Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[C:38]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:40])[CH3:39]
Reactant: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reaction time: 2 h
Yield: 70.4 %

Procedure:
A solution of N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (61 mg, 0.14 mmol) in CH2Cl2 (3 mL) was treated with pyridine (0.058 mL, 0.72 mmol) and acetic anhydride (0.13 mL, 1.4 mmol). The resultant mixture was stirred at RT for 2 days. The reaction was quenched with saturated aqueous NaHCO3 and was further stirred for 2 h. The mixture was diluted with EtOAc (30 mL) and was washed with saturated aqueous NaHCO3 (20 mL), water (20 mL) and brine (20 mL). The mixture was concentrated in vacuo and purified by silica gel chromatography to provide N-(4-(2-acetamidopyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (46 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ10.56 (s, 1H), 10.54 (s, 1H), 9.96 (s, 1H), 8.18 (d, J=5.8 Hz, 1H), 7.92 (t, 1H), 7.65 (d, J=1.9 Hz, 1H) 7.59 (m, 2H), 7.24 (dd, J=11.2, 2.5 Hz, 1H), 7.15 (m, 2H), 7.01 (m, 1H), 6.68 (dd, J=5.7, 2.3 Hz, 1H), 2.02 (s, 3H), 1.60-1.52 (m, 4H); MS (ESI) m/z: 467.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:22]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:23])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1OC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of ethyl 2-hydroxybenzoate (0.5 g, 3.0 mmol) in CH2Cl2 (8 mL) was added 2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (0.8 g, 3.0 mmol), EDCI (0.63 g, 3.3 mmol) and dimethylaminopyridine (0.037 g, 0.3 mmol). The reaction was stirred (RT, 3 h) and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2 and the combined organic extracts were dried over MgSO4. The crude material was purified by silica chromatography (0-10% MeOH/CH2Cl2) to afford 1.2 g of ethyl 2-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)benzoate. Mass calculated for C235H27NO6=413.46. found: [M+Na]+=437.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:37])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]NC2N=C(NCCC3C=CC(OC)=C(OC)C=3)C=CN=2)=[CH:12][CH:11]=1.COC1C=C(CCNC2C=CN=C(NCC3C=CC(C(O)=O)=CC=3)N=2)C=CC=1OC.[O:68]=[C:69]1[NH:73][C:72](=[O:74])[CH:71](CC2C=CC(C(O)=O)=CC=2)[S:70]1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:37])[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH:71]2[S:70][C:69](=[O:68])[NH:73][C:72]2=[O:74])=[CH:14][CH:15]=1
Reactant: COc1ccc(CCNc2ccnc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)n2)cc1OC
Reactant: O=C1NC(=O)C(Cc2ccc(C(=O)O)cc2)S1
Agent: COc1ccc(CCNc2ccnc(NCc3ccc(C(=O)O)cc3)n2)cc1OC
Product: Nc1ccccc1NC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Yield: 51 %

Procedure:
Following the procedure described for the synthesis of compound 10a (scheme 2, Example 2) but replacing acid 9 by the acid 352, title compound was obtained in 51% yield. 1H NMR: (400 MHz, DMSO-d6, δ (ppm): 12.04 (br s, 1H), 9.62 (s, 1H), 7.90 (d, j=8.2 Hz, 2H), 7.36 (d, j=8.2, 2H), 7.16 (d (dd) J=8.4, 1H), 7.13 (d (dd), J=6.7, 1H), 6.95 (dd, J=1.6 Hz, J=7.8 Hz, 1H), 6.75 (dd, j=1.4 Hz, j=8.0 Hz, 1H), 6.57 (dd, j=1.4 Hz, 7.6 Hz, 1H), 4.99 (dd, J=4.7 Hz, J=9.0 Hz, 1H), 4.96 (br s, 2H), 3.45 (dd, J=4.5 Hz, J=14.1 Hz, 1H), 3.22 (dd, J=9.0 Hz, J=14.3 Hz, 1H). LRMS: 341.3 (calcd.), 342.3 [MH]+ (found).
Reaction SMILES: CO[C:3]1([O:10]C)[CH:8]=[CH:7][C:6](=[O:9])[CH:5]=[CH:4]1.[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[CH:23]=[C:22]2[C:3]2([OH:10])[CH:4]=[CH:5][C:6](=[O:9])[CH:7]=[CH:8]2)(=[O:19])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: COC1(OC)C=CC(=O)C=C1
Product: COc1ccc2c(c1)cc(C1(O)C=CC(=O)C=C1)n2S(=O)(=O)c1ccccc1
Yield: 32 %

Procedure:
The title compound was prepared from 4,4-dimethoxy-cyclohexa-2,5-dienone and 1-benzenesulfonyl-5-methoxy-1H-indole, according to Method C, described above. Yield 32%; mp 126-128° C.; 1H NMR (CDCl3) δ 7.73-7.83 (m, 3H), 7.40-7.49 (m, 2H), 7.33-7.40 (m, 2H), 6.76-6.84 (m, 3H), 6.64 (s, 1H), 6.20 (d, J=10 Hz, 2H), 5.40 (s, 1H), 3.67 (s, 3H); 13C NMR (CDCl3) δ 196.6, 185.3, 157.3, 147.9, 141.8, 137.7, 134.3, 133.2, 129.8, 129.7, 129.3, 127.9, 126.9, 116.8, 115.4, 114.4, 104.2, 81.2, 67.9, 55.9; MS (AP+) m/z 396.09 (M++1), 378.08.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[CH:11][C:12]([CH3:20])(O[Si](C)(C)C)[CH:13]=[CH2:14])=[C:4]([CH3:21])[C:3]1=[O:22].[C:23]1([S:29]([OH:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na]>C(O)(=O)C>[OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[CH:11][C:12]([CH3:20])=[CH:13][CH2:14][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])=[C:4]([CH3:21])[C:3]1=[O:22]
Reactant: C=CC(C)(C=CC1=C(C)C(=O)C(O)CC1(C)C)O[Si](C)(C)C
Reactant: O=S(O)c1ccccc1
Agent: [Na]
Solvent: CC(=O)O
Product: CC(C=CC1=C(C)C(=O)C(O)CC1(C)C)=CCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-hydroxy-3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-3-trimethylsiloxy-1,4-pentadiene (200 mg, 0.62 mmol) in 1 ml glacial acetic acid is added benzenesulfinic acid, sodium salt (153 mg, 0.93 mmoles) and the mixture is stirred overnight at ambient temperature. The mixture is concentrated in vacuo and the remanecens is taken up in 10 ml diethylether and 10 ml 1M sodium hydroxide. The aqueous layer is separated and extracted twice with 10 ml diethylether. The combined ether phases are dried and concentrated in vacuo yielding the title compound as a slightly yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Mg]C.C([Li])CCC.[CH3:20][S:21]SC>C1COCC1>[F:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([S:21][CH3:20])[CH:10]=1
Reactant: CSSC
Reactant: O=C(O)c1ccc(F)cc1Br
Agent: C[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc(F)ccc1C(=O)O
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
A solution of 2-bromo-4-fluorobenzoic acid (15 g, 68.5 mmol, Aldrich) in THF (150 mL) under Argon at 0 degrees C. was treated with chloro(methyl)magnesium (5.64 g, 75.34 mmol, 2.94 M in THF) over 5 minutes. The temperature during addition was maintained below 10 degrees C. The resulting solution was cooled to −78 degrees C. and n-butyllithium (9.65 g, 150.7 mmol, 2.5M in hexanes) was added over 10 minutes. The reaction was kept below −65 degrees C. during the addition. The reaction was stirred at −78 degrees C. for 50 minutes. A solution of (methyldithio)methane (38.71 g, 410.9 mmol) in THF (20 mL), precooled to −78 degrees C., was added by cannula. The reaction was stirred for 10 minutes, warmed to zero degrees C. and stirred at zero degrees C. for 2 hours until a solid began to precipitate. The reaction was allowed to warm to 25 degrees C. The material was filtered and the solid partitioned between ethyl acetate (400 mL) and water (400 mL). The water layer was acidified with HCl to pH of less than 1 and then extracted with ethyl acetate (4×500 mL). The organic was dried over Na2SO4, filtered, and reduced to a small volume in vacuo to produce crystals. The crystals were filtered and dried in vacuo to afford the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][O:14]2)=[CH:9][C:8]=1[F:22])(=O)=O.[F:25][C:26]1[CH:27]=[C:28]([CH:50]=[C:51]([F:57])[C:52]=1[C:53]([F:56])([F:55])[F:54])[O:29][C:30]([F:49])([F:48])[C:31]1[C:36]([F:37])=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:32]=1[F:47].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:26]1[CH:27]=[C:28]([CH:50]=[C:51]([F:57])[C:52]=1[C:53]([F:54])([F:56])[F:55])[O:29][C:30]([F:48])([F:49])[C:31]1[C:32]([F:47])=[CH:33][C:34]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][CH3:21])[CH2:15][O:14]3)=[CH:9][C:8]=2[F:22])=[CH:35][C:36]=1[F:37]
Reactant: CCC[C@H]1CC[C@H](c2ccc(OS(=O)(=O)C(F)(F)F)c(F)c2)OC1
Reactant: CC1(C)OB(c2cc(F)c(C(F)(F)Oc3cc(F)c(C(F)(F)F)c(F)c3)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCC1CCC(c2ccc(-c3cc(F)c(C(F)(F)Oc4cc(F)c(C(F)(F)F)c(F)c4)c(F)c3)c(F)c2)OC1

Procedure:
A mixture of 10.0 g (27.0 mmol) of 2-fluoro-4-(trans-5-propyltetrahydropyran-2-yl)phenyl trifluoromethanesulfonate and 14.3 g (29.4 mmol) of 2-{4-[(3,5-difluoro-4-trifluoromethylphenoxy)difluoromethyl]-3,5-difluorophenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolan, 1.50 g (1.30 mmol) of tetrakis(triphenylphosphine)palladium(0) and 30 ml of 2 N sodium carbonate solution in 100 ml of toluene/ethanol (1:1) is heated under reflux for 20 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=7:3). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 2-{4′-[(3,5-difluoro-4-trifluoromethylphenoxy)difluoromethyl]-2,3′,5′-trifluorobiphenyl-4-yl}-5-propyltetrahydropyran as a colourless solid (m.p. 95° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([CH2:14][CH2:15][NH:16][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CCN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CCNC(=O)OCc2ccccc2)CC1
Reaction time: 4 h

Procedure:
To a solution of cis-[4-(2-amino-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (4.84 g, 20 mmol) in CH2Cl2 (50 mL) and triethylamine (3.06 mL, 22 mmol) was added benzyl chloroformate (3.13 mL, 22 mmol) and the mixture was stirred for 4 hr. The resulting mixture was washed with water, 1 M aqueous HCl, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, CH2Cl2 to 10% MeOH in CH2Cl2) to give cis-[4-(2-benzyloxycarbonylamino-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (5.46 g, 73%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)C4CC4)cc3CO1)CC2
Yield: 73.8 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (100 mg, 0.323 mmol) and cyclopropancarbonyl chloride (32 ul, 0.356 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (90 mg, 74%), MS (ISP) m/e=378.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[N:16]=[N:17][S:18][C:19]=2[CH2:20][O:21][Si](C(C)C)(C(C)C)C(C)C)[CH:5]=[CH:6][C:7]=1[F:8].CO.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[N:16]=[N:17][S:18][C:19]=2[CH2:20][OH:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1snnc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=c1onc(-c2nnsc2CO)n1-c1ccc(F)c(Cl)c1
Temperature: 70 °C
Yield: 87.9 %

Procedure:
Into a round bottom flask was added 4-(3-chloro-4-fluorophenyl)-3-(5-[(triisopropylsilyl)-oxy]methyl-1,2,3-thiadiazol-4-yl)-1,2,4-oxadiazol-5(4H)-one (89 mg, 0.18 mmol), anhydrous MeOH (1.5 mL), and hydrogen chloride in 1,4-dioxane (1.5 mL, 4.0 M). The reaction was heated to 70° C. for 2.5 h. The reaction was concentrated in vacuo and the crude purified by flash chromatography to give the desired product (52 mg, 86%). MF=C11H6ClFN4O3S; LCMS calculated for C11H7ClFN4O3S (M+H)+: m/z=329.0.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH3:12])[CH:3]=1.NC(N)=[S:15]>C(O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([SH:15])[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)[CH3:12]
Reactant: CCc1cc(Cl)n2nccc2n1
Reactant: NC(N)=S
Solvent: CCO
Product: CCc1cc(S)n2nccc2n1

Procedure:
5.0 g (27.5 mmol) of the chloride from Example 1, Step B and 4.2 g (55.2 mmol) thiourea were heated in 100 ml dry ethanol for 5 h. The solvent was distilled off in vacuo and the residue crystallized from ethanol / water to give the title compound in yellow crystals, m.p. 178°-180° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:6]([Cl:16])[N:5]=[CH:4][N:3]=1.[Cl-].[OH:18][C@@H:19]1[C@H:23]([OH:24])[C@@H:22]([CH2:25][OH:26])[CH2:21][C@H:20]1[NH3+:27].CCN(CC)CC>C(O)C>[Cl:16][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:27][C@@H:20]2[CH2:21][C@H:22]([CH2:25][OH:26])[C@@H:23]([OH:24])[C@H:19]2[OH:18])[C:7]=1[CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: CCOC(Cc1c(Cl)ncnc1Cl)OCC
Reactant: [NH3+][C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(Cc1c(Cl)ncnc1N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O)OCC

Procedure:
A mixture of 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (5.35 g, 20.2 mmol) and (1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentanaminium chloride (9.29 g, 24.3 mmol) was taken up in ethanol (236 mL), treated with Et3N (11.2 mL, 80.8 mmol) and heated at reflux for 23 h; HPLC/LC MS indicated consumption of starting materials and presence of product. The reaction mixture was concentrated to afford a tan slurry, which was carried on crude: MS (ESI+) for C16H26ClN3O5 m/z 376.2 (M+H)+; MS (ESI−) for C16H26ClN3O5 m/z 374.2 (M−H)−; HPLC purity >95% (ret. time, 2.436 min). Variation on route from J. Med. Chem. 10, 665 (1967).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]#[CH:10]>C1COCC1.C(OCC)(=O)C>[CH2:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:9]#[CH:8]
Reactant: C#CCBr
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.3g of morpholine (84 mmol) in 80 mL of THF was slowly added 3-bromo-propyne (5.0 g, 42 mmol). A precipitate formed. The reaction was stirred at room temperature for 1 hour. The reaction mixture was then diluted with 300 mL of ethyl acetate (“EtOAc”), and washed sequentially with 2×200 mL water, and 1×100 mL brine. The organic layer was then dried over MgSO4, and concentrated to yield 4-prop-2-ynyl-morpholine as a light yellow liquid (yield. 50%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[O:9]=[C:10]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][C:18](=[O:73])[NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](=[O:72])[NH:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:71]=[CH:70][C:43]([C:44]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67](O)=[O:68])=[CH:48][CH:47]=2)=[O:45])=[CH:42][CH:41]=1.C(Cl)CCl>C(Cl)Cl>[O:9]=[C:10]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][C:18](=[O:73])[NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](=[O:72])[NH:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([O:1][N:2]3[C:6](=[O:7])[CH2:5][CH2:4][C:3]3=[O:8])=[O:68])=[CH:48][CH:47]=2)=[O:45])=[CH:70][CH:71]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
N-hydroxysuccinimide (438 mg, 4.00 mmol) was added to a solution of crude 1-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (3.00 g) in anhydrous DCM (20 ml) was added followed by EDC (946 mg, 5.00 mmol). The reaction was stirred at r.t. for 2-3 hs. Upon completion, reaction was concentrated under reduced pressure and purified by silica gel chromatography (DCM to DCM:iPrOH gradient) to provide 2.15 g (2.12 mmol) of 2,5-dioxopyrrolidin-1-yl 1-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as slightly yellow oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][NH2:35])=[CH:33][C:28]=2[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[Cl:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50]([Cl:64])[C:51]=1[S:52][C:53]1[S:57][C:56]([C:58](O)=[O:59])=[CH:55][C:54]=1[N+:61]([O-:63])=[O:62]>ClCCl>[Cl:64][C:50]1[CH:49]=[N:48][CH:47]=[C:46]([Cl:45])[C:51]=1[S:52][C:53]1[S:57][C:56]([C:58]([NH:35][CH2:34][C:32]2[CH:31]=[CH:30][C:29]3[O:25][CH2:26][CH2:27][C:28]=3[CH:33]=2)=[O:59])=[CH:55][C:54]=1[N+:61]([O-:63])=[O:62]
Reactant: NCc1ccc2c(c1)CCO2
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccc2c(c1)CCO2)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 5.3 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (76.4 mg, 0.51 mmol), 2,3-dihydrobenzofuran-5-ylmethanamine (165.5 mg, 1.28 mmol) and diisopropylethylamine (12 mg, 0.12 mmol) was added to a suspension of 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) in dichloromethane (3 mL) and the resulting mixture was stirred at ambient temperature for 6 hours. TLC analysis showed no acid remaining so the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried (Na2SO4), filtered and the solvent was removed to afford a solid. The crude material was purified by silica gel chromatography using a 70:30 mixture of hexane and ethyl acetate as eluent to afford the title product as a brown solid (11 mg, 5% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.28 (1H, m), 8.99 (2H, m), 8.46 (1H, s), 7.14 (1H, m), 7.00 (1H, m), 6.69 (1H, m), 4.48 (2H, m), 4.30 (2H, m), 3.15 (2H, m). MS m/z: 480.11, 482.11 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:19]5=[N:24][N:25]([CH2:27][C:28]6[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=6)[CH:26]=[C:18]5[CH:17]=[C:16]([CH3:36])[C:15]=4[N:14]=3)=[CH:11][C:10]([O:37][CH3:38])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1>O1CCCC1.C(N)(C)C>[CH:12]([NH:8][C:21]([C:20]1[C:19]2[C:18](=[CH:26][N:25]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[N:24]=2)[CH:17]=[C:16]([CH3:36])[C:15]=1[NH:14][C:13]([C:12]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=[C:10]([O:37][CH3:38])[CH:11]=1)=[O:22])=[O:23])([CH3:13])[CH3:11]
Reactant: COc1ccc(Cn2cc3cc(C)c4nc(-c5cc(OC)nn5-c5ncccc5Cl)oc(=O)c4c3n2)cc1
Solvent: CC(C)N
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc3cc(C)c(NC(=O)c4cc(OC)nn4-c4ncccc4Cl)c(C(=O)NC(C)C)c3n2)cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-2-(4-methoxy-benzyl)-5-methyl-2H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one (0.100 g, 0.189 mmol) in tetrahydrofurane (2 ml) was treated with 16 drops of isopropyl amine and stirred at 20° C. for three hours. The reaction mixture was evaporated and the crude product was purified by flash chromatography on silica gel using a mixture of 75% ethyl acetate 25% cyclohexane. The desired product showed the physical data reported in the corresponding table (P.34.).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:21]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[C:21]([NH:26][CH2:27][C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC(=O)c2cccnc2NCc2ccncc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(NC(=O)c2cccnc2NCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of N-(4-{2-[(tert-butoxy)carbonylamino]-ethyl}phenyl){2-[(4-pyridylmethyl)amino](3-pyridyl)}carboxamide (96 mg, 0.22 mmol, Example 71) in CH2Cl2 (3 mL) was added TFA (3 mL). The mixture was stirred for 3 h at RT. The reaction mixture was concentrated and dried in vacuo to yield N-[4-(2-aminoethyl)phenyl]{2-[(4-pyridylmethyl)-amino](3-pyridyl)}carboxamide. MS (ES+):348 (M+H); (ES−):346 (M−H). Calc'd. for C20H21N5O—347.17.