Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C@@H:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH2:11])=[CH:4][CH:3]=1.[O:20]([CH2:24][CH2:25]Br)[CH2:21][CH2:22]Br.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C@H:10]([N:11]2[CH2:25][CH2:24][O:20][CH2:21][CH2:22]2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: BrCCOCCBr
Reactant: N[C@H](Cc1ccccc1)C(=O)Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(Br)cc1)[C@@H](Cc1ccccc1)N1CCOCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 70.5 %

Procedure:
To a solution of N-(4-bromophenyl)-D-phenylalaninamide (500 mg) in N,N-dimethylformamide (5 mL) were added 1,1′-oxybis(2-bromoethane) (545 mg) and diisopropylethylamine (607 mg) and the mixture was stirred at 50° C. for 6 hours. After being cooled to 5° C., the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford (2R)—N-(4-bromophenyl)-2-morpholin-4-yl-3-phenylpropanamide (430 mg) as a powder.
Reaction SMILES: [OH:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][CH:6]=1.[OH-].[Na+].OO>O1CCCC1.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>[OH:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:19]=[CH:2]/[CH2:3][CH2:4][CH3:5])=[CH:7][CH:6]=1
Reactant: CC(C)(O)C#Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC/C=C/c1ccc(C#CC(C)(C)O)cc1
Temperature: 25 °C
Yield: 163.5 %

Procedure:
In a four necked flask equipped with a stirrer, a reflux condenser and a thermometer which had been replaced by a nitrogen atmosphere, 4-(3-hydroxy-3,3-dimethyl-1-propynyl)-1- trifluoromethanesulfonyloxybenzene (3.6 g, 15 mmol), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05 mmol), sodium hydroxide (1.2 g, 30 mmol) and tetrahydrofuran (60 ml) were charged. Then, to the mixture, a solution of E-1-pentenylcatecholborane prepared in Reference Example 1 (20 mmol) in tetrahydrofuran (50 ml) was dropwise added at room temperature, followed by heat refluxing for 6 hours while stirring. After cooling the reaction mixture to room temperature, 30% aqueous hydrogen peroxide (2 ml) was added to the mixture, followed by stirring for 1 hour. The mixture was extracted with toluene and water. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. After evaporating the solvent off, the residue was purified by silica gel column chromatography to obtain 4-(3-hydroxy-3,3-dimethyl-1-propynyl)-1-(1-trans-pentenyl)benzene (2.8 g). Yield: 82%.
Reaction SMILES: C([O:8][N:9]([C@@H:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)C1C=CC=CC=1.Cl.[NH4+].[OH-]>[Pd].CO>[Cl:19][C:14]1[CH:13]=[C:12]([CH2:11][C:10]([N:9]([OH:8])[C@@H:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:20])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N(OCc1ccccc1)[C@H](CN1CCCC1)c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N(O)[C@H](CN1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 80.1 %

Procedure:
A suspension mixture of N-benzyloxy-2-(3,4-dichlorophenyl)-N-[1-(S)-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide (1.60 g, 3.3 mmol), 10% palladium on carbon (0.16 g), and HCl gas saturated methanol (20 ml) in methanol (20 ml) was stirred under hydrogen atmosphere at room temperature for 13 h. After removal of the catalyst by Celite filtration, the filtrate was concentrated to give 1.63 g of violet colored viscous oil, which was basified with NH4OH and extracted with CH2Cl2 (20 ml×3). The extract combined was dried (Na2SO4) and concentrated to afford a brown colored crystalline, which was collected by filtration and washed with ether/hexane to give 1.04 g (80%) of pale yellow powder, mp 118-120° C.
Reaction SMILES: C([S:9][CH:10]([CH:21]([O:23][CH3:24])[CH3:22])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=O)C1C=CC=CC=1.C(SCC(CSC)C(N1CCC[C@H]1C(O)=O)=O)(=O)C>>[SH:9][CH:10]([CH:21]([O:23][CH3:24])[CH3:22])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: COC(C)C(SC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CSCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Product: COC(C)C(S)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-[2-benzoylthio-3-methoxybutanoyl]-L-proline for the 1-[3-acetylthio-2-(methylthiomethyl)-propanoyl]-L-proline in the procedure of Example 17, 1-[2-mercapto-3-methoxybutanoyl]-L-proline is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: Sc1ccccc1
Solvent: CCO
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccccc2)c2ccccc2N1
Temperature: 180 °C

Procedure:
(Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one (0.05 g, 0.19 mmol) and thiophenol (Aldrich) (0.04 mL, 0.38 mmol) were dissolved in ethanol (2 mL). The reaction mixture was heated to 180° C. using a microwave reactor for 20 minutes. The solid was precipitated upon cooling. The material was filtered and washed with a minimal amount of ethanol, and then dried in vacuo. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.86 (s, 3H) 6.77 (s, 1H) 7.56 (t, J=7.58 Hz, 1H) 7.62 (s, 1H) 7.63 (d, J=2.53 Hz, 2H) 7.71-7.76 (m, 2H) 7.79 (t, J=7.58 Hz, 1H) 7.84-7.89 (m, 1H) 8.08 (d, J=8.34 Hz, 1H); ESI-MS: m/z calc'd for C19H15N3OS 333.09. found 334.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17]Br)=[O:5])[CH3:2].[CH2:19]([O:21][C:22](=[O:36])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][N:24]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccccc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
A mixture of 4-bromomethyl-2-phenyl-thiazole-5-carboxylic acid ethyl ester (5.29 g, 16.3 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (4.12 g, 16.3 mmol) and potassium carbonate (3.37 g, 24.4 mmol) in anhydrous dimethylformamide (50 mL) was stirred at room temperature for 16 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (5.72 g): MS: (+) m/z 499.0 (M+H+), 521.2 (M+Na+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.B([C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+].O>CC#N.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>[C:11]([O:10][C:9]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[N:6]=[CH:7][C:2]([C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)=[N:3][C:4]=1[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccccc2)no1
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: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2ccc(C(=O)O)cc2)nc1-c1cc(-c2ccccc2)no1
Temperature: 110 °C
Yield: 99 %

Procedure:
Tert-butyl N-[5-bromo-3-(3-phenylisoxazol-5-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (184 mg, 0.3379 mmol), 4-boronobenzoic acid (56.07 mg, 0.3379 mmol) and Na2CO3 (71.63 mg, 0.6758 mmol) were suspended in MeCN (2.896 mL)/water (2.896 mL) and the mixture de-gassed (×5) and treated with Pd(PPh3)4 (39.05 mg, 0.03379 mmol). The reaction was de-gassed again and heated at 110° C. in the microwave for 30 minutes. The reaction mixture was concentrated to half its original volume and washed with DCM. The aqueous phase was acidified to pH4 by (2M HCl) and resulting precipitate collected, washed with water and dried under vacuum (120 mg, 99% Yield). MS (ES+) 359.12
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:16])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([CH2:14][CH3:15])[C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][N:26]=1)CCC>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[N:3]=[C:4]([CH3:16])[C:5]2[CH:11]=[C:10]([C:22]3[S:23][CH:24]=[CH:25][N:26]=3)[C:9](=[O:13])[N:8]([CH2:14][CH3:15])[C:6]=2[N:7]=1
Reactant: CCn1c(=O)c(Br)cc2c(C)nc(N)nc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(-c2nccs2)cc2c(C)nc(N)nc21
Temperature: 110 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
To a pressure tube charged with 2-amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 1.77 mmol) and 2-tributylstannylthiazole (793 mg, 3.54 mmol) in dry toluene (6.0 mL) was added Pd(PPh3)4 (204 mg, 0.177 mmol). The pressure tube was sealed under nitrogen and heated to 110° C. After 12 h, the reaction was cooled to room temperature and concentrated in vacuo. The residue was redissolved in ethyl acetate and 40% KF on alumina (2 g) added. After 30 minutes, the alumina was filtered and the filtrate washed consecutively with 1M aqueous KF and brine. The organic layer was separated and dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with methylene chloride and hexanes to provide 2-amino-8-ethyl-4-methyl-6-(1,3-thiazol-2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (178 mg, 35% yield) as a yellow solid. MS calculated for C13H13N5OS 287.346, MS (EI) observed 288.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([O:20]CC)=[O:19])[NH:6]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[CH3:1][C:2]1[C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([OH:20])=[O:19])[NH:6]2
Reactant: CCOC(=O)c1cc2c(C)c3sc4ccccc4c3cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: Cc1c2cc(C(=O)O)[nH]c2cc2c1sc1ccccc12
Temperature: 25 °C

Procedure:
Ethyl 4-methyl-1H-[1]-benzothieno[2,3-f]indole-2-carboxylate (1.0 g, 3.2 mmol) was suspended in a mixture of methanol (110 ml) and water (30 ml). Caesium carbonate (10 g) was added and the mixture was heated at reflux under nitrogen for 2 h. The solution was allowed to cool to room temperature, and the methanol was removed in vacuo. The solution was acidified with 0.1 Molar Hydrochloric acid and the resulting yellow precipitate was collected by filtration and washed with water. The wet precipitate was dissolved in acetone and the solvent removed in vacuo to give the product as a yellow solid with m.p. 271-272° C.; δH [2H6 ]-DMSO 11.88 (1H, s, 1-NH), 8.29 (1H, dd, J 6, 3, 9-H), 8.18 (1H, s, 10-H), 7.89-7.99 (1H, m, 6-H), 7.44-7.54 (2H, m, 7-H, 8-H), 7.35 (1H, d, J 2, 3-H), 2.72 (3H, s, 4-CH3), m/z (%) 281 (90, M+), 263 (100) 235 (69).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C@:8]([CH3:12])([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@@:8]2([CH3:12])[CH2:9][O:10][C:15]([CH3:20])([CH3:16])[O:11]2)=[CH:13][CH:14]=1
Reactant: C[C@@](O)(CO)COc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OC[C@](C)(COc2ccc(Br)cc2)O1
Yield: 1729.3 %

Procedure:
(R)-3-(4-Bromophenoxy)-2-methylpropane-1,2-diol (25 g, 0.1 mol) and p-toluenesulfonic acid (0.91 g, 4.8 mmol) were dissolved in acetone (300 g), followed by stirring under reflux for 5.5 hours. The progress of reaction was monitored by TLC. The generated water was removed by azeotropic distillation with 300 g of solvent under atmospheric pressure, and 300 g of acetone was added during the reaction. After the reaction was completed, the solvent was removed under a reduced pressure and the resulting concentrated residue was dissolved in isopropyl acetate (250 mL). The organic layer thus obtained was washed with a 1 M sodium hydroxide aqueous solution (100 mL). Thereafter, the organic layer was concentrated and dried, obtaining 25 g of (S)-4-(4-bromophenoxy)methyl-2,2,4-trimethyl-1,3-dioxolane (yield: 82%).
Reaction SMILES: O=C1C2(CCNCC2)C(=O)CC1.O1[C:17]2([CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]4=[O:39])=[CH:25][C:24]=3[F:40])[CH2:19][CH2:18]2)[O:16]CC1.CC(C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[F:40][C:24]1[CH:25]=[C:26]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][C:17](=[O:16])[CH2:18][CH2:19]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)C12CCNCC2
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
Using a commercially available 1,4-dioxo-8-aza-spiro[4.5]decane, (S)-N-{3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}- acetamide is synthesized by the same method as in Step 1. To an acetone solution (70 ml) of this compound (3.79 g), water (20 ml) and p-toluenesulfonic acid monohydrate (3.66 g) are added successively and the mixture is heated under reflux for 3 hours. After the reaction mixture is cooled to room temperature, acetone is distilled off and the aqueous layer is neutralized with triethylamine. The solution is extracted with methylene chloride and the organic layer is washed with brine, dried over anhydrous sodium sulfate. The solvent is evaporated and the residue is purified by silica gel column chromatography (solvent: chloroform/methanol=50/1-25/1) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([NH2:10])[CH:3]=1
Reactant: CCc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.9 %

Procedure:
To a solution of 4-chloro-1-ethyl-2-nitro-benzene (0.57 g, 3.08 mmol) in a mixture of ethyl acetate and ethanol (1/1, 30 mL) was added stannous chloride (1.7 g, 9.24 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and basified by addition of potassium carbonate until pH>10. The resulting mixture was extracted with dichloromethane; the organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography to afford 0.503 g of 5-chloro-2-ethyl-phenylamine as a brown oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:32]=[CH:33][C:34]=4[C:35]([OH:37])=O)[C:20]=3[NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[N:17][C:18]4[N:19]([N:32]=[CH:33][C:34]=4[C:35]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:37])[C:20]=3[NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]4[C:31]=3[N:30]=[CH:29][CH:28]=[CH:27]4)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(Nc3cccc4cccnc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc4cccnc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 30 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(4-phenylpiperidine-1-carbonyl)-7-(8-quinolylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.04 g, 0.08 mmol) obtained in step 2 and ethanesulfonamide (0.055 g, 0.5 mmol), the title compound (0.014 g, 30%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([C:35](=[O:37])[CH3:36])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3cc(C)on3)CC2)C1
Reaction time: 0.75 h

Procedure:
To a solution of trans-8-chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50 mg, 0.13 mmol) and triethylamine (0.036 ml, 0.26 mmol) in dichloromethane (1.3 ml) was added acetyl chloride (0.019 ml, 0.26 mmol) at room temperature. Stirring for 45 minutes was followed by quenching with methanol (0.5 ml). The mixture was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (24 mg, 43%) as white solid. MS m/e: 426 ([M+H]+).
Reaction SMILES: [O:1]([C:8]1[C:9]([NH2:18])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:19]([NH:27][C:28]([NH:18][C:9]1[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][C:12]([C:14]([F:17])([F:15])[F:16])=[CH:11][N:10]=1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ncc(C(F)(F)F)cc1Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(C(F)(F)F)cc1Oc1ccccc1)c1ccccc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
3-Phenoxy-5-(trifluoromethyl)pyridin-2-amine (0.472 g, 1.86 mmol) was combined with benzoyl isothiocyanate (0.376 mL, 2.79 mmol) and THF (5 mL). The mixture was heated to 55° C. and agitated overnight. The solvent was evaporated and the residue purified by column chromatography on silica gel, eluted with 10% ethyl acetate/hexane to afford 1-benzoyl-3-(3-phenoxy-5-(trifluoromethyl)pyridin-2-yl)thiourea (0.460 g, 59.4% yield) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:9][CH:10]=[CH:11][CH:12]=1>C(O)(=O)C.[Pt]=O>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C@H:7]1[CH2:12][CH2:11][CH2:10][NH:9][C@H:8]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccccc1CNc1cccnc1-c1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COc1ccccc1CN[C@H]1CCCN[C@H]1c1ccccc1
Reaction time: 2.5 h
Yield: 58.8 %

Procedure:
3-(2-Methoxybenzylamino) -2-phenylpyridine (25 mg) was dissolved in 3 mL of acetic acid. To this solution was added 3 mg of platinum oxide and the mixture was placed on a Parr apparatus (35-40 p.s.i. H2) for ca. 2.5 hours. During this period, three additional 2.5 mg portions of catalyst were added to the system. The mixture was filtered through Celite® which had been rinsed well with ethanol and the filtrate was concentrated with a rotary evaporator. The residue was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, the layers were separated and the aqueous phase was extracted with three portions of CH2Cl2. The combined organic fractions were dried (Na2SO4) and concentrated to afford 15 mg of the title compound contaminated with a trace of 3-(2-methoxy-benzylamino)-2-phenylpyridine and a trace of material in which the 2-phenyl substituent had been reduced to a cyclohexyl moiety. The material prepared in this manner has spectral properties identical to those of the free base of the title compound of Example 1C.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:7][C:6]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:5][C:4]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH:34]([C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1)=O>>[CH3:2][C:3]1[S:7][C:6](/[CH:8]=[CH:34]/[C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)=[N:5][C:4]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Product: COC(=O)c1ccc(/C=C/c2nc(-c3ccccc3)c(C)s2)cc1

Procedure:
(5-Methyl-4-phenyl-2-thiazolylmethyl)triphenylphosphonium chloride and methyl 4-formylbenzoate were reacted in the same manner as in Reference Example 10 to yield methyl (E)-4-[2-(5-methyl-4-phenyl-2thiazolyl)vinyl]benzoate, which was then recrystallized from ethyl acetate to yield colorless plates having a melting point of 156°-157° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH2:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][CH:13]=1.BrC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C1COC(c2ccc(Cc3nc4ccccc4n3C)cc2)=N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Product: COC(=O)c1coc(-c2ccc(Cc3nc4ccccc4n3C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A stirred solution of methyl {2-{4-[(1-methyl-1H-benzimidazol-2-yl)methyl]-phenyl}-4,5-dihydro-1,3-oxazol-4-yl}carboxylate (1.5 g, 5 mmol) in CH2Cl2 was treated with bromotrichloromethane (1.22 g, 6 mmol) and DBU (0.70 g, 4.6 mol), stirred at room temperature overnight and concentrated in vacuo. The resultant residue was purified by column chromatography (silica, CHCl3:MeOH 1%) to give the title compound in 15% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, CDCl3): 8.2 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.3 (d, J=8.0 Hz, 2H), 7.27 (m, 4H), 4.3 (s, 2H), 3.95 (s, 3H), 3.63 (s, 3H). LCMS (ESI+) 348 (MH+).