Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12]([O:48][CH3:49])=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:15]=[C:14]2[C:39]1[S:43][C:42]2[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=2[CH:40]=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[OH-].[Pd+2].[OH-].[C]>[S:43]1[C:39]([C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([NH2:10])[C:12]=3[O:48][CH3:49])[N:16]([C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:15]=2)=[CH:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]1=2
Reactant: COc1c(NC(=O)OCc2ccccc2)ccc2c1c(-c1cc3ccccc3s1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(N)ccc2c1c(-c1cc3ccccc3s1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 60.9 %

Procedure:
A total of 939 mg of (3-benzo[b]thiophen-2-yl-4-methoxy-1-trityl-1H-indazol-5-yl)-carbamic acid benzyl ester obtained in Production Example II-39-a was dissolved in 20 ml of a 2:1 solvent mixture of ethyl acetate and methanol. 300 mg of 20% palladium hydroxide-carbon was added thereto, and the mixture was subjected to catalytic hydrogenation at room temperature and at normal atmospheric pressure in the presence of. The reaction mixture was filtrated through Celite, and the solvent was removed, to give 458 mg of the title compound.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][C:32](=[O:34])[C:31]2[CH:30]=[CH:29][C:28]([S:27][CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:36][CH:35]=2)[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: O=C(NC1CC1)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 87.4 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 47 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]+.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
A solution of diketene (0.32 ml, 4.15 mmol) in toluene (2 ml) was added to an 80° C. solution of 4-bromo-2-nitroaniline (900 mg, 4.15 mmol) in toluene (7 ml) and the solution was heated at reflux for 5 h. Triethylamine (0.58 ml, 4.15 mmol) in toluene (2 ml) was added and refluxing was continued for 30 min. The cooled solution was concentrated in vacuo and the crude product purified by column chromatography on silica gel eluting with 2:1 hexane/EtOAc to give the title compound as a yellow solid (920 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([O:29][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:33][CH:32]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Br)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-bromophenol: ESMS m/e: 568.8 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][NH2:10].[C:11]([O:15]C(=O)CC)(=O)[CH2:12][CH3:13]>>[CH3:9][N:10]([CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[C:11](=[O:15])[CH2:12][CH3:13]
Reactant: O=Cc1ccncc1
Reactant: CCC(=O)OC(=O)CC
Reactant: CN
Product: CCC(=O)N(C)Cc1ccncc1
Yield: 72 %

Procedure:
Pyridine-4-carboxaldehyde, methyl amine, and propionic anhydride were reacted on a 0.1 mole scale in a manner similar to that given for Example 1 to give the desired amide (12.72 g, 72%).
Reaction SMILES: N([Si](C)(C)C)=[N+]=[N-].[CH3:8][C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1.[I:16]I>N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[I:16][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH2:14][C:9]=1[CH3:8]
Reactant: CC1=CC(=O)CCC1
Reactant: II
Agent: C[Si](C)(C)N=[N+]=[N-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1=C(I)C(=O)CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Freshly distilled azidotrimethylsilane (2.65 mL, 20 mmol) was added to a stirred solution of 3-methyl-2-cyclohexen-1-one (Compound 1, 1.13 mL, 10 mmol) and dichloromethane (15 mL) at 0° C. under argon. The solution was stirred for 2 hours at 0° C. before adding a solution of iodine (5.08 g, 20 mmol) in 15 mL of pyridine and 15 mL of dichloromethane. The resulting solution was stirred for 4 hours at room temperature, diluted with ethyl acetate, and was washed successively with 20% aqueous Na2S2O3, 10% aqueous HCl, water, and brine. The solvents were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (7:1, hexanes: ethyl acetate) to give the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.[CH3:21][C:22]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>ClCCl.[N+](C)([O-])=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[C:30]([N+:31]([O-:33])=[O:32])[C:22]=3[CH3:21])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)c1[nH]c2cc(Br)ccc2c1C(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 6-bromo-1H-indole-2-carboxylate (4.40 g, 16.41 mmol) in dichloromethane (70 mL) at 0° C. was added tin (IV) chloride in dichloromethane (20.51 mL, 20.51 mmol) over 15 min. The resulting yellow heterogeneous mixture was stirred at room temperature for 30 min before a solution 2-methyl-3-nitrobenzoyl chloride (4.42 g, 22.16 mmol) in nitromethane (70 mL) was added over 20 min. The mixture was stirred at room temperature for 4 hr and then poured into ice-cold water (200 mL). The resulting mixture was stirred at room temperature for 20 min and diluted with ethyl acetate (800 ml). The mixture was washed with water (100 mL), saturated NaHCO3 solution (2×100 ml), water (100 mL), and brine (100 mL). The organic solution was dried over anhydrous MgSO4. Removal of solvent under vacuum gave the desired product (7.04 g, 16.33 mmol, 99% yield) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][C:14]([C:15]([O:17]C)=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1
Reactant: COC(=O)c1[nH]c(=O)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1[nH]c(=O)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A mixture of 4.02 g (0.01 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, methyl ester, 150 ml of methanol, 15 ml of water and 2 g (0.035 mole) of potassium hydroxide was heated to reflux for 5 hours under a nitrogen atmosphere. The solution was then concentrated down to 40 ml, acidified by addition of 4 ml of glacial acetic acid and crystallized by diluting with water. The precipitate was collected, dried and recrystallized from tetrahydrofuran/methanol/ethyl acetate to yield 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid which was decarboxylated as follows: A solution of 1 g of this acid in 5 ml of ethylene glycol was heated to reflux for 45 min and then partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic layer was washed with bicarbonate solution and water, dried and evaporated. Crystallization of the residue from ethyl acetate/ether gave end product which was further purified by chromatography over 20 g silica gel using methylene chloride/ethyl acetate 1:3. Crystallization from ethyl acetate/ether yielded the pure colorless product with mp 236°-238°. nmr (CDCl3) δ 4.15 ppm (broad d, 1) and 4.86 (broad d, 1) (AB-system, J= 13 Hz, C4 -H) 6.25 (d, 1, J=2 Hz, C3 -H) 6.98 (d, 1, J=2.5 Hz, C7 -H) 7.1-7.7 (m, 5, aromatic H) 8.0 (d, 1, J=8 Hz, C10 -H) 10.4 (broad s, 1, NH).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1)=[O:4].[N+:18]([O-])([OH:20])=[O:19].C(OCC)(=O)C.CCCCCC>O>[CH3:17][CH:2]([CH3:1])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:18]([O-:20])=[O:19])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)C(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Ethyl 4-(2-methylpropionylamino)benzoate (Chemical Abstract 114(11) 101280u; Vagaonescu; Marisa, N-Acyl Derivatives of Anesthesin. Stud Univ. Banes-Bolyai Chem. 1989, 34, 12-14) was added slowly over a 50-min period to fuming nitric acid at 10° C. The reaction was stirred for 30 min at room temperature. Thin-layer chromatographic analysis (SiO2, 1:1 ethyl acetate:hexane) showed disappearance of the starting material along with the formation of a new higher-running spot (Rf =0.9). The reaction was poured into water and then extracted with ethyl acetate (3×500 mL). Next, the organic layer was washed with 1% sodium bicarbonate (500 mL) solution and then water (500 mL). The ethyl acetate layer was concentrated and the residue chromatographed (SiO2, 1:5 ethyl acetate:hexane). The fractions containing product were concentrated to give 17 g (49%) of ethyl 4-(2-methylpropionylamino)-3-nitrobenzoate as a yellow solid, mp 74°-76° C. An analytical sample was prepared by recrystallization from hexane. This material was collected by filtration and dried in vacuo at acetone reflux.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[C:14]([N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=1)(=[O:10])=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[C:14]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[C:15]2[O:19][CH:18]=[CH:17][C:16]=2[CH:20]=1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(NS(=O)(=O)c3ccccc3Cl)cc3ccoc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cc(N2CCNCC2)c2occc2c1)c1ccccc1Cl
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
tert-Butyl 4-(5-{[(2-chlorophenyl)sulfonyl]amino}-1-benzofuran-7-yl)piperazine-1-carboxylate (0.66 g, 1.34 mmol; Intermediate 19) was dissolved in DCM (5 mL) and TFA was added (30% solution of TFA in DCM; 5 mL) and the mixture was stirred for 30 min. The solvents were evaporated. The residue was dissolved in water, pH adjusted to pH 8 and extracted with EtOAc. The organic layer was dried and evaporated to give 0.41 g (80%) of the title product that was used in the next step without further purification. HPLC purity 93%, RT=1.61 min (System A; 10-97% MeCN over 3 min).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[C:6]1([PH+:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25](=O)(OC)OC>>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:25][P+:12]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)OC
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: F[B-](F)(F)F
Product: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In a reactor wherein air was replaced by N2, 300.0 g of (1.1 mol) triphenyl phosphine and 500 mL of methanol were added and cooled to 10° C. by a ice-bath. 250.8 g (1.1 mol) of fluoroboric acid aqueous solution (40 wt %) was then added dropwise under strong stirring. After one hour of reaction, the reaction temperature was increased to about 50° C., and the unreacted materials as well as the solvents, including water and methanol, were removed by distillation under vacuum to obtain triphenylphosphonium tetrafluoroborate. The phosphonium salt was then transferred to an autoclave, and 202.0 g (2.2 mol) of dimethyl carbonate was also introduced. After 6 hours of reaction at temperature of 160° C. and at pressure of from 1.4 MPa to 1.5 MPa, the crude product was obtained after distilling off the unreacted materials and solvent. 375.0 g of methyl triphenyl phosphonium tetrafluoroborate was obtained after washing and drying at 60° C. and 0.1 kPa for 4 hours.
Reaction SMILES: [CH3:1][O:2]C1C=CC(N)=C([N+]([O-])=O)C=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26](C(F)(F)F)=[CH:27][C:22]=2[N:21]=[C:20]1/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42]>C(OCC)(=O)C>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26]([O:2][CH3:1])=[CH:27][C:22]=2[N:21]=[C:20]1/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [OH-].[Li+:2].[SH:3][CH2:4][C:5]([OH:7])=[O:6]>CC(O)C>[OH2:6].[Li+:2].[Li+:2].[SH:3][CH2:4][C:5]([O-:7])=[O:6].[SH:3][CH2:4][C:5]([O-:7])=[O:6]
Reactant: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Product: O
Product: O=C([O-])CS
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 166.2 %

Procedure:
Finely crushed lithium hydroxide (1.03 g, 43 mmol) was added to a solution of mercaptoacetic acid (1.5 mL, 1.97 g, 21.5 mmol) in 2-propanol (20 mL). The mixture was stirred for 1.5 hours at room temperature. All solvent was removed by rotary evaporation. This gave a fine white powder (2.55 g, 97%). The mass recovery and NMR suggest that the salt forms as a monohydrate.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:31][NH:32][CH3:33].C1COCC1>CN(C=O)C.O>[CH3:31][N:32]([CH3:33])[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6]
Reactant: CNC
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N(C)C)c3)n2)c(C)c1
Yield: 3 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (200 mg, 0.60 mmol, 1.0 equiv), caesium carbonate (2.73 g, 0.6 mmol, 15 equiv) and 2.0 M dimethylamine in THF (3.4 mL, 6.7 mmol, 12 equiv) in DMF (6.0 mL) was heated at reflux for 16 h. The mixture was poured into icy H2O (10.0 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15% EtOAc in hexanes as eluant) to provide 2-(dimethylamino)-N-(4-mesityl-thiazol-2-yl)isonicotinamide (5.5 mg, 0.10 mmol) as yellow solids in 3.0% yield: 1H NMR (CDCl3, 500 MHz) δ 8.32 (d, J=5.1 Hz, 1 H), 7.02 (s, 1 H), 6.92 (s, 2 H), 6.85 (d, J=5.1 Hz, 1 H), 6.80 (s, 1 H), 3.16 (s, 6 H), 2.31 (s, 3 H), 2.09 (s, 6 H); ESI-MS: m/z 367.1 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]([C:24]([F:27])([F:26])[F:25])([C:20]([F:23])([F:22])[F:21])[C:10]([O:12][Si](C(C)(C)C)(C)C)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[F:34][C:35]1[CH:41]=[C:40]([S:42][C:43]2[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[CH:45][CH:44]=2)[CH:39]=[CH:38][C:36]=1[NH2:37]>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[F:34][C:35]1[CH:41]=[C:40]([S:42][C:43]2[CH:48]=[CH:47][C:46]([S:49][CH3:50])=[CH:45][CH:44]=2)[CH:39]=[CH:38][C:36]=1[NH:37][C:10](=[O:12])[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([C:20]([F:23])([F:22])[F:21])[C:24]([F:26])([F:25])[F:27]
Reactant: CSc1ccc(Sc2ccc(N)c(F)c2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(=O)C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1ccc(Sc2ccc(NC(=O)C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)c(F)c2)cc1
Reaction time: 17 h
Yield: 20.4 %

Procedure:
To a stirred solution of 2-t-butyldimethylsilyloxy-2-trifluoromethyl-3,3,3-trifluoropropanoic acid, t-butyldimethylsilyl ester (Method 56) (1.05 g) in DCM (10 ml) was added DMF (2 drops) and oxalyl chloride (0.23 ml). The reaction mixture was stirred for 17 hours and was then added to a solution of 2-fluoro-4-(4-methylsulphanylphenylsulphanyl) aniline (Method 6) (0.63 g) in DCM (5 ml) and pyridine (0.22 ml). The reaction mixture was stirred at ambient temperature for 48 hours, evaporated under reduced pressure and the residue purified by chromatography on a silica gel Mega Bond Elut column eluting with 5-20% ethyl acetate/iso-hexane to give the title compound (0.278 g) as a yellow gum. NMR (CDCl3): 0.29 (s, 6H), 0.98 (s, 9H), 2.48 (s, 3H), 6.96-7.0 (m, 1H), 7.06 (d, 1H), 7.2 (d, 2H), 7.31 (d, 2H), 8.23 (t, 1H), 8.62 (brs, 1H).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[C:11]([CH3:12])[C:6]2=[CH:5][CH:4]=1)#[N:2].Cl.[OH2:14]>>[C:1]([C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[C:11]([CH3:12])[C:6]2=[CH:5][CH:4]=1)(=[O:14])[NH2:2]
Reactant: Cc1nccn2c(C#N)ccc12
Reactant: O
Agent: Cl
Product: Cc1nccn2c(C(N)=O)ccc12
Temperature: 25 °C

Procedure:
To 2.0 g of 6-cyano-1-methylpyrrolo[1,2-a]pyrazine prepared in Preparation Example 4 were added 10 ml of water and 5 ml of hydrochloric acid; and the reaction mixture was reacted at 80° C. for 2 hours, cooled to room temperature, extracted with ethyl acetate, and concentrated. The residue was chromatographed over silica gel to obtain 1.0 g of title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:48]([Cl:50])[Cl:49]>C(O)(=O)C>[NH3:1].[CH2:48]([Cl:50])[Cl:49].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:19]3[CH2:24][CH2:23][CH:22]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(NC2CCNCC2)nc1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: N
Product: c1ccc(NC2CCN(Cc3ccc(OCCCN4CCCCC4)cc3)CC2)nc1
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (240 mg), piperidin-4-yl-pyridin-2-yl-amine (166 mg), and acetic acid (0.12 mL) in DCM (5 mL) was treated with sodium triacetoxyborohydride (290 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (7 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (3% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (188 mg). 1H NMR (400 MHz, CDCl3): 8.06 (m, 1H), 7.38 (m, 1H), 7.20 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 6.53 (m, 1H), 6.34 (d, J=8.3 Hz, 1H), 4.36 (br, m, 1H), 3.99 (t, J=6.6 Hz, 2H), 3.60 (m, 1H), 3.45 (s, 2H), 2.81 (m, 2H), 2.47 (m, 2H), 2.47 (br, 3H), 2.15 (m, 2H), 2.05-1.93 (m, 4H), 1.62-1.54 (m, 4H), 1.50 (m, 1H), 1.44 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[I:12].[C:13](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[I:12][C:3]1[C:4]2[O:8][CH2:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[O:1][CH3:13]
Reactant: O=C1COc2c1ccc(O)c2I
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1ccc2c(c1I)OCC2=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 49.8 %

Procedure:
A solution of 6-hydroxy-7-iodobenzofuran-3(2H)-one (2.58 g, 9.35 mmol) in DMF (37 mL) was added with potassium carbonate (1.55 g, 11.2 mmol) and methyl iodide (0.697 mL, 11.2 mmol), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was added with water (400 mL), and the precipitated solid was collected by filtration to obtain 7-iodo-6-methoxybenzofuran-3(2H)-one (1.35 g, 49%).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[CH2:17][CH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C([O-])([O-])=O.[K+].[K+].C(C(C)=O)C(C)C>CN1CCCC1=O>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH:19]1[CH2:18][CH2:17][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5]1
Reactant: ICCC1Cc2ccccc2C1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)CC(C)C
Product: c1ccc2c(c1)CC(CCN1CCN(c3cccc4[nH]ccc34)CC1)C2
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A mixture of 4-(piperazin-1-yl)-1H-indole (1.5 g), 2-(2-iodoethyl)indane (2.0 g), K2CO3, methyl isobutyl ketone (150 ml), and N-methylpyrrolidone (10 ml) was boiled under reflux for 3 h. The mixture was allowed to cool to room temperature, filtered, and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1:2) to give a crystalline compound, which was recrystallized (ethyl acetate) to give the title compound (1.2 g, 47%).