7]=2)=[C:25]([O:32][CH3:33])[CH:26]=1
Reactant: COc1cc(Cl)c(C)cc1Br
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: CCO
Product: COc1cc(Cl)c(C)cc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 33), 5-bromo-2-chloro-4-methoxytoluene (0.12 g), 2M aqueous sodium carbonate (0.57 ml) and tetrakis(triphenylphosphine)palladium (0) (0.014 g) in ethanol (5 ml) with heating at 90° C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.13 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].ClC(N(C)C)=C(C)C.N1C=CC=CC=1.O[C@H:25]([C@@H:47]([NH:55][C:56](=[O:75])[C@H:57]([CH2:71][C:72](=[O:74])[NH2:73])[NH:58][C:59]([C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[N:62]=1)=[O:60])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:26][N:27]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:28][C:29](=[O:39])[C@H:30]([CH:36]([CH3:38])[CH3:37])[NH:31][C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl.O1CCOCC1.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9][C@H:25]([C@@H:47]([NH:55][C:56](=[O:75])[C@H:57]([CH2:71][C:72](=[O:74])[NH2:73])[NH:58][C:59]([C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[N:62]=1)=[O:60])[CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:26][N:27]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[NH:28][C:29](=[O:39])[C@H:30]([CH:36]([CH3:38])[CH3:37])[NH:31][C:32]([O:34][CH3:35])=[O:33])=[O:8]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)C(C)C
Reactant: O=C(O)c1ccccn1
Agent: CC(C)=C(Cl)N(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccccc1)C[C@H](OC(=O)c1ccccn1)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)C(C)C
Reaction time: 18 h

Procedure:
Analogously to Example 108, 51 mg (0.416 mmol) of 2-picolinic acid in 0.8 ml of methylene chloride are converted with 59 μl (0.416 mmol) of 1-chloro-N,N,2-trimethyl-1-propenamine into the acid chloride. After the addition of 0.5 ml of dioxane and 0.4 ml of pyridine to the latter, the mixture is reacted with 148 mg (0.208 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[phenylmethyl]-2-[N-(methoxycarbonyl)-(L)-valyl]-hydrazine (Example 109) in 5 ml of dioxane in the presence of 0.5 mg of DMAP. Since, after 18 h, not all of the educt has been acylated according to HPLC, further acid chloride is added. Column chromatography (SiO2, methylene chloride→methylene chloride/methanol 15:1) yields the title compound: FAB-MS (M+H)+ +817.
Reaction SMILES: CON(C)C(C1SC=NC=1)=O.CON(C)[C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[CH3:27][N:28]1[C:32](C(C2SC=NC=2)=O)=[CH:31][N:30]=[CH:29]1>>[CH3:27][N:28]1[C:32]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:25])=[CH:31][N:30]=[CH:29]1
Reactant: CON(C)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cn1cncc1C(=O)c1cncs1
Agent: CON(C)C(=O)c1cncs1
Product: Cn1cncc1C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared by substituting N-methoxy-N-methylthiazole-5-carboxamide (Intermediate 11: step a) with N-methoxy-N-methyl-4-nitrobenzamide (Intermediate 20: step a) then following the procedure described for the preparation of (1-methyl-1H-imidazol-5-yl)(thiazol-5-yl)methanone (Intermediate 13).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=2)[CH:8]=1)(=O)=O.[CH:30]1[C:39]2[C:34](=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCOCC1.O>[CH:30]1[C:39]2[C:34](=[C:35]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[C:12]([NH:17][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:11]=[CH:10]4)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1
Reactant: COc1ccc(C(=O)Nc2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)cc1
Reactant: OB(O)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3cc(-c4cccc5cnccc45)ccc3c2)cc1
Reaction time: 0.17 h
Yield: 3 %

Procedure:
To a microwave vial containing 6-(4-methoxybenzamido)naphthalen-2-yl trifluoromethanesulfonate (0.100 g, 0.2 mmol), in 1,4-Dioxane (3 mL), was added isoquinolin-5-ylboronic acid (0.129 g, 0.8 mmol), Fibrecat catalyst (0.005 g, 5% by wt.), 2 M Potassium Carbonate (0.50 mL, 1 mmol). The vial was capped and placed into CEM Microwave for 10 minutes at 80° C., while supplying 50 Watts of power through power-max. The diluted the mixture [with DCM (2 mL) and water (2 mL)] was extracted with DCM (3×10 mL). The dried organics (over sodium sulfate) was filtered, and concentrated in-vacuo. The crude was purified from reverse-phase HPLC. This gave a tan colored amorphous solid, which was titled product (0.0023 g, 0.006 mmol) MS (ESI pos. ion) m/z: 405 (M+H). Calc'd Exact Mass for C27H20N2O2: 404.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].O[CH2:19][C:20]1[O:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:19][C:20]3[O:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(CO)o1
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(CO)o1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 5-(hydroxymethyl)furfural (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.