Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCCC=CCCC.C([NH:22][C@H:23]([C:26]([OH:28])=O)[CH2:24][OH:25])(OCC1C=CC=CC=1)=O.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)(C)C(Cl)=O.CCCCCN.P(=O)(O)(O)O.O.O.C(O)(=O)C(O)=O>C(O)C.O.C(OCC)(=O)C>[CH2:30]([NH:29][C:26](=[O:28])[C@H:23]([CH2:24][OH:25])[NH2:22])[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: c1ccncc1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: CCCC=CCCCCCC
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCN
Solvent: CCO
Product: CCCCCNC(=O)[C@@H](N)CO
Temperature: 50 °C

Procedure:
Under an inert atmosphere, 1,8-diazabicyclo 5.4.0!undec-7-ene (5.10 g, 33.5 mmol) was added to a suspension of Part A carbobenzyloxy-L-serine (7.50 g, 31.4 mmol) in ethanol. Ethyl acetate was added and the mixture was agitated (optionally, with heating up to about 50° C.) to obtain a clear solution. Pyridine (0.25 g, 3.2 mmol) was added and the mixture was cooled to about -30° C. Trimethylacetyl chloride (4.12 g, 34.2 mmol) was added and the mixture was maintained at about -30° C. With cooling, n-amylamine (3.00 g, 34.4 mmol) was added and the mixture was stirred at about -10° C. for about 2 hours. Cooling was discontinued and aqueous phosphoric acid was added. The mixture was warmed to about 10° C. and the phases were separated. The organic solution was washed sequentially with aqueous phosphoric acid, aqueous potassium carbonate, and brine. Throughout these extractions, the aqueous phase was back extracted with ethyl acetate. The combined organic solution was distilled under vacuum at about 25° C. while ethanol was added until all of the ethyl acetate was removed. Under an inert atmosphere, 10% palladium on carbon (50% water, 0.75 g) was added. The resulting mixture was purged with nitrogen and then stirred in the presence of hydrogen at about 25° C. for about 6 hours. The catalyst was removed by filtration, and the clear filtrate was partially concentrated under vacuum at about 30° C. The concentrated filtrate was added to a solution of oxalic acid dihydrate (4.35 g, 34.5 mmol) in ethanol and water and a thick precipitate was formed. The suspension was heated to reflux to obtain a clear solution. Water was added at the reflux temperature until a slight turbidity was observed. The mixture was cooled to about 0° C. and stirred until crystallization was complete (about 1 hour). The product was collected and the cake was washed with ethanol. The product was dried under vacuum at about 25° C. to afford the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O)(=O)C>O>[N:22]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: C1COCCN1
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCOCC3)cc2c1=O
Temperature: 140 °C

Procedure:
A mixture of 100 mg (0.314 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 0.274 ml (3.14 mmol) of morpholine is heated at 140° C. (oil bath temperature) for 1 hour in a closed vial. After cooling, the residue is dissolved in water, the solution acidified with 2 M acetic acid to pH ˜5 and allowed to stand at room temperature. An orange precipitate forms which is filtered and recrystallized from DMSO/water yielding 81 mg of the title compound as an orange powder, m.p. >260° C.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:31][CH:32]([C:35]#[N:36])[C:33]#[N:34]>O1CCCC1>[NH2:36][C:35]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([OH:10])=[N:31][C:32]=1[C:33]#[N:34]
Reactant: N#CC(N)C#N
Reactant: O=C=NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nc(O)n(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 107.5 %

Procedure:
Benzylisocyanate (25 g, 188 mmol) and N,N-diisopropylethylamine (23.5 ml, 130 mmol) were added to aminomalononitrile p-toluenesulfonate (45 g, 178 mmol) suspended in tetrahydrofuran. The mixture was stirred at room temperature for 14 hours and then the solvent was removed in vacuo. To the residue was added ethyl acetate and the solution was washed and the organic layer was dried on magnesium sulfate. The solvent was removed in vacuo. To the residue was added tetrahydrofuran and 1N aqueous sodium hydroxide. The solution was stirred at 50° C. for 20 minutes, and neutralized with 15% aqueous potassium hydrogen sulfide. The resulting crystals were filtered and dried to give the subject compound (41 g, 106%). The crude product was used for next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:5]([C:2]([CH2:3][O:4][C:10]([CH3:11])=[O:12])([F:9])[Cl:1])([F:8])([F:7])[F:6]
Reactant: CC(=O)OC(C)=O
Reactant: OCC(F)(Cl)C(F)(F)F
Product: CC(=O)OCC(F)(Cl)C(F)(F)F

Procedure:
Example 6 illustrates the esterification of 2-chloro-2,3,3,3-tetrafluoropropanol (CF3CClFCH2OH) with acetic anhydride to produce CF3CClFCH2OC(═O)CH3 and the reaction products obtained from this esterification.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH:12]=O>CO.[Pd]>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][NH:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCCC1
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(CNC1CCCCCC1)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of cycloheptanamine (8.62 g) in methanol (20 mL) was added 2,2-dimethoxyacetaldehyde (11.49 mL) and the mixture stirred at room temperature for 5 h. Palladium on carbon 10% (1 g) was added and the mixture hydrogenated at 5 bar for 16 h. It was filtered and concentrated under vacuum to give N-(2,2-dimethoxyethyl)cycloheptanamine as an oil (15.26 g). 1H NMR (300 MHz, CDCl3) δ 4.47 (t, J=5.6 Hz, 1H), 3.39 (s, 6H), 2.73 (d, J=5.6 Hz, 2H), 2.67-2.55 (m, 1H), 1.90-1.25 (m, 12H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1Br.[Li+].CCC[CH2-].[O:20]1[CH2:25][CH2:24][O:23][C:22]([C:26](N2CCCC2)=[O:27])=[N:21]1.[Cl-].[NH4+]>O1CCCC1.O.C(OCC)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:26]([C:22]1[O:23][CH2:24][CH2:25][O:20][N:21]=1)=[O:27]
Reactant: O=C(C1=NOCCO1)N1CCCC1
Reactant: Brc1ccccc1OC1CCCCO1
Agent: [CH2-]CCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(C1=NOCCO1)c1ccccc1OC1CCCCO1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
5 g (0.0193 mol) of 1-(tetrahydropyran-2-yloxy)-2-bromobenzene (Synthesis 1987, page 951) are dissolved in 20 ml of tetrahydrofuran, and the solution is cooled to −40° C. First, 10.8 g (0.0388 mol) of N-butyllithium (23% strength solution in hexane) and then a 50% strength solution of 7.2 g (0.0195 mol) of 1-(5,6-dihydro-1,4,2-dioxazin-3-yl)-1-(pyrrolidin-1-yl)-methanone in tetrahydrofuran are added dropwise at this temperature, and the mixture is stirred for 10 minutes at −40° C. A solution of 4.2 g (0.0785 mol) of ammonium chloride in 25 ml of water is then added dropwise, diethyl ether is added, the organic phase is separated off, and the aqueous phase is extracted repeatedly using diethyl ether. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue crystallizes upon trituration with pentane. The crystals are filtered off and washed twice using 5 ml of diisopropyl ether. 2.4 g (35.8% of theory) of 3-[2-(tetrahydropyran-2-yloxy)-benzoyl]-5,6-dihydro-1,4,2-dioxazine (content according to HPLC analysis: 84%) are obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][CH2:6][C:7]1[C:8]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[CH:20][C:9]=2[S:10][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]>ClCCl.C(OCC)(=O)C>[Br:5][CH2:6][C:7]1[C:8]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[C:20]([N+:1]([O-:4])=[O:2])[C:9]=2[S:10][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1sc2cc(O)c(O)cc2c1CBr)N1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1CBr)N1CCOCC1
Reaction time: 2 h

Procedure:
A solution of 1 M HNO3 in dichloromethane (1.02 ml) was added to a solution of (3-bromomethyl-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (0.35 g) in ethyl acetate (50 ml) and stirring continued at 60° C. for 2 hours. The cooled mixture was washed with water, dried and evaporated to dryness. The product was recrystallized from acetone.
Reaction SMILES: [C:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6]1)([O:3][CH3:4])=[O:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1C=CC=CC=1>[C:1]([C:5]1[N:6]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1Cc2cc(OC)ccc2C(c2ccccc2)=N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: COC(=O)c1cc2cc(OC)ccc2c(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 3-carbomethoxy-6-methoxy-1-phenyl-3,4-dihydro-isoquinoline (257 mg) and DDQ (217 mg) in benzene (35 mL) was heated at reflux for 1 hr. the mixture was cooled to r.t., filtered through celite washing with toluene and the filtrate was concentrated. Flash chromatography of the residue (silica gel; toluene/EtOAc (85:15)) provided the title compound as a solid.
Reaction SMILES: O1C=CC[CH:2]1C(O)=O.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[C:19]([OH:21])=[O:20].CC(C)([O-])C.[K+].C[Si](C)(C)[N-][Si](C)(C)C.[K+]>O1CCCC1>[CH3:2][C:10]1([C:19]([OH:21])=[O:20])[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1
Reactant: O=C(O)C1CC=CO1
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: CC(C)(C)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCc2ccccc2C1

Procedure:
The title compound was prepared following the procedures described for Reference Example 5 substituting 2,3-dihydrofuran-2-carboxylic acid with 1,2,3,4-tetrahydro-2-naphthoic acid at Step A and potassium tert-butoxide in tetrahydrofuran with potassium hexamethyldisilazide (0.5 M in toluene) at Step B. 1H NMR (500 MHz, CD3OD): δ 7.12-7.0 (m, 4H), 3.71 (d, 1H), 3.22 (d, 1H), 2.84 (t, 1H), 2.65 (d, 1H), 2.17 (m, 1H), 1.77 (m, 1H), 1.28 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH2:25][CH2:26]O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)[N:4]=1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>O1CCCC1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH2:25][CH2:26][N:52]4[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CCCO)ccn34)c12
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CCCN5CCN(C)CC5)ccn34)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 11.3 %

Procedure:
N-(3-Ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(3-hydroxypropyl)imidazo[1,2-a]pyridine-3-carboxamide (77 mg, 0.16 mmol) was dissolved in tetrahydrofuran (0.8 mL) and treated with triethylamine (66 μL, 0.48 mmol) followed by dropwise addition of methanesulfonyl chloride (38 mL, 0.49 mmol). The mixture was stirred at ambient temperature for 2.5 hours. 1-Methyl piperazine (365 μL, 3.3 mmol) was added and the mixture was heated to 60° C. for 10 hours. The mixture was quenched with the addition of saturated sodium bicarbonate solution and extracted with dichloromethane 3 times. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified using preparative thin layer chromatography (silica, 2 mm) eluting with 10% methanol/dichloromethane with 0.2% ammonium hydroxide to give N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(3-(4-methylpiperazin-1-yl)propyl) imidazo[1,2-a]pyridine-3-carboxamide (10 mg). MS m/z 551.4 (M+1, APCI+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([F:27])=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][NH:13][C:14]([C@@H:16]1[C@H:20]([N:21]=[N+:22]=[N-:23])[CH2:19][CH2:18][NH:17]1)=[O:15].COC([C@@H]1[C@@H](N=[N+]=[N-])CCN1C(OC(C)(C)C)=O)=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:10]([F:27])=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][NH:13][C:14]([C@@H:16]1[C@@H:20]([N:21]=[N+:22]=[N-:23])[CH2:19][CH2:18][NH:17]1)=[O:15]
Reactant: [N-]=[N+]=N[C@@H]1CCN[C@@H]1C(=O)NCc1cccc(Cl)c1F
Agent: COC(=O)[C@@H]1[C@@H](N=[N+]=[N-])CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=N[C@H]1CCN[C@@H]1C(=O)NCc1cccc(Cl)c1F

Procedure:
was prepared in a similar manner as described in procedure 1 for (2S,3R)-3-azido-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide trifluoroacetate from (2S,3S)-3-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [361367-99-9]. MS (LC/MS): 298 [M+H]+; tR (HPLC conditions b): 2.68 min.
Reaction SMILES: BrC1C=C(C=CC=1Br)CO.[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15](O)=[O:16]>>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:15][OH:16]
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: OCc1ccc(Br)c(Br)c1
Product: Cc1ccc(CO)cc1Br

Procedure:
in a similar manner to that hereinbefore described in Example 1 for the preparation of 3,4-dibromobenzyl alcohol but replacing the 3,4-dibromobenzoic acid by 3-bromo-4-methylbenzoic acid [described by Jannasch and Dieckmann, Ann., 171, 83 (1874)]; there was obtained 3-bromo-4-methylbenzyl alcohol as a clear orange oil of sufficient purity for subsequent reaction; and
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[N:5]=1.[CH2:13]([O:16][C:17]1[CH:25]=[C:24]([S:26][CH3:27])[CH:23]=[CH:22][C:18]=1[C:19](O)=O)[CH2:14][CH3:15]>>[ClH:1].[CH2:13]([O:16][C:17]1[CH:25]=[C:24]([S:26][CH3:27])[CH:23]=[CH:22][C:18]=1[C:19]1[NH:10][C:9]2[C:4]([N:3]=1)=[N:5][C:6]([O:11][CH3:12])=[CH:7][CH:8]=2)[CH2:14][CH3:15]
Reactant: COc1ccc(N)c(N)n1
Reactant: CCCOc1cc(SC)ccc1C(=O)O
Agent: Cl
Product: CCCOc1cc(SC)ccc1-c1nc2nc(OC)ccc2[nH]1

Procedure:
Prepared analogously to Example 5 from 2,3-diamino-6-methoxypyridine dihydrochloride and 2-propoxy-4-methylmercapto-benzoic acid.
Reaction SMILES: CCN[C:4]([C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[C:17](NCCC4C=CC(CCC(O)=O)=CC=4)[N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:35])[C@@H:7]1[OH:36])=[O:5].C(O)C(N)(CO)CO.Cl>CS(C)=O>[C@@H:9]1([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:6]([CH2:4][OH:5])[C@@H:7]([OH:36])[C@H:8]1[OH:35]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(NCCc4ccc(CCC(=O)O)cc4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CS(C)=O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
To 100 μl of the purified cell suspension, 80 μL of tritium-labeled CGS-21680 {3H-2-[p-(2-carboxyethyl)phenethylamino]-5′-(N-ethylcarbox amido)adenosine: 40 Ci/mmol; New England Nuclear [The Journal of Pharmacology and Experimental Therapeutics, Vol. 251, p. 888, 1989]} (final concentration of 6.0 mmol/L), and 20 μL of the test compound solution (dimethylsulfoxide solution of test compound diluted with Tris HCl buffer) are added. The mixture is allowed to stand at 25° C. for 120 minutes, followed by rapid suction filtration using glass-fiber filter paper (GF/C; Whatman), and then immediately washed three times with 200 μL of ice-cooled Tris HCl buffer (50 mmol/L). The glass-fiber filter paper is then placed in a vial, and MicroScinti liquid (PKI) is added. Then, the radioactivity is measured with a TopCount (PerkinElmer).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[N:49]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:36].C(N(CC)C(C)C)(C)C.ClCCl.CO>C(#N)C>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:53][CH2:54][CH2:55][N:49]([C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:50][CH2:51]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 22 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.92 g, 1.95 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (1.6 g, 2.9 mmol), and N,N-diisopropylethylamine (2.2 mL, 12.6 mmol) in acetonitrile (36 mL). Heat to reflux. After 22 hours, cool and partition the residue between a saturated aqueous sodium bicarbonate solution and ethyl acetate. Separate the organic layer and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel eluting with dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1 to give the title compound.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])#[N:3]>ClCCl>[C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:1])=[O:8])#[N:3]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: N
Solvent: ClCCl
Product: N#Cc1cccc(C(N)=O)c1
Reaction time: 0.33 h

Procedure:
0.88 Ammonia solution (30 ml) was slowly added to a solution of 3-cyanobenzoyl chloride (10 g, 60.3 mmol) in dichloromethane (100 ml) at 0° C. under nitrogen and the reaction was stirred for 20 minutes. The mixture was filtered and the solid was washed with water (50 ml) then diethylether (50 ml), azeotroped with toluene and dried in vacuo to provide the title compound (9 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.Br[CH2:44][CH2:45][O:46][C:47](Cl)=[O:48].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.CN(C=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]([C@H:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:1]4[CH2:44][CH2:45][O:46][C:47]4=[O:48])=[CH:35][CH:34]=3)[C@@H:13]([CH3:33])[CH2:14]2)[C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN)cc2)c2ccccc21
Reactant: O=C(Cl)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCOC3=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,4R)-N-{1-[4-(3-Amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (50 mg, 0.102 mmol) was dissolved in methylene chloride (3 mL) and triethylamine (0.150 mL, 1.08 mmol) and cooled to −40° C. 2-Bromoethylchloroformate (0.016 mL, 0.153 mmol) was added and the reaction was allowed to warm to room temperature. After 1 hour at room temperature, DMF (2 mL) and Cs2CO3 (100 mg, 0.307 mmol) were added and the mixture was stirred over night. The mixture was partitioned between methylene chloride and water; the methylene chloride layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (1/1 hexanes/ethyl acetate-ethyl acetate gradient) to afford the product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[CH:10]=[CH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1.Cl.[NH2:22][CH2:23][C@H:24]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[C:28]([O:27][C:25](=[O:26])[C@@H:24]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:23][NH:22][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([CH:11]=[CH:10][C:2]2[NH:1][C:9]3[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=3)=[CH:20][CH:19]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc(C=Cc2nc3ncccc3[nH]2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(C=Cc2nc3ncccc3[nH]2)cc1)NS(=O)(=O)c1ccccc1
Reaction time: 18 h

Procedure:
A DMF solution (10 mL) containing 31-3 (301 mg, 1.0 mmol) 2-1 (336 mg, 1.0 mmol), HOBT (206 mg, 1.35 mmol), EDC (258 mg, 1.35 mmol) and NMM (440 μl, 4.0 mmol) was stirred under ambient conditions for 18 h. The DMF was evaporated and the residue partitioned between CH2Cl2 and H2O. The organic layer was dried (MgSO4) and concentrated to a yellow gum which was purified by flash chromatography (silica, 4:1, CHCl3 ·NH3 /IPA) to provide impure 31-4 which was rechromatographed (silica, 9:1 EtOAc/IPA) to give 31-4 as a colorless foam.
Reaction SMILES: [CH2:1]([N:8]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:9][C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([N:8]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccccc2)cc1
Yield: 98.6 %

Procedure:
Ethyl 2-{benzyl[(4-methoxyphenyl)sulfonyl]amino}acetate (11.62 g, 31.97 mmol) was dissolved in ethanol (100 ml), and 1N sodium hydroxide (100 ml) was added thereto. After being reacted for 16 hours at room temperature, the solvent was evaporated out. 3N hydrochloric acid (150 ml) was added to the residue and the water phase was extracted with ethyl acetate (200 ml×2). The organic layer was washed with saturated brine, and then dried over sodium sulfate. The solvent was evaporated out and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1), to give 2-{benzyl[(4-methoxyphenyl)sulfonyl]amino}acetic acid (10.57 g, 99%).