Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)([CH3:7])[CH3:6].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.CCN(CC)CC>C1C=CC=CC=1>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]([C:4]2[N:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)[C:27](=[S:28])[NH:2][CH:3]=2)([CH3:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: COc1ccc(C(C)(C)C(=O)CN)cc1OC
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)(C)c2c[nH]c(=S)n2-c2ccc(F)cc2)cc1OC
Yield: 90.7 %

Procedure:
A mixture of 1-amino-3-(3,4-dimethoxyphenyl)-3-methylbutan-2-one hydrochloride (210 mg, 0.77 mmol), 4-fluorophenyl isothiocyanate (141 mg, 0.92 mmol), and Et3N (0.16 mL, 1.15 mmol) in benzene (7 mL, anhyd) was refluxed for 8 h. The volatiles were removed under reduced pressure. The residue was combined with acetic acid (5 mL) and heated at reflux 4 h. After concentration, the crude product was purified by flash chromatography to provide 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (260 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 6.87 (t, 2H), 6.80 (d, 1H), 6.67 (d, 1H), 6.62-6.59 (m, 2H), 6.48 (d, 1H), 6.46 (s, 1H), 3.87 (s, 3H), 3.75 (s, 3H), 1.44 (s, 6H).
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=4)[N:23]=[CH:22][C:21]=3[F:32])[OH:19])[CH2:13]2)C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[NH2:10][CH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[N:23]=[CH:22][C:21]=2[F:32])[OH:19])[CH2:13]1
Reactant: COc1ccc2ncc(F)c([C@@H](O)CN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ncc(F)c([C@@H](O)CN3CC[C@@H](CN)C3)c2n1
Reaction time: 12 h
Yield: 99.3 %

Procedure:
To a solution of phenylmethyl[((3S)-1-{(2R)-2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-hydroxyethyl}-3-pyrrolidinyl)methyl]carbamate (250 mg, 0.55 mmol) in EtOH (5 mL) was added Pd(OH)2 (20 mg). The suspension was hydrogenated at 1 atm of H2 using a balloon. After 12 h, the mixture was filtered and washed several times with MeOH. The filtrate was concentrated to afford the title compound (175 mg, 100%) as an off-white foam, which was used without further purification: LC/MS (ES) m/e 321 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:34]([CH3:35])=[CH:33][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C1COCC1.CN(C=O)C>CO.C(O)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:34]([CH3:35])=[CH:33][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH2:30]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(CC)CC4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CCN(c2cc(-c3nc4cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(-c5ccc(Cl)cc5)c4s3)ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(4-ethylpiperazin-1-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (26.7 mg, 0.044 mmol), 5M NaOH (176 μL, 0.879 mmol)) in methanol (0.2 mL) and THF (1.0 mL) was stirred at 45° C. for 2 h, then stirred overnight at rt. Acetic acid (1 drop) and DMF (0.3 mL) were added and mixture concentrated to ˜0.3 mL, diluted with methanol, filtered and purified by Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give product after lyophilization. LCMS-ESI+: calc'd for C31H36ClN4O3S: 579.2 (M+H+); Found: 579.3 (M+H+); 1H NMR (400 MHz, CD3OD) δ 8.27 (d, J=5.4 Hz, 1H), 7.84 (s, 1H), 7.66 (dd, J=8.5, 1.7 Hz, 1H), 7.63-7.52 (m, 3H), 7.50 (s, 1H), 7.32 (dd, J=5.4, 1.3 Hz, 1H), 5.25 (s, 1H), 4.81-4.18 (m, 2H), 4.81-4.18 (m, 2H), 3.7-2.99 (m, 4H), 3.27 (dd, J=14.8, 7.5 Hz, 3H), 2.59 (s, 3H), 1.39 (t, J=7.3 Hz, 3H), 0.96 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([OH:13])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.CCOCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C[C@@H](OS(C)(=O)=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 60.1 %

Procedure:
A solution of 0.29 g (1.19 mmol) of the resultant compound of Example 31 and 0.25 ml (1.8 mmol) of triethylamine in 7 ml of dichloromethane was cooled to 0° C. and treated with 0.12 ml (1.55 mmol) of methanesulfonyl chloride. After 45 min, the solution was diluted with ether, washed sequentially with 10% aqueous citric acid, aqueous NaHCO3 and saturated brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 3:1 hexane:ethyl acetate provided 0.23 g (61%) of the desired compound (Rf 0.48, 3:2 hexane:ethyl acetate).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=O)[NH:5][N:4]=1)[CH3:2].N#N.P(Cl)(Cl)([Cl:20])=O.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[Cl:20][C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]([CH2:1][CH3:2])=[N:4][N:5]=1
Reactant: CCc1n[nH]c(=O)c2ccc(OC)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCc1nnc(Cl)c2ccc(OC)cc12
Yield: 89 %

Procedure:
A suspension of 4-ethyl-6-methoxy-2H-phthalazin-1-one (1.3 g, 6.76 mmoles), prepared as described in example 9, in dry acetonitrile (20 ml), under stirring and dry N2 at room temperature, was added with phosphorous oxychloride (2.07 g, 13.52 mmoles). The mixture was refluxed and after 2 hours cooled, brought to small volume, taken up in water, added with Na2CO3 in excess and extracted three times with CH2Cl2. The organic phases were anhydrified and brought to dryness to give 1.34 g of the title compound (yield: 89%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].[NH2:32][CH:33]([C:35]1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=N[CH:36]=1)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C2C(=CC=CC=2C(O)=O)C=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:29]=[CH:30][CH:31]=[C:2]4[C:3]=3[N:32]=[CH:33][CH:35]=[CH:36]4)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:22]=[C:21]([O:23][CH3:24])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cccc2cccnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc4cccnc34)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.123 g, 0.40 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.152 g, 0.40 mmol), quinoline-8-carboxylic acid (0.070 g, 0.40 mmol), diisopropylethylamine (0.14 mL, 0.80 mmol) in DMF (2 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)quinoline-8-carboxamide (0.180 g) as an orange solid. 1H NMR (CDCl3): δ8.95 (dd, J=4.4, 1.8 Hz, 1H), 8.83 (dd, J=7.4, 1.6 Hz, 1H), 8.50 (s, 1H), 8.30 (dd, J=8.2, 1.8 Hz, 1H), 7.99 (dd, J=8.3, 1.6 Hz, 1H), 7.71-7.65 (m, 1H), 7.53-7.48 (m, 1H), 7.42 (bs, 1H), 6.95 (s, 2H), 5.60 (p, J=7.1 Hz, 1H), 3.88 (s, 6H), 3.82 (s, 3H), 1.87 (d, J=7.1 Hz, 3H). MS m/z 461 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:32]=[CH:33][CH:34]=2)[O:17][CH:18]2[CH2:21][N:20]([C:22]3[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=3[C:24](O)=[O:25])[CH2:19]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:59][C:60]1([C:63]2[CH:72]=[CH:71][C:66]([C:67]([O:69][CH3:70])=[O:68])=[CH:65][CH:64]=2)[CH2:62][CH2:61]1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:31][C:28]1[CH:27]=[C:23]([C:24](=[O:25])[NH:59][C:60]2([C:63]3[CH:72]=[CH:71][C:66]([C:67]([O:69][CH3:70])=[O:68])=[CH:65][CH:64]=3)[CH2:62][CH2:61]2)[C:22]([N:20]2[CH2:21][CH:18]([O:17][C:16]3[CH:15]=[C:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]4)[CH:34]=[CH:33][CH:32]=3)[CH2:19]2)=[N:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(OC3CN(c4ncc(Cl)cc4C(=O)O)C3)c2)CC1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 66.6 %

Procedure:
A suspension of 2-(3-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenoxy)azetidin-1-yl)-5-chloronicotinic acid (D110) (150 mg, 0.306 mmol), 1-Hydroxybenzotriazole hydrate (47 mg, 0.306 mmol) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (88 mg, 0.46 mmol) in dimethylformamide (2 ml) was stirred 40 min at room temperature. A solution of methyl 4-(1-aminocyclopropyl)benzoate (D7) (68.9 mg, 0.306 mmol) and triethylamine (0.042 ml, 0.306 mmol) in dimethylformamide (2 ml) was added and the resulting mixture was stirred 40 min at room temperature. Water (2 ml) was added and the resulting precipitate was collected by filtration and purified by Biotage column (10 g) eluting with a mixture dichloromethane/ethylacetate from 100/0 to 80/20. Collected fractions, after solvent evaporation, afforded tert-butyl 4-(3-((1-(5-chloro-3-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)pyridin-2-yl)azetidin-3-yl)oxy)phenyl)piperazine-1-carboxylate (135 mg)
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16]1([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]1)[C:17](=[O:24])[N:18]2[CH3:23])(=[O:13])[CH3:12].O>O1CCCC1>[CH3:23][N:18]1[C:19]2[C:15](=[C:14]([C:11](=[O:13])[CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10])[CH:22]=[CH:21][CH:20]=2)[C:16]2([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]2)[C:17]1=[O:24]
Reactant: CC(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a suspension of sodium hydride (60% w/w dispersion in mineral oil, 0.11 g, 2.8 mmol) in anhydrous tetrahydrofuran (10 mL) at ambient temperature was added diethyl carbonate (0.26 mL, 2.1 mmol) and the mixture was heated at reflux for 5 min. 4′-Acetyl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.50 g, 1.4 mmol) was added in one portion and the reaction mixture was heated at reflux for 16 h, allowed to cool to ambient temperature and poured into water (75 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography and eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane, followed by recrystallization from dichloromethane/diethyl ether to afford ethyl 3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)-3-oxopropanoate (0.235 g, 39%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.50-7.43 (m, 2H), 7.14-7.09 (m, 1H), 6.51 (s, 1H), 6.02 (s, 1H), 4.97-4.78 (m, 2H), 4.20-4.03 (m, 6H), 3.89 (d, J=15.6 Hz, 1H), 3.65 (d, J=15.6 Hz, 1H), 3.29 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); MS (ES+) m/z 445.8 (M+23).
Reaction SMILES: [CH2:1](O)[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10]O)O)O)O)O.C[C:14]1([CH3:21])[O:18][C@@H:17]([CH2:19][OH:20])[CH2:16][O:15]1>>[CH2:14]([O:15][CH2:16][C@H:17]([CH2:19][OH:20])[OH:18])[CH2:21][CH2:1][CH2:2][CH2:4][CH2:6][CH2:8][CH2:10][CH2:1][CH2:2][CH2:4][CH2:6][CH2:8][CH2:10][CH2:1][CH2:2][CH2:4][CH3:6]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC1(C)OC[C@H](CO)O1
Product: CCCCCCCCCCCCCCCCCCOC[C@@H](O)CO

Procedure:
According to the procedure of the reference [FEBS Letters, Vol. 116, 161 (1980)], D-mannitol was used as a starting material to give 25 g of the desired compound (needles) through 1,2-isopropylidene-sn-glycerol.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18](=O)[O:19]CC(Cl)(Cl)Cl)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][N:41]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:26]([O:30][C:31]([N:33]1[CH2:34][CH2:35][CH:36]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:18]([NH:17][C:7]3[N:8]([C:10]4[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=4)[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)=[O:19])=[CH:42][N:41]=2)[CH2:37][CH2:38]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(N)cn2)CC1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid, 2,2,2-trichloro-ethyl ester (Preparation 38, 2.0 mmol, 0.8 g) over a solution of 4-(5-amino-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.0 mmol, 0.6 g) and potassium carbonate (2.20 mmol, 0.3 g) in acetonitrile (25 mL). Stir the solution for 12 hours at room temperature. Add water and extract with CH2Cl2. Combine the organic layers and wash with saturated aq. sodium chloride, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Subject residue to silica gel chromatography eluting with CH2Cl2: MeOH in gradient (from 0.5 to 20%) to yield 4-{5-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester. MS(ES+): m/z=548 [M+H])
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[O:15][C:16]([CH3:19])=[N:17][N:18]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>C(O)(=O)C.O>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[O:15][C:16]([CH3:19])=[N:17][N:18]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCOc1cccc2sc(-c3nnc(C)o3)cc12
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc(-c2cc3c(O)cccc3s2)o1
Temperature: 80 °C
Yield: 119 %

Procedure:
2-(4-(Methoxymethyloxy)benzo(b)thiophen-2-yl)-5-methyl-1,3,4-oxadiazole (1.4 g) was dissolved in a mixed solvent (10 ml) of acetic acid-water (1:1) and the mixture was heated at 80° C. for 4 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily compound (1.4 g).
Reaction SMILES: Cl.CNC.[C:5]1(=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C-]#N.[K+].CN(C)C1(C#N)CCCC1.[CH3:25][N:26]([CH3:35])[C:27]1([C:33]#[N:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C1([Li])C=CC=CC=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>O.C(OCCCC)CCC.C1COCC1>[NH2:34][CH:33]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:27]1([N:26]([CH3:35])[CH3:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CN(C)C1(C#N)CCCCC1
Reactant: O=C1CCCCC1
Agent: CN(C)C1(C#N)CCCC1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCOCCCC
Product: CN(C)C1(C(N)c2ccccc2)CCCCC1
Yield: 26.9 %

Procedure:
The title compound was prepared in two stages from (i) dimethylamine hydrochloride (3.26 g, 0.04 mol), cyclohexanone (3.9 g, 0.04 mol) and potassium cyanide (2.60 g, 0.04 mol) in water (25 ml) in a similar manner to that described in D1 to make 1-(dimethylamino)cyclohexanecarbonitrile (6.6 g, 100%). This was reacted directly in (ii) with phenyl lithium in dibutyl ether (10.5 ml of a 1.9M solution, 0.02 mol) in THF (30 ml) followed by sodium borohydride (1.51 g, 0.04 mol) in a similar manner to that described in D2 to afford the title compound (2.5 g, 36%). 1H NMR (CDCl3) δ: 0.85 (1H, m), 1.00 (1H, m), 1.25 (2H, m), 1.35-1.60 (6H, br m), 1.70 (1H, m), 2.10 (1H, m), 2.46 (6H, s), 4.15 (1H, s), 7.20-7.32 (5H, m).
Reaction SMILES: C[Mg]Br.[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[C:5]1=[O:14])[CH2:11]2.[CH2:15](Cl)Cl>C(OCC)C.O1CCCC1>[CH3:15][C:5]1([OH:14])[CH:6]2[CH2:12][CH:10]3[CH2:9][CH:8]([CH2:13][CH:4]1[CH2:11]3)[CH2:7]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: ClCCl
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
110 ml of a solution of methyl magnesium bromide (3.0 M) in diethyl ether was diluted with 100 ml of anhydrous tetrahydrofuran (THF). Then, the solution was put into a 1 liter flask and then maintained at 0° C. 2-adamantanone (45 g, 0.3 mol) was dropped slowly using a dropping funnel and then the reaction was stirred at room temperature for about 12 hours. After completion of the reaction, excess THF was removed using a rotary evaporator and then the resultant product was poured into water. Then, the resultant product was neutralized with dilute sulfuric acid and extracted using diethyl ether and was then dried over magnesium sulfate. The obtained crude product was recrystallized using n-hexane and a methylene chloride cosolvent to yield the desired product 2-methyl-2-adamantanol (yield: 80%).
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=[O:3])C.[CH3:31][N:32](C)[C:33](Cl)=O>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([C:1]([N:32]([CH3:33])[CH3:31])=[O:3])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CN(C)C(=O)Cl
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(C(=O)N(C)C)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting dimethylcarbamyl chloride and making non-critical variations provided the title compound as an oil:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([N:6]1[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.5 %

Procedure:
To an ice cold (0° C.) suspension of cis-2,6-dimethylpiperazine (4.0 g, 35 mmol) in DMF (100 mL) was benzyl bromide (6.0 g, 35.0 mmol) added in portions under a period of 45 min and the reaction mixture was stirred at room temperature for 48 h. The solvent was evaporated from the suspension and the residue was dissolved in aqueous HCl and washed twice with CHCl3. The aqueous phase was made alkaline and extracted twice with CHCl3. The combined organic phases were washed with H2O and brine, dried (MgSO4), and concentrated to give 4.9 g (68%) of the title product as a colorless oil.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])([O-])=O.[Na+].[Na+].[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([NH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:29]
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCNC(=O)CCl
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a rapidly stirred mixture of oleylamine (118.5 g), diether (200 mL), Na2CO3 (50.29 g) and water (500 mL) is added chloroacetyl chloride (54.16 g) dropwise over 60 min. Intermittent cooling is applied to maintain temperature between 10-15° C. After completion of addition, the mixture is stirred for 60 min, and the phases are allowed to separate. Analysis (H-NMR) of a sample of the upper ether layer indicates that a small amount of amine is not reacted. Additional Na2CO3 (7 g) and water (50 mL) is added, followed by chloroacetyl chloride (7 g). The upper ether phase is removed, the aqueous phase extracted with additional ether (200 mL), and the combined organic phase is washed with water (2×125 mL portions), saturated NaCl (125 mL), dried over anh. Na2SO4, and the solvent removed in vacuo to give 149 g of 2-chloro-N-oleylacetamide.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:20][CH:21]([O:23][C:24](ON1C(=O)CCC1=O)=[O:25])[CH3:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:20][CH:21]([O:23][C:24]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:25])[CH3:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (1.1 g, 7.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl benzoate (800 mg, 2.6 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 23 (160 mg, 18% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.87-0.96 (m, 2H), 1.21-1.38 (br. m, 3H), 1.57 (d, J=5.6 Hz, 3H), 1.71-1.74 (m, 2H), 1.88-1.91 (m, 2H), 2.1-2.2 (m, 1H), 2.84-2.88 (m, 2H), 6.92 (q, J=5.6 Hz, 1H), 7.54-7.58 (m, 3H), 7.70 (m, 1H), 7.94-7.96 (m, 2H), 12.05 (br. s, 1H). MS (ESI) m/z 372.10 (M+Na)+; 348.05 (M−H)−.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1)[CH:2]=C.[BH4-].[Na+].[NH4+].[Cl-].C([OH:17])C>C(Cl)Cl>[NH2:10][C:7]1[N:8]=[CH:9][C:4]([CH2:1][CH2:2][OH:17])=[N:5][CH:6]=1
Reactant: C=CCc1cnc(N)cn1
Reactant: CCO
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Nc1cnc(CCO)cn1
Reaction time: 1 h

Procedure:
5-allylpyrazin-2-amine (180 mg, 1.332 mmol) in DCM (26.6 mL) was cooled down to −78° C., then Ozone was bubbled through for 10 min until the solution turned to blue color. Then Nitrogen was purged through for 5 min. NaBH4 (151 mg, 4.00 mmol) in ethanol (10 mL) was added slowly, The reaction mixture was allowed to return to room temperature. After 1 h, Sat. NH4Cl was added slowly, the reaction mixture was then extracted by CHCl3/IPA (7:3) (3 times), the organic was dried and concentrated to yield the crude product. The crude product is used in next step reaction without purification. LCMS (m/z): 140.0 (MH+), 0.21 min.