Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CCO>[CH3:14][N:15]([CH:17]=[C:9]1[CH2:8][CH2:7][C:5]2[N:6]=[C:2]([N:1]=[CH:14][N:15]([CH3:17])[CH3:16])[S:3][C:4]=2[C:10]1=[O:11])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: Nc1nc2c(s1)C(=O)CCC2
Solvent: CCO
Product: CN(C)C=Nc1nc2c(s1)C(=O)C(=CN(C)C)CC2
Temperature: 150 °C
Yield: 58.7 %

Procedure:
A mixture of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (0.5 g, 3 mmol) and N,N-dimethylformamide dimethyl acetal (1.96 mL, 1.76 g, 14.8 mmol) in EtOH (2 mL) was heated under microwave irradiation (300 W, 150° C.) for 30 min. The mixture was concentrated under vacuum before purification by flash column chromatography (50% EtOAc:hexane) to afford the title product as a tan solid (0.49 g, 59%): mp 185-186° C. Anal. RP-HPLC: tR 9.3 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 8.23 (s, 1H, CH), 7.44 (s, 1H, CH), 3.13 (s, 3H, CH3), 3.11 (s, 3H, CH3), 3.08 (s, 6H, N(CH3)2), 3.00 (t, 2H, J 6.6, CH2), 2.83 (t, 2H, J 6.6, CH2). MS (ESI+): m/z 279.15 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:30][C:25]1[CH:24]=[C:23]([CH2:22][N:3]2[C:4]3[CH:10]=[C:9]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)[CH:8]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[C:5]=3[N:6]=[C:2]2[CH3:1])[CH:28]=[CH:27][C:26]=1[CH3:29]
Reactant: Cc1ccc(CCl)cc1C
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C)n2Cc1ccc(C)c(C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate prepared as described in Example 26, step d (0.22 g, 0.799 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added in 4-(chloromethyl)-1,2-dimethylbenzene (0.185 g, 1.199 mmol) and potassium carbonate (0.331 g, 2.397 mmol). The resulting reaction mixture was stirred at 80° C. for 3 h. It was cooled to room temperature and poured into water (30 mL). The mixture was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL) and concentrated. The crude material was subjected to normal phase purification (0˜40% EtOAc/Hexane) then (0˜1% MeOH/DCM) to give the product (0.24 g, 76%). MS (ES+) m/e 394.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:17]3[C:13]([C:14]([CH3:21])([CH3:20])[CH:15]([OH:19])[N+:16]=3[O-])=[CH:12][C:11](=[O:22])[C:10]=2[CH:23]=1)[CH2:2][CH2:3][CH3:4].Cl.C1(=O)C=CC(=[O:31])C=C1>CCO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:17]3[C:13]([C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[N:16]=3)=[C:12]([OH:31])[C:11](=[O:22])[C:10]=2[CH:23]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1)C(=O)C=C1C2=[N+]([O-])C(O)C1(C)C
Reactant: O=C1C=CC(=O)C=C1
Agent: Cl
Solvent: CCO
Product: CCCCOc1ccc2c(c1)C(=O)C(O)=C1C2=NC(=O)C1(C)C

Procedure:
A solution of 7-Butoxy-2-hydroxy-3,3-dimethyl-2,3-dihydro-5H-benzo[g]indol-5-one 1-oxide (compound 6 prepared in step (ii) above)(13 mg, 0.036 mmol) in EtOH (2 mL) with conc. HCl in EtOH (0.5 mL) was heated at 60° for 1 h. The yellow solution turned red. When no starting material remained, benzoquinone (39 mg, 0.36 mmol) was added and the mixture was heated 1 h. The solvent was evaporated and the crude product was purified on RP-HPLC. Yield. 12 mg. (24%). 1H NMR (400 MHz, CDCl3) δ 1.00 (tr., 3H), 1.51 (m, 2 H), 1.55 (s, 6 H), 1.82 (m, 2 H), 4.10 (tr., 2H), 7.20 (dd, 1 H), 7.46 (d, 1 H), 7.70 (d, 1 H), 9.62 (br.s, 1 H). MS (EI) m/z 313 (M+).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][C:18](O)=[O:19])=[O:8])=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[N:40]=[C:41]([NH2:45])[CH2:42][CH2:43][OH:44].N1C=CC=CC=1>O1CCCC1>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([CH2:17][C:18]2[O:19][N:45]=[C:41]([CH2:42][CH2:43][OH:44])[N:40]=2)[N:9]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:2][CH:3]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](CC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: NC(CCO)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CON=C1C[C@@H](Cc2nc(CCO)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 32.3 %

Procedure:
To a solution of [(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid (Intermediate 7, 50 mg, 0.14 mmol) in tetrahydrofuran (2 ml) was added CDI (37 mg, 0.23 mmol). The reaction mixture was stirred 1 h30. A solution of N′,3-dihydroxypropanimidamide (16 mg, 0.16 mmol), pyridine (34 ml, 0.14 mmol) in tetrahydrofuran was then added and the reaction mixture was stirred at reflux overnight The solvent was removed and ethyl acetate was added. The organic phase was washed with citric acid 5%, NH4Cl, NaHCO3 then brine. The organic phase was dried (MgSO4), concentrated and purified on silica gel column chromatography (Ethyl acetate) to afford (3EZ,5S)-1-(biphenyl-4-ylcarbonyl)-5-{[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]methyl}pyrrolidin-3-one O-methyloxime (19 mg). Yield: 27%. HPLC purity: 94%
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH:22]=[C:21]([C:33]([F:36])([F:35])[F:34])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([C:33]([F:35])([F:34])[F:36])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.9 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.34 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) and crystallization (MeOH/diethyl ether) to yield the title compound as a light yellow solid (0.23 g, 62%). MS (ISN) 520.3 [(M−H)−]; mp 282° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].CCOCC>C(#N)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:18][CH2:19][CH2:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[O:22])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)COc1ccc(SCCCC(=O)c2ccc(Cl)cc2)c2c1CCC2

Procedure:
Compound 1D (300 mg, 1.26 mmol), 4-chloro-1-(4-chloro-phenyl)-butan-1-one (327 mg, 1.51 mmol), and cesium carbonate (616 mg, 1.89 mmol) in 10 ml anhydrous acetonitrile were stirred at ambient temperature for 72 hours. The reaction was then run through 0.5 g SiO2 eluting with Et2O. The eluant was collected and concentrated to give the title compound, pure enough for subsequent use. MS m/z 419 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH2:8])=[O:7])=[CH:2]1.C(Cl)(=O)[C:10](Cl)=[O:11]>ClCCl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([N:8]=[C:10]=[O:11])=[O:7])=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccoc1
Solvent: ClCCl
Product: O=C=NC(=O)c1ccoc1
Temperature: 25 °C

Procedure:
3-Furancarboxamide (167 mg) was dichloromethane (10 ml), followed by addition of oxalyl chloride (0.20 ml) under ice-cooling, and the temperature of the reaction mixture was raised to room temperature. The reaction mixture was refluxed for 10 hours and the solvent was distilled off to give crude 3-furoyl isocyanate. In the same manner as in Example 8, the above product was reacted with fumagillol (213 mg) with stirring at room temperature for 30 minutes. Purification by silica gel column chromatography (eluent: n-hexane-ethyl acetate =2:1) gave colorless, powdery O-[N-(3-furoyl)carbamoyl]fumagillol (120 mg) (38% yield).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:24]=[CH:23][C:22]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[NH:15][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:27][CH:26]=1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(F)(F)F)cc2)C(N)C1
Product: NC(=O)c1ccnc2c(NC3CNCCC3c3ccc(C(F)(F)F)cc3)ncnc12

Procedure:
Compound 25 was prepared following general synthesis scheme 9 wherein 4-hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylic acid amide was reacted with tert-butyl 3-amino-4-(4-(trifluoromethyl)phenyl)piperidine-1-carboxylate to give the title compound. LC-MS [417 (M+H)], 1H NMR (400 MHz, DMSO-d6) δ 9.77 (d, 1H), 8.99 (d, 1H), 8.93-8.82 (m, 1H), 8.82-8.70 (m, 1H), 8.65 (d, 1H), 8.36 (d, 2H), 8.16 (d, 1H), 7.48 (t, 4H), 5.37-5.21 (m, 1H), 3.75-3.42 (m, 1H), 3.26-3.06 (m, 1H), 2.02 (d, 1H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31](Cl)[N:30]=[N:29][C:28]=2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[C:31]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:30]=[N:29][C:28]=2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(OCCCN2CCOCC2)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 76.1 %

Procedure:
To a stirred solution of 3-morpholin-4-yl-propan-1-ol (1.0 mmol, 0.145 g) in THF (3 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (1.3 mmol, 0.052 g) and continued stirring for 15 min. The reaction mixture was allowed to come to room temperature. To the mixture was added 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 0.74 mmol, 0.26 g). After completion of addition, the reaction mixture was warmed to 70° C. for 3 h. The reaction was concentrated onto SiO2 and purified via flash chromatography using 20-50% ethyl acetate in hexanes to give 4-{3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-propyl}-morpholine (0.26 g, 75%). The free amine may be dissolved in DCM and 2 N HCl in diethyl ether followed by evaporation of the solvents to provide the title compound. LCMS: m/z 463 [M+1]. 1H NMR (400 MHz, CDCl3): δ 7.32-7.49 (5H, m), 7.21-7.26 (2H, m), 7.03-7.09 (2H, m), 6.74 (1H, s), 5.12 (2 H, s), 4.58 (2 H, t), 3.67-3.76 (4H, m), 2.83-2.91 (2H, m), 2.41-2.56 (6 H, m), 1.98-2.08 (2 H, m), 1.56-1.68 (2 H, m), 1.21-1.33 (2 H, m), 0.83 (3H, t).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][C:39]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:42]([NH2:44])=[O:43])[CH2:38][CH2:37]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH2:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][C:39]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:42]([NH2:44])=[O:43])[CH2:40][CH2:41]3)[CH2:19][CH2:18][N:17]([C:20](=[O:33])[C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)[CH2:16]2)=[CH:13][CH:14]=1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(O)cc3)C2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
Combine 1-[2-[3-[4-(tert-butyldimethylsilyloxy)-phenyl]-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl -piperidine-4-carboxylic acid amide (6 mmol) and THF (20 mL). Cool using an ice bath. Add a 1M THF solution of tetrabutylammonium fluoride (7 mL) in dropwise fashion. After 30 minutes, concentrate in vacuo to obtain a residue. Add dichloromethane (50 mL) to the residue. Extract with water (3×15 mL), dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Purify to obtain the title compound.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.[Cl:16][C:17]1[CH:18]=[C:19]([F:24])[C:20](F)=[N:21][CH:22]=1.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.CC1CCCCC1>CS(C)=O.O>[F:24][C:19]1[C:20]([O:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([O:12][CH3:25])=[O:11])=[CH:14][CH:15]=2)=[N:21][CH:22]=[C:17]([Cl:16])[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Fc1cc(Cl)cnc1F
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CC1CCCCC1
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 654960.38 %

Procedure:
A solution of NaOH (2.7 g, 0.068 mol) in a few ml of water was added to 2-(4-hydroxyphenoxy)propionic acid (6.09 g, 0.033 mol) in 55 ml DMSO and the mixture was stirred for 20 minutes under nitrogen. 5-Chloro-2,3-difluoropyridine (5.0 g, 0.033 mol) was added and the mixture was heated at 70° C. for 5 hours. The reaction was then poured over ice and extracted with CH2Cl2. The organic layer was washed with water, dried over Na2SO4 and the solvent removed by rotary evaporation. The residual oil was dissolved in 130 ml dry methanol, p-toluene sulfonic acid (0.5 g, 0.003 mmol) was added and the mixture was stirred at room temperature for 24 hours. The methanol was removed by rotary evaporation. The residue was taken up in ether, washed with dilute aqueous NaOH, and dried over Na2SO4. The ether was removed by rotary evaporation to yield a tan oil which solidified on trituration with methylcyclohexane to give a white solid (6.4 g, 59%, m.p. 53°-56° C.).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]1=[O:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1.C(O)C>CN(C)C=O>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][N:4]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]3=[O:21])[CH2:33][CH2:32]2)=[O:30])=[CH:27][CH:28]=1
Reactant: O=c1c2ccccc2n(-c2ccccc2)c(=O)n1CCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)c3ccccc3n(-c3ccccc3)c2=O)CC1
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 6 parts of 3-(2-chloroethyl)-1-phenyl-2,4(1H,3H)-quinazolinedione, 8.3 parts of (4-fluorophenyl) (4-piperidinyl)methanone and 48 parts of ethanol is stirred and refluxed. N,N-dimethylformamide is added at reflux temperature till all solid enters solution. Stirring is continued overnight at reflux. The reaction mixture is evaporated. The residue is purified twice by column-chromatography over silica gel using first a mixture of trichloromethane and methanol (95:5 by volume) and then a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 2.2 parts (23%) of 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-1-phenyl-2,4(1H,3H)-quinazolinedione; mp. 166.1° C.
Reaction SMILES: COC1C=CC(S)=CC=1.B([O-])([O-])OC1C=CC=CC=1.[CH2:20]([NH2:23])[CH2:21][NH2:22].[CH3:24][CH2:25][CH:26]([CH2:28][CH:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([NH:41][C@@H:42]1[C:73](=[O:74])[NH:72][C@@H:71]([C@H:75]([OH:77])[CH3:76])[C:69](=[O:70])[N:68]2[C@@H:64]([CH2:65][C@@H:66]([OH:78])[CH2:67]2)[C:62](=[O:63])[NH:61][C@@H:60]([C@H:79]([OH:89])[C@@H:80]([OH:88])[C:81]2[CH:86]=[CH:85][C:84]([OH:87])=[CH:83][CH:82]=2)[C:58](=[O:59])[NH:57][C@@H:56]([C@H:90]([OH:95])[CH2:91][C:92]([NH2:94])=O)[C:54](=[O:55])[N:53]2[C@@H:49]([C@@H:50]([OH:96])[CH2:51][CH2:52]2)[C:47](=[O:48])[NH:46][C@H:45](O)[C@H:44]([OH:98])[CH2:43]1)=[O:40])[CH3:30])[CH3:27]>>[CH3:24][CH2:25][CH:26]([CH2:28][CH:29]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([NH:41][C@@H:42]1[C:73](=[O:74])[NH:72][C@@H:71]([C@H:75]([OH:77])[CH3:76])[C:69](=[O:70])[N:68]2[C@@H:64]([CH2:65][C@@H:66]([OH:78])[CH2:67]2)[C:62](=[O:63])[NH:61][C@@H:60]([C@H:79]([OH:89])[C@@H:80]([OH:88])[C:81]2[CH:86]=[CH:85][C:84]([OH:87])=[CH:83][CH:82]=2)[C:58](=[O:59])[NH:57][C@@H:56]([C@H:90]([OH:95])[CH2:91][CH2:92][NH2:94])[C:54](=[O:55])[N:53]2[C@@H:49]([C@@H:50]([OH:96])[CH2:51][CH2:52]2)[C:47](=[O:48])[NH:46][C@H:45]([NH:22][CH2:21][CH2:20][NH2:23])[C@H:44]([OH:98])[CH2:43]1)=[O:40])[CH3:30])[CH3:27]
Reactant: NCCN
Reactant: CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](O)NC(=O)[C@@H]2[C@@H](O)CCN2C(=O)[C@H]([C@H](O)CC(N)=O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O
Agent: COc1ccc(S)cc1
Agent: [O-]B([O-])Oc1ccccc1
Product: CCC(C)CC(C)CCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](NCCN)NC(=O)[C@@H]2[C@@H](O)CCN2C(=O)[C@H]([C@H](O)CCN)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O

Procedure:
According to WO2010008493A2, Pneumocandin B0 as the starting material reacts with 4-methoxy thiophenol, the resulting product is protected by phenyl borate, the amide group in Pneumocandin B0 is reduced to amine group under the condition of dehydration by 3A molecular sieve, and then the resulting product reacts with ethylenediamine to obtain caspofungin.
Reaction SMILES: Cl.C(O)C([NH2:8])(CO)CO.CC1C=CC(S([NH:20][C@H:21]([C:29](CCl)=[O:30])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)(=O)=O)=CC=1.[CH2:33]([OH:38])CCCO>C(O)CCCO.O.O.[Zn]>[CH3:33][O:38][C:29](=[O:30])[C@H:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:8])=[CH:25][CH:24]=1)[NH2:20]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)CCl)cc1
Reactant: OCCCCO
Reactant: NC(CO)(CO)CO
Agent: Cl
Agent: [Zn]
Solvent: O
Product: COC(=O)[C@@H](N)Cc1ccc(N)cc1

Procedure:
HCl were dissolved in 2 ml of butane-1,4-diol. To this solution were added approximately 2 ml of 0.5 M tris-base in butane-1,4-diol/H2O (4:1, v/v), until the pH (glass electrode) was 6.5. 100 mg of solid Zn-free insulin were added to 3.1 ml of the buffered methyl ester solution. Most of the insulin went into solution after incubation at 37° C. for 30 minutes. Trypsin (12 mg. Worthington TPCK grade) was dissolved in 120 μl of water and 100 μl of the solution were added. After 90 minutes at 37° C. during which time the insulin dissolved completely, cellulose-acetate electrophoresis at pH 8 revealed that more than half of the insulin had been converted to a product that migrated more slowly than insulin. Since the pK of an aromatic amino group is well below 8, this is the expected behaviour of the desired product. The reaction mixture was cooled and 3.1 ml of glacial acetic acid were added to stop the enzymic reaction. The resulting mixture was then diluted with an equal volume of 10% (v/v) acetic acid and subjected to gel filtration on a 90×2.6 cm column of Sephadex G-50 (fine), elution with 1% (v/v) acetic acid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][CH:38]=[C:39]([CH:42]=2)[C:40]#[N:41])O1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:35]3[CH:36]=[N:37][CH:38]=[C:39]([C:40]#[N:41])[CH:42]=3)[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncc(C#N)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide (Stage 179.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.05 min, m/z=474.3 [M+H]+, m/z=472.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.70 (s, 3H) 3.48 (d, J=5.38 Hz, 2H) 3.56 (d, J=5.38 Hz, 2H) 4.66 (br. s, 1H) 7.36 (d, J=9.05 Hz, 2H) 7.81-7.93 (m, 2H) 8.15 (d, J=2.45 Hz, 1H) 8.46 (t, J=2.08 Hz, 1H) 8.77 (d, J=2.20 Hz, 1H) 9.01 (dd, J=7.21, 2.08 Hz, 2H) 10.23 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C=O)C>[N+:23]([C:22]1[C:17]([O:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: N#Cc1cccc(O)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ncccc2[N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
3-Cyanophenol (187 mg, 1.06 mmol) was dissolved in DMF (1 mL) and cesium carbonate (360 mg, 1.1 mmol) was added followed by a solution of 2-chloro-3-nitropyridine (158 mg, 1.0 mmol) in DMF (1 mL). The reaction mixture was heated with shaking at 80° C. for 18 h. The mixture was concentrated. The residue was dissolved in ethyl acetate (4 mL) and washed with water (0.6 mL), saturated NaHCO3 (0.5 mL) and water (2×0.5 mL). The organic phase was concentrated and the resulted mixture containing mainly 106a was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]([OH:22])[CH3:21].[CH2:23]([OH:25])[CH3:24].C(=O)(O)[O-].[Na+].C[Cl:32]>C(O)(C)C>[Cl-:32].[CH3:20][NH2+:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:23]([OH:25])[CH3:24].[CH2:20]([OH:22])[CH3:21]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC[NH2+]C
Product: [Cl-]
Temperature: 100 °C

Procedure:
A 2-liter autoclave was charged with 858.3 gm. (2.4 mol) diethanol octadecyl amine, 20 gm. sodium bicarbonate and 420 ml. isopropyl alcohol. The temperature was raised to 100° C. Methyl chloride was introduced and was added periodically until the pressure remained constant (65 psig) for one hour.