Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([NH:22][NH2:23])=[O:21])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]2[O:21][C:34](=[O:36])[NH:23][N:22]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cncc(-c2ccc3[nH]cc(C(=O)NN)c3c2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4n[nH]c(=O)o4)c3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
To a solution of 5-(6-isopropoxypyrazin-2-yl)-1H-indole-3-carbohydrazide (1 g, 3.2 mmol) in DCM (100 mL) and DIPEA (1.19 mL, 19 mmol) was added a solution triphosgene (1.1 g, 3.7 mmol) in DCM (3 mL) dropwise. The reaction was stirred at RT for 2 h, then the solution was concentrated in vacuo. The residue was purified with silica gel chromatography (eluting with 0-10% MeOH in DCM) to give 5-(5-(6-isopropoxypyrazin-2-yl)-1H-indol-3-yl)-1,3,4-oxadiazol-2(3H)-one (50 mg, 5%) as a white solid. MS (ESI, pos. ion) m/z: 338.0 (M+1); 1H NMR (DMSO-d6) δ ppm: 12.32 (s, 1H), 12.1 (s, 1H), 8.75 (s, 1H), 8.69 (s, 1H), 8.00-8.17 (m, 3H), 7.6 (d, J=8.4 Hz, 1H), 5.38-5.45 (m, 1H), 1.49 (d, J=6.0 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([C:14]#[N:15])[C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([C:14]#[N:15])[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CC(C(=O)O)=C(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To 200 ml. of methanol:water (1:4) solution containing 55 g. (0.2 mole) of ethyl β,β-diphenyl-α-cyanoacrylate (CYASORB N-35, American Cyanamid), 18 g. of 50% NaOH (0.22 mole) is added and the soluton is stirred at about 20° C. overnight. After it is washed with ether, the aqueous solution is neutralized with dilute HCl to precipitate the product. The yield is 48 g., 97%, m.p., 207°-209° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH2:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.[OH-].[Na+]>O>[C:2]1([CH2:1][O:8][CH2:9][C:10]([NH:23][CH:19]([C:16]2[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=2)[C:20]([OH:22])=[O:21])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(C(=O)O)c1ccccc1
Reactant: O=C(Cl)COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(COCc1ccccc1)NC(C(=O)O)c1ccccc1
Reaction time: 8 h

Procedure:
Benzyloxyacetyl chloride (6.3 mL, 40 mmol) is added to a solution of DL-phenylglycine (3.00 g, 19.8 mmol) and NaOH (2.32 g, 58.0 mmol) in 100 mL H2O and allowed to stir overnight. The reaction pH is adjusted to 11 with 3M NaOH 5 and washed with (3×50 mL) Et2O, then brought to pH=3 with concentrated HCl. The resulting precipitate is collected, washed with H2O and dried to obtain the title compound as an off-white solid. mp 127°-30° C.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][CH2:5][C:6]1(O)[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH-].[Na+]>>[CH3:26][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2
Reactant: CN(C)CCCC1(O)c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCC=C1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21
Temperature: 70 °C

Procedure:
5-(3-Dimethylaminopropyl)-5-hydroxy-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (13.62 g., 0.037 mole) is dissolved in 136 ml. of trifluoroacetic acid. Trifluoroacetic anhydride, 68 ml., is added and the solution heated under reflux for 1 hour in a water-bath at 70° C. The dark green solution is cooled and poured into 250 ml. of ice-water. The mixture is rendered alkaline with 10 N. sodium hydroxide solution while stirring and cooling and extracted with benzene. The benzene extract is washed with water, dried over sodium sulfate and the benzene distilled under reduced pressure. The mixed geometric isomers of 5-(3-dimethylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene is obtained as a brown oily residue in a yield of 13.19 g. (theory, 13.08 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]2[NH:17][C:16]([C@@H:18]([NH:28]C(=O)OCC3C=CC=CC=3)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25])=[N:15][CH:14]=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1>CCOC(C)=O.CO.[Pd]>[NH2:28][C@H:18]([C:16]1[NH:17][C:13]([C:12]2[C:3]([O:2][CH3:1])=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:14][N:15]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:26][CH3:27])=[O:25]
Reactant: CNC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1ncc(-c2cc3ccccc3nc2OC)[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)CCCCC[C@H](N)c1ncc(-c2cc3ccccc3nc2OC)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A3 was dissolved in EtOAc/MeOH (1:1) (0.01 M) and treated with Pd/C. Mixture was purged with N2 and stirred under H2 atmosphere at room temperature for 24 h. Then, reaction mixture was filtered through a pad of silica and filtrate was concentrated under vacuum to give the title compound which was used as such in the next step. MS (ES+) C21H27N5O2: 382 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Br[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: Cc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(F)c(C(F)(F)F)c2)ccn1
Temperature: 88 °C
Yield: 99.3 %

Procedure:
To a stirred suspension of 4-fluoro-3-(trifluoromethyl)phenylboronic acid (42.6 g, 205 mmol) in toluene (200 mL) were added 4-bromo-2-methylpyridine (34.4 g, 200 mmol) and 2 M aqueous potassium carbonate (200 mL). After the addition of 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (81.7 mg, 0.1 mmol), the two-phase, yellowish reaction mixture was stirred under reflux at 88° C. for 23 h. The resultant brownish reaction mixture was cooled to room temperature and extracted with toluene (200 mL). After washing with 10% brine (200 mL), the toluene layer was dried with Na2SO4 (50 g) and then treated under stirring with charcoal (2 g) for 30 min. Filtration and evaporation (50° C./≧10 mbar) afforded the crude title product (50.7 g, 99.4%) as an off-white, crystalline residue which was used without purification in the next step. 1H NMR (CDCl3, 400 MHz) δ 2.64 (s, 3H), 7.25-7.36 (m, 3H), 7.76-7.82 (m, 1H), 7.84 (dd, J1=6.7 Hz, J2=2.4 Hz, 1H), 8.58 (d, J=5.0 Hz, 1H). ESI-MS (m/z) [M+H]+256.3 (100).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27](O)(=O)[CH:28]=[CH2:29]>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:29]([CH:28]=[CH2:27])[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: C=CC(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: C=Cc1nc([C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)no1
Yield: 20 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and acrylic acid, this compound was obtained in 20% yield (89.4% purity by HPLC).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH:30]=[N:29][CH:28]=[CH:27]3)O1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]=[N:29][CH:28]=[CH:27]4)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Reactant: CC1(C)OB(c2ccc3cnccc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCNc1ccc2ncc(-c3ccc4cnccc4c3)n2n1
Temperature: 150 °C
Yield: 68.8 %

Procedure:
A mixture of (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-butyl-amine (100 mg, 0.37 mmol), 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoquinoline (from part A, ˜1 mmol), K2CO3 (153 mg, 1.11 mmol) and dichlorobis(triphenylphosphine)palladium(II) (13 mg, 0.019 mmol) in MeCN/water (4 ml/1 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the reaction mixture was diluted with MeCN (3 ml) and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (80.8 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.03 (t, J=7.33 Hz, 3H) 1.53 (dq, J=14.97, 7.39 Hz, 2H) 1.74-1.81 (m, 2H) 3.48-3.54 (m, 2H) 4.58 (t, J=5.05 Hz, 1H) 6.54 (d, J=9.60 Hz, 1H) 7.68 (d, J=5.56 Hz, 1H) 7.75 (d, J=9.60 Hz, 1H) 8.01-8.05 (m, 2H) 8.25 (dd, J=8.72, 1.64 Hz, 1H) 8.55 (d, J=5.81 Hz, 1H) 8.86 (s, 1H) 9.25 (s, 1H). LRMS (ESI) m/z 318.2 [(M+H)]+, calc'd for C19H19N5: 317.40.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[SH:21][C:22]1[N:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[CH3:20][C:7]1[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][S:21][C:22]1[C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=[CH:29][N:30]=1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Reactant: O=C(O)c1cccnc1S
Product: Cc1c(SCCCSc2ncccc2C(=O)O)ccnc1CSc1ccncc1
Yield: 57 %

Procedure:
According to the procedure indicated in Example 21, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 2-mercaptonicotinic acid, and subsequent establishment of a pH of about 6 gives the title compound as a colorless solid; m.p. 219° C., dec.; yield 57% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:33]=[CH:32][C:20]([CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:18]=1.C1C(=O)N([Cl:41])C(=O)C1>CN(C=O)C>[Cl:41][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:33]=[CH:32][C:20]([CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Yield: 55.9 %

Procedure:
Following General Procedure H, tert-butyl 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethyl(methyl)carbamate (200 mg, 0.43 mmol) in (DMF) was reacted with NCS (70 mg, 0.50 mmol) to afford the desired product (120 mg, 55%) as a yellow solid: ESI MS m/z 500 [C26H27ClN2O4S+H]+.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH2:14][CH2:15][O:16][CH3:17])[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>CC#N>[CH3:17][O:16][CH2:15][CH2:14][N:4]1[C:5](=[O:13])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([NH:29][C:28]2[CH:27]=[CH:26][C:25]([N:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[CH:31][CH:30]=2)[C:3]1=[O:18]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Solvent: CC#N
Product: COCCN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)C1=O
Temperature: 130 °C
Yield: 90.6 %

Procedure:
3-Chloro-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione (0.26 mmol, 70 mg) and 4-morpholinoaniline (0.53 mmol, 94 mg) was dissolved in dry CH3CN (2 mL) and the reaction mixture was subjected to microwave heating single node 130° C. for 10 min and purified on SiO2 (EtOAc:heptane, 1:1) to give 96 mg (89%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 7.73 (bs, 1H), 7.17-7.04 (m, 3H), 6.98-6.93 (m, 2H), 6.70-6.64 (m, 2H), 6.59-6.54 (m, 2H), 3.75-3.70 (m, 6H), 3.58 (t, J=5.6 Hz, 2H), 3.33 (s, 3H), 2.98-2.95 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[C:13]([F:18])[C:12]([F:19])=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Zn].O>[CH2:1]([O:8][C:9]1[C:10]([F:20])=[CH:11][C:12]([F:19])=[C:13]([F:18])[C:14]=1[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)c(F)cc(F)c1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1c(F)c(F)cc(F)c1OCc1ccccc1
Temperature: 60 °C

Procedure:
A round bottom flask containing 2-benzyloxy-1,4,5-trifluoro-3-nitrobenzene (0.44 g, 1.54 mmol), zinc dust (0.50 g, 7.71 mmol) and solid ammonium chloride (0.17 g, 3.08 mmol) is added a mixture of ethanol and water (2:1 ratio, 15 mL total). The resulting slurry is heated at 60° C. for 90 min. The mixture is filtered, washed with methanol and the filtrate is concentrated. The residue is extracted twice with EtOAc and water, dried over MgSO4 and concentrated. The crude product is used directly in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH:32][CH2:31][CH2:30][CH2:29][N:26]4[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]4)[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CN1CCN(CCCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)cc12

Procedure:
A stirred suspension of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methyl ester (440 mg, 1.30 mmol) in 1,4-dioxane (10 mL) is treated with 3-(4-methyl-piperazin-1-yl)- propylamine (610 mg, 3.90 mmol) and diisopropylethylamine (500 mg, 3.90 mmol), the resultant mixture is heated at 90° C. under nitrogen for 16 hours. After concentration and subsequent chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 1-10%, the title compound is isolated as a solid (310 mg, 51% yield).
Reaction SMILES: [N:1]1([N:6]=[CH:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([NH:17][C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=O)=[CH:14][CH:15]=3)[N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:9]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:35]([Si:39]([CH3:47])([CH3:46])[O:40][CH2:41][C:42]#[C:43][CH2:44][NH2:45])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([Si:39]([CH3:47])([CH3:46])[O:40][CH2:41][C:42]#[C:43][CH2:44][NH:45][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[NH:17][C:13]1[CH:12]=[C:11]2[C:16]([C:8]([CH:7]=[N:6][N:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)=[N:9][N:10]2[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])=[CH:15][CH:14]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: C[Si](C)(C)CCOCn1nc(C=Nn2cccc2)c2ccc(Nc3ccccc3C(=O)O)cc21
Reactant: CC(C)(C)[Si](C)(C)OCC#CCN
Product: CC(C)(C)[Si](C)(C)OCC#CCNC(=O)c1ccccc1Nc1ccc2c(C=Nn3cccc3)nn(COCC[Si](C)(C)C)c2c1

Procedure:
Prepared in a similar manner to that described for Example 6 above except using 2-[3-(Pyrrol-1-yliminomethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzoic acid and 4-(tert-Butyl-dimethyl-silanyloxy)-but-2-ynylamine. 1H NMR (DMSO-d6) δ 10.04 (1H, s 9.16 (1H, t, J=5.3 Hz), 9.10 (1H,s), 8.31 (1H, d, J=8.7 Hz), 7.78 (1H, d, J=7.9 Hz), 7.67 (4H, m), 7.49 (1H, t, J=8.5 Hz), 7.24 (1H, dd, J=1.7, 8.7 Hz), 7.03 (1H, t, J=7.4 Hz), 6.33 (2H, t, J=2.3 Hz), 5.85 (2H, s), 4.83 (2H, s), 4.19 (2H, d, J=5.5 Hz), 3.66 (2H, t, J=7.9 Hz), 0.94 (2H, m), 0.89 (9H, s), 0.13 (6H, s), 0.00 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.C[Li].[CH2:9]([Sn:13](Cl)([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12]>CCOCC>[CH3:1][C:2]1[N:3]=[C:4]([Sn:13]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][CH2:10][CH2:11][CH3:12])[S:5][CH:6]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1cscn1
Agent: [Li]C
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-Methylthiazole (0.5 ml, 5.50 mmol) was dissolved in Et2O (10 ml) and cooled to −78° C. Methyllithium (1.6 M in hexanes, 5.15 ml, 8.24 mmol) was added slowly and the mixture stirred at −78° C. for 1 hour. Tri-n-butyltin chloride (1.640 ml, 6.05 mmol) was then added slowly, the mixture stirred briefly at −78° C. then allowed to warm to RT and stirred overnight. The reaction mixture was quenched with water and extracted with Et2O. The organic phase was washed with brine, dried over sodium sulphate and evaporated under vacuum to afford the title product as a crude pale yellow oil. The material was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Cl[C:14]1[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=1.O1CCOCC1.C([O-])(O)=O.[Na+]>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.O>[NH2:20][C:18]1[N:19]=[C:14]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:12])[CH:5]=2)[CH:15]=[C:16]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:17]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(NCc2ccccc2)n1
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: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(NCc3ccccc3)nc(N)n2)cc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To (4-cyano-3-fluorophenyl)boronic acid (190 mg, 1.15 mmol) and 6-chloro-N4-(phenylmethyl)-2,4-pyrimidinediamine (300 mg, 1.28 mmol) into a sealable flask were added 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (3 mL). The mixture was degassed with nitrogen gas for 10 minutes. Pd(Ph3P)4 (74 mg, 0.064 mmol) was added and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto EtOAc and water. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were filtered, then washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue was chromatographed on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH). The material (367 mg) was carried on as is into the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[CH3:37])[CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=O)=[CH:14][C:13]=2[F:38])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[NH2:40][OH:41].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[CH3:37])[CH2:19]/[C:20](=[N:40]\[OH:41])/[C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=[CH:14][C:13]=2[F:38])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(Cl)c(C(=O)O)c2)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(Cl)c(C(=O)O)c2)c(F)c1

Procedure:
In analogy to example 151, step 3, 2-chloro-5-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-2-fluoro-phenoxy}-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI−): m/z=567.2 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:24][CH2:23][C@@H:22]([OH:25])[C@@H:21]([OH:26])[CH2:20]1>>[CH3:16][C:4]1[C:5]([C:8]2[S:12][C:11]([C:13]([N:19]3[CH2:24][CH2:23][C@@H:22]([OH:25])[C@@H:21]([OH:26])[CH2:20]3)=[O:15])=[CH:10][CH:9]=2)=[N:6][O:7][C:3]=1[C:2]([F:1])([F:18])[F:17]
Reactant: O[C@@H]1CCNC[C@@H]1O
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)N3CC[C@@H](O)[C@@H](O)C3)s2)noc1C(F)(F)F
Yield: 81 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and (3S,4R)-3,4-Piperidinediol (CAS [868051-84-7]) in the same manner as the (3R,4S) isomer (Example 87) to afford product as a colorless solid (303 mg, 81%). LC/MS 5.43 min, [M+1]+ 377.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][SH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: SCCCc1ccccc1
Product: O=Cc1ccc(SCCCc2ccccc2)cc1
Yield: 101.2 %

Procedure:
By the method of Preparation 7, 3-phenylpropyl mercaptan (41.1 g) and 4-bromobenzaldehyde (53.7 g) were converted to 70 g of present title product, isolated as an oil following chromatography on silica gel using 9:1 hexane:ethyl acetate as eluant; tlc Rf 0.4 (1:4 ethyl acetate:hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[N:10]1([C:16]([S:18][CH3:19])=[S:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:13]1[CH2:14][CH2:15][N:10]([C:16]([S:18][CH3:19])=[S:17])[CH2:11][CH2:12]1
Reactant: CSC(=S)N1CCNCC1
Reactant: Cc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CSC(=S)N1CCN(Cc2ccccc2C)CC1
Yield: 28.2 %

Procedure:
1.405 g (10 mmol.) of 2-methylbenzyl chloride, 1.76 g (10 mmol.) of methyl 1-piperazinecarbodithioate, 1.06 g (10 mmol.) of anhydrous sodium carbonate and 14 ml of ethanol. The mixture was refluxed under heating for 2.5 hours. Ethanol was distilled off under reduced pressure. The residue was mixed with water and ether. The organic solvent portion was taken out, and to the portion was added 15 ml of 3-N hydrochloric acid. The aqueous portion was neutralized with 1-N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate portion was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was purified over a silica gel column to give 790 mg of methyl 4-(2-methylbenzyl)-1-piperazinecarbodithioate as a white crystalline product, yield 28.2%.