Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[N:5]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=2)[C:6](=O)[CH:7]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:6]1[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)n2nc(-c3ccccc3)cc2[nH]1
Product: Cc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
5-Methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (210 mg, 0.932 mmol) is heated in phosphoryl chloride (1.74 mL, 18.6 mmol) in a sealed vial at 100° C. for 2 hr. The reaction mixture is cooled to room temperature and slowly poured over ice. The resulting suspension is extracted with dichloromethane and washed with brine. The organic layer is dried over Na2SO4, filtered and concentrated in vacuo. The crude material is purification by column chromatography (eluent 0-100% ethyl acetate:hexanes) to provide 7-chloro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine (123 mg, yield 54%). LCMS: (AA) M+1 244; 1H NMR (400 MHz, DMSO) δ 8.07-8.02 (m, 2H), 7.53-7.47 (m, 2H), 7.46-7.41 (m, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 2.53 (s, 3H).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14]O)[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][Cl:19])[C:9]=1[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCOc1ccnc(CO)c1C
Solvent: ClC(Cl)Cl
Product: CCCCCCOc1ccnc(CCl)c1C
Yield: 185.8 %

Procedure:
12.2 g (0.055 mol, 1.0 eq.) of 4-hexyloxy-2-hydroxymethyl-3-methylpyridine was dissolved in 620 mL of chloroform, and 33.4 g (0.281 mol, 5.1 eq.) of thionyl chloride was added dropwise at 23 to 29° C. Subsequently, the mixture was heated to reflux for one hour and then concentrated, to obtain 24.7 g of 4-hexyloxy-2-chloromethyl-3-methylpyridine as a brown oily matter.
Reaction SMILES: Br[C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[C:9]([O-:17])(=[S:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cs+]>CN(C=O)C.CCOCC>[C:9]([S:16][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[C@H](Br)C(=O)O
Reactant: [O-]C(=S)c1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)[C@@H](SC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.5 %

Procedure:
To a solution of (S)-(−)-2-bromo-3-methylbutyric acid (4.20 g, 23.2 mmol) in DMF (41 mL) was added cesium thiobenzoate (6.08 g, 22.5 mmol). The mixture was stirred at rt for 20 h. The resulting solution was diluted with ether (200 mL) and washed with H2O (4×40 mL). The ethereal layer was dried (Na2SO4), and concentrated. The crude residue was recrystallized from hexanes to afford (R)-2-benzoylthio-3-methylbutanoic acid as a pale yellow solid (4.05 g, 75%); 1H NMR (300 MHz, CDCl3) δ 1.09 (d, J=7.4 Hz, 3H), 1.11 (d, J=7.4 Hz, 3H), 2.40 (m, 1H), 4.37 (d, J=5.9 Hz, 1H), 7.45 (t, J=7.4 Hz, 2H), 7.57 (t, J=7.4 Hz, 1H), 7.97 (d, J=7.4 Hz, 2H), 11.9 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 19.8, 20.6, 30.5, 53.1, 127.6, 128.8, 133.9, 136.3, 177.9, 190.3; IR (neat) 3100, 2967, 1709, 1669 cm−1; [α]D22=+95.6 (c 1, CH2Cl2). All spectral data was identical to that previously published (Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1986, 51, 3664).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:39])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1[CH3:38])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:38][C:31]1[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:30]=1[C:29](=[O:39])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Reactant: COc1ccc(C(=O)NC(C)(C)C)c(C)c1
Product: COc1ccc(C(=O)NC(C)(C)C)c(CC(=O)[C@@H](Cc2ccccc2F)NC(=O)OC(C)(C)C)c1

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.4 g, 4.29 mmol) and N-tert-Butyl-4-methoxy-2-methyl-benzamide (2.8 g, 13 mmol) followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:16][CH3:17])[CH2:11][C:12](OC)=[O:13])=[CH:5][CH:4]=1.[NH3:20]>CO>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:16][CH3:17])[CH2:11][C:12]([NH2:20])=[O:13])=[CH:5][CH:4]=1
Reactant: N
Reactant: CC[C@H](CC(=O)OC)Nc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: CC[C@H](CC(N)=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 63 h
Yield: 48 %

Procedure:
403 mg (1.47 mmol) of methyl (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoate produced in Example 12 was dissolved in methanol (20 mL) and further mixed with a 28 wt % aqueous ammonia solution (30 mL) at room temperature. After stirring at the same temperature for further 63 hours, the reaction solution was concentrated under reduced pressure and subjected to extraction with ethyl acetate. The product was then dried with anhydrous magnesium sulfate. The residue obtained by removing the solvent by distillation under reduced pressure was purified on silica gel column chromatography to obtain (R)-3-[4-(trifluoromethyl)phenylamino]-pentanoic acid amide as a white solid (183 mg, isolated yield: 48%). The optical purity of the product was determined by HPLC analysis (column; Daicel Chiral Pack AD-H 4.6×250 mm: eluent; hexane/isopropanol=95/5: flow rate; 1.0 mL/min: column temperature; 30° C.: detector; UV 210 nm: retention time; (S) antipode=23.5 minutes, (R) antipode=24.8 minutes) to be 100% ee. 1H-NMR (CDCl3, 400 MHz/ppm): δ 0.98 (3H, t), 1.65 (2H, m), 2.45 (2H, d), 3.76 (1H, m), 4.28 (1H, d), 5.58 (2H, brs), 6.64 (2H, d), 7.38 (2H, d)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:14]#[N:15])[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([CH2:14][NH2:15])[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C#N)CC12CCCCC2
Agent: [Ni]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CN)CC12CCCCC2
Reaction time: 70 h
Yield: 69.2 %

Procedure:
To a solution of 1-cyano-spiro[2.5]octane-1-carboxylic acid ethyl ester (7.1 g, 34.2 mmol) in 95 mL ethanol (EtOH) was added triethylamine (5.0 mL) and Raney nickel (4.0 g). The mixture was hydrogenated in a Parr shaker at 48 psi for 70 hours, filtered, and concentrated. Flash chromatography of the residue (5→10→15% MeOH/methylene chloride (CH2Cl2)) provided 5.0 g (69%) of 1-aminomethyl-spiro[2.5]octane-1-carboxylic acid ethyl ester as a colorless oil. 1H NMR δ 4.15 (q, J=7.1 Hz, 2H), 3.23 (d, J=13.9 Hz, 1H), 2.65 (d, J=13.9 Hz, 1H), 1.41–1.57 (m, 10H), 1.24 (m, 4H), 0.53 (d, J=4.9 Hz, 1H).
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH2:14][CH3:15])[C:11](=[O:16])[NH:10][C:9]=2[CH:17]=1)=O.[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>>[CH3:18][C:2]1[N:21]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]2=[N:19][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH2:14][CH3:15])[C:11](=[O:16])[NH:10][C:9]=2[CH:17]=1
Reactant: CCC1Oc2ccc(C(=O)C(C)Br)cc2NC1=O
Reactant: Cc1ccnc(N)c1
Product: CCC1Oc2ccc(-c3nc4cc(C)ccn4c3C)cc2NC1=O
Yield: 25.5 %

Procedure:
6-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-2-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.82 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.12 g) and 2-amino-4-methylpyridine (3.24 g). mp. 194°-195° C (dec.).
Reaction SMILES: CN(C)C(N(C)C)=N.[C:9]([O:13][C:14]([CH:16](P(OC)(OC)=O)[C:17]([O:19][CH3:20])=[O:18])=[O:15])([CH3:12])([CH3:11])[CH3:10].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[F:36].O>C(Cl)Cl>[C:9]([O:13][C:14](/[C:16](=[CH:32]\[C:31]1[CH:34]=[CH:35][C:28]([Cl:27])=[C:29]([F:36])[CH:30]=1)/[C:17]([O:19][CH3:20])=[O:18])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: COC(=O)C(C(=O)OC(C)(C)C)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)/C(=C/c1ccc(Cl)c(F)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
1,1,3,3-Tetramethylguanidine (2.11 mL, 16.8 mmol) was added to a 0° C. solution of methyl 2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)-acetate (5.00 g, 16.8 mmol) in DCM (70 mL). The reaction mixture stirred at 0° C. for 30 minutes, then a solution of 4-chloro-3-fluorobenzaldehyde (2.67 g, 16.8 mmol) in DCM (10 mL) was added by syringe. The reaction mixture was stirred for 10 minutes and then warmed to room temperature with continued stirring for 1 hour. H2O was then added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The resulting solids were recrystallized from IPA to give (Z)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)acrylate (3.76 g, 67.8% yield) as a white powder (2 crops). LCMS (APCI−) m/z 328 [M−H]−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([CH2:29][CH:30]4[CH2:34][CH2:33][N:32]([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[C:31]4=[O:41])=[C:24]([Cl:42])[CH:23]=3)=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:35]1([N:32]2[CH2:33][CH2:34][CH:30]([CH2:29][C:25]3[C:24]([Cl:42])=[CH:23][C:22]([C:19]4[CH:18]=[CH:17][C:16]([C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:15])=[CH:21][CH:20]=4)=[CH:27][C:26]=3[Cl:28])[C:31]2=[O:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCNCC1
Temperature: 0 °C
Yield: 93.1 %

Procedure:
Dissolve racemic 4-[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.843 g, 1.37 mmol) in dichloromethane (25 mL) and cool in ice bath to 0° C. while stirring under an inert atmosphere. Add triethylsilane (0.5 mL) and trifluoroacetic acid (5.0 mL) to the mixture and allow the temperature to rise to room temperature. Monitor the reaction via TLC. Once starting material is consumed, dilute the reaction with dichloromethane and quench with saturated sodium bicarbonate. Collect the organic phase and the extract aqueous phase with dichloromethane (2×50 mL). Combine organic phases and dry over magnesium sulfate. Extract desired material with resin bound acidic media (SCX) to obtain 0.656 g (93%) of white solid: MS (m/z): 514.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.CCN(CC)CC>[C:24]1([S:30]([O:14][C:11]2[CH:10]=[CH:9][C:8]([C:3]([C:15]3[CH:20]=[CH:19][C:18]([O:21][S:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:32])=[O:31])=[CH:17][CH:16]=3)([C:4]([F:6])([F:5])[F:7])[C:2]([F:22])([F:23])[F:1])=[CH:13][CH:12]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc(C(c2ccc(OS(=O)(=O)c3ccccc3)cc2)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1
Yield: 89.2 %

Procedure:
An oven-dried 100 ml 3-necked flask is equipped with a magnetic stirring bar, a reflux condenser carrying a CaCl2 -Drierite drying tube, and a heating mantle, and is charged with 4,4'-(hexafluoroisopropylidene)diphenol (Aldrich) (5.45 grams, 16.2 mmol), 4-dimethylaminopyridine (0.4 gram, 3.3 mmol), and anhydrous Et3N (40 ml). The solution is stirred and treated slowly with benzenesulfonyl chloride (4.7 ml, 36.8 mmol) via syringe. The resulting mixture is heated at reflux for 9 hours. Workup consists of partitioning the reaction mixture between CH2Cl2 (100 ml) and a mixture of H2O (150 ml) and concentrated HCl (40 ml), washing the organic phase successively with 100 ml portions of H2O, 5 percent NaOH, H2O, and saturated brine, drying (MgSO4), filtration and concentration. This gives 10.6 grams of a reddish oily residue. TLC analysis on silica gel shows one main component (Rf =0.54; CH2Cl2). Chromatography on a column packed with flash-grade silica gel (3"×1" i.d.), eluting with CH2Cl2, gives 9.32 grams of a faintly yellowish oil. which solidifies on standing. Recrystallization from EtOAc-MeOH-H2O (20 ml:100 ml:10 ml)affords 8.91 grams crystalline solid. m.p. 133° C. to 134° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:15]2[O:14][CH2:13][C:12](=[O:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2].[BrH:18].[NH+]1C=CC=CC=1.O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[C:15]2[O:14][CH:13]([Br:18])[C:12](=[O:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)COc1cccc2c1OCC2=O
Reactant: Br
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1cccc2c1OC(Br)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl[(3-oxo-2,3-dihydrobenzofuran-7-yl)oxy]acetate (1.00 g, 4.23 mmol) in chloroform (30 mL) was added pyridinium hydrobromide perbromide (1.35 g, 4.23 mmol) at 0° C. and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water. The organic layer was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 1.20 g of ethyl[(2-bromo-3-oxo-2,3-dihydrobenzofuran-7-yl)oxy]acetate. A mixture of this compound (1.20 g, 3.80 mmol) and 1-phenyl-2-thiourea (580 mg, 3.80 mmol) in acetic acid (20 mL) was refluxed for 3 hours. The solvent was then distilled off under reduced pressure. To that residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:5) to provide 180 mg of the title compound. Yield 12%.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:14]([F:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:6]=1[C:7](OC)=[O:8]>CCO>[F:15][C:14]1[CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=[C:6]2[C:5]=1[NH:3][N:2]=[C:7]2[OH:8]
Reactant: NN
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(F)c1F
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(F)c2[nH]nc(O)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Hydrazine monohydrate (1.91 ml) was added to an EtOH (40 ml) solution containing methyl 2,3-difluoro-5-nitrobenzoate (1.71 g) obtained in the 2nd step, followed by stirring at room temperature for 10 minutes. An insoluble precipitate was removed by filtration and washed with EtOH. 7-Fluoro-5-nitro-1H-indazol-3-ol (956 mg) was thus obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]1[N:21]=[C:20](Cl)[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([NH:27][C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[CH3:36][N:37](C=O)C>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-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]1[N:21]=[C:20]([C:36]#[N:37])[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([NH:27][C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1c(Cl)nc(N2CCCCC2CNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1c(C#N)nc(N2CCCCC2CNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of methyl 2-(2-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)-4-chloro-6-(m-tolylamino)pyrimidine-5-carboxylate (399.7 mg, 0.816 mmol), tetrakis(triphenylphosphine)palladium(0) (96.3 mg, 0.083 mmol), and zinc cyanide (53.2 mg, 0.453 mmol) in DMF (5 mL) was stirred at 120° C. for 1 h under microwave irradiation. Water (50 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The organic layers were washed with saturated aq NaHCO3 (50 mL), water (50 mL), and brine (50 mL), were dried over anhydrous Na2SO4, and then filtered (DM1020). The filtrate was concentrated under reduced pressure and was purified by column chromatography (SiO2, hexanes/EtOAc=4/1) to give the title compound as a colorless oil (315.0 mg, 80%). 1H NMR (500 MHz, CDCl3) δ ppm 1.34-1.77 (m, 15H), 2.36-2.39 (m, 3H), 3.00-3.21 (m, 2H), 3.49-3.69 (m, 1H), 3.97 (s, 3H), 4.49-5.10 (m, 3H), 6.96-7.02 (m, 1H), 7.24-7.41 (m, 3H), 10.14-10.45 (m, 1H). [M+H] calc'd for C25H33N6O4, 481. found, 481.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9](=[O:18])[CH2:8][O:7][C:6]=2[CH:19]=1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.C([O-])(O)=O.[Na+]>[O:18]=[C:9]1[CH2:8][O:7][C:6]2[CH:19]=[C:2]([NH:1][C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[NH:27])[CH:3]=[CH:4][C:5]=2[N:10]1[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)OCC(=O)N2CCN1CCCC1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)OCC(=O)N2CCN1CCCC1)c1cccs1
Reaction time: 48 h
Yield: 90.4 %

Procedure:
A solution of 7-amino-4-(2-(pyrrolidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (0.125 g, 0.478 mmol) in dry ethanol (5 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.27 g, 0.956 mmol) at room temperature. The resulting mixture was stirred for 2 days. The reaction was then diluted with saturated NaHCO3 solution (20 mL), and the product was extracted into CH2Cl2 (2×20 mL). The combined CH2Cl2 layers were washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (3:97 (2 M NH3 in MeOH):CH2Cl2) to obtain the title compound 3 (0.16 g, 90%) as a solid. 1H NMR (DMSO-d6) δ 1.64-1.72 (m, 4H), 2.46-2.54 (m, 4H, merged with DMSO-d6 resonance), 2.60 (t, 2H, J=7.2 Hz), 3.99 (t, 2H, J=7.2 Hz), 4.58 (s, 2H), 6.47-6.57 (m, 4H), 7.06-7.12 (m, 2H), 7.60 (d, 1H, J=4.2 Hz), 7.73 (d, 1H, J=3.3 Hz); ESI-MS (m/z, %): 371 (MH+, 66), 150 (63), 128 (100); ESI-HRMS calculated for C19H23N4O2S (MH+), calculated: 371.1536, observed: 371.1548; HPLC purity 93.17% by area.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])C.CN(C(ON1N=NC2C=[CH:22][CH:23]=[N:24][C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:7]1([N:3]2[CH2:2][CH2:1][C:6]3([CH2:22][CH2:23][NH:24][CH2:19]3)[CH2:4]2)[CH2:8][CH2:9]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: C1CC2(CCN(C3CC3)C2)CN1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To an ice-cold solution of acid S3 (0.612 mmol) and DIPEA (1.3 mmol) in THF (2.5 ml) was added HATU (0.612 mmol) and the reaction mixture was stirred for 15 min. Then a solution of amine A12 (0.735 mmol) in THF (1 ml) was added slowly and allowed to stir at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure and diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography using 1-5% MeOH in DCM as eluent. Yield: 50% 2. To a solution of step-1 product (180 mg) in MeOH (5 ml) was added 1N NaOH solution (5 ml) at 0° C. Then the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography on neutral alumina using 1-10% MeOH in DCM as eluent. m/z=530.7 [MH]+
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[S:11][C:10]([NH:12][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:25]([O:24][CH3:23])[CH:26]=3)=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: COc1ccc(-c2nc(N)sc2Cc2ccc(F)cc2)cc1
Product: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2Cc2ccc(F)cc2)cc1
Yield: 69.1 %

Procedure:
A procedure similar to that in Example 4 was used. 5-(4-fluoro-benzyl)-4-(4-methoxy-phenyl)-thiazol-2-ylamine prepared in Example 21 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (100:0-10:1) to obtain a product as a white solid in a yield of 69.1%, mp: 140-142 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.80 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.18 (2H, s, CH2), 6.79 (1H, d, J=8.68 Hz, ArH), 6.82 (2H, d, J=8.68 Hz, ArH), 7.00 (2H, t, 3JFH=3JHH=8.68 Hz, ArH), 7.21 (2H, dd, 3JHH=8.12 Hz, 4JFH=5.32 Hz, ArH), 7.35 (4H, d, J=9.28 Hz, ArH), 11.00 (1H, br, CONH, exchangable); EI-MS m/e (%): 478.2 (M+, 88), 165.0 (100); HREI-MS Calcd. for C26H23FN2O4S: 478.1363. found: 478.1361. Anal. Calcd. for C26H23FN2O4S: C, 65.26; H, 4.84; N, 5.85. found: C, 65.11; H, 4.68; N, 5.96.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][SH:7].[CH3:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][CH2:12][CH2:11][C:10]([O:9][CH3:8])=[O:13]
Reactant: C=CC(=O)OC
Reactant: SCc1cccs1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCNCC1
Product: COC(=O)CCSCc1cccs1

Procedure:
A solution of 2-thiophenemethanethiol (12 grams), methylacrylate (7.94 grams), piperidine (3 mL) and N-benzyltrimethylammonium hydroxide (3 mi) was stirred for 16 hours at room temperature. The reaction mixture was distilled in vacuo to yield the desired title compound. Yield: 16.5 grams (83%). Bp: 140° C. at 1 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[C:2]=1[Cl:1])[C:15]#[N:16]
Reactant: CN1CCN(c2cc(C#N)cc(NC(=O)OC(C)(C)C)c2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cc(C#N)cc(N)c2Cl)CC1
Yield: 84.9 %

Procedure:
To a solution of tert-butyl 2-chloro-5-cyano-3-(4-methylpiperazin-1-yl)phenylcarbamate (135 mg, 0.385 mmol) in DCM (1.4 mL) was added TFA (0.6 mL, 3.89 mmol). The mixture was stirred at reaction mixture. The solvent was evaporated under vacuum, the residue was dissolved in EtOAc, washed with small amount of sat NaHCO3, and brine, dried over MgSO4, filtered, concentrated, and the residue was purified by ISCO (12 g, EtOAc/DCM=0-60%) to give 82 mg of 3-amino-4-chloro-5-(4-methylpiperazin-1-yl)benzonitrile