Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[NH2:6][C:7]1[S:8][CH:9]=[C:10](/[C:12](=[N:16]/[O:17][CH3:18])/[C:13]([OH:15])=O)[N:11]=1.C(N(CC)C(C)C)(C)C.[NH2:28][C@@H:29]1[C:53](=[O:54])[N:31]2[C:32]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)=[O:42])=[C:33]([C@@H:36]3[CH2:40][CH2:39][CH2:38][O:37]3)[CH2:34][S:35][C@H:30]12.N1C=CC=CC=1>CN(C=O)C>[NH2:6][C:7]1[S:8][CH:9]=[C:10](/[C:12](=[N:16]/[O:17][CH3:18])/[C:13]([NH:28][C@@H:29]2[C:53](=[O:54])[N:31]3[C:32]([C:41]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=4)=[O:42])=[C:33]([C@@H:36]4[CH2:40][CH2:39][CH2:38][O:37]4)[CH2:34][S:35][C@H:30]23)=[O:15])[N:11]=1
Reactant: COc1ccc(COC(=O)C2=C([C@@H]3CCCO3)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
Methanesulphonyl chloride (203 μl, 2.62 mmol) was added to 2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid (528 mg, 2.63 mmol) and N,N-diisopropylethylamine (458 μl, 2.63 mmol) in DMF (8 ml) at -30° C. After stirring at -30±10° C. for 30 min., a solution of 4-methoxybenzyl (6R,7R)-7-amino-3-[(S)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (930 mg, 2.38 mmol) in DMF (5 ml) was added, followed by pyridine (213 μl, 2.63 mmol). The reaction mixture was transferred to an ice-bath and stirring continued for a further 1 h. After dilution with ethyl acetate, the solution was washed successively with saturated sodium hydrogen carbonate solution, 5% aqueous citric acid, water (x2) and brine, dried and then concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 50, 70 and 90% ethyl acetate in hexane to give the title compound as a yellow foam (1.138 g, 83%); νmax (CH2Cl2) 3389, 1783, 1732, 1682, 1516 cm-1 ; δH (CDCl3, 250 MHz) 1.53-1.70 (1 H, m), 1.88-2.01 (2 H, m), 2.28-2.41 (1 H, m), 3.33 and 3.62 (2 H, ABq, J 18.7 Hz), 3.79-3.98 (2 H, m), 3.81 (3 H, s), 4.08 (3 H, s), 4.94 (1 H, dd, J 9.0, 6.7 Hz), 5.04 (1 H, d, J 4.8 Hz), 5.18 (2 H, s), 5.88 (2 H, br s, exch.), 5.98 (1 H, dd, J 9.0, 4.8 Hz), 6.90 (2 H, d, J 8.6 Hz), 6.94 (1 H, s), 7.35 (2 H, d, J 8.6 Hz), 7.50 (1 H, br. d, J 9.0 Hz, exch.). [Mass spectrum: +ve ion (thioglycerol) MH+ (574)].
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)Cl)C=CC=CC=1>N1C=CC=CC=1>[N:10]1[CH:2]=[C:3]2[C:7]([NH:6][CH:5]=[N:4]2)=[N:8][CH:9]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: c1ncc2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.3 g of 6-chloro-9-β-D-ribofuranosyl-9H-purine and 15 g of triphenylchlorosilane were dissolved in 500 ml of pyridine and stirred for one hour at room temperature. Pyridine was distilled away and the residue was dissolved in benzene. The benzene layer was washed with 1N HCl and brine, and then dried over sodium sulfate anhydride. The solvent was distilled off and the residue was recrystallized from a mixture of hexane and ethyl acetate to give 21.5 g of 6-chloro--9-15-O-triphenylsilyl-β-D-ribofuranosyl)-9H-purine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.FC(F)(F)S(O[C@H:44]1[CH2:49][CH2:48][O:47][C:45]1=[O:46])(=O)=O.O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([O:30][C@@H:44]2[CH2:49][CH2:48][O:47][C:45]2=[O:46])[CH:27]=[CH:28][CH:29]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(OCCCN(Cc2cccc(O)c2)c2nc3ccccc3o2)cc1
Reactant: O=C1OCC[C@@H]1OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OCCCN(Cc2cccc(O[C@@H]3CCOC3=O)c2)c2nc3ccccc3o2)cc1
Reaction time: 0.08 h

Procedure:
In an argon atmosphere, N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydroxybenzylamine (200 mg) was dissolved in dichloromethane (1.5 mL), and triethylamine (0.11 mL) was added dropwise to the solution at room temperature, followed by stirring for 5 minutes at the same temperature. Subsequently, a solution of (S)-2-trifluoromethanesulfonyloxybutyrolactone (174 mg) in dichloromethane (1 mL) was added dropwise to the mixture over 10 minutes at room temperature, followed by stirring for 5 hours at the same temperature. The reaction mixture was added to water (50 mL), and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate and concentrating under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=1/1), to thereby yield a colorless oil (242 mg, 100′, 98.1% ee).
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][CH:25]2[CH2:27][CH2:26]2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C>[CH:25]1([CH2:24][CH2:23][C:12]2[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=2)[CH2:27][CH2:26]1
Reactant: C(#CC1CC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Solvent: CCO
Product: O=c1[nH]nc(CCC2CC2)cc1O
Yield: 14 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(cyclopropylethynyl)pyridazine (Intermediate 18) except that the reaction was carried out in ethanol. The resulting crude product was purified by preparative HPLC under acidic conditions to afford 6-(2-cyclopropylethyl)-4-hydroxypyridazin-3(2H)-one as a cream solid (14% yield).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4]([C:14]([NH2:16])=O)=[CH:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.Cl>C(Cl)(Cl)(Cl)Cl.ClCCl.C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:5][C:4]([C:14]#[N:16])=[CH:3]1
Reactant: NC(=O)c1cc(=O)cc(-c2ccccc2)o1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(=O)cc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-oxo-6-phenyl-4H-pyran-2-carboxamide (4.26 g), triphenylphosphine (10.48 g) and triethylamine (2.8 ml) in carbon tetrachloride (40 ml) and dichloromethane (80 ml) was stirred at room temperature for 4 hours. The reactant slowly dissolved. Dilute hydrochloric acid (1 M, 50 ml) and chloroform (100 ml) were added. The organic layer was separated, washed with water, dried over anhydrous magnesium sulphate, filtered and evaporated. The brown residue was recrystallised twice from carbon tetrachloride to yield the title product as off-white crystals (mp 146°-149° C.).
Reaction SMILES: [CH:1]([C:4]([C:7]([C:10]([C:13]([C:16]([CH2:19][S:20]([OH:22])=[O:21])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH2:23].BrBr>C(O)(=O)C>[CH:1]([C:4]([C:7]([C:10]([C:13]([C:16]([CH2:19][S:20]([OH:23])(=[O:22])=[O:21])([F:17])[F:18])([F:15])[F:14])([F:11])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O
Reactant: O=S(O)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: BrBr
Solvent: CC(=O)O
Product: O=S(=O)(O)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Reaction time: 12 h

Procedure:
H(CF2)6CH2SO2H (1.00 g, 2.63 mmol) was put in a 100 ml flask, and was dissolved in acetic acid (20 ml) in the air. After the reaction system was dipped in ice bath and water (1.0 ml) was added thereto, bromine (1.1 g, 6.84 mmol) was added and stirring was continued at room temperature for 12 hours. After completion of the reaction, the inside of the system was brought to reduced pressure, and after removing the solvent and bromine, the reaction product was dried in vacuo at 60° C. for 12 hours to obtain H(CF2)6CH2SO3H (1.04 g, 2.63 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=1[F:24]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
4.00 g of 5-(4-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 20 ml of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 4.16 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (i) of the present invention).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18]C)=[O:17])=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1>[NH2:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2c(F)cccc2F)ccc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To a solution of methyl 3-amino-6-(2,6-difluorophenyl)picolinate (1.0 equiv) in THF (0.5M), was added 1M LiOH (4.0 equiv). After stirring for 4 hours at 60° C., 1 N HCl (4.0 equiv.) was added and the THF was removed in vacuo. The resulting solid was filtered and rinsed with cold H2O (3×20 mL) to yield 3-amino-6-(2,6-difluorophenyl)picolinic acid (90%). LCMS (m/z): 251.1 (MH+); LC Rt=2.1 min.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[C:4]([C:24]2[CH:25]=[C:26]([CH3:34])[C:27]([O:32][CH3:33])=[C:28]([CH2:30]O)[CH:29]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:13]=2)[N:3]=1.[BrH:35].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:35][CH2:30][C:28]1[CH:29]=[C:24]([C:4]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[CH:23]=[N:22][CH:21]=[N:20][CH:19]=4)[CH:13]=3)[C:5]3[C:10](=[C:9]([F:11])[CH:8]=[CH:7][CH:6]=3)[C:2]([NH2:1])=[N:3]2)[CH:25]=[C:26]([CH3:34])[C:27]=1[O:32][CH3:33]
Reactant: Br
Reactant: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1CBr
Temperature: 25 °C
Yield: 65 %

Procedure:
To (5-(3-amino-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-1-yl)-2-methoxy-3-methylphenyl)methanol (250 mg, 0.55 mmol) in DCM (5 mL) was added HBr (33% in acetic acid) (5 mL, 92.08 mmol) and the mixture was stirred at rt over night. Aqueous Na2CO3 was added to the mixture to reach pH ˜9. The water layer was extracted with DCM and the combined extracts were dried (MgSO4) and concentrated under reduced pressure to afford 185 mg (65%) of the title compound. MS (ES+) m/z 517, 519 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]1[CH:22]=[C:23](B2OCC(C)(C)CO2)[CH:24]=[CH:25][CH:26]=1>>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]1[CH:22]=[C:23]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)[CH:24]=[CH:25][CH:26]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)COB(c2cccc(-c3ccco3)c2)OC1
Product: FC(F)(F)c1ccc2c(-c3cccc(-c4ccco4)c3)ccnc2n1
Yield: 48.1 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2-(3-furan-2-ylphenyl)-5,5-dimethyl[1,3,2]-dioxaborinane (72 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(3-furan-2-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (36 mg, 49%). δH (360 MHz, CDCl3) 6.53 (1H, q, J 1.8), 6.75 (1H, d, J 3.2), 7.35-7.38 (1H, m), 7.51 (1H, d, J 1.1), 7.55-7.62 (2H, m), 7.79-7.86 (3H, m), 8.57 (1H, d, J 8.4), 9.29 (1H, d, J 4.2). m/z (ES+) 341 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[C:59]([NH2:76])=[N:60][CH:61]=[C:62]([C:64]3[CH:69]=[CH:68][N:67]=[C:66]([N:70]4[CH2:75][CH2:74][O:73][CH2:72][CH2:71]4)[CH:65]=3)[N:63]=2)=[CH:54][CH:53]=1>C(Cl)Cl.CN(C=O)C.O>[NH2:76][C:59]1[C:58]([C:55]2[CH:56]=[CH:57][C:52]([NH:51][C:8]([C:5]3[C:4](=[O:11])[N:3]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:10])=[CH:53][CH:54]=2)=[N:63][C:62]([C:64]2[CH:69]=[CH:68][N:67]=[C:66]([N:70]3[CH2:75][CH2:74][O:73][CH2:72][CH2:71]3)[CH:65]=2)=[CH:61][N:60]=1
Reactant: Nc1ccc(-c2nc(-c3ccnc(N4CCOCC4)c3)cnc2N)cc1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(-c3nc(-c4ccnc(N5CCOCC5)c4)cnc3N)cc2)c(=O)n(-c2ccccc2)n1C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To the compound prepared in Example 1 (0.100 g) in 5 mL of DCM, 1.0 mL of DMF and N,N-diisopropylethylamine (DIEA) (0.072 g) was added the HATU (0.164 g) and stirred for 30 minutes. To the activated ester was added the compound prepared in Example 13 (0.15 g) and stirred for 1 hour. The reaction mixture was diluted with water, extracted with additional DCM, and the organic layer was washed with water, brine and dried over anhydrous Na2SO4. The DCM layer was filtered and concentrated, and the crude was chromatographed on silica gel using 10:1 DCM:MeOH to give the title compound (0.2 g) having the following physical data.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:8][N:7]=[C:6]([C:9]([O:11]C)=O)[N:5]=1)=[O:2].[CH3:13][S:14][CH2:15][S:16]([CH3:18])=[O:17].[H-].[Na+].C(Cl)Cl>CN(C)C=O>[CH:1]([NH:3][C:4]1[S:8][N:7]=[C:6]([C:9](=[O:11])[CH:15]([S:14][CH3:13])[S:16]([CH3:18])=[O:17])[N:5]=1)=[O:2]
Reactant: CSCS(C)=O
Reactant: COC(=O)c1nsc(NC=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSC(C(=O)c1nsc(NC=O)n1)S(C)=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a mixture of methyl 5-formamido-1,2,4-thiadiazole-3-carboxylate (9.2 g) and methyl methylthiomethyl sulfoxide (6.1 g) in N,N-dimethylformamide (100 ml) was added 50% sodium hydride (7.1 g) with cooling in an ice-bath. The mixture was stirred for an hour at ambient temperatures and for an additional one hour at 40° C. After cooling to ambient temperature, methylene chloride (300 ml) was added to the reaction mixture, and the resulting precipitates were collected by filtration and washed with methylene chloride. The precipitates were added to a stirred mixture of hydrochloric acid (14.7 ml), ice-water (200 ml) and methylene chloride (200 ml). An insoluble material was filtered off and the methylene chloride layer was separated from the filtrate. The solution was dried over anhydrous magnesium sulfate, evaporated and the residue was triturated with diethyl ether to give the title compound (4.5 g), m.p. 130° to 132° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=1>C1C=CC=CC=1>[SH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[O:18][CH2:17][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(S)cc1
Reactant: OCc1cccnc1
Solvent: c1ccccc1
Product: O=C(Nc1ccc(S)cc1)OCc1cccnc1
Yield: 78 %

Procedure:
p-Mercaptophenyl isocyanate (0.9g., 0.00595 mole) was added to a solution of 3-pyridyl carbinol (0.65g., 0.00595 mole) in 50 ml. of benzene and the reaction mixture was allowed to stand over the weekend. It was then heated to reflux to assure completion of the reaction and then cooled to give a white solid. This was isolated as 1.2g. and was a 78% yield of 3-pyridylmethyl N-(4'-mercaptophenyl)carbamate.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H-].[Na+].[CH3:19]I>>[C:10]([N:1]([CH3:19])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CI
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Yield: 73 %

Procedure:
Methylation of BocLeuOH (12.5 g.) using sodium hydride and methyl iodide gave BocMeLeuOH in 73% yield. Condensation of BocMeLeuOH (3.7 g.) and HMetNH2 hydrochloride salt (2.8 g.) by the mixed anhydride method using isobutyl chloroformate gave BocMeLeu-MetNH2 in 56% yield. De-t-butoxycarbonylation of BocMeLeu-MetNH2 (3.3 g.) using hydrogen chloride in ethyl acetate gave MeLeu-MetNH2 in 64% yield.
Reaction SMILES: O1C=C(CN)N=C1.[O:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][NH2:14].[F:15][C:16]1[CH:37]=[CH:36][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=3)[C:29](O)=[O:30])[C:22]2=[O:35])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=3)[C:29]([NH:14][CH2:13][C:9]3[O:8][CH:12]=[CH:11][N:10]=3)=[O:30])[C:22]2=[O:35])=[CH:36][CH:37]=1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: NCc1ncco1
Agent: NCc1cocn1
Product: O=C(NCc1ncco1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 49 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with oxazol-2-ylmethanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(oxazol-2-ylmethyl)isonicotinamide was obtained as a colorless solid in 49% yield: mp 148-150° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.36 (t, J=5.7 Hz, 1H), 8.60 (s, 1H), 8.38 (d, J=5.1 Hz, 2H), 8.03 (s, 1H), 7.36-7.31 (m, 3H), 7.18-7.07 (m, 2H), 4.55 (d, J=5.7 Hz, 2H), 4.39 (s, 2H), 3.94 (t, J=8.1 Hz, 2H), 3.45 (t, J=8.0 Hz, 2H); MS (ES+) m/z 396.0 (M+1).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:8]=1)(=O)=O.[SH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23].CS([O-])(=O)=O.OC1C=C(C=CC=1)C=O>>[N:13]1([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[CH2:6][S:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22][OH:23])[CH:14]=[CH:15][CH:16]=[CH:17]1
Reactant: O=Cc1cccc(S)c1
Reactant: CS(=O)(=O)OCc1cccc(-n2cccc2)c1
Agent: CS(=O)(=O)[O-]
Agent: O=Cc1cccc(O)c1
Product: OCc1cccc(SCc2cccc(-n3cccc3)c2)c1

Procedure:
3-[3-(3-thienyl)benzyloxy]benzyl alcohol, 3-[4-(3-thienyl)-2-thienylmethylthio]benzyl alcohol, 3-[3-(5-oxazolyl)benzylthio]benzyl alcohol, 3-[3-(5-oxazolyl)benzylthio]benzyl alcohol and 3-[3-(1-pyrrolyl) benzyloxy]benzyl alcohol are obtained by performing the same reaction as in Referential Example 57 except that instead of the starting 3-(1-pyrrolyl)benzyl methanesulfonate and/or 3-mercaptobenzaldehyde, the corresponding methanesulfonate and/or 3-hydroxybenzaldehyde are used.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:15]([C:18]1[NH:22][N:21]=[C:20]([NH:23][C:24]2[C:25]3[CH2:41][CH2:40][CH2:39][C:26]=3[N:27]=[C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[C:35](OC)=[O:36])[N:29]=2)[CH:19]=1)([CH3:17])[CH3:16]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:9])[C:35]([C@H:31]2[CH2:32][CH2:33][CH2:34][N:30]2[C:28]2[N:29]=[C:24]([NH:23][C:20]3[CH:19]=[C:18]([CH:15]([CH3:17])[CH3:16])[NH:22][N:21]=3)[C:25]3[CH2:41][CH2:40][CH2:39][C:26]=3[N:27]=2)=[O:36])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Reactant: CNc1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)N(C)c3ccc(F)nc3)nc3c2CCC3)n[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 6.8 %

Procedure:
To a solution of 6-fluoro-N-methylpyridin-3-amine (272 mg, 2.16 mmol) in THF (70 mL) was added isopropyl magnesium chloride solution 2M in THF (1.08 mL, 2.16 mmol) dropwise at 0° C. The mixture was allowed to stir at 0° C. for 20 min. Then, a solution of (R)-methyl 1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (200 mg, 0.54 mmol) in THF (3 mL) was added and the reaction mixture was allowed to stir at RT for 2 h. The reaction was quenched with saturated ammonium chloride solution (50 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue that was purified by reverse phase HPLC to afford 17 mg of (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide. 1HNMR (400 MHz, CDCl3) δ (ppm): 1.20-1.35 (m, 6H), 1.79-2.25 (m, 6H), 2.57-2.68 (m, 2H), 2.79-2.82 (m, 2H), 2.91-3.01 (m, 1H), 3.30 (s, 3H), 3.59-3.80 (m, 2H), 4.35-4.45 (m, 1H), 6.16 (s, 1H), 6.90-7.05 (m, 2H), 8.01 (brs, 1H), 8.40 (brs, 1H). The other enantiomer is prepared using the (S) chiral starting material.
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]([NH:14][OH:15])=[O:13])=[N:10][CH:9]=[C:8]2[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=[CH:18][C:7]=12)C>CO.Cl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]2[C:8]3[CH:9]=[N:10][C:11]4[C:12](=[O:13])[N:14]([OH:15])[CH:4]=[CH:5][C:6]=4[C:7]=3[CH:18]=[CH:17]2)=[CH:25][CH:24]=1
Reactant: CCO/C=C/c1c(C(=O)NO)ncc2c1ccn2Cc1ccc(F)cc1
Agent: Cl
Solvent: CO
Product: O=c1c2ncc3c(ccn3Cc3ccc(F)cc3)c2ccn1O

Procedure:
A solution of 4-[(E)-2-ethoxyvinyl]-1-(4-fluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxamide (100 mg, 0.28 mmol) in methanol (10 mL) and hydrochloric acid (37 w %, 1 mL) was refluxed for 16 hours. It was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified by pre-HPLC to provide the title compound as white powder. 1H NMR (DMSO-d6) δ; 11.50 (s, 1H), 9.04 (s, 1H), 7.88 (d, 1H, J=3.0 Hz), 7.84 (d, 1H, J=7.5 Hz), 7.13-7.19 (m, 3H), 6.93 (d, 1H, J=7.5 Hz), 5.65 (s, 2H). MS (APCl, M+H+): 310.1. HRMS calcd for C17H13N3O2F1 (M+H+) 310.0992, found 310.0991. HPLC: 94.3% purity.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[NH2:5].N1C=CC=CC=1.CO.[C:21](=O)=[O:22].Cl>C(Cl)(Cl)Cl.CCOCC.CCCCCC>[CH3:1][O:2][C:3]([C@H:4]1[NH:5][C:21](=[O:22])[N:11]2[CH:10]=[N:9][CH:8]=[C:7]2[CH2:6]1)=[O:12]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C=O
Agent: Cl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H]1Cc2cncn2C(=O)N1
Reaction time: 0.25 h

Procedure:
3.38 g (20 mmol) of L-histidine methyl ester and 3.16 g (40 mmol) of pyridine (distilled over ninhydrin) are dissolved in 100 ml of chloroform and cooled with methanol/dry ice to -30° to -40° C. At this temperature, a weak stream of HCl-free phosgene is introduced for 15 minutes and the mixture is stirred for 15 minutes in the cold state. Then the batch is poured into 400 ml of cold ether/hexane (2:1). A fine, white, readily deliquescent precipitate is obtained which is suctioned off and washed with ether. The precipitate is taken up in 200 ml of 1N sodium bicarbonate solution and extracted six times with respectively 50 ml of chloroform. The CHCl3 phase is dried over sodium sulfate and concentrated under vacuum. Remaining traces of pyridine are removed under a high vacuum. The compound is crystallized from methanol in beautiful, colorless crystals.