Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C@@H:18]([NH3+:20])[CH3:19])[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][C:46]([C:50](O)=[O:51])=[CH:47][CH:48]=3)[C:43]([CH3:53])=[C:42]2[CH3:54])=[CH:36][CH:35]=1)=[O:27])(C)(C)C>>[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C@@H:18]([NH:20][C:50]([C:46]2[CH:45]=[C:44]3[C:49](=[CH:48][CH:47]=2)[N:41]([CH2:40][C:37]2[CH:36]=[CH:35][C:34]([C:29]4[C:28]([C:26]([OH:27])=[O:25])=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:39][CH:38]=2)[C:42]([CH3:54])=[C:43]3[CH3:53])=[O:51])[CH3:19])[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H]([NH3+])C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)C3CCN(C(=O)OCc4ccccc4)CC3)cc12

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with ((S)-1-(1-((benzyloxy)carbonyl)piperidin-4-yl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-H-indole-5-carboxylic acid. ESI-MS (m/z): 643 [M+1]+.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:33])[C:14]=2[NH:18][C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[C:23]([F:31])[CH:22]=2)[C:9]1=[O:34])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:31][C:23]1[CH:22]=[C:21]([CH2:20][C:19]([NH:18][C:14]2[C:13]([CH3:33])=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[CH:17][N:8]([C@@H:6]([CH3:7])[CH2:5][OH:4])[C:9]3=[O:34])=[O:32])[CH:26]=[CH:25][C:24]=1[C:27]([F:30])([F:28])[F:29]
Reactant: CC(=O)OC[C@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(=O)n([C@@H](C)CO)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (S)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)-acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (200.00 mg, 0.41803 mmol), potassium carbonate (173 mg, 0.00125 mol), methanol (15 mL, 0.37 mol) and few drops of water. The reaction was stirred at room temperature for 1 h. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was extracted with IPA:chloroforn, 1:3, washed with water and the solvent was removed under reduced pressure. The residue was purified by reverse phase prep HPLC to give the desired compound as light orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:28][CH:29]=4)=[N:11][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:38]1([C:41](O)=[O:42])[CH2:40][CH2:39]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[CH:38]1([C:41]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:17]=[N:16][C:15]4[C:14]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[N:13][C:12]([C:24]5[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[N:28][CH:29]=5)=[N:11][C:10]=4[CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:42])[CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(N)c4)cc3n2)cn1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)C5CC5)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.9 %

Procedure:
To a 25 mL round bottom flask, tert-butyl (5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (0.2 g, 0.0004 mol), cyclopropane carboxylic acid (0.041 g, 0.00048 mol) and DMF (8 mL) were added. To the same flask, HATU (0.46 g, 0.0012 mol) and TEA (0.22 mL, 0.0016 mol) were added. The reaction mass was stirred at room temperature for 12 hours. The volatiles were evaporated to dryness under reduced pressure to provide a residue. The residue was stirred with water to provide a solid and the solid was collected by filtration. The solid was washed with diethyl ether to provide the crude product. The crude product was purified by flash column chromatography (1-2% methanol in chloroform) to afford the title compound (0.15 g, 66%). 1H NMR (300 MHz, DMSO-d6): δ 10.42 (br s, 2H), 9.48 (s, 1H), 9.07 (d, J=2.4 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 7.47-7.67 (m, 3H), 4.57 (br s, 4H), 3.84 (s, 4H), 1.84-1.80 (m, 1H), 1.49 (s, 9H), 0.85-0.83 (m, 4H): LC-MS (ESI): Calculated mass: 568.2; Observed mass [M+H]+: 569.2 (RT=1.56 min).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Br:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[Br:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
t-Butyl amine (5.9 mL, 56 mmol, 1.0 eq) and DIPEA (9.7 mL, 56 mmol, 1.0 eq) were added to 350 ml DCM. The solution was cooled to 0° C. and a solution of 4-bromomethylbenzenesulfonyl chloride (15.1 g, 56 mmol, 1.0 eq) in 100 mL DCM was added drop-wise via an addition funnel. The mixture was then slowly warmed to room temperature and stirred for 3 hours. The mixture was concentrated under reduced pressure and the residue was dissolved into 350 mL EtOAc. The organic was washed with 1N aq. HCl, saturated bicarbonate, water, saturated aqueous NaCl, dried over MgSO4, and filtered. The filtrate was concentrated to yield intermediate (2a) (13.6 g).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][NH2:14])[CH2:8][CH2:7][CH2:6]2.[CH3:15][C:16]([CH3:18])=O.C([BH3-])#N.[Na+]>CO>[ClH:1].[CH:16]([NH:14][CH2:13][CH:9]1[C:10]2[C:5](=[CH:4][C:3]([F:2])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)([CH3:18])[CH3:15]
Reactant: NCC1CCCc2cc(F)ccc21
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)NCC1CCCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 75 (1.5 g) was added to a solution of acetone (25 ml) and MeOH (25 ml) then 95% sodium cyanoborohydride (1.32 g) was added in portions. The pH of the reaction was adjusted to ca. pH 5 after complete addition of the NaBH3CN. The reaction was then stirred at room temperature for 8 hrs. The reaction was evaporated to dryness, then dilute HCl and CH2Cl2 (50 ml) was added. The aqueous layer was separated, basified then CH2Cl2 added. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was taken up in Et2O (300 ml) then ethereal HCl added. The resulting precipitate was filtered and recrystallized from EtOAc/MeOH giving the desired compound, m.p. 212°-14° C.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Br)[CH:8]=1.[C-:20]#[N:21].[Na+].CC(C)=O>C(O)C>[Br:1][C:2]1[O:3][C:4]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C:20]#[N:21])[CH:8]=1
Reactant: Clc1ccc2oc(Br)c(-c3cccc(CBr)c3)c2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: N#CCc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1

Procedure:
The product of Step D, 2-bromo-3-(3-bromomethylphenyl)-5-chlorobenzofuran is reacted with sodium cyanide by heating to reflux in a solvent mixture of acetone and ethanol. Evaporation provides the desired product, 2-bromo-5-chloro-3-(3-cyanomethylphenyl)benzofuran.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([C:4]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc2[nH]ccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1c(OCc2ccccc2)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
4-Allyl-1H-indol-5-ol (Example 54, 2.67 g, 15.4 mmol), benzyl bromide (2.90 g, 17.0 mmol), and Cs2CO3 (6.03 g, 18.5 mmol) were combined in DMF (50 mL), and water (15 drops) was added. After stirring for 12 h at rt, the reaction mixture was concentrated under reduced pressure. The residue was taken up in water, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:7) gave 3.3 g (82%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.74 (d, 2H), 5.00 (d, 1H), 5.09 (d, 1H), 5.10 (s, 2H), 6.07 (m, 1H), 6.55 (s, 1H), 6.98 (d, 1H), 7.20 (m, 2H), 7.31 (m, 1H), 7.38 (m, 2H), 7.48 (m, 2H), 8.03 (br, 1H).
Reaction SMILES: O=[C:2]1C2C(=CC=CC=2)C(=O)N1C(CC1C=CC=CC=1)C(N[C@@H](CNCC=CC(=O)C(F)(F)F)C(OC)=O)=O.[CH2:39]([O:46][C:47]([NH:49][C@H:50]([C:53]([OH:55])=[O:54])[CH2:51][NH2:52])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.S(=O)(=O)(O)O>CO.C(OCC)C>[CH2:39]([O:46][C:47]([NH:49][C@H:50]([C:53]([O:55][CH3:2])=[O:54])[CH2:51][NH2:52])=[O:48])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)[C@H](CNCC=CC(=O)C(F)(F)F)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
N-[2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-(S)-3-[(trifluoroacetyl-2-propenyl)amino]-2-amino-propionic acid, methyl ester Dissolve Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine (47.6 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give Nα -(benzyloxycarbonyl )-β-(amino)-L-alanine, methyl ester.
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[CH3:10][C:11]([C@@H:45]([OH:57])[C:46]([NH:48][CH2:49][CH2:50][C:51]([NH:53][CH2:54][CH2:55][SH:56])=[O:52])=[O:47])([CH2:13][O:14][P:15]([O:18][P:19]([O:22][CH2:23][C@H:24]1[O:28][C@@H:27]([N:29]2[C:33]3[N:34]=[CH:35][N:36]=[C:37]([NH2:38])[C:32]=3[N:31]=[CH:30]2)[C@H:26]([OH:39])[C@@H:25]1[O:40][P:41]([OH:44])([OH:43])=[O:42])([OH:21])=[O:20])([OH:17])=[O:16])[CH3:12].C[O:59][C:60]1C(O)=C(OC)[CH:63]=[C:62](/C=C/C(O)=O)[CH:61]=1>FC(F)(F)C(O)=O.C(#N)C>[C:60]([S:56][CH2:55][CH2:54][NH:53][C:51](=[O:52])[CH2:50][CH2:49][NH:48][C:46](=[O:47])[C@H:45]([OH:57])[C:11]([CH3:10])([CH3:12])[CH2:13][O:14][P:15]([OH:17])(=[O:16])[O:18][P:19]([OH:21])(=[O:20])[O:22][CH2:23][C@H:24]1[O:28][C@@H:27]([N:29]2[C:33]3[N:34]=[CH:35][N:36]=[C:37]([NH2:38])[C:32]=3[N:31]=[CH:30]2)[C@H:26]([OH:39])[C@@H:25]1[O:40][P:41]([OH:44])([OH:43])=[O:42])(=[O:59])/[CH:61]=[CH:62]/[CH3:63]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS
Reactant: COc1cc(/C=C/C(=O)O)cc(OC)c1O
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C/C=C/C(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O

Procedure:
The assay mixture contained 50 mM Tris-HCl (pH 7.5), 1 mM CoA ester, and about 1 μg cell free extract. Reactions were allowed to proceed at room temperature and were stopped by adding 1 volume 10% trifluroacetic acid (TFA). The reaction mixtures were purified prior to MALDI-TOF MS analysis using Sep Pak Vac C18 50 mg columns (Waters, Inc.). The columns were conditioned with 1 mL methanol and then equilibrated with two washes of 1 mL 0.1% TFA. The sample was applied to the column, and the flow through was discarded. The column was washed twice with 1 mL 0.1% TFA. The sample was eluted in 200 μL 40% acetonitrile, 0.1% TFA. The acetonitrile was removed by centrifugation in vacuo. Samples were prepared for MALDI-TOF MS analysis by mixing 1:1 with 110 mM sinapinic acid in 0.1% TFA, 67% acetonitrile. The samples were allowed to air dry.
Reaction SMILES: [Br:1]Br.[O:3]1[C:7]2[CH:8]=[C:9]([C:12](=[O:14])[CH3:13])[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4]1>CO>[Br:1][CH2:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][CH2:4][O:3][C:7]=2[CH:8]=1)=[O:14]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)OCC2
Solvent: CO
Product: O=C(CBr)c1ccc2c(c1)OCC2
Reaction time: 3 h

Procedure:
Br2 (0.36 ml, 7.01 mmol) was added dropwise to a stirring solution of 1-(2,3-dihydro-benzofuran-6-yl)-ethanone (1.13 g, 6.97 mmol) in MeOH (20 mL) held at 0° C. The reaction mixture was slowly allowed to reach room temperature. After 3 h, the reaction was quenched by the addition of NaHCO3 (aq, saturated)(until pH=8). Most of the methanol was removed under reduced pressure and the residue was extracted twice with EtOAc (2×20 mL). The organic extracts were pooled, washed with brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC using a gradient of 40-70% MeCN in a 0.1M ammonium acetate buffer as eluent. The fractions containing the desired product were pooled and most of the MeCN was removed under reduced pressure. The residue was extracted with EtOAc (2×20 mL) and the combined organic layers was washed with brine, dried over MgSO4 and concentrated. The obtained was finely washed MeOH to give the title compound.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:12][C:13]([OH:15])=O.[CH2:16]([C@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C@H:23]1[CH2:27][N:26]([C:13](=[O:15])[CH2:12][N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)[C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)CN1CCc2ccccc2C1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CN1CCc2ccccc2C1
Yield: 34.7 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,4-dihydroisoquinolin-2(1H)-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 82, (2S,4R)-4-benzyl-1-(2-(3,4-dihydroisoquinolin-2(1H)-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (13.7 mg, 34.7%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.98 (s, 1H), 7.56 (d, 2H), 7.23-7.15 (m, 10H), 7.09 (m, 3H), 6.94 (m, 2H), 4.49 (m, 1H), 3.74 (m, 1H), 3.63 (d, 2H), 3.36 (m, 1H), 3.29 (s, 2H), 2.78-2.73 (m, 4H), 2.61 (m, 3H), 1.91 (m, 2H). MS (EI) for C35H34FN3O3. found 564.7 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[OH:17].C(N(CC)CC)C>CN1C(=O)CCC1>[O:4]1[CH2:5][CH2:6][N:1]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[OH:17])[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(O)c1
Temperature: 200 °C

Procedure:
Morpholine (59.9 mg, 0.688 mmol) was added to a solution of 2-bromo-5-nitrophenol (100 mg, 0.459 mmol) and triethylamine (0.070 ml, 0.505 mmol) in NMP. The reaction mixture was heated via microwave irradiation to 200° C. for 1 h. The reaction was monitored by TLC. After completion of the reaction and following cooling, the solvent was removed in vacuo and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) to provide the title compound as a solid. 1H NMR: (CDCl3, 400 MHz): δ 7.82-7.79 (m, 2H), 7.20 (m, 1H), 6.69 (bs, 1H), 3.89 (m, 4H), 2.95 (m, 4H). ESI-MS: 225.1 [M+H]+.
Reaction SMILES: ClCl.[CH2:3]=[CH2:4].[CH2:5]=[CH:6][CH3:7]>O>[CH2:6]1[CH:7]2[CH:4]3[CH:3]=[CH:5][CH:6]([CH:4]2[CH:3]=[CH:5]1)[CH2:7]3
Reactant: C=C
Reactant: C=CC
Agent: ClCl
Solvent: O
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
4 liters of chlorine gas (20°C, 1 atmosphere) were passed during a period of 30 minutes at 25°C in diffuse daylight through a dispersion of 35 g of a terpolymer in 1 liter of water. The terpolymer was composed of 53.9% by weight of ethylene, 42% by weight of propylene, and 4.1% by weight of 5-ethylidenenorbornene-2. The dispersed terpolymer particles ranged in size from 3 -22 mm. The dispersion was intensively stirred during the passage of the chlorine gas. After the passage of the chlorine gas was complete, the dispersion was ventilated and pure nitrogen gas was passed through the dispersion to remove any excess chlorine. The chlorinated terpolymer was recovered by filtration, and the resulting rubbery crumb was washed with distilled water and dried. The resulting terpolymer contained 3.3% by weight of chlorine. According to the N.M.R. analysis the copolymer thus prepared contained no allylic bounded chlorine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl.[NH2:17][CH2:18][CH2:19][CH:20]([NH:29][C:30](=[O:46])[CH2:31][NH:32][S:33]([C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)(=[O:35])=[O:34])[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>>[CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:44]=[CH:45][C:36]=1[S:33]([NH:32][CH2:31][C:30]([NH:29][CH:20]([C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:19][CH2:18][NH:17][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:46])(=[O:35])=[O:34]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: NCCC(NC(=O)CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Agent: Cl
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CCNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Yield: 17 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with N-[3-amino-1-(piperidinocarbonyl)propyl]-2-(2-naphthalenesulphonamido)-acetamide hydrochloride salt to give 2-(2-naphthalenesulphonamido)-N-{1-piperidinocarbonyl-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-propyl}acetamide in 17% yield;
Reaction SMILES: [C:1](=[S:4])([NH2:3])[CH3:2].Cl[CH:6]([C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl>CCO>[CH3:2][C:1]1[S:4][C:6]([C:7]([OH:9])=[O:8])=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccccc2)c(C(=O)O)s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a solution of ethanethioamide (80.0 g, 1.06 mol) in EtOH (600 mL), was added ethyl 2-chloro-3-oxo-3-phenylpropanoate (141.5 g, 0.64 mol), which was prepared by published procedure in M. Altuna-Urquijo, et al.; Tetrahedron; 65; 2009; 975-984, and the mixture was stirred at 80° C. for 2 h. The reaction mixture was allowed to cool to 50° C., 8N aqueous sodium hydroxide solution (120 mL) was added, and the mixture was stirred 80° C. for 2 h. The reaction mixture was allowed to cool to 50° C., 8N aqueous sodium hydroxide solution (240 mL) was added, and the mixture was stirred 80° C. for 1 h. The reaction mixture was allowed to cool to 0° C., and was then neutralized by the addition of 6N hydrochloric acid (400 mL). The mixture was stirred at rt for 12 h and the resulting precipitate was collected by filtration and washed with water, EtOH and diethyl ether sequentially to give the title compound (105.6 g, 75%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:9]=[C:8]([C:10]3[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=3)[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:6][N:5]2[CH:24]=1.[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:25][C:24]1[N:5]2[CH:6]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH:14]=[O:15])=[CH:16][CH:17]=3)=[N:9][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2c1Br
Yield: 79 %

Procedure:
0.2 g (0.64 mmol) 4-(2-Methyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)benzaldehyde, described in intermediate example 15.1, are dissolved in 2.8 mL chloroform and treated with 170 mg (0.96 mmol) N-bromosuccinimide. The mixture is heated for 2.5 hours at reflux. The solvent is removed and the residue purified by chromatography (silicagel, dichloromethane/methanol). 198.4 mg (75.3%) of the desired compound are obtained.
Reaction SMILES: [CH2:1]([Sn:9](=[O:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19](O)[CH2:20][OH:21]>C1(C)C=CC=CC=1>[CH2:1]([Sn:9]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[O:21][CH2:20][CH2:19][O:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OCCO
Reactant: CCCCCCCC[Sn](=O)CCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCC[Sn]1(CCCCCCCC)OCCO1
Temperature: 60 °C
Reaction time: 25.5 h
Yield: 97.6 %

Procedure:
2.0005 g (5.54 mol) of dioctyltin oxide and 0.344 g (5.54 mmol) of ethylene glycol were introduced into a 100 ml reaction vessel equipped with a Dean-Stark device, and the atmosphere in the reaction vessel was replaced by argon. 70 ml of toluene was added, and the mixture was dehydrated by azeotropic distillation at 135° C. and stirred for 25.5 hours during which it became an uniform solution. After left and cooled to 60° C., the toluene was distilled off under reduced pressure. The resulting white solids were dried at 60° C. for 5 hours in vaccuo to give 1,1-dioctylstanna-2,5-dioxacyclopentane, 2.19 g (97.6% yield).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[S:8][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:10][N:11]=1)=[O:5])[NH2:3].[CH2:18]=O.[OH-].[K+]>CO>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[S:8][C:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:10][N:11]=2)[CH2:18][NH:3]1
Reactant: CN(N)C(=O)Nc1nnc(C2CCCCC2)s1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1NCN(c2nnc(C3CCCCC3)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-Methyl-4-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-methyl-4-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.