Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1C(CC2C=CC(C3C(C(OC(C)(C)C)=O)=CC=CC=3)=CC=2)=C2CCCCN2N=1)[CH2:9]CC.BrCC(=O)C>CC(C)=O>[CH3:12][C:8]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1
Reactant: CCCCc1nn2c(c1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)CCCC2
Reactant: Nc1ccccn1
Agent: CC(=O)CBr
Solvent: CC(C)=O
Product: Cc1cn2ccccc2n1
Yield: 245.9 %

Procedure:
A mixture of 5 g of 2-amino pyridine and 250 ml of acetone were added at ambient temperature to a mixture of 7.25 g of 1 bromo 2-propanone and 20 ml of acetone and the mixture was refluxed for 30 minutes. Using the procedure of Stage C of Example 22, 5.3 g of the expected product were obtained in the form of an orange oil.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:57])[CH2:21][C:22]1([CH2:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=2[CH:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:36][CH2:35]2)[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.CN1C(=O)CCC1>C(#N)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:33][C:31]2[CH:30]=[CH:29][C:28]([CH:34]3[CH2:35][CH2:36][N:37]([CH2:40][CH2:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:38][CH2:39]3)=[C:27]([C:24]3[CH2:23][C:22]([CH2:49][C:50]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:56])([CH2:21][C:20](=[O:57])[O:19][C:15]([CH3:16])([CH3:17])[CH3:18])[O:26][N:25]=3)[CH:32]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CCN1CCC(c2ccc(O)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CCN1CCC(c2ccc(OC(=O)c3ccc(NC(=N)N)cc3)cc2C2=NOC(CC(=O)OC(C)(C)C)(CC(=O)OC(C)(C)C)C2)CC1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (23.57 mg) was added to a mixture of tert-butyl 3-(4-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)piperidin-1-yl)propanoate (60.7 mg), pyridine (0.2 mL), and NMP (0.2 mL) at 50 C, and the obtained mixture was stirred at 50 C for 30 minutes. 4-Carbamimidamidobenzoyl chloride hydrochloride (23.57 mg) was further added thereto, and the obtained mixture was stirred at 50 C for 30 minutes. 4-Carbamimidamidobenzoyl chloride hydrochloride (23.57 mg) was further added thereto, and the obtained mixture was stirred at 50 C for 30 minutes. 4-Carbamimidamidobenzoyl chloride hydrochloride (23.57 mg) was further added thereto, and the obtained mixture was stirred overnight at 50 C. To the reaction mixture, acetonitrile was added. The precipitate was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane, subsequently methanol/ethyl acetate) to obtain the title compound (42.7 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CCO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Palladium (10 wt. %) on carbon (50 mg) was added in one portion to a solution of crude ethyl 4-(4-nitrophenoxy)cyclohexanecarboxylate in a mixture of EtOH (15 mL) and THF (10 mL). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 h then filtered and concentrated in vacuo to give a solid that was purified by chromatography, using 30-60% EtOAc in isohexane as eluent, to give the title compound (127 mg, 4% over 2 steps) as a solid; 1H NMR (CDCl3) δ1.16-1.20 (3H, t), 1.31-1.42 (2H, m), 1.43-1.52 (2H, m), 1.96-2.01 (2H, m), 2.05-2.10 (2H, m), 2.20-2.28 (1H, m), 3.35 (2H, br s), 3.89-3.96 (1H, m), 4.05 (2H, q), 6.53-6.57 (2H, d), 6.65-6.69 (2H, d); MS m/e MH+ 264.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
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: COCCOC
Solvent: O
Product: CC1(C)CC(=O)c2ccc(-c3ccc(Cl)cc3)cc21
Temperature: 25 °C

Procedure:
To a stirred solution of trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester (0.25 g, 0.81 mmol) in glyme (7 mL) was added 4-chlorophenyl boronic acid (0.19 g, 1.22 mmol), a solution of sodium carbonate (0.26 g, 2.43 mmol) in water (1.5 mL), and tetrakis(triphenylphosphine)palladium (0) (0.05 g, 0.04 mmol). The resulting solution was heated to reflux for 2 hours. The mixture was cooled to room temperature, concentrated, taken up in ethyl acetate and filtered through a pad of the Celite® reagent. The filtrate was concentrated and the residue was purified by Gilson high performance liquid chromatography (HPLC—10 to 100 acetonitrile in water) to afford 5-(4-chlorophenyl)-3,3-dimethylindan-1-one as a white solid. (0.11 g, 50%). MS (ES) m/z 271.0; HRMS: calcd for C17H15ClO+H+, 271.0884; found (ESI, [M+H]+), 271.0877.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:19](=O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:11]([NH:13][C:14](=[O:18])[CH:15]([NH2:17])[CH3:16])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[N:17][CH:15]([CH3:16])[C:14](=[O:18])[NH:13][C:11]=3[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(NC(=O)C(C)N)c2C(=O)c2ccccc2Cl)C1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NC(C)C(=O)N3)C1
Yield: 49.3 %

Procedure:
636.8 g of 6-acetyl-2-(2-aminopropionylamino)-3-(2-chlorobenzoyl)-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine was dissolved in 2.3 liters of toluene, 637 ml of pyridine and 94.3 ml of acetic acid and refluxed over day and night while removing water from the reaction system. After removal of the reaction solution by distillation, benzene was added, followed by cooling and filtering the resultant crystals to obtain 300 g of the intended product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH2:23][OH:24])=[C:21](Cl)[N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:22]([CH2:23][OH:24])=[CH:21][N:20]=[C:19]3[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1ncc(CO)n1Cc1ccc(-c2cccc(C(=O)OC)c2)cc1
Reaction time: 0.08 h
Yield: 36 %

Procedure:
A mixture of 1.00 g of 10% palladium/carbon and 1.00 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl imidazole in 20 mL of methanol was stirred at 25° for five minutes. Hydrogen gas was bubbled into the solution, and the mixture was stirred under H2 (g) (1 atm.) at 25° for 3.5 hours. The mixture was filtered, and the resulting solution concentrated in vacuo. Column chromatography (elution: 0-5% methanol/chloroform) furnished 0.33 g of 1-[(3'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-5-hydroxymethyl imidazole. NMR (200 MHz, DMSO-d6) δ 8.20 (s, 1H); 7.98 (d, 2H); 7.65 (t, 1H); 7.41 (A2M2, 4H); 6.80 (s, 1H); 5.30 (s, 2H); 5.12 (t, 1H); 4.37 (d, 2H); 3.90 (s, 3H); 2.52 (t, 2H); 1.51 (quint., 2H); 1.27 (sext., 2H); 0.80 (t, 3H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH:13]=O)=[CH:12][C:4]1=2)[CH3:2].[NH2:17][OH:18].Cl.CC([O-])=O.[Na+].CC(=O)OCC>C1COCC1.O>[CH2:1]([C:3]1([CH2:15][CH3:16])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:11]([CH:13]=[N:17][OH:18])=[CH:12][C:4]1=2)[CH3:2]
Reactant: CCC1(CC)OB(O)c2ccc(C=O)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1(CC)OB(O)c2ccc(C=NO)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a mixture of 3,3-diethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carb-aldehyde (1.1 g, 5.04 mmol) and NH2OH.HCl (420 mg, 6.05 mmol) in THF (20 ml) and H2O (5 ml) at rt was added NaOAc (578 mg, 7.06 mmol). The mixture was stirred at rt for 16 h, diluted with H2O and extracted with EA (20 ml×2). The combined organic layers were washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1 to 1:1) to give the product (600 mg, yield 51%) as white solid: MS: m/z=234 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:18])[CH2:16]Cl)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc2ccc(OCC(O)CCl)cc2o1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CC(O)COc2ccc3cc(C(N)=O)oc3c2)CC1

Procedure:
The procedures of Example 9b were repeated except that 1.3 g (0.005 mole) of 2-carbamoyl-6-(3-chloro-2-hydroxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine were employed to give the desired compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][C:6]2[CH:8]=[C:9]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=[C:11]([O:12]CCCC(O)=O)[C:5]=2[C@@H:4]2[CH2:24][C:25]([CH3:28])=[CH:26][CH2:27][C@@H:3]12.[OH-].C[N+](C)(C)C.CCCCN(C(SC(N(CCCC)CCCC)=S)=S)CCCC.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O.[Al]>[CH3:23][CH2:22][CH2:21][CH2:20][CH2:19][C:9]1[CH:10]=[C:11]([OH:12])[C:5]2[C@H:4]3[C@H:3]([C:2]([CH3:1])([CH3:29])[O:7][C:6]=2[CH:8]=1)[CH2:27][CH2:26][C:25]([CH3:28])=[CH:24]3
Reactant: CCCCCc1cc(OCCCC(=O)O)c2c(c1)OC(C)(C)[C@@H]1CC=C(C)C[C@@H]21
Agent: CCCCN(CCCC)C(=S)SC(=S)N(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: C[N+](C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Reaction time: 24 h

Procedure:
A 1.25 ml aliquot of a stock solution (1.009 g of (6aR,10aR)-4-[(6a,7,10,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-yl)oxy]butanoic acid and 1.00 ml of 25% aqueous tetramethyl ammonium hydroxide diluted to 10 ml with water) was mixed with 8.75 ml of N,N-dimethyl formamide (DMF, Fisher, Lot 761531) to give a final volume of 10 ml with a concentration of 12.6 mg/ml. Two hundred fifty mg of Bovine Serum Albumin (BSA-Pentex-Miles Labs. Lot 260) was dissolved in 25.0 ml of distilled water and 2.5 ml of DMF. Five ml of the above solution was slowly added while stirring to the BSA solution. This solution became slightly turbid, and 6.3 ml of distilled water was added to decrease the turbidity. The remaining 5.0 ml of the above solution was slowly added. Turbidity developed again, and 6.0 ml of distilled water was added. The resultant total volume of the above solution was 49.8 ml. To this 49.8 ml of solution, 0.2 ml of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (EDCI; 500 mg/ml solution) was added, giving a final volume of 50.0 ml. The pH of the final solution was 8.4. A beaker with the 50.0 ml of final solution was wrapped in aluminum foil and placed on a magnetic stirrer in a cold room (5° C.) for 24 hrs. The solution was transferred to a dialysis bag (Spectrum Medical Industries Spectrapor #1) and dialyzed against 25% DMF-75% H2O (5x) and against distilled water (2x) for four days in the cold room. Total volume recovered after dialysis was 51 ml. The dialyzate was tested by immunoelectrophoresis using IEP buffer (0.05 ionic strength, pH 8.6 buffer-5.4 g sodium diethyl barbiturate, 2.6 g sodium acetate.3H2O, 58.2 ml 0.1 N hydrochloric acid, 942 ml distilled water); 1% agarose (Kallestad) in IEP buffer; 0.1% bromophenol blue in IEP buffer and goat anti-BSA serum and a precipitin band indicated that the immunogen was different from BSA.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])=[C:9]([Br:24])[C:8]2=[O:25])=[CH:4][CH:3]=1.CN1CCOCC1.[C:35]([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=[O:37])[CH3:36].CN=C=O>ClCCl>[C:35]([O:38][CH:39]([CH3:43])[C:40]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])=[C:9]([Br:24])[C:8]2=[O:25])=[CH:26][CH:27]=1)=[O:41])(=[O:37])[CH3:36]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(N)cc1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: CN=C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)OC(C)C(=O)Nc1ccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added compound of Example 611 (0.300 g, 0.69 mmol) and dichloromethane (3.0 mL). A stock solution of N-methylmorpholine (0.30 M, 3.0 mL) was added and the parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 10 minutes. (S)-(−)-2-Acetoxypropionyl chloride (0.131 mL, 1.04 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature for 1.5 hours. At this time the reaction was diluted with dichloromethane (20 mL) and treated with approximately 2.1 g of polyamine resin (2.63 mmol/g) and approximately 3.8 g of methylisocyanate fucntionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature overnight. The reaction vessel was then opened and the solution Phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with dichloromethane (2×10 mL). The filtrate was evaporated by blowing N2 over the vial to afford an off-white solid (0.375 g, 99%). 1H NMR (400 MHz, DMF-d6) δ 10.14 (s, 1H), 7.75 (app dt, J=6.98, 8.59 Hz, 1H), 7.67-7.64 (m, 2H), 7.30 (ddd, J=2.55, 9.26, 11.81 Hz, 1H), 7.21-7.17 (m, 3H), 6.61 (s, 1H), 5.37 (s, 4H), 5.11 (q, J=6.85 Hz, 1H), 2.40 (s, 3H), 2.10 (s, 3H), 1.46 (d, J=6.85 Hz, 3H). ES-HRMS m/z 549.0790 (M+H calcd for C25H23BrF2N2O5 requires 549.0831).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[Cl:10])#[N:2].BrN1C(=[O:17])CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:10][C:4]1[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:9]=[O:17]
Reactant: Cc1cccc(C#N)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cccc(C=O)c1Cl
Yield: 107.5 %

Procedure:
To a solution of 2-chloro-3-methylbenzaldehyde (19.4 g) in ethanol (45 ml) was added an aqueous hydroxylamine hydrochloride (9.7 g) solution (12 ml), and an aqueous sodium hydroxide (6.9 g) solution (10 ml) was added. The mixture was stirred at room temperature for 1.5 hours. Water (500 ml) was added and the precipitated crystals were collected by filtration. The obtained white crystals (16.1 g) were dissolved in acetic anhydride (50 ml) and the mixture was heated under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (5:1)) to give 2-cyano-6-methylchlorobenzene (10.9 g) as a white solid. A suspension of 2-cyano-6-methylchlorobenzene (10.9 g), N-bromosuccinimide (12.8 g) and benzoyl peroxide (523 mg) in carbon tetrachloride (100 ml) was heated under reflux for 3.5 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (20:1)) to give 2-chloro-3-cyanobenzaldehyde (12.8 g) as a colorless oil. Subsequently, the title compound was prepared from 2-chloro-3-cyanobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=1>>[CH3:14][N:13]([CH3:15])[CH:10]1[CH2:11][CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23]([C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][N:21]=3)=[O:24])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Cl)cn3)cc2)C1

Procedure:
[1-(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-chloropyridine-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 344.85 (C18H21 ClN4O); MS (ESI): 345 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[N:19]4[C:14]([CH:15]=[N:16][C:17](S(C)(=O)=O)=[N:18]4)=[CH:13][CH:12]=3)[C:4]=2[O:3]1.[OH-].[Na+].C(O)(=[O:29])C>O1CCCC1.O>[F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[N:19]4[C:14]([CH:15]=[N:16][C:17]([OH:29])=[N:18]4)=[CH:13][CH:12]=3)[C:4]=2[O:3]1
Reactant: CS(=O)(=O)c1ncc2ccc(-c3cccc4c3OC(F)(F)O4)n2n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ncc2ccc(-c3cccc4c3OC(F)(F)O4)n2n1
Temperature: 60 °C
Yield: 91.7 %

Procedure:
7-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-2-methanesulfonyl-pyrrolo[2,1-f][1,2,4]triazine (0.410 g) was suspended in Tetrahydrofuran (2.00 mL), 5.0 M of Sodium hydroxide in Water (1.00 mL, 5.00 mmol) was added and the mixture was heated in a vial, in a block at 60° C. for 3 h. The mixture was then treated with a solution of Acetic acid (0.500 mL, 8.79 mmol) in Water (5.50 mL), generating an orange ppt. The mixture was cooled, the solids collected, washing with 10 mL water. Dry on the Buchner to afford 7-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (0.310 g; Yield=78.6%). LCMS (HPLC): 0.97 min, m/z=292 (M+H); 1H-NMR (DMSO-d6): 11.97 (s, 1H), 9.10 (s, 1H), 8.38 (d, 1H, 8.0 Hz), 7.44 (d, 1H, J=7.9 Hz), 7.38 (m, 1H), 7.25 (d, 1H, J=4.8 Hz), 7.09 (d, 1H, J=4.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.S(Cl)([Cl:12])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:12])=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Br)cs1

Procedure:
According to the procedure of Example 32, 2.48 g (12.0 mmoles) of 4-bromo-2-thiophenecarboxylic acid (prepared according to Lawesson, S.O., Arkiv. for Kemi. 11:317 (1957)) and 10 ml of thionyl chloride were combined and heated. The reaction gave 2.99 g of 4-bromo-2-thiophenecarbonyl chloride as a dark oil. Following the procedure of Example 32, the acid chloride, 2.11 g (10.0 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 3.67 g (30.0 mmoles) of 4-(N,N-dimethylamino)pyridine were reacted in N,N-dimethylformamide to give 4.03 g of a crude orange solid. Recrystallization gave 2.67 g (6.68 mmoles, 66.8% yield) of title compound as a yellow crystalline solid, m.p. 217°-219° C. (dec.) (2-butanone).
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[C:4]([CH3:13])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=4)[CH2:33][CH2:32]3)[C:3]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[C:4]([CH3:13])[C:5]=2[O:9]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2c(Br)cc3c(c2C)OC(C)(C)C3)cc1
Product: Cc1ccc(-c2c(N3CCN(c4ccc(F)cc4)CC3)cc3c(c2C)OC(C)(C)C3)cc1
Yield: 154.8 %

Procedure:
By using 5-bromo-2,2,7-trimethyl-6-(4-methylphenyl)-2,3-dihydro-1-benzofuran (150 mg, 1.49 mmol) synthesized in Reference Example 157 and 1-(4-fluorophenyl)piperazine (82.0 mg, 0.450 mmol), the reaction was carried out in the same manner as Example 129 to obtain 300 mg of the title compound as a colorless solid (yield 15%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[NH:14][C:13]2=[O:29])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:37][N:14]1[C:15]2[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=2[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:18][CH:12]([NH:11][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[C:13]1=[O:29])[CH3:36]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Product: CCOC(=O)CCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 1,3-dihydro-3-phenylmethyloxycarbonylamino-5-phenyl-2H-1,4-benzodiazepin-2one and ethyl bromopropionate. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.: m.p. 57°-59° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.CN(C)CCCN=C=NCC.O>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([Br:21])=[CH:23][CH:24]=2)=[O:19])[N:15]=1)([CH3:8])[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)Nc2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101 %

Procedure:
{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid (3.0 g) synthesized in Example 3 and 4-bromoaniline (1.63 g) were dissolved in dichloromethane (50 mL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (2.72 g) and 4-dimethylaminopyridine (DMAP) (1.73 g) were successively added thereto, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (4.5 g) as a colorless oil.