Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Cl:16][CH2:17][C:18](Cl)=[O:19].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:16][CH2:17][C:18]([NH:1][CH2:2][C:3]1([CH3:15])[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)CN
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1(C)CNC(=O)CCl

Procedure:
A solution of tert-butyl 2-(aminomethyl)-2-methylpyrrolidine-1-carboxylate (1.2 g), excess 2-chloroacetyl chloride (2 mL) and diisopropyl ethyl amine (2 mL) in DCM was stirred at room temperature for about 2 h. The reaction was monitored by LC-MS. After the solution was concentrated in vacuo, 0.7 g of the desired product was obtained by column chromatography purification. MS (ESI): 291, 293 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:7]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1)=[C:8]=[O:9]>C1(C)C=CC=CC=1>[N:1]1([C:8]([NH:7][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.5 %

Procedure:
To a solution of morpholine (0.684 g, 7.85 mmol, 0.687 mL) in toluene (8 mL) was added dropwise ethyl 4-isocyanatobenzoate (1.50 g, 7.85 mmol) in toluene (8 mL). After stirring for 18 h at room temperature, the precipitate was filtered, washed with cold toluene, and dried under vacuum to give 2.00 g (91%) of the title compound as a white solid. 1H NMR: δ7.96 (d, J=8.8 Hz, 2H, aryl), 7.45 (d, J=8.8 Hz, 2H, aryl), 6.80 (br s, 1H, NH), 4.35 (q, J=7.1 Hz, 2H, CO2CH2), 3.75-3.70 (m, 4H, CH2OCH2), 3.53-3.47 (m, 4H, CH2NCH2), 1.38 (t, J=7.1 Hz, 3H, CH3). 13C NMR: δ166.3, 154.4, 143.2, 130.7, 124.7, 118.5, 66.4, 60.8, 44.3, 14.3. IR (KBr): 3328, 1716, 1645, 1592, 1526, 1423, 1308, 1279, 1247 cm−1. MS (DCI/CH4): m/z (rel intensity) 307 (M+C2H5+, 39), 279 (MH+, 100). Anal. (C14H18N2O4): C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][C@@H:35]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[CH2:36][OH:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][C@H:35]([CH2:36][OH:37])[C@@H:38]([CH3:41])[CH2:39][CH3:40])(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-bromo-N-((2S,3S)-1-hydroxy-3-methylpentan-2-yl)benzene-sulfonamide. MS (ESI): mass calcd. for C22H25FN4O3S, 444.16; m/z found, 445.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.16-8.13 (m, 1H), 8.06 (d, J=1.4, 1H), 7.86 (m, 1H), 7.67-7.62 (m, 1H), 7.58-7.53 (m, 1H), 7.39-7.28 (m, 3H), 3.46-3.35 (m, 2H), 3.13 (q, J=5.4, 1H), 1.60-1.49 (m, 1H), 1.48-1.36 (m, 1H), 1.07-0.93 (m, 1H), 0.84-0.74 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[C:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:23].CCOC(C)=O.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[CH:27][CH:26]=1)#[N:23]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cc1
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (60 mg, 0.162 mmol), [4-(cyanomethyl)phenyl]boronic acid (52.0 mg, 0.323 mmol) and K2003 (67.0 mg, 0.485 mmol) in 1,4-dioxane (0.18 mL) and water (0.08 mL) was degassed in a Biotage microwave vial for 10 min. PdCl2(dppf) (11.83 mg, 0.016 mmol) was added, the vial sealed, and the reaction heated at 100° C. for 5 min (microwave reaction). EtOAc (3 mL) and water (1 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (4×2 mL). The combined organic layers were washed with saturated NaCl (1×2 mL), dried (Na2SO4), and concentrated under a stream of nitrogen at 50° C. Recovered 27 mg (42%) of the title compound.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].CC1(C)N([O])C(C)(C)CCC1.C([O-])(=[O:26])C.C([O-])(=O)C.C1([I+2])C=CC=CC=1.Cl>O1CCOCC1.O>[O:12]=[C:3]([CH:2]=[CH2:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:26])=[O:11]
Reactant: C=CC(O)CCCCCCCO
Reactant: CC(=O)[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Agent: [I+2]c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C=CC(=O)CCCCCCC(=O)O

Procedure:
To a solution of 1-decene-3,10-diol (920 mg, 5.34 mmol, 1.00 eq.) in 1,4-dioxane (15.0 mL) and H2O (10.0 mL), were added a catalytic amount of TEMPO and phenyliodine diacetate (2.06 g, 6.41 mmol, 1.20 eq.) at room temperature. The mixture was allowed to react at the same temperature for 20 hours, and then the reaction solution was poured into 1 M aqueous hydrochloric acid solution and a saturated salt solution. The organic phase was extracted with chloroform. Then, the resulting organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=97:3) to obtain 8-oxo-9-decenoic acid as shown below (915 mg, 4.97 mmol, 93%).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][N:9]([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][CH2:38]2)[CH2:10][CH2:11][CH2:12][C:13]2[N:17]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[N:15][N:14]=2)C(=O)C2=CC=CC=C12.O.NN.[Br:56][C:57]1[CH:62]=[CH:61][C:60]([N:63]=[C:64]=[O:65])=[CH:59][CH:58]=1>CCO>[Br:56][C:57]1[CH:62]=[CH:61][C:60]([NH:63][C:64](=[O:65])[NH:5][CH2:6][CH2:7][CH2:8][N:9]([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][CH2:38]2)[CH2:10][CH2:11][CH2:12][C:13]2[N:17]([C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[N:15][N:14]=2)=[CH:59][CH:58]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCN(CCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C1CCCc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: O=C(NCCCN(CCCc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C1CCCc2ccccc21)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of 3-[[(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]-1-[1-(triphenylmethyl)tetrazol-5-yl]propane (50 mg, 0.073 mmol) in EtOH (1 ml) was added hydrazine monohydrate (17 μl, 0.36 mmol), and the mixture was stirred at RT for 3 h. The reaction mixture was concentrated under vacuum, and then water was added. The mixture was extracted with chloroform, washed with brine, dried over sodium sulfate, and filtered. To the filtrate was added 4-bromophenyl isocyanate (17 mg, 0.088 mmol), and the mixture was stirred at RT for 1 h. The reaction mixture was concentrated under vacuum to dryness, and the residue was adsorbed on a plate of silica gel and then developed with 3% methanol/chloroform to afford 3-[[3-(4-bromophenylureido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]-1-[1-(triphenylmethyl)tetrazol-5-yl]propane (Compound 217, 33 mg, 60%): MS(ES+) m/e 756 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.62 (m, 1H), 7.53 (br, 1H), 7.34 (m, 10H), 7.09 (m, 12H), 5.79 (br, 1H), 4.05 (m, 1H), 3.48 (m, 1H), 3.31 (m, 1H), 3.17 (m, 1H), 2.74 (m, 4H), 2.55 (m, 1H), 2.44 (m, 2H), 1.96 (m, 3H), 1.86 (m, 1H), 1.72 (m, 2H), 1.61 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([CH3:21])[CH3:20])=[O:18].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:19]([C:17]([O:16][CH3:15])=[O:18])([CH3:21])[CH3:20])=[CH:30][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
0.780 g (3.78 mMol) of 4-amino-piperidine-carboxylic acid tert-butyl ester was suspended in 10 mL of MeCl2 at rt under argon; then, 0.80 g (3.60 mmol) of 4-(1-methoxycarbonyl-1-methyl-ethyl)-benzoic acid, 0.845 g (1.20 eq.) of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride and 0.583 g (1.30 eq.) of N,N-dimethyl-4-aminopyridine were added. The reaction mixture became a clear solution after stirring for 1 h at rt. After 5 hours, the solution was evaporated i.V. and the residue was purified by chromatography (silicagel, eluent:MeCl2) to yield 1.28 g of the title compound as colorless foam. MS: 405.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[C:31](Cl)(Cl)=[O:32]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25]3[O:26][C:31](=[O:32])[NH:28][N:27]=3)=[CH:29][CH:30]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NN)cc2)c1Sc1ccc(Cl)cc1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-c3n[nH]c(=O)o3)cc2)c1Sc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 4-{5-[(4-chlorophenyl)thio]-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl}benzohydrazide (Step 1 of Example 48, 120 mg, 0.27 mmol) in THF (1 mL) was added phosgene (PhMe solution, 0.55 mmol) at −78° C. After stirring at −78° C. for 60 min, the reaction was quenched with aq NaHCO3 and the product was extracted with EtOAc. The combined extracts were washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was re-crystallized in MeCN/MeOH to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.68 (d, 1H), 8.42 (broad d, 1H), 8.28 (d, 2H), 7.91 (d, 2H), 7.89 (m, 1H), 7.37 (m, 1H), 7.27 (d, 2H), 7.06 (d, 2H), 4.17 (s, 3H). LCMS: m/z 462 (M+H)+.
Reaction SMILES: [C@@H:1]1(N2C=CC(=O)NC2=O)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH:18]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[NH:31][CH:32]=[N:33][C:26]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[K+]>>[NH:18]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31]([C@@H:1]3[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]3[OH:3])[CH:32]=[N:33][C:26]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: c1ccc(Nc2ccnc3[nH]cnc23)cc1
Agent: [K+]
Agent: [OH-]
Product: OC[C@H]1O[C@@H](n2cnc3c(Nc4ccccc4)ccnc32)[C@H](O)[C@@H]1O
Yield: 90.9 %

Procedure:
Uridine (50 mmoles, 12.3 g) and 7-anilino-3H-imidazo[4,5-b]pyridine (33 mmole, 7.0 g), were suspended in 65 mL of 7.6 mM KxHxPO4, pH 8.0. After stirring, the pH of this suspension was adjusted from pH 6.6 to 7.4 with potassium hydroxide. The enzyme catalysts purified from Escherichia coli, purine nucleoside phosphorylase (13,000 I.U.) and uridine phosphorylase (335 I.U.) (Krenitsky et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) were then added and the suspension stirred at 38° C. for 5 days. The reaction mixture was filtered. The solids were washed with water and suspended in 250 mL of methanol, brought to a boil, and filtered while hot. The filtrate was dried and extracted with water at room temperature. The product in the washed solids was further purified by several recrystallizations from boiling water. Analytically pure 7-anilino-3-β-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine (30 mmole, 10.46 g), m.p. 189° C. was obtained representing a yield of 91% with respect to the amount of 7-anilino-3H-imidazo[4,5-b]pyridine base used.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:22].[Na+].OO>C1COCC1.O>[C:7]1([CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH2:3][OH:22])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [OH-]
Reactant: C=CCOCCc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled (0° C.) solution of 2-allyloxyethylbenzene (5. g; 30.8 mmol) dissolved in THF (75 ml) is slowly added a 0.5M THF solution of 9-BBN [9-borabicyclo [3.3.1]nonane] (68 ml; 34 mmol) and the reaction mixture warmed to room temperature and stirred for 4 hours. The reaction mixture is then cooled to 0° C. and 5 ml H2O is added followed by slow addition of 6N NaOH (30 ml; 7.2 g/30 ml). After stirring for 5 minutes, 30% H2O2 (20 ml) is added over 15 min. The reaction mixture warms significantly but is kept from refluxing. After addition is complete, it is stirred for 15 minutes allowing the mixture to come to room temperature. It is then diluted with. Et2O, washed with H2O 2×, Na2S2O3 2×, NaHCO3 and brine, dried (MgSO4) and concentrated to dryness. The residue is purified by column chromatography using Et2O to obtain 3-(2-phenylethoxy)-1-propanol which is used directly in Step C.
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([Cl:18])=[N:10][CH:9]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)CCC>CCOC(C)=O>[Cl:18][C:11]1[CH:12]=[C:13]([C:8]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[CH:9][N:10]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COC(=O)c1cc(Cl)ncc1Br
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ncc1-c1nccs1
Temperature: 65 °C

Procedure:
To a 100 mL round bottom flask was added bis(tri-tertbutylphosphine)palladium(0) (204 mg, 0.40 mmol, 0.1 equiv). The flask was then flushed with nitrogen and charged with 1,4-dioxane (20 mL), methyl 5-bromo-2-chloroisonicotinate (7-1, 1000 mg, 4.0 mmol, 1 equiv) and 2-(tributylstannyl)-1,3-thiazole (1.5 mL, 4.8 mmol, 1.2 equiv). The reaction mixture was heated for 3 hours at 65° C., diluted with EtOAc (20 mL) and filtered through celite. The filtrate was concentrated and the residue purified by normal phase column chromatography (0-40% EtOAc in hexanes) to afford the title compound (7-2) as a yellow solid. ESI+MS[M+H]+C10H8ClN2O2S=255.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15].C(N(C(C)C)C(C)C)C.[F:25][C:26]([F:44])([F:43])[C:27]1[CH:28]=[C:29]([C:37]([CH3:42])([CH3:41])[C:38](Cl)=[O:39])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.C(=O)(O)[O-].[Na+]>ClCCl>[F:34][C:33]([F:35])([F:36])[C:31]1[CH:30]=[C:29]([C:37]([CH3:41])([CH3:42])[C:38]([N:14]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH3:15])=[O:39])[CH:28]=[C:27]([C:26]([F:43])([F:25])[F:44])[CH:32]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: 37.5 °C
Yield: 88.4 %

Procedure:
A solution of 12.2 g (55.8 mmol) [4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine and 15.3 ml (89 mmol) N-ethyldiisopropylamine in 130 ml dichloromethane was cooled in an ice bath and a solution of 19 g (59.6 mmol)2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 30 ml dichloromethane was added dropwise. The reaction mixture was warmed to 35-40° C. for 20 h, cooled to room temperature again and was stirred with 250 ml saturated sodium bicarbonate solution. The organic layer was separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography to give 24.7 g (88%) of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>>[ClH:1].[CH:13]1([NH:18][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:21]3[C:20]([CH3:19])=[CH:24][C:23]([CH3:25])=[N:22]3)[N:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(C)[nH]n1
Reactant: NC1CCCC1
Product: Cc1cc(C)n(-c2nc(NC3CCCC3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, cyclopentylamine and 3,5-dimethylpyrazole Mp. 263.2° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25](=[O:32])[NH:24][C:23]3[CH:33]=[CH:34][CH:35]=[N:36][C:22]2=3)=[O:20])[CH2:14][CH2:13]1.[C:37]1([N:46]=[C:47]=[S:48])[CH:42]=[CH:41][CH:40]=[C:39]([N:43]=[C:44]=[S:45])[CH:38]=1.C(OCC)(=O)C>CN(C=O)C>[N:43]([C:39]1[CH:38]=[C:37]([NH:46][C:47]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25](=[O:32])[NH:24][C:23]4[CH:33]=[CH:34][CH:35]=[N:36][C:22]3=4)=[O:20])[CH2:14][CH2:13]2)=[S:48])[CH:42]=[CH:41][CH:40]=1)=[C:44]=[S:45]
Reactant: S=C=Nc1cccc(N=C=S)c1
Reactant: NCCCCCCCCCCN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2cccnc2N(C(=O)CN2CCN(CCCCCCCCCCNC(=S)Nc3cccc(N=C=S)c3)CC2)c2ccccc21
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
5,11-Dihydro-11-[(4-[10-aminodecyl]-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one (2.8 mg, 5.7 μmol) was dissolved in 0.2 mL DMF and treated with 1,3-phenylenediisothiocyanate (6 mg, 31 μmol). After 0.5 h, ethyl acetate (1 mL) and petroleum ether (3 mL) were added, and the cloudy mixture was stored at 4° C. overnight. The supernatant was decanted from the oily residue. The residue solidified upon trituration with dry ether to give 2.0 mg (51% yield) of pure product (Rf =0.35, silica, chloroform:methanol:acetic acid, 85:10:5, by volume). FAB-MS spectrum showed a parent ion peak at 685 m/z (m+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([Cl:9])C(=O)C)[CH3:2].C([O-])(=O)C.[Na+].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:24][CH2:25][CH2:26][C:27]#[CH:28])=[C:21]([NH2:23])[CH:22]=1.[N:29]([O-])=O.[Na+]>Cl.O>[CH2:1]([O:3][C:4](=[O:10])[C:5]([Cl:9])=[N:29][NH:23][C:21]1[CH:22]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=1[O:24][CH2:25][CH2:26][C:27]#[CH:28])[CH3:2]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: C#CCCOc1ccc(Br)cc1N
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C#CCCOc1ccc(Br)cc1NN=C(Cl)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
2-Chloro-3-oxo-butyric acid ethyl ester (1.94 g, 11.2 mmol) and sodium acetate (1.45 g, 17.8 mmol) were stirred in IMS (100 mL) to give a clear solution, then cooled to 0° C. Separately, 5-bromo-2-but-3-ynyloxy-phenylamine (2.68 g, 11.2 mmol) in 6M hydrochloric acid (6.8 mL) was cooled to 0° C. and a solution of sodium nitrite (0.77 g, 11.2 mmol) in water (11.2 mL) was added dropwise with stirring, keeping the temperature below 5° C. The aqueous acidic solution was added to the IMS solution, washed in with a little water, keeping the temperature below 5° C. After 1 h at 0-5° C., the mixture was diluted with water and extracted several times with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give Chloro-(5-bromo-2-but-3-ynyloxyphenylhydrazono)acetic acid ethyl ester as a pale brown solid (3.96 g, 95%). LCMS: RT=4.97 min, [M+Na]+=395/397/399.
Reaction SMILES: [Cl-:1].[NH4+:2].C[Al](C)C.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12].CO>C1(C)C=CC=CC=1.CCCCCC>[ClH:1].[Br:7][C:8]1[CH:9]=[C:10]([C:11](=[NH:2])[NH2:12])[CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: [Cl-]
Reactant: [NH4+]
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cl
Product: N=C(N)c1cccc(Br)c1
Temperature: 0 °C

Procedure:
1.18 g (22 mmol, 2 equiv.) ammonium chloride are suspended in 40 ml of dry toluene under an argon atmosphere, and the mixture is cooled to 0° C. 11 ml (22 mmol, 2 equiv.) of a 2M solution of trimethylaluminium in hexane are added dropwise, and the reaction mixture is stirred at room temperature until no more evolution of gas is observed. After addition of 2.0 g (11 mmol, 1 equiv.) 3-bromo-benzonitrile, the mixture is stirred at 80° C. bath temperature over night. It is then cooled down to 0° C. and 50 ml of methanol are added with subsequent stirring of 1 hour at room temperature. After filtration, the solid is washed with methanol for several times, the solution is evaporated to dryness in vacuo and the residue washed with methanol.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:20]([OH:22])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CN1CCOCC1.ClC(OCC)=O.[NH2:46][C@H:47]([C:56]([NH:58][C@H:59]([C:66]([NH:68][C@H:69]([C:71]([OH:73])=[O:72])[CH3:70])=[O:67])[CH2:60][O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:57])[CH2:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52]>CN(C)C=O>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C@H:2]([C:20]([NH:46][C@H:47]([C:56]([NH:58][C@H:59]([C:66]([NH:68][C@H:69]([C:71]([OH:73])=[O:72])[CH3:70])=[O:67])[CH2:60][O:61][C:62]([CH3:63])([CH3:64])[CH3:65])=[O:57])[CH2:48][C:49](=[O:55])[O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:22])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: C[C@H](NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](C)C(=O)O)cc1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
In 290 ml of dimethylformamide is dissolved 16.2 g (35 millimoles) of Z-Arg(Tos)-OH, and 3.85 ml of N-methylmorpholine is added to the solution and the mixture is cooled to -5° C. Then, 3.35 ml of ethyl chloroformate is dropped to the mixture under agitation and the mixture is stirred for 15 minutes and is then mixed with a cooled liquid formed by suspending 15.5 g (38.5 millimoles) of H-Asp(OBut)-Ser(But)-Ala-OH (having a melting point of 122° to 133° C.) in 290 ml of dimethylformamide and adding 4.3 ml of N-methylmorpholine. The resulting mixture is stirred for 3 hours, and the insoluble substances are removed by filtration. The filtrate is concentrated under reduced pressure and solidification is effects by addition of ether to obtain 26.6 g of intended glassy Z-Arg(Tos)-Asp(OBut)-Ser(But)-Ala-OH (the yield being 90%).