Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH3:15])=[C:4]([F:18])[CH:3]=1.[N:19]1([C:25]([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN(C)C=O.[Cu](I)I>[F:18][C:4]1[CH:3]=[C:2]([N:29]2[CH:28]=[C:27]([C:25]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[O:26])[CH:31]=[N:30]2)[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH3:15]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(Br)cc1F
Reactant: O=C(c1cn[nH]c1)N1CCOCC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N3CCOCC3)cn2)cc1F
Temperature: 130 °C
Reaction time: 6 h
Yield: 36 %

Procedure:
To a solution of (2R)-1-[3-(4-bromo-2-fluorophenoxy)propyl]-2-methylpyrrolidine obtained in Example 62-(2) (0.72 g) and morpholin-4-yl(1H-pyrazol-4-yl)methanone (0.45 g) in N,N-dimethylformamide (3 mL), cesium carbonate (1.6 g), copper iodide (0.1 g) and (1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (0.36 mL) were added and the mixture was heated to 130° C., at which it was stirred for 6 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=11:1 to 3:1) and NH-type silica gel column chromatography (eluting solvent: chloroform:methanol=10:0 to 100:1) to give the titled compound (0.34 g, 36%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1Br.C(O[C:16]([S-:18])=[S:17])C.[K+].O>CN1CCCC1=O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:16]([SH:18])[S:17][C:3]=2[CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc2nc(S)sc2c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 25.8 %

Procedure:
4-Amino-3-bromobenzotrifluoride (2.40 g) was dissolved in N-methyl-2-pyrrolidone (10 mL), and potassium ethylxanthate (3.52 g) was added thereto. The mixture was stirred at 160° C. for 3 hr with heating. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and brine, and concentrated under reduced pressure to give 6-trifluoromethyl-2-mercaptobenzothiazole (607 mg) as an orange powder.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[F:1][C@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:7][NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)OCc2ccccc2)[C@H](F)C1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@@H]1CNC[C@@H]1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of (±)-1,1-dimethylethyl trans-3-fluoro-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (1.0 g, 2.84 mmole) in DCM (50 mL) at RT was added TFA (25 mL). After 2 h, the reaction solution was concentrated under vacuum and the residue placed under high vacuum for 3 hr. The residue was dissolved in DCM (200 mL) and MP-carbonate resin (11.4 mmole, 4.2 g) was added with vigorous stirring at RT. After 4 h, the reaction contents were filtered through a scintered-glass funnel washing with MeOH (100 mL). The filtrate was concentrated under vacuum to give the title compound (0.54 g, 75%) as a light orange oil: LC-MS (ES) m/e 253 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1([NH:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:32]([CH:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: C1CCC(NC2CCCCC2)CC1
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CN(C4CCCCC4)C4CCCCC4)n3)c2[C@@H]2CCN12
Yield: 51.2 %

Procedure:
1.13 g (3 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one were stirred at 65° overnight with 5 ml (25 mmol) of dicyclohexylamine and 7 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.8 g (51%) of (S)-8-chloro-1-(5-dicyclohexylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 155°-185°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.0 g), 2-(4-methanesulfonylbenzyl)-3-oxopentanoic acid methyl ester (1.4 g), polyphosphoric acid (5 mL) and dioxane (20 mL) was heated at 130° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and the pH adjusted to 4 by the addition of sodium acetate. The mixture was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a honey coloured gum, 2.3 g.
Reaction SMILES: C(C1C=CC=CC=1C#N)#C.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].[I:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I>[Pd]>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:15]#[C:16][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[I:17]
Reactant: Ic1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: [Pd]
Agent: C#Cc1ccccc1C#N
Product: C[Si](C)(C)C#Cc1ccccc1I
Yield: 58 %

Procedure:
Alternatively, 2-ethynylbenzonitrile (a3) may be prepared according to the procedures set forth in M. J. Wu et al. (1999), Organic Letters, 1 (5):767-768, which is incorporated herein by reference in its entirety. Specifically, palladium-catalyzed coupling reaction of trimethylsilylacetylene with 1,2-diiodobenzene produced 2-(2-trimethylsilylethynyl)iodobenzene in 58% yield; 2-(2-trimethylsilylethynyl)iodobenzene was then coupled with Zn(CN)2 using palladium(0) as a catalyst to give 2-(2-trimethylsilylethynyl)benzonitrile in 45% yield; and finally, 2-(2-trimethylsilylethynyl)benzonitrile was treated with tetrabutylammonium fluoride to give 2-ethynylbenzonitrile (a3) in 97% yield.
Reaction SMILES: [CH2:1]([C@@H:3]1[NH:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(=O)(OC1C=CC(S(N2C3C(=CC=C(F)C=3)NC(=O)[C@@H]2CC)(=O)=O)=CC=1)OCC>>[CH2:1]([C@@H:3]1[N:12]([S:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2]
Reactant: CC[C@@H]1Nc2ccc(F)cc2NC1=O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(F)ccc3NC(=O)[C@@H]2CC)cc1
Product: CC[C@H]1C(=O)Nc2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1

Procedure:
(3S)-3-Ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one was treated with 4-methoxybenzenesulfonyl chloride according to the procedure for the preparation of ethyl 4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl carbonate (see Example 20) to yield (3S)-3-ethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−12.1° (c=0.006 G/ML, DMSO); MS (ESI) m/z 365 ([M+H]+); MS (ESI) m/z 363 ([M−H]−); Anal. Calcd for C17H17FN2O4S: C, 56.03; H, 4.70; N, 7.69. Found: C, 55.99; H, 4.57; N, 7.62.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[CH2:16][N:15]([C:17]([N:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([CH3:27])[CH2:21][C@@H:20]4[CH3:28])=[O:18])[C:14]([CH3:30])([CH3:29])[C:11]=3[NH:12][N:13]=2)[C:5]([F:31])=[CH:4][N:3]=1.[CH2:32](B1OC(C)(C)C(C)(C)O1)[CH:33]=[CH2:34].C(=O)([O-])[O-].[Cs+].[Cs+].O>[Pd].C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C1COCC1>[F:31][C:5]1[C:6]([NH:8][C:9]2[C:10]3[CH2:16][N:15]([C:17]([N:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([CH3:27])[CH2:21][C@@H:20]4[CH3:28])=[O:18])[C:14]([CH3:30])([CH3:29])[C:11]=3[NH:12][N:13]=2)=[N:7][C:2]([CH2:32][CH2:33][CH3:34])=[N:3][CH:4]=1
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: C[C@H]1CN(C)C(C)(C)CN1C(=O)N1Cc2c(Nc3nc(Cl)ncc3F)n[nH]c2C1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ncc(F)c(Nc2n[nH]c3c2CN(C(=O)N2CC(C)(C)N(C)C[C@@H]2C)C3(C)C)n1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a pressure vessel was added [3-(2-Chloro-5-fluoro-pyrimidin-4-ylamino)-6,6-dimethyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl]-((S)-2,4,5,5-tetramethyl-piperazin-1-yl)-methanone (0.150 g, 0.330 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.12 g, 6.66 mmol), cesium carbonate (0.543 g, 1.66 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.0408 g, 0.0498 mmol), H2O (0.3 mL), and THF (3 mL). The suspension was purged with argon for 2 min, then stirred at 100° C. for 15 h. The cooled solution was filtered to remove undissolved solids and the volatiles removed in vacuo. The residue was redissolved in MeOH (5 mL) and 10% palladium on carbon (0.0400 g, 0.380 mmol) was added. The suspension was evacuated and backfilled with hydrogen for 3 times and allowed to stir for 15 h under hydrogen. The suspension was filtered through Celite, the filter cake washed with CH2Cl2, and the filtrate concentrated. Preparative HPLC provided the desired product I1 as a white solid (0.025 g, 14%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].C1(C2[O:40][CH2:39][CH:38]([O:41][NH2:42])[CH2:37][O:36]2)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[OH:36][CH2:37][CH:38]([O:41][NH:42][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])[CH2:39][OH:40]
Reactant: NOC1COC(c2ccccc2)OC1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC(CO)CO)c(=O)n(C)c1=O
Temperature: 50 °C

Procedure:
Phenyl 6-(2-fluoro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (compound 2A, 100 mg, 0.2 mmol, 1 eq) and O-(2-phenyl-1,3-dioxan-5-yl)hydroxylamine (79 mg, 0.404 mmol, 2 eq) (see, Vonhoff et al., Helv. Chim. Acta, 81(9), 1998; 1710-1725; European Patent Application No. EP1666485) were mixed in THF and subjected to microwave irradiation at 100° C. for 45 minutes. The reaction was complete by LCMS. Upon cooling, the intended product precipitated as a tan solid. 62 mg (51%). This solid was then dissolved in methanol (2 ml) and THF (2 ml) with ethylene glycol (100 μl). p-Toluenesulfonic acid (18 mg, 1 eq) was added and the mixture heated at 50° C. for 30 minutes. Purification by HPLC chromatography afforded the title compound as a white solid. 28 mg (53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.96 (s, 3 H) 3.22 (s, 3 H) 3.42-3.58 (m, 4 H) 4.00-4.08 (m, J=1.67, 0.78, 0.78, 0.78, 0.78 Hz, 2 H) 4.75 (t, J=5.94 Hz, 2 H) 5.76 (s, 1 H) 7.53-7.62 (m, 1 H) 7.80 (dd, J=9.73, 1.39 Hz, 1 H) 11.99 (s, 1 H) 12.23 (s, 1 H) [M+H] calc'd for C16H18FIN4O6, 509; found, 509.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH:8]([CH2:16][C:17]1[CH:22]=[CH:21][N+:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:19][C:18]=1[C:31]([NH:33][CH3:34])=[O:32])[CH2:7]2.C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH:8]([CH2:16][CH:17]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH:19]=[C:18]1[C:31]([NH:33][CH3:34])=[O:32])[CH2:7]2
Reactant: CNC(=O)c1c[n+](Cc2ccccc2C)ccc1CC1Cc2cc(OC)c(OC)cc2C1=O
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: CNC(=O)C1=CN(Cc2ccccc2C)C=CC1CC1Cc2cc(OC)c(OC)cc2C1=O

Procedure:
The title compound 168 is prepared according to the procedure reported in Example 39.1 with compound 143 (89.1 mg, 0.2 mmol) and BNAH (1 equiv) as reactants. Pale yellow solid. (Yield 35.7 mg, 40%).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[F:28][C:29]([F:40])([F:39])[O:30]C1C=C(C=CC=1)C=O>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:30][C:29]([F:40])([F:39])[F:28])[CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2cccc(OC(F)(F)F)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 3-trifluoromethoxybenzaldehyde gave 4-iodomethyl-5-methyl-2-(3-trifluoromethoxyphenyl)oxazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=1)[CH2:6][CH2:5]2.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH:22][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:19]=[CH:18][C:16]=3[N:17]=1)[CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2)C1CC1
Yield: 57 %

Procedure:
Prepared from rac-N2-(5-fluoro-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 11) (100 mg, 0.336 mmol) and cyclopropylcarbonyl chloride (34 ul, 0.370 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (70 mg, 57%), MS (ISP) m/e=366.1 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[CH3:15][N:16]=[C:17]=[O:18]>C(#N)C>[CH3:15][NH:16][C:17]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)=[O:18]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)NCCSCc1csc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Following the above reaction sequence, a solution of 0.93 g of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine in 10 ml. of anhydrous acetonitrile was prepared. A solution of 0.22 ml. of methyl isocyanate in 5 ml. of anhydrous acetonitrile was added thereto. The reaction was stirred at ambient temperature for about 2.5 hours at which time the solvent was removed by evaporation. The resulting residue slowly crystallized and was recrystallized from cylcohexane to yield about 0.97 g of N-methyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylurea melting at about 56°-59° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:4][C:5]([SH:10])=[C:6]([O:8][CH3:9])[CH:7]=1.O.NN>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([SH:10])=[CH:4][C:3]=1[NH2:11]
Reactant: COc1cc(Cl)c(N2C(=O)c3ccccc3C2=O)cc1S
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(N)cc1S
Yield: 77.8 %

Procedure:
To a solution of 5-chloro-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-mercaptoanisole (0.65 g) in tetrahydrofuran (20 mL) was added hydrazine monohydrate (0.5 mL), and the mixture was heated at reflux for 1.5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (0.3 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([CH2:15][NH:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[N:25][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1)=O)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:15][NH:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[N:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CCc1ncc(-c2cccc(NCC(=O)OC(C)(C)C)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cccc(-c2cnc(CCC(=O)OC)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 187.7 %

Procedure:
0.12 ml (1.6 mmol, 5 eq) of trifluoroacetic acid is added to a solution of 118 mg (0.32 mmol, 1 eq) of methyl 3-{5-[3-(tert-butoxycarbonylmethylamino)phenyl]pyrimidin-2-yl}propanoate in 4 ml of dichloromethane. The reaction mixture is stirred for 16 hours at room temperature. The reaction is stopped by adding 20 mL of 1 N sodium hydroxide solution and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (99/1 dichloromethane/methanol). 163 mg of methyl 3-[5-(3-methylaminophenyl)pyrimidin-2-yl]propanoate are obtained in the form of a colorless oil. Yield=99%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([OH:9])=O.CCN=C=NCCCN(C)C.Cl.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([C:37]#[C:38][C:39]2[CH:52]=[CH:51][C:42]([CH2:43][NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:41][CH:40]=2)=[CH:33][CH:32]=1)[CH2:28][CH2:29][CH3:30]>>[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([C:37]#[C:38][C:39]2[CH:52]=[CH:51][C:42]([CH2:43][N:44]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:7]([C:6]3[CH:10]=[CH:11][C:12]([F:13])=[C:4]([CH:5]=3)[C:3]([O:2][CH3:1])=[O:14])=[O:9])=[CH:41][CH:40]=2)=[CH:33][CH:32]=1)[CH2:28][CH2:29][CH3:30]
Reactant: COC(=O)c1cc(C(=O)O)ccc1F
Reactant: CCCCCCNCc1ccc(C#Cc2ccc(CCCC)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)C(=O)c1ccc(F)c(C(=O)OC)c1
Yield: 73.9 %

Procedure:
The title compound was prepared following procedure described in Example 19, step c) from 4-fluoro-isophtalic acid-3-methylester (199 mg; 1.01 mmol), EDC.HCl (212 mg; 1.11 mmol) and N-{4-[(4-butylphenyl)ethynyl]benzyl}-1-hexanamine (350 mg, 1.01 mmol). Purification of the crude (503 mg) by flash chromatography using silicagel (EtOAc/c-Hex, 20:80) afforded 394 mg (74%) of the title compound as a colorless oil. HPLC, Rt: 6.19 min (purity: 99.8%), LC/MS, M+(ESI): 528.4.1HN (CDCl3) δ: 7.99 (d, J=5.1 Hz, 1H), 7.98 (m, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 7.31 (m, 1H), 7.15 (d, J=8.1 Hz, 4H), 4.73 (s, 1H), 4.48 (s, 1H), 3.91 (s, 3H), 3.44 (s, 1H), 3.11 (s, 1H), 2.60 (t, J=7.6 Hz, 2H), 1.35 (m, 4H), 1.08-1.37 (m, 8H), 0.90 (t, J=7.3 Hz, 3H), 0.83 (m, 3H).
Reaction SMILES: C(C1C2[C:7](=CN=CC=2)[N:6](CC(O)=O)[CH:5]=1)(=O)C.[NH2:17][C@@H:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])[CH2:19][CH2:20]O>>[Cl:28][C:24]1[C:23]([F:29])=[C:22]([C@H:18]([NH2:17])[CH2:19][CH2:20][N:6]([CH3:7])[CH3:5])[CH:27]=[CH:26][CH:25]=1
Reactant: N[C@H](CCO)c1cccc(Cl)c1F
Reactant: CC(=O)c1cn(CC(=O)O)c2cnccc12
Product: CN(C)CC[C@@H](N)c1cccc(Cl)c1F

Procedure:
was prepared using similar procedures as described for the synthesis of (3-acetyl-pyrrolo[2,3-c]pyridin-1-yl)-acetic acid in Scheme C4 from (R)-3-amino-3-(3-chloro-2-fluoro-phenyl)-propan-1-ol. 1H-NMR (400 MHz, DMSO): δ (ppm): 8.89 (m, 2H), 7.73 (m, 2H), 7.39 (t, 1H), 4.69 (m, 1H), 3.13 (m, 1H), 2.98 (m, 1H), 2.73 (s, 6H), 2.47 (m, 1H), 2.34 (1H).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.II.[C:13]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>C(OCC)C>[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:13]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Fc1ccccc1CCl
Reactant: O=C1CCCCCC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: OC1(Cc2ccccc2F)CCCCCC1
Temperature: 30 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 16.05 g of magnesium turnings in 200 ml of anhydrous diethyl ether was added a solution of 71.34 ml of o-fluorobenzyl chloride in 250 ml of ether at a rate sufficient to maintain the pot temperature at about 30° C. while cooling the flask in an ice water bath. The reaction was initiated by addition of a few iodine crystals. After the completion of the addition the mixture was stirred under nitrogen at ambient temperature for 45 minutes, and thereafter a solution of 58.9 ml of cycloheptanone in 200 ml of ether was added over a 25 minute period, keeping the pot temperature at about 20° C. with cooling. After the addition the mixture was stirred at ambient temperature for 1 hour and thereafter cooled to 8° C. and treated with 500 ml of saturated ammonium chloride solution (cautiously at first). After 10 minutes of vigorous stirring, the mixture was poured into a separatory funnel, the phases were separated and the aqueous phase was extracted with ether (2×250 ml). The combined ether extracts were washed with 250 ml of saturated ammonium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to an oil weighing 109.94 g which crystallized to a solid (mp 35°-40° C.) after removal from high vacuum. A 10 g portion of this material was purified by preparative high performance liquid chromatography (HPLC hereafter) preparative using dichloromethane as a solvent; m.p. 35°-38° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[N:12]=[C:11]([NH:13]C(=O)C(C)(C)C)[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Nc1cccc(COCC2CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(COCC2CC2)n1
Temperature: 100 °C
Yield: 94.2 %

Procedure:
N-(6-cyclopropylmethoxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.884 g) in ethanol (50 mL) was treated at RT with 3M aqueous NaOH (5.62 mL) and then heated at 100° C. for 20 h. The mixture was cooled to RT, partitioned between water and AcOEt. The layers were separated, the organic layer dried over magnesium sulphate, filtered and evaporated in vacuo to give 6-cyclopropylmethoxymethyl-pyridin-2-ylamine (0.566 g) as a light brown liquid. MS (ESI): 179.1 (MH+).