Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[O:27]=[C:28]1[NH:32][CH:31]([C:33](O)=[O:34])[CH2:30][NH:29]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:33]([CH:31]4[CH2:30][NH:29][C:28](=[O:27])[NH:32]4)=[O:34])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C1NCC(C(=O)O)N1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)C5CNC(=O)N5)c4)CC3)cccc2n1
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2-oxo-4-imidazolidinecarboxylic acid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[CH2:27]([O:26][C:24]([N:8]1[CH2:12][CH2:11][CH:10]([C@@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(Cc2ccccc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H]1C[C@H]1C1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 15.5 h
Yield: 75.1 %

Procedure:
To 30 ml of a dichloromethane solution of 1.466 g (4.86 mmol) of 1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine (isomer A) was added 1.39 ml (9.72 mmol) of benzyl chloroformate at room temperature, and the mixture was stirred at the same temperature for 15.5 hours, followed by heat-refluxing for 1 hour. To the reaction mixture was further added 0.70 ml (4.86 mmol) of benzyl chloroformate, followed by heat-refluxing for 1.5 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to give 1.261 g (75.1%) of the title compound as a colorless oily substance.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>O>[OH:3][N:2]1[C:9](=[O:10])[C:8]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]1=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1O
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 54.6 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with hydroxylamine hydrochloride (5 g, 73 mmol) in water, then slowly added 50% of NaOH solution. To this stirred solution, added phthalic anhydride (11.26 g, 76 mmol), stirred at 90° C. for 40 min. Then cooled to RT, yellowish solid was removed by filtration. The filtrate was neutralized with 30% of H2SO4 and solid was precipitated. The solid was filtered off on Buchner flask and dried under line vacuum to obtain the title compound (6.5 g, Yield: 55.34%): 1H NMR (300 MHz, DMSO-d6): δ 10.80 (s, 1H), 7.84 (s, 4H).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][CH:16]1[NH:20][C:19](=O)[CH2:18][CH2:17]1>>[CH3:15][CH:16]1[N:20]=[C:19]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:18][CH2:17]1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1CCC(=O)N1
Product: CC1CCC(N2c3ccccc3Oc3ccccc32)=N1

Procedure:
Reaction of phenoxazine with 5-methyl-2-pyrrolidinone according to the procedure of Example 1 affords the free base 10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE, m.p. 135°-137°C., from n-heptane. Conversion of the free base to the hydrochloride salt provides 10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 229.5°-236.0°C. (dec.) (corr.), in a 57% overall yield.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4](Cl)=[N:5][OH:6].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]=[CH2:14].C(=O)(O)[O-].[K+]>ClC1C=CC=CC=1.O>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]1[O:6][N:5]=[C:4]([C:3]([N:2]([CH3:9])[CH3:1])=[O:8])[CH2:14]1
Reactant: C=Cc1c(F)cccc1F
Reactant: CN(C)C(=O)C(Cl)=NO
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: Clc1ccccc1
Product: CN(C)C(=O)C1=NOC(c2c(F)cccc2F)C1
Temperature: 10 °C

Procedure:
To a 1000-mL round bottom flask equipped with a mechanical stirrer, thermometer and addition funnel were added 2-(dimethylamino)-N-hydroxy-2-oxoethanimidoyl chloride (94.0 g, 0.62 mol) and a solution of 2,6-difluorostyrene (84.0 g, 0.60 mol) in chlorobenzene (275 g). The reaction mixture was cooled to 10° C., and then a solution of potassium bicarbonate (70 g, 0.70 mol) in water (350 mL) was added dropwise over 1 h while maintaining the temperature between 10 to 15° C. When gas chromatography analysis of the reaction mixture showed about 3% of 2-(dimethylamino)-N-hydroxy-2-oxo-ethanimidoyl chloride remaining, water (200 mL) was added to the reaction mixture, and the layers were separated. The organic layer was washed with water (300 mL) and concentrated under reduced pressure. Toluene was added to the resulting residue, and the mixture was concentrated under reduced pressure to provide the title compound as an oil (144g).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH:12]=O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:27][NH2:28].C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH2:12][NH:28][CH2:27][C:26]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:24]([C:23]([F:22])([F:36])[F:37])[CH:25]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2C=O)CCCCCC1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC1(c2ccc(C(F)(F)F)cc2CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzaldehyde (167 mg; 0.556 mmol) and 3,5-bistrifluoromethyl benzylamine (150 mg; 0.616 mmol) in toluene (4 mL) was heated at reflux for 16 hours, after which solvent was removed. Ethanol (4 mL) and sodium borohydride (31 mg; 0.819 mmol) were added to the residue. The resulting mixture was stirred at room temperature for 16 hours. Solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with water and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-25% ethyl acetate in heptane) to yield 194 mg (66.1% for 2 steps) of the title compound as a gum. MS (ES+): Calc: 527.4 Found: 528.4 (M+H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:46]1(=[O:52])[NH:50][C:49](=[O:51])[CH:48]=[CH:47]1>>[C:34]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:50]2[C:46](=[O:52])[CH:47]=[CH:48][C:49]2=[O:51])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1C=CC(=O)N1
Reactant: OCCCCCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C=CC(=O)N1CCCCCc1ccccc1

Procedure:
Reagents: Ph3P (0.65 g, 2.5 mmol), DIAD (0.5 ml, 2.5 mmol), 5-phenyl-1-pentanol (0.63 ml, 3.75 mmol) and maleimide (0.24 g, 2.5 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.CN.[CH3:28][N:29](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:28][NH:29][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:23]
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC)ccc21
Yield: 49.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid methylamide (77.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (150.0 mg), methylamine (2.0 M solution in THF, 1.0 mL), HBTU (190 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 387; and 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (1H, br. s), 8.08 (1H, br. s), 7.95 (1H, m), 7.73 (2H, m), 7.51 (1H, m), 7.41-7.38 (1H, m), 4.21 (1H, bs. s), 2.82-2.80 (3H, d), 1.34-1.30 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:13]=O)[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH3:1][O:2][C:3]([C:5]1([CH:13]=[N:29][O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:8]1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: CCCCC1CC(C=O)(C(=O)OC)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCC1CC(C=NOCc2ccccc2)(C(=O)OC)C1
Yield: 64.9 %

Procedure:
A mixture of 3-butyl-1-formyl-cyclobutanecarboxylic acid methyl ester (7.2 g, 36.7 mmol), sodium acetate (6.1 g, 73.4 mmol) and O-benzylhydroxylamine hydrochloride (11.9 g, 73.4 mmol) were stirred in methanol (90 mL) for 18 h. The methanol was removed in vacuo, water (100 mL) was added and the aqueous phase was extracted with EtOAc (75 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. The residue was purified by flash column chromatography using an eluting system of hexane/EtOAc (9:1) to yield the title compound as a clear colorless oil (7.23 g, 64%). MH+304.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[F:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([F:19])[CH:21]=2)=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Reactant: O=C=Nc1ccc(F)c(F)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(F)c2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 3,4-difluoro phenyl isocyanate (0.041 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 51 as a colorless solid (0.096 g, 80%). LCMS m/z (%)=467 M+H+ (81Br, 88), 465, M+H+ (79Br, 95)1H NMR (400 MHz, DMSO-d6) δ: 8.816 (bs, 1H), 8.681 (bs, 1H), 7.5 (s, 1H), 7.412 (d, J=2.51 Hz, 2H), 7.389 (d, J=2.51 Hz, 2H), 7.199 (t, 1H), 7.167 (s, 1H), 6.983 (t, 1H), 3.989 (m, 1H), 3.596 (s, 3H), 1.225 (d, J=6.61 Hz, 3H), 1.078 (d, J=6.61 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][CH2:13][CH2:12][N:11]([C:15]3[C:16]([F:36])=[CH:17][C:18]4[N:27]=[CH:26][C:25]5[N:24]([CH3:28])[CH:23]=[C:22]([C:29]([O:31]CC)=[O:30])[C:21](=[O:34])[C:20]=5[C:19]=4[CH:35]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]>C(O)C.[OH-].[K+].O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][CH2:13][CH2:12][N:11]([C:15]3[C:16]([F:36])=[CH:17][C:18]4[N:27]=[CH:26][C:25]5[N:24]([CH3:28])[CH:23]=[C:22]([C:29]([OH:31])=[O:30])[C:21](=[O:34])[C:20]=5[C:19]=4[CH:35]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(N4CCNC(c5ccc(C)c(C)c5)C4)cc3c2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C2CN(c3cc4c(cc3F)ncc3c4c(=O)c(C(=O)O)cn3C)CCN2)cc1C
Temperature: 100 °C
Yield: 70.7 %

Procedure:
A stirred suspension of 1.47 g of ethyl 9-[3-(3,4-dimethylphenyl)piperazin-1-yl]-8-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate in 25 cm3 of ethanol, 3.60 cm3 of 1 N aqueous potassium hydroxide and 15 cm3 of water was heated in the region of 100° C. for 4 hours. The reaction mixture was filtered, evaporated to dryness, the residue was suspended in 100 cm3 of water, the medium was acidified with 3.5 cm3 of a 1 N aqueous hydrochloric acid solution, 10 cm3 of ethanol was added, the medium was heated to 100° C. and filtered at high temperature. The residue was washed 3 times with 25 cm3 of water and then with 10 cm3 of ethanol. 0.98 g of 9-[3-(3,4-dimethylphenyl)piperazin-1-yl]-8-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylic acid was obtained in the form of a yellow solid, which melted at 325° C.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:26])[C@H:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH:17]=[CH2:18])C1C=CC=CC=1.[OH:27]O.O[Li].O>C1COCC1.O>[CH2:19]([C@H:15]([CH2:16][CH:17]=[CH2:18])[C:14]([OH:26])=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: OO
Reactant: C=CC[C@@H](CCCCCCC)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@H](CCCCCCC)C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of 8.69 g (0.024 mol) of the product from Example 3 in 425 mL of THF/H2O (3:1), cooled to 0 degrees, was added 10.8 mL (0.097 mol) of 30% hydrogen peroxide solution followed by 2.03 g (0.049 mol) of LiOH-H2O. The resulting solution was stirred at 0° C. for 1.5 h and then quenched with a solution of 15.4 g of sodium sulfite in 100 mL of H2O. The reaction mixture was then acidified to pH 3 with aqueous HCl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 4.33 g (90%) of the desired product as a colorless oil. CI Mass Spec: 199 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CN2CCNCC2)nc1

Procedure:
A solution of 0.11 g (0.4 mmol) of the title compound from Step A above in 1 mL dichloromethane and 1 mL trifluoroacetic acid was stirred at ambient temperature for 1 h. All volatiles were removed in vacuo and the crude light brown residue was carried forward without purification. LC/MS: m/z (ES) 178.2 (MH)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.[OH-].[Na+]>CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][C:16]2[NH:8][CH:9]=[N:10][C:11]=2[CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncn2C(=O)OC(C)(C)C)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 6,7-dihydro-4H-imidazo[4,5-c]pyridine-1,5-dicarboxylic acid di-tert-butyl ester (Preparation 19, 26.8 g, 82.9 mmol) in methanol (210 mL) was added 1M sodium hydroxide aqueous solution (170 mL, 170 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with 10% citric acid aqueous solution (250 mL), basified to pH8 and extracted with DCM (2×500 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound as a brown foam (18.5 g) in a 97% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].CS[C:9](=[NH:11])[NH2:10].OS(O)(=O)=O>O>[NH:1]([CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])[C:9]([NH2:11])=[NH:10]
Reactant: NCCCCN
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)NCCCCN
Reaction time: 12 h

Procedure:
To 1.8 g. of 1,4-diaminobutane dissolved in 50 ml. of H2O was added, dropwise, a solution of 2 g. of S-methylthiopseudourea.H2SO4 in 20 ml. of H2O. Throughout the addition, the solution was stirred vigorously and continued for 12 hours after the completion of addition. Then H2O was lyophilized, giving viscous colorless oil, which upon addition of 50 ml. of methanol precipitated 1.05 g. of white powder. Mass spec. (FD.) ions at m/e 228 and 130 for H2N--(CH2)4 --NHC(=NH)--NH2.H2O4 and H2N--(CH2)4 --NHC(=NH)--NH2, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([CH:17]4[CH2:22][CH2:21][N:20](C(OCC5C=CC=CC=5)=O)[CH2:19][CH2:18]4)=[CH:16][C:11]3=[N:10][C:9]=2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH:5]=[CH:4][N:3]=1.[Si](I)(C)(C)C>CC#N>[F:39][C:36]1[CH:35]=[CH:34][C:33]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:38][CH:37]=1
Reactant: Nc1nccc(-c2c(-c3ccc(F)cc3)nc3cc(C4CCN(C(=O)OCc5ccccc5)CC4)ccn23)n1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)nc3cc(C4CCNCC4)ccn23)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl carbonate 37 (190 mg, 0.36 mmol) was slurried in CH3CN (5 mL) in a 28 mL Pyrex Plus tube. TMSI (720 mg, 3.6 mmol) was then added, and the reaction was allowed to stir at room temperature for 2 hours. The reaction was then concentrated under reduced pressure. The crude product was then dissolved in 10 mL CH2Cl2, plus a few drops of methanol, then loaded onto a 40 g Isco RediSep normal phase silica cartridge, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% methylene chloride and ended at 90% methylene chloride, 9% methanol, 1% concentrated ammonium hydroxide. Fractions containing desired product were pooled and concentrated under reduced pressure. Yield of 38: 140 mg (100%). 1H NMR (400 MHz, CDCl3) δ 1.67 (m, 2H), 1.84 (m, 2H), 2.67 (m, 1H), 2.74 (m, 2H), 3.18 (m, 2H), 5.03 (s, 2H), 6.44 (d, J=5.2 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 7.05 (t, J=8.8 Hz, 2H), 7.43 (bs, 1H), 7.56 (m, 2H), 8.04 (d, J=5.2 Hz, 1H), 9.36 (d, J=7.2 Hz, 1H). MS (ESI+) 389.2.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].CCN(C(C)C)C(C)C.[CH2:19](Cl)[O:20][CH3:21].[NH4+].[Cl-]>ClCCl>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][CH2:19][O:20][CH3:21]
Reactant: OCc1ccccc1I
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCc1ccccc1I
Temperature: 23 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To stirring solution of 2-iodobenzyl alcohol (6.02 g, 25.72 mmol) in dichloromethane (40 mL) was added sequentially Hunig's base (6.8 mL, 38.51 mmol) followed by MOMCl (3.0 mL, 39.13 mmol), and stirred at 23° C. overnight. The reaction was treated with saturated NH4Cl (30 mL), stirred vigorously for several minutes, then the phases separated. The organic phase was extracted with dichloromethane (2×). The combined organics were dried (MgSO4), filtered and concentrated to an amber oil which was purified on Biotage Horizon (10-100% (7:3 hexane:EtOAc)/hexane, 40+M, SiO2) to afford the product (6.06 g) as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (dd, J=7.83, 1.26 Hz, 1H), 7.45 (dd, J=7.70, 1.64 Hz, 1H), 7.35 (td, J=7.52, 1.14 Hz, 1H), 6.99 (td, J=7.58, 1.77 Hz, 1H), 4.76 (s, 2H), 4.59 (s, 2H), 3.43 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:24]3[CH:23]=[N:22][C:21]([NH2:20])=[N:26][CH:25]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cn1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 2-aminopyrimidine-5-boronic acid pinacol ester with reaction time of 17 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.[Li]CCCC.[CH2:18]1[O:20][CH2:19]1.O>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[CH2:18][CH2:19][OH:20]
Reactant: C1CO1
Reactant: Cn1cnc(-c2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccccc2)nc1CCO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
A solution of 674 mg (4.26 mmol) of 1-methyl-4-phenylimidazole (Kashima, C.; Harada, Y.; Hosomi, A. Heterocycles 1993, 35, 433) in 8.5 mL of THF at −78° C. was treated with 1.9 mL (4.69 mmol) of a 2.5 M nBuLi in hexanes solution. After stirring for 10 min, 1.1 mL (21.3 mmol) of ethylene oxide was added. The reaction was stirred for min then warmed to 25° C. and stirred for 1 h. Upon cooling to 0° C., 1.1 mL (21.3 mmol) of ethylene oxide was added, and the reaction was warmed to 25° C. and stirred overnight. The reaction was poured into H2O and extracted with Et2O. The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using EtOAc/MeOH (95:5), and the collected product was recrystallized from CH2Cl2/EtOAc to give 178 mg (21%) of title compound as a white solid: low resolution MS (ES) m/e 225 (MNa+), 203 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21]CC)=[O:20])[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1ccc2ccnc(NCc3ccc(OC)cc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CNc2nccc3ccc(C(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
To a solution of ethyl 1-(4-methoxybenzylamino)isoquinoline-7-carboxylate (430 mg, 1.28 mmol) in methanol (8.5 mL) was added 6 N aqueous sodium hydroxide (1.1 mL, 6.4 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated. The residue was taken up in water and acidified with 1 N aqueous hydrochloric acid until a precipitate formed. The solid was collected by filtration and dried under vacuum to give the title compound (328 mg, 83%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ): 8.92 (s, 1H), 8.30 (t, J=5.8 Hz, 1H), 8.06 (dd, J=8.4, 1.4Hz, 1H), 7.88 (d, J=5.7 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.24-7.31 (m, 2H), 6.88 (d, J=5.7 Hz, 1H), 6.79-6.85 (m, 2H), 4.62 (d, J=5.9 Hz, 2H), 3.67 (s, 3H).