Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:18]=[C:17]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36]C(=O)OC(C)(C)C)[N:16]=2)=[CH:10][CH:9]=1)=[O:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:17]1[N:18]=[C:19]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])[N:20]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]([NH:5][CH2:4][CH2:3][CH2:2][Cl:1])=[O:7])=[CH:9][CH:10]=2)[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCCCNc1nc(Nc2ccc(C(=O)NCCCCl)cc2)nc(OCC(F)(F)F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCCCCCNc1nc(Nc2ccc(C(=O)NCCCCl)cc2)nc(OCC(F)(F)F)n1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
tert-butyl (8-((4-((4-((3-chloropropyl)carbamoyl)phenyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)octyl)carbamate (264 mg, 0.418 mmol) was dissolved in a 1:1 TFA (1 ml, 12.98 mmol)/DCM (1 mL). The reaction was stirred for 1 h. The solvent was removed under vacuum and the residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution, then brine. The organic layer was collected and dried over sodium sulfate, and concentrated under vacuum to give 222 mg (100%) 4-(4-(8-aminooctylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(3-chloropropyl)benzamide as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:11]=[C:10]([Br:12])[S:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[N+:18]([O-])([OH:20])=[O:19]>>[Br:6][C:7]1[C:11]([N+:18]([O-:20])=[O:19])=[C:10]([Br:12])[S:9][C:8]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1sc(Br)cc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1sc(Br)c([N+](=O)[O-])c1Br
Temperature: -5 °C
Reaction time: 1 h
Yield: 59.54 %

Procedure:
Sulfuric acid (27.6 g, 15.0 ml, 281.0 mmol) was added in a dropwise manner to ethyl 3,5-dibromothiophene-2-carboxylate (Prepared according to procedure reported in JCS Perkin Trans-1:Organic and Bioorganic Chemistry (1972-1999), 1973, p 1766-1770), 5.0 g (15.92 mmol), at room temperature (about 25° C.). The reaction mixture was then cooled to −5° C. and to the cooled mixture was added nitric acid (2.0 g, 2.04 ml, 31.84 mmol) slowly. The reaction mixture was then stirred at 0° C. for 1 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then poured onto ice-water (150 ml). The mixture so obtained was extracted with ethyl acetate (2×100 ml). The combined organic layer was dried over sodium sulphate and was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in hexanes as an eluent to obtain the title compound (3.40 g, 59.54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=O)[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:42]CCl>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]=[C:14]([Cl:42])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17]
Reactant: O=C(Nc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)C(F)(F)F
Reactant: ClCCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Cl)c(N=C(Cl)C(F)(F)C(F)(F)F)c(Cl)c1
Reaction time: 18 h

Procedure:
First, 4.3 g (11 mmol) of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,3,3,3-pentafluoropropionamide was dissolved in 22 ml of dichloromethane, to which 1.8 ml of carbon tetrachloride and 4.5 g (17 mmol) of triphenylphosphine were added at room temperature, and the mixture was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of hexane, and undissolved matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3.8 g of N-(2,6-dichloro-4-trifluoromethylphenyl)-2,2,3,3,3-pentafluoropropionimidoyl chloride.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:55])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:54])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:53])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:52])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:51])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:50])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:49])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:48])[CH2:42][CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46])=[CH:7][CH2:8]O.N1C=CC=CC=1>CCCCCC>[Br:2][CH2:8][CH:7]=[C:6]([CH3:5])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:55])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:54])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:53])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:52])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:51])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:50])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:49])[CH2:38][CH2:39][CH:40]=[C:41]([CH3:48])[CH2:42][CH2:43][CH:44]=[C:45]([CH3:47])[CH3:46]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCBr
Temperature: 10 °C
Yield: 168.8 %

Procedure:
Under an atmosphere of argon, a solution of phosphorus tribromide (8.32 g, 30.7 mmol) in 27 ml of n-hexane was added in dropwise to a mixture of 3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaen-1-ol (40 g, 57.3 mmol) and pyridine (1.92 ml, 23.8 mmol) in 587 ml of n-hexane at the temperature below 10° C. The solution was stirred at 10° C. for an hour, allowed to warm slowly from 10° to 20° C., stirred at 20°-25° C. for an hour and poured into cracked ice with stirring. The resulting precipitate was filtered off and the filtrate was extracted with n-hexane. The organic layer was washed with 5% sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness to afford 39.5 g (90.4%) of the desired compound, as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][N:43]([CH3:69])[CH2:44][CH2:45][O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH2:64])[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:69][N:43]([CH3:42])[CH2:44][CH2:45][O:46][C:47](=[O:68])[C@@:48]([CH2:66][OH:67])([CH3:65])[CH2:49][C@H:50]([NH:64][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:51][C:52]1[CH:53]=[CH:54][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:56][CH:57]=1
Reactant: CN(C)CCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.1 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (0.0274 g, 0.242 mmol), DIPEA (169 μL, 969 μmol) and HATU (92 mg, 242 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-dimethylamino-ethyl ester (93 mg, 240 μmol), predissolved in DMF (0.2 mL) and DIPEA (0.5 eq.). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product was purified by preparative HPLC and lyophilized to yield the title compound (30 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H33N5O4, 480.25. found 480.4.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O.C1COCC1.O>[CH2:22]([O:21][C:19]([NH:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCC[C@H](N)C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
12 g (66.1 mmol) of rac-methyl norleucinate hydrochloride were initially charged in 974 ml of water/THF (8:1), and 28.3 g (204.8 mmol) of potassium carbonate were added. The reaction mixture was cooled to 0° C. 12.3 ml (72.7 mmol) of benzyl chloroformate were slowly added dropwise and the reaction mixture was stirred at RT overnight. The mixture was diluted with 480 ml of water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate=4:1). This gave 18.0 g (97.6% of theory, purity 100%) of the target compound.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:12](Cl)(=[O:23])[O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.CCN(CC)CC>C(Cl)Cl>[N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][N:4]([C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:23])[CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
A mixture of ethyl piperazine-1-carboxylate (300 mg, 1.90 mmol), 4-nitrophenyl carbonochloridate (460 mg, 2.28 mmol) and Et3N (576 mg, 5.69 mmol) in anhydrous CH2Cl2 (7 mL) was stirred at room temperature for 24 h, and then the reaction mixture turned to a yellow solution. Extraction with NaHCO3(aq.) until the organic layer turns to transparent solution. And then the organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column with elution of EtOAc/hexane (1:1.5) to give 1-ethyl 4-(4-nitrophenyl) piperazine-1,4-dicarboxylate (172 mg, 45% yield). C14H17N3O6; pale yellow solid; mp 125-128° C.; IR vmax (neat) 3512, 3082, 2983, 2930, 2867, 1730, 1701, 1594, 1523, 1459, 1425, 1348, 1288, 1209, 1163, 1085, 1055, 996, 957 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.23 (1H, d, J=8.8 Hz), 7.28 (1H, t, J=8.8 Hz), 4.17 (2H, q, J=6.8 Hz), 3.66 (2H, br s), 3.56 (6H, br s), 1.28 (3H, t, J=7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 155.7, 155.1, 151.9, 144.7, 124.9 (2×), 122.1 (2×), 61.8, 44.5, 43.8, 43.4 (2×), 14.8.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[CH:12]12[NH:19][CH:16]([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH:16]12[N:19]([C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=3)[CH:12]([CH2:18][CH2:17]1)[CH2:13][CH2:14][CH2:15]2
Reactant: C1CC2CCC(C1)N2
Reactant: N#Cc1ccc(F)cc1Cl
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2C3CCCC2CC3)cc1Cl
Temperature: 120 °C

Procedure:
2-Chloro-4-fluorobenzonitrile (0.97 g, 6.2 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (0.92 g, 6.2 mmol), and N,N-diisopropylethylamine (1.6 g, 12 mmol) were combined in DMSO (15 mL) and heated at 120° C. for 16 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The aqueous phase was separated and extracted with diethyl ether. The organic layers were combined, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]2[O:18][CH2:17][O:16][C:15]=12)[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7]>CO.[Pd]>[OH:7][CH:6]([C:5]1[CH:13]=[C:14]2[O:18][CH2:17][O:16][C:15]2=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(=O)c1cc(OC)c2c(c1)OCO2
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(O)c1cc(OC)c2c(c1)OCO2
Yield: 100.2 %

Procedure:
200 mg of methyl 3-methoxy-4,5-methylenedioxybenzoylacetate (10) was suspended together with 20 mg of 5% Pd/C in 5 ml of methanol and subjected to hydrogenation at normal temperature and pressure. After the absorption of a predetermined amount of hydrogen was ascertained, the reaction mixture was filtered to remove the catalyst and then washed with methanol. On concentrating the filtrate, there was obtained 202 mg of methyl 3-hydroxy-3-(3-methoxy-4,5-methylenedioxyphenyl)propionate (11) as an oil with a quantitative yield.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:14])[CH:13]=2)=[CH:5][CH:4]=1.[Br:19]Br.C(O)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:19][C:13]1[C:12](=[O:14])[C:11]2([CH2:15][CH2:16][CH2:17][CH2:18]2)[O:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: CSc1ccc(C2=CC(=O)C3(CCCC3)O2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CSc1ccc(C2=C(Br)C(=O)C3(CCCC3)O2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 147 mg of 2-{4-(methylthio)phenyl}-1-oxa-spiro[4,4]non-2-en-4-one in 30 ml carbon tetrachloride, were added 1 ml bromine and 0.1 ml acetic acid. The reaction mixture was stirred for 1 hour at room temperature. Then the reaction was quenched by adding saturated aqueous sodium thiosulfate solution until the characteristic color of bromine disappeared. The quenched solution was extracted with dichloromethane (10 ml×3). The organic layer was concentrated under reduced pressure and the resulting residue was purified by column chromatography (hexane/ethylacetate) to yield 50 mg of 3-bromo-2-{4-(methylthio)phenyl}-1-oxa-spiro[4,4]non-2-en-4-one. NMR: δ1.98 (m, 4H), 2.11 (m, 4H), 2.55 (s, 3H), 7.32 (d, J=8.7 Hz, 2H), 8.13 (d, J=8.7 Hz, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[CH:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:2][O:3][C:4](=[O:14])[C@@H:5]([NH:13][C:25](=[O:26])[CH2:24][O:23][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCC(=O)Cl
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Temperature: -78 °C
Yield: 73 %

Procedure:
500 mg of 2-amino-3-phenyl-propionic acid methylester hydrochloride dissolved in 10 ml of chloroform was cooled to −78° C., 0.96 ml of triethylamine and 0.23 ml of methoxyacetylchloride were added thereto, and the solution was reacted at room temperature for 2 hours. The reacted solution dissolved in distilled water was adjusted to pH 9 by adding saturated sodium bicarbonate solution, extracted with organic solvent, dried over magnesium sulfate, and filtered and distilled under a reduced pressure to obtain the title compound (427 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:24][CH2:25][O:26]C3CCCCO3)[C:16]3([C:21]([OH:23])=O)[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:33][C:34]([NH2:36])=[NH:35])=[N:4][CH:3]=1.Cl>CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]3[CH2:24][CH2:25][O:26][C:21](=[O:23])[C:16]43[CH2:17][CH2:18][CH2:19][CH2:20]4)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([N:33]=[C:34]([NH2:35])[NH2:36])=[N:4][CH:3]=1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CCOC3CCCCO3)C3(C(=O)O)CCCC3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(N)=Nc1ncc(Cl)c2ccc(S(=O)(=O)N3CCOC(=O)C34CCCC4)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 1945.9 %

Procedure:
1-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl][2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino}cyclopentanecarboxylic acid (20 mg, 0.037 mmol) was dissolved in EtOAc (20 ml), ethereal HCl (10 ml) added, and the reaction stirred at room temperature for 18 h. The resulting precipitate was filtered, washed with EtOAc and dried under vacuum to give N"-{4-Chloro-7-[(10-oxo-9-oxa-6-azaspiro[4.5]dec-6-yl)sulphonyl]-1-isoquinolinyl}guanidine hydrochloride (17 mg, 0.36 mmol).
Reaction SMILES: C[C:2]1([CH3:20])[CH2:15][N:14]2[C:5](=NC3C([C:13]2=O)=CC=C(C(O)=O)C=3)[CH2:4][CH2:3]1.[OH:21][NH:22][C:23](=[NH:30])C1C=CC=CN=1.CC[N:33]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:4]1[CH:3]2[CH:2]([C:20]3[O:21][N:22]=[C:23]([NH2:30])[N:33]=3)[CH2:15][N:14]([CH2:13]2)[CH2:5]1
Reactant: N=C(NO)c1ccccn1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC1(C)CCc2nc3cc(C(=O)O)ccc3c(=O)n2C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Nc1noc(C2CN3CCC2C3)n1
Temperature: 25 °C

Procedure:
A solution of an acid (e.g., 8,8-dimethyl-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazoline-3-carboxylic acid, 1 equiv), N-hydroxypicolinimidamide (1.5 equiv), EDCI (1.5 equiv) and HOBt (1.5 equiv) in DMF was stirred at 80° C. overnight. The reaction was cooled to room temperature, then the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude residue was purified by preparative chromatography to give the desired oxadiazole-containing product (e.g., 8,8-dimethyl-3-(3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl)-6,7,8,9-tetrahydropyrido[2,1-b]quinazolin-11-one).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]/[C:10](/[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11]\[OH:12])=[CH:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O/N=C(\CC(c1ccccc1)c1ccc(Br)cc1)c1ccncc1
Product: Cc1ccc(-c2ccc(C(C/C(=N\O)c3ccncc3)c3ccccc3)cc2)cn1

Procedure:
In analogy to example 22, from (E)-3-(4-bromo-phenyl)-3-phenyl-1-pyridin-4-yl-propan-1-one oxime (example 5) and 6-methylpyridine-3-boronic acid was prepared the title compound as a colorless oil, MS (ESI+): m/z=394.1 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[Si:15]([O:22][CH2:23][CH2:24]O)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[C:18]([Si:15]([CH3:17])([CH3:16])[O:22][CH2:23][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([O:13][CH3:14])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: CO[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via the Mitsunobu coupling procedure with 2-(tert-butyldimethylsilanyloxy)ethanol (Standard Procedure B).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[I:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>>[I:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH:25][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1cccc(I)c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: Ic1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-iodobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 428.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.59 (s, 1H); 8.44 (d, J=4.7 Hz, 1H); 8.02 (br s, 1H); 7.86 (m, 1H); 7.79 (s, 1H); 7.65 (d, J=7.8 Hz, 1H); 7.38 (m, 3H); 7.12 (t, J=7.8 Hz, 1H), 6.87 (d, J=5.3 Hz, 1H); 5.78 (br s, 1H); 4.71 (d, J=5.9 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[CH:16]=NCC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=O)C(O)=[O:28].CO>O1CCOCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[CH:16]=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)O
Reactant: Fc1cccc(NCc2ccccc2)c1C=NCc1ccccc1
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1c(F)cccc1NCc1ccccc1
Reaction time: 1 h
Yield: 786.3 %

Procedure:
To a solution of Example 1A (11.95 g, 3.9 mmol) in dioxane was added water (40 mL) until the solution just clouded and then dioxane was added until the solution became clear again(˜5 mL). Oxalic acid (9.83 g, 78.0 mmol) was added in a single portion to give a dark orange solution which became a thick slurry. To the slurry was added in sequence: water (110 mL), dioxane (60 mL), and methanol (20 mL). This gave a mostly homogeneous solution with some small crystals which eventually dissolved as the reaction mixture was stirred for 1 hour. The volume of the reaction was reduced to ⅓ of the original volume by concentration under vacuum. The resulting solution was extracted (3×, ethyl acetate). The organic extracts were combined and washed (2×, 10% aqueous HCl; 2×, saturated aqueous NaHCO3; 2×, brine), dried (Na2SO4), filtered and concentrated under vacuum to give a thick orange-yellow oil which was dried under vacuum at 45° C. to a constant weight providing the title compound (7.03 g, 79%) as a orange-yellow solid. This material was pure by 1H NMR. A small portion was recrystallized from ether/hexanes.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH2:7]([O:11][CH:12]([O:14][NH:15][C:16]([C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH:28]3[CH:26]([CH:27]3[NH:30][CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=3)[CH2:25]2)=[N:22][CH:23]=1)=[O:17])[CH3:13])[CH:8]([CH3:10])[CH3:9].[CH2:42]([N:44]([CH2:47]C)[CH2:45][CH3:46])[CH3:43]>CN(C=O)C.C(Cl)Cl>[CH2:7]([O:11][CH:12]([O:14][NH:15][C:16]([C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:25][CH:26]3[CH:28]([CH:27]3[N:30]([C:1](=[O:5])[CH2:2][CH2:47][N:44]([CH2:45][CH3:46])[CH2:42][CH3:43])[CH2:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=3)[CH2:29]2)=[N:22][CH:23]=1)=[O:17])[CH3:13])[CH:8]([CH3:10])[CH3:9]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)COC(C)ONC(=O)c1cnc(N2CC3C(C2)C3NCc2ccc3ccccc3c2)nc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)CCC(=O)N(Cc1ccc2ccccc2c1)C1C2CN(c3ncc(C(=O)NOC(C)OCC(C)C)cn3)CC21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-N,N-Diethylaminopropionic acid (73 mg, 0.5 mmol) was suspended in oxalyl chloride (1 ml, 11.2 mmol) and DMF (1 drop) was added. The resultant mixture was stirred at r.t. overnight. The reaction mixture was then evaporated under reduced pressure and azeotroped with DCM. The residue was dissolved in DCM (1 ml) and added to an ice-cooled solution of N-(1-isobutoxyethoxy) 2-{6-[(naphthalen-2-ylmethyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}-pyrimidine-5-carboxamide (100 mg, 0.21 mmol) in DCM (3 ml) and triethylamine (0.3 ml, 2.15 mmol). After stirring at 0° C. for 20 min, the resulting mixture was stirred at r.t. overnight. The reaction mixture was partitioned between DCM (5 ml) and water (5 ml). The aqueous layer was extracted twice more with DCM (2×5 ml) and the combined organics washed with brine (2×5 ml), dried (MgSO4) and evaporated to dryness. The title compound was obtained as a white solid (199 mg, quant.). m/z 603 [M+H]+.