Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:9]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)(Cl)Cl.C(N)(=O)C1C=CC=CC=1>[Cl:9][CH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccnc1Cl
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: NC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: ClCc1nccnc1Cl
Yield: 43.7 %

Procedure:
Prepare the title compound using the chlorination procedure as essentially described by Jeromin, G. E.; et al., DE3519364, 1986, and Russell, M. G. N.; et al. J. Med. Chem. 2005, 48, 1367-1383. Dissolve 2-methyl-3-chloropyrazine (24.3 g, 189 mmol) in CHCl3 (100 mL). Add benzamide (100 mg, 0.8 mmol) and heat to reflux. At reflux, add solid trichloroisocyanuric acid (17.6 g, 75.6 mmol) and continue to reflux for 96 h. Cool and filter through 200 g silica gel, eluting with methylene chloride. Purify by silica gel chromatography using a gradient of 35% chloroform/hexane to 60% chloroform/hexane over one hour. Obtain the title compound as a colorless oil, 5.39 g pure title compound and 9.4 g that is >70% desired product. 1H-NMR (CDCl3) δ 8.50 (d, 1H, J=2.2 Hz), 8.37 (d, 1H, J=2.6 Hz), 4.80 (s, 2H), 2.50 (s, 3H); GC/MS M=162+164.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([O:14][CH3:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2].[CH2:29](Br)[CH2:30][Br:31]>CCO>[CH2:1]([O:3][C:4](=[O:16])[C@@H:5]([O:14][CH3:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:29][CH2:30][Br:31])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OC
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Temperature: 25 °C

Procedure:
A mixture containing (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester obtained in Step 1 (0.223 mol, 50 mg), potassium carbonate (0.446 mol, 50 mg), magnesium sulfate (powdered, 50 mg, 1 g/g), ethylene dibromide (3.35 mol. 628 mg) and EtOH (25 mL) was heated at reflux (78–76° C.) for 24 hours and cool to room temperature. The mixture was heated again to reflux (76.5–77° C.) and 2 mL of ethylene dibromide was added. The mixture was heated for another 12 hours at 79.5–80.1° C. and then cooled to room temperature and vacuum filtered. The filtrate was concentrated under vacuum, and the residue was purified by column chromatography (silica gel, hexanes/ethyl acetate 6:1, Rf 027) to produce a colorless oil. MS (ES) for C14H19BrO4 [M+Na]+: 353.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:21]([S:28][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)c1cc(Br)ccc1F
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)c1cc(SCc2ccccc2)ccc1F
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
To a solution of 1-(5-bromo-2-fluorophenyl)ethanone (Matrix Scientific, 3 g, 13.8 mmol), Xantphos (0.800 g, 1.38 mmol), and N,N-diisopropylethylamine (4.83 mL, 27.6 mmol) in 1,4-dioxane (15 mL) was added Pd2(dba)3 (0.633 g, 0.691 mmol). The vial was sparged with argon, sealed, and stirred at 80° C. for 10 minutes. After 10 minutes, the reaction was cooled to ambient temperature, and benzyl mercaptan (1.70 mL, 14.5 mmol) was added. The reaction was flushed with argon, sealed, and stirred at 80° C. After 45 minutes, the reaction mixture was concentrated, diluted with dichloromethane, and passed through a silica-gel pad, eluting with DCM. The filtrate was concentrated and purified by column chromatography, eluting with 10-60% ethyl acetate in heptane, to provide 1-(5-(benzylthio)-2-fluorophenyl)ethanone (3.6 g, quantative yield) as a yellow oil. m/z (ESI) 261.0 (M+H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=2)[C:11]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:10]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:25]([C:24]1[CH:23]=[CH:22][C:21]([C:11]2[C:12]3[C:17](=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[N:9]([NH:8][C:5](=[O:7])[CH3:6])[CH:10]=2)=[CH:28][CH:27]=1)#[N:26]
Reactant: N#Cc1ccc(-c2cn(N)c3cc([N+](=O)[O-])ccc23)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nn1cc(-c2ccc(C#N)cc2)c2ccc([N+](=O)[O-])cc21
Reaction time: 3 h
Yield: 37.9 %

Procedure:
Add acetic anhydride (214 mg, 2.1 mmol) to a mixture of 4-(1-Amino-6-nitro-1H-indol-3-yl)-benzonitrile (400 mg, 1.4 mmol) and di-isopropylethylamine (194 mg, 2.1 mmol) and N,N-dimethylaminopyridine (2 mg) in DMF (20 mL) and stir for 3 h. Add additional acetic anhydride (214 mg, 2.1 mmol) and di-isopropylethylamine (194 mg, 2.1 mmol) and stir overnight. Dilute the mixture with water and extract with EtOAc. Wash the combined extracts with water and brine, and dry over MgSO4. Purify the crude residue using silica gel chromatography to give 170 mg (38% yield) of N-[3-(4-Cyano-phenyl)-6-nitro-indol-1-yl]-acetamide.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:10][C:7]1[CH:8]=[N:9][C:2]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(F)cnc1Cl
Reactant: OB(O)c1ccc(F)cc1
Product: N#Cc1cc(F)cnc1-c1ccc(F)cc1
Yield: 68 %

Procedure:
Prepared in 68% yield from the product of Example 169A and 4-fluorophenylboronic acid according to the procedure described for Example 153A. 1H NMR (DMSO-d6) δ 7.39-7.45 (m, 2H), 7.87-7.92 (m, 2H), 8.58 (dd, J=8.6, 2.9 Hz, 1H), 8.99 (d, J=3.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[OH:12][CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15].CS([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([O:12][CH:13]2[CH2:18][CH2:17][O:16][C:14]2=[O:15])[N:3]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: O=C1OCCC1O
Agent: CS(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(OC2CCOC2=O)n1
Reaction time: 2 h

Procedure:
1.75 g (10 mmol) of 2-chloro-4,6-dimethoxypyrimidine, 1.02 g (10 mmol) of α-hydroxy-γ-butyrolactone and 0.26 g (2.5 mmol) of sodium methanesulfinate were heated in the presence of 2.07 g (15.0 mmol) of potassium carbonate in 10 ml of N,N-dimethylformamide to 120° C. with stirring. After 2 hours, the solvent was removed in a rotary evaporator at 70° C./20 mbar. The residue was taken up in 30 ml of water and 30 ml of dichloromethane. After the organic phase had been separated off, the aqueous phase was again extracted with 20 ml of dichloromethane. The combined organic phases was washed with water, dried over magnesium sulfate and evaporated. The title product was obtained in a yield of 0.43 g (15.5 percent of theory) in the form of a pale brown oil (GC content 94 percent). Other data concerning the title compound was:
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH3:8])[N:3]=1.[C:9]([NH:19][C@H:20]([C:28]([NH:30][C@H:31]([C:33](O)=[O:34])[CH3:32])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:8][O:7][C:4]1[N:3]=[C:2]([NH:1][C:33](=[O:34])[C@H:31]([CH3:32])[NH:30][C:28](=[O:29])[C@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:19][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[S:6][N:5]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1nsc(N)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1nsc(NC(=O)[C@H](C)NC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)n1
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-3-methoxy-[1,2,4]thiadiazole (0.37 g, 2.8 mmol) and N-carbobenzyloxy-L-phenylalanyl-L-alanine, N-Cbz-Phe-Ala-OH, (1.0 g, 2.7 mmol) in DMF (25 mL) was added 1,3-dicyclohexylcarbodiimide, DCC, (0.56 g, 2.7 mmol). After stirring for 30 min, 1-hydroxybenzotriazole hydrate, HOBT, (0.36 g, 2.7 mmol) was added and the resulting mixture was stirred at room temperature for 20 h. Volatile materials were removed in vacuo and the residue was purified by column chromatography on silica gel using a solvent mixture of dichloromethane and methanol (96/4) thereby affording the title compound as a white solid (1.2 g). Further purification by cristallization and chromatography on silica gel gave 3-methoxy-5-(N-carbobenzyloxy-L-phenylalanyl-L-alaninamido]-[1,2,4]thiadiazole (0.87 g, 67% yield). M.p. 161-162° C.; 1H-NMR (CDCl3) δ7.14-7.38 (m, 12H, 10Ar-H and 2 NH), 5.92 (br. s, 1H, NH), 5.06 (s, 2H, OCH), 4.38 (m, 1H, CHCH2Ar), 4.00 (m, 1H, CHCH3), 3.97 (s, 3H, OMe), 3.00-3.08 (m, 2H, CHCH2Ar), 1.34 (d, J=8.9 Hz, 3H, Me); MS (m/z) 484 (M+ +1), 416, 361, 316, 285, 185, 132, 75. The latter compound was also prepared by using diphenylphosphoryl azide and triethylamine instead of DCC/HOBT in 27.7% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([O:33]CC)=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[O:36])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1.O[Li].O.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([OH:33])=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[O:36])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 25 °C
Yield: 92.6 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-propyl-butoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (130 mg, 0.198 mmol), LiOH.H2O (1 g, 24.6 mmol), H2O (5 mL) and methanol (15 mL) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated and then the water phase was acidified to “pH” 1-2 by addition of concentrated HCl solution and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (115 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:5]
Reactant: Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1cc(Cl)c(C(=O)c2ccccc2)c(Cl)c1
Temperature: 80 °C
Yield: 138.8 %

Procedure:
An ambient temperature solution of 2,6-dichloro-4-methylbenzoyl chloride (5.5 g, 25 mmol) in benzene (30 ml) was treated in portions with aluminum chloride (3.45 g, 25.9 mmol). When hydrogen chloride evolution ceased, the mixture was heated at 80° C. for 15 hours. The mixture was cooled, quenched by addition of ice and concentrated hydrochloric acid (5 ml), and diluted with diethyl ether (50 ml). The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under vacuum. The semisolid residue was chromatographed on a column of silica gel (300 g) eluted with 4:1 (v/v) hexanedichloromethane to provide 4.60 g (69%) 2,6-dichloro-4-methylbenzophenone, m.p. 75.5°-76.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH2:16])=O)=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[NH2:1][C:2]1[C:3]([C:14]#[N:16])=[N:4][CH:5]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: NC(=O)c1ncc(N2CCOCC2)cc1N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ncc(N2CCOCC2)cc1N
Temperature: 25 °C

Procedure:
A stirred solution of 3-amino-5-morpholinopicolinamide (0.35 g, 1.57 mmol) in acetonitrile (10 mL) was treated with phosphorus oxychloride (0.29 mL, 3.15 mmol). The reaction was heated at reflux for 1 h. After this time the reaction was cooled to rt and evaporated in vacuo. The residue was dissolved in Et2O (10 mL) and treated with 4.0M HCl in dioxane (0.2 mL). The resulting solid was filtered and dried under vacuum to give 3-amino-5-morpholinopicolinonitrile. Mass Spectrum (ESI) m/e=205.2 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH:6]1[C:15]2[C:10](=[CH:11][C:12]([CH3:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[CH:19]([N:22](CC)C(C)C)(C)C.N#CBr>C(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][CH2:7][CH:6]2[C:2]2[N:3]([C:19]#[N:22])[CH2:4][CH2:5][N:1]=2)=[CH:11][C:12]=1[CH3:18]
Reactant: COc1cc2c(cc1C)CCCC2C1=NCCN1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CBr
Solvent: ClCCl
Product: COc1cc2c(cc1C)CCCC2C1=NCCN1C#N
Temperature: 0 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
In a 9.5 dram screw cap vial was placed 0.20 gram (0.0008 mole) of Compound 50 (prepared as set forth in Example 2), 0.11 gram (0.0008 mole) of N,N-diisopropylethylamine, and 25 mL of methylene chloride; followed by 2.4 mL (0.0008 mole) of a stock solution of 1 mL of cyanogen bromide in 30 mL of methylene chloride. The reaction mixture was then gently shaken during an 18 hour period using a mechanical shaker. After this time the reaction mixture was poured into ice water in a separatory funnel, and the mixture was extracted with three portions of methylene chloride. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The residual oil was purified by column chromatography on Grade II alumina (basic-3% water) using methylene chloride as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 0.19 gram of Compound 201. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1.Br[C:23]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:23]=[N:21][C:4]=2[CH:3]=1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Reactant: CSc1nc2ccc(CNc3ccc(Br)cc3N)cc2s1
Product: CSc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1

Procedure:
6-((5-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole was synthesized as a white solid (630 mg, 62% over two steps) using a procedure analogous to that described in Step 3 of Example 41, substituting 4-bromo-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine from the previous step for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.00 (s, 1H), 7.87 (d, J=1.7 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.33-7.45 (m, 2H), 5.62 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 390, 392 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH2:13]O.[Br:15]P(Br)Br>ClCCl>[Br:15][CH2:13][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: COc1cc(Cl)c(CO)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1cc(Cl)c(CBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.5 %

Procedure:
To a solution of (2-chloro-4-methoxy-5-nitrophenyl)methanol (5.0 g, 23 mmol) in dichloromethane (50 mL) at 0° C., tribromophosphine (3.08 g, 11.5 mmol) was added in portions and the resulting mixture was stirred at RT for 2 h. The mixture was poured into ice-water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=10:1) to afford the desired product (3.5 g, 54.2% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: N#Cc1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.1 g, 9.8 mmol) was dissolved in 100 mL dry diethyl ether under an argon atmosphere, added dry pyridine (3.3 mL, 32.5 mmol), cooled to 0° C. then added oxalyl chloride (1.4 mL, 16.3 mmol) dropwise. A precipitate forms immediately upon addition of oxalyl chloride and therefore reaction requires vigorous stirring. Stirred at 0° C. for one hour than at ambient temperature for 2 hours. Dry diethyl ether (100 mL) was added and the solids were filtered off, washing with more diethyl ether. The filtrates were concentrated, then redissolved in dry DCM under argon, cooled to 0° C., added 1 mL dry pyridine then added 4-amino-benzonitrile (0.96 g, 8.1 mmol) in one portion. Stirred at ambient temperature for 2 hours, concentrated, redissolved in ethyl acetate (250 mL), washed with 10% citric acid (3×100 mL), water, brine, dried with MgSO4, filtered and concentrated to yield title compound as a white foam. (2.4 g, 93%) APCI (AP−): 314.1 (M−H)−.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].Cl.CN1CCOCC1.[NH:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:23]([C:34](O)=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(OCC)(=O)C.O>[NH:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:23]([C:34]([NH:1][C@@H:2]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:35])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1
Reactant: CCCC[C@@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCCC[C@@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a suspension of H-DNle-OtBu.HCl (603 mg) in dichloromethane (10 ml) were added NMM (297 μl), Boc-DTrp-OH (903 mg), HOBT.H2O (413 mg) and EDCI.HCl (569 mg) successively under ice cooling. The mixture was stirred at the same temperature for 2 h and at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed with 10% aq. citric acid, sat. aq. NaHCO3, water and brine successively, dried over MgSO4 and evaporated in vacuo to give Boc-DTrp-DNle-OtBu (1.22 g). To a solution of the dipeptide derivative in dichloromethane (12 ml) were added methyl chloroformate (1 ml), pulverized NaOH (103 mg) and TBAHS (20 mg). After being stirred of the mixture at room temperature for 30 min, pulverized NaOH (103 mg) was added. This procedure was repeated twice more. The reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3, 10% aq.citric acid, water and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was recrystallized from ethyl acetate and hexane to give Boc-DTrp(COOMe)-DNle-OtBu (1.15 g). The dipeptide derivative (1.03 g) was dissolved in TFA (10 ml) and the solution was stirred under ice cooling for 10 min. After evaporation of the reaction mixture, the residue was dissolved in ethyl acetate. The solution was washed with sat. aq NaHCO3, water and brine successively, dried over MgSO4 and concentrated under reduced pressure to give H-DTrp(COOMe)-DNle-OtBu as a free base. To a solution of the free base (750 mg) in methanol was added 3.78N - hydrogen chloride/1,4-dioxane (0.47 ml) under ice cooling. The solution was evaporated vacuo to to give H-DTrp(COOMe)-DNle-OtBu.HCl (810 mg). FAB-MS(m/e, (C23H33N3O5 +H)+):432
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>>[CH:12]([C:15]1[CH:21]=[CH:20][C:18]([NH:19][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(CNc2ccc(C(C)C)cc2)cc1
Yield: 96.1 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-isopropylbenzaldehyde (1.5 g) and 4-isopropylaniline (1.4 g) as starting materials, (4-isopropylphenyl)[(4-isopropylphenyl)methyl]amine (2.6 g) was obtained.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.[OH-].[Na+]>CCO>[CH2:25]([N:22]([CH2:23][CH3:24])[CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH:9]=[CH:10]2)[CH3:26]
Reactant: CCN(CC)CCCCOc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Yield: 96 %

Procedure:
3.9 g (10.8 mmol) 5-(4-Diethylamino-butoxy)-indole-1-carboxylic acid tert-butyl ester in 4 ml EtOH were treated with 0.4 ml halfconc. NaOH at 60° C. for 2 h. The suspension was concentrated in vacuo and the residue dissolved in EtOAc and water. The organic phase was washed with water and dried over Na2SO4. Evaporation yielded 2.7 g (96%) Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine as brown oil, MS: 261 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:37][C:38]#[N:39].[NH4+].[Cl-]>C(#N)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:37][C:38]#[N:39])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CC#N)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (20 mg, 0.048 mmol) in acetonitrile (0.5 mL) was added Cs2CO3 (31 mg, 0.096 mmol) and chloroacetonitrile (7 mg, 0.096 mmol). The resulting mixture was stirred at room temperature for 14 h before it was treated with saturated aqueous NH4Cl (1 mL) and extracted with EtOAc (3×2 mL). The organic layers were combined, concentrated, and the residue was purified by preparative RP-HPLC to provide 2-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)acetonitrile; ESMS m/z 455.2 (M+H+).