Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[CH:33]1[CH:34]=[CH:35][C:36]2[N:41]([OH:42])[N:40]=[N:39][C:37]=2[CH:38]=1.[H-].[Na+].[OH-].[Na+]>CN(C)C=O.O>[N:41]1([O:42][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[C:8](=[C:18]4[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:20][CH2:19]4)[C:9]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=4[CH2:11][CH2:12][C:3]=23)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=2[N:39]=[N:40]1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Reactant: On1nnc2ccccc21
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(On4nnc5ccccc54)ccnc32)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
The 4,8-dichloro compound from Example 250 (0.8 grams) was added to a solution of HOBT (1.2 grams) and sodium hydride (0.14 grams, 60% in mineral oil) in anhydrous dimethyl-formamide (60 mL). The resulting solution was irradiated with a 200 W lamp while stirring at 25° C. for 60 hours. The solution was poured into 1N aqueous NaOH while stirring and an additional 400 mL of water was added to the resulting mixture. Filtration provided a solid which was washed with water several times. The solid was dissolved in CH2Cl2 -acetone, dried over anhydrous MgSO4, and concentrated in vacuo to proved the title compound (0.87 grams, 90%, mp=120°-122° C., MH+ 563).
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:3](=[O:8])[C:4]([O:6]C)=[O:5].[Li+].[OH-].Cl>CO.O>[CH3:1][N:2]([CH2:9][C:10]([F:11])([F:12])[F:13])[C:3](=[O:8])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(=O)N(C)CC(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CC(F)(F)F)C(=O)C(=O)O
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of methyl 2-(methyl(2,2,2-trifluoroethyl)amino)-2-oxoacetate (1.2 g, 6.03 mmol) in methanol (15 mL) and water (15.00 mL) was added LiOH (0.506 g, 12.05 mmol) and the mixture stirred for 2 h. The solution was then acidified with conc. HCl and concentrated. The solid was washed with CH2Cl2 (2×100 mL), filtered and the filtrate concentrated to afford the title compound (600 mg, 53.8% yield) (mixture of rotational isomers at room temperature) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ: 4.32 (1 H, q, J=9.36 Hz), 4.23 (1 H, q, J=9.46 Hz), 3.07 (2 H, s), 2.97 (1 H, s).
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=O.[OH-].[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O.[BH4-].[Na+]>>[O:7]=[C:5]1[N:1]([CH2:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4]1
Reactant: N[C@H](CCC(=O)O)C(=O)O
Reactant: O=Cc1ccccn1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
D-glutamic acid (2.21 g, 15 mmol) was dissolved in 2N aqueous sodium hydroxide (15 ml, 30 mmol) at 0° C. and then treated with pyridine-2-carboxaldehyde (1.43 ml, 15 mmol). The mixture was stirred at room temperature for 45 minutes and then cooled to 0° C. and treated with sodium borohydride (0.189 g, 5 mmol). The mixture was allowed to warm to room temperature with stirring over 4 hrs then after washing twice with diethyl ether it was acidified to pH5-6. The aqueous layer was concentrated then azeotroped three times with toluene and then with a 1:1 ethanol:toluene mixture and finally with ethanol. The residue was then taken up in ethanol (50 ml) and refluxed for 8 hrs. Concentration gave an oil which when dried in vacuo gave 5-oxo-1-(2-pyridinylmethyl)proline (2.60 g) as a foam which was used without any further purification.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=3)[CH:15]=[CH:14][C:13]2=[O:23])[CH2:6][C@H:5]1[OH:24].C(N(CC)CC)C.[O:32]1[C:41]2[CH:40]=[C:39]([CH:42]=O)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[ClH:1].[O:32]1[C:41]2[CH:40]=[C:39]([CH2:42][NH:3][C@H:4]3[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]4[C:21]5[C:16](=[N:17][CH:18]=[C:19]([F:22])[CH:20]=5)[CH:15]=[CH:14][C:13]4=[O:23])[CH2:6][C@H:5]3[OH:24])[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: N[C@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ncc(F)cc2n1CCN1CC[C@H](NCc2cc3c(cn2)OCCO3)[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-{2-[(3R,4S)-4-Amino-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one dihydrochloride (100 mg, 0.2637 mmol) was stirred in 9:1 v:v chloroform:MeOH (5 ml) at rt under argon and triethylamine (129 μl, 3.5 eq.) was added. The mixture was stirred at rt for 10 mins, then 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (44 mg, 0.264 mmol) was added and the mixture was stirred at rt for 1 h before being treated with sodium triacetoxyborohydride (168 mg) added in one portion. The mixture was then stirred at rt over the weekend. Saturated aqueous sodium hydrogen cabonate (2 ml) was then added and the organic phase was diluted with DCM to bring the total volume to ca. 20 ml. The organic phase was separated using a hydrophobic frit and the aqueous phase was extracted with DCM (2×20 ml). The combined DCM extracts were evaporated under reduced pressure and purified by MDAP to give the free base of the title compound as an off-white foam (66 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[CH:13][S:14][C:7]=12.[Na+].[I-:22]>CC(C)=O>[I:22][CH2:2][CH2:3][C@H:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[CH:13][S:14][C:7]=12
Reactant: ClCC[C@@H](Oc1ccnc2ccsc12)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICC[C@@H](Oc1ccnc2ccsc12)c1ccccc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
To a solution of 7-[(1R)-(3-Chloro-1-phenyl-propoxy)]-thieno[3,2-b]pyridine (703 mg, 2.3 mmol) in 15 mL of acetone was added NaI (3.5 g, 23 mmol). The resulting solution was allowed to stir at 55° C. for 18 h before removing the acetone in vacuo. The residue was taken up in CH2Cl2 and water. The layers were separated and the aqueous phase was further extracted 2 times with CH2Cl2. The combined organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with hexane:ethyl acetate [100:0 to 1:1] to yield the title compound (0.79 g, 87%); mass spectrum (ion spray): m/z=395.98 (m+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14]O)=[CH:5][CH:4]=1.O1CCCC1.S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1>[Cl:25][CH2:14][C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnoc1-c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2oncc2CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a mixture of 5-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (5.65 g), tetrahydrofuran (20 ml) and toluene (80 ml) was added dropwise thionyl chloride (4.15 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were filtrated and recrystallized from ethyl acetate-hexane to give 4-chloromethyl-5-(4-trifluoromethylphenyl)isoxazole (4.70 g, yield 77%) as a colorless prism. melting point: 99–100° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][NH:34][C:35](=[O:45])[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH:30]=2)[NH:25][CH:24]=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][NH:34][C:35](=[O:45])[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH:30]=2)[NH:25][CH:24]=1
Reactant: COc1ccc(CC(=O)NCCc2ccc3[nH]cc(CCO)c3c2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CC(=O)NCCc2ccc3[nH]cc(CCBr)c3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
Triphenylphosphine (149 mg) in dry CH2Cl2 (0.5 ml) was added dropwise at -10° to -5° under nitrogen to a stirred solution of the compound of section (a) (155 mg) and CBr4 (139 mg) in dry CH2Cl2 (10 ml). After stirring at room temperature for 20 h (overnight) the solution was evaporated in the presence of silica gel and the resultant fine powder was chromatographed [elution with EA:hexane (1:1)] to give the title compound as a pale yellow viscous oil (117 mg). T.l.c. EA, Rf 0.51 (major).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=3)[N:6]2[CH:30]=1)=O.[N+](=[C:33](P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[CH:28][CH:29]=3)[N:6]2[CH:30]=1)#[CH:33]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=O)cn23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cn2c(-c3ccc(C(=O)OC(C)(C)C)cc3)cnc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of compound 81a (239 mg, 0.580 mmol) in anhydrous THF (8 mL) and anhydrous MeOH (3 mL), dimethyl (1-diazo-2-oxopropyl)phosphonate (164 mg, 0.850 mmol) in MeOH (2 mL) was added followed by potassium carbonate (252 mg, 1.82 mmol). The resulting yellow suspension was stirred at rt for 18 h. The mixture was filtered through a pad of diatomaceous earth. The filter cake was washed CH2Cl2. The combined filtrates were concentrated under reduced pressure. The residue was dissolved in DCM and washed with diluted NaHCO3, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on preparative TLC (EtOAc/CH2Cl2; 2:3, v/v) to afford compound 81b. Mass Spectrum (LCMS, ESI pos.): Calcd. for C23H25N4O3: 405.2 (M+H). found: 405.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH3:49][CH:50]1[CH2:55][O:54][CH2:53][CH2:52][NH:51]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:49][CH:50]1[N:51]([C:2]2[CH:3]=[C:4]([NH2:14])[C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH2:52][CH2:53][O:54][CH2:55]1
Reactant: CC1COCCN1
Reactant: Nc1cc(Br)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC1COCCN1c1cnc(N2CCOCC2)c(N)c1
Temperature: 65 °C
Reaction time: 2.25 h

Procedure:
To a stirred solution of 5-bromo-2-morpholinopyridin-3-amine (0.5 g, 1.94 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.074 g, 0.16 mmol), Pd2dba3 (0.071 g, 0.08 mmol) and 3-methylmorpholine (0.98 g, 9.7 mmol) in THF (3.9 mL). To this mixture was added LHMDS in THF (1.0 M, 10.65 mL, 10.65 mmol) and the resulting reaction was heated to 65° C. The reaction was stirred for 2.25 h. After which, the reaction was cooled to rt and then poured into water (50 mL) and extracted with EtOAc (2×50 mL) and DCM (2×50 mL). The combined organic layers were dried over magnesium sulfate and the crude product was purified on basic alumina (0-100% EtOAc/hexane) to give 5-(3-methylmorpholino)-2-morpholinopyridin-3-amine. Mass Spectrum (ESI) m/e=279.2 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][CH2:31]Br)[C:14]1=[O:33])=[O:11].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(OC(C)C)(C)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][CH2:31][N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)[C:14]1=[O:33])=[O:11]
Reactant: CN1CCNCC1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCBr)C1=O)c1cc2ccccc2[nH]1
Solvent: CC(C)OC(C)C
Product: CN1CCN(CCN2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)N=C(c3ccccc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-1-(2-bromoethyl)-5-phenyl-2H-1, 4-benzodiazepine-2-one (0.3 g) and 1-methylpiperazine (3.0 ml) was stirred for 4.0 hours at room temperature and diisopropyl ether (20 ml) was added thereto. The resultant precipitates were collected by filtration and dissolved in diluted hydrochloric acid. The solution was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the resultant precipitates were collected by filtration to give (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-1-[2-(4-methyl-1-piperazinyl) ethyl]-5phenyl-2H-1,4-benzodiazepine-2-one (0.20 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]1[CH2:9][C@@H:8]([OH:10])[C@H:7]([CH:11]([CH3:13])[CH3:12])[CH2:6][CH2:5]1.[C:14](#[N:17])[CH:15]=[CH2:16].C(O)(=O)C>ClCCl.O>[CH3:3][C@@H:4]1[CH2:5][CH2:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C@H:8]([O:10][CH:15]([CH3:16])[C:14]#[N:17])[CH2:9]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: C=CC#N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C#N)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1 g of a sodium hydride suspension (50% strength) in paraffin oil was added at a temperature of 0° C. to a solution of 30 g of L-menthol in 300 ml of dichloromethane. A solution of 12.5 ml acrylonitrile in 50 ml dichloromethane was slowly added dropwise, and the reaction mixture was then stirred at room temperature for a further 5 hours. The reaction mixture was worked up by cautiously adding 10 ml of glacial acetic acid, followed by 200 ml of water, and then extracting the mixture with dichloromethane. The dichloromethane extract was dried over sodium sulfate, filtered and concentrated. After chromatographic purification of the residue on silica gel using n-hexane/dichloromethane as the eluent, 25.03 g of crude 2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)propionitrile were obtained and used for the next reaction step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[CH:18]=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1C(=O)N([Br:26])C(=O)C1.O>CN(C=O)C>[Br:26][C:18]1[C:11]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[N:15][CH:14]=[N:13][C:12]=2[NH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(-c2ncnc3[nH]ccc23)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2ncnc3[nH]cc(Br)c23)c1
Reaction time: 0.5 h

Procedure:
To 4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (12 g, 50 mmol) in DMF (167 mL) was added NBS (10.2 g, 57.4 mmol) and the mixture stirred for 30 minutes. Water (833 mL) was added which led to the precipitation of the desired product. The reaction mixture was allowed to stir for 15 minutes before being filtered and washed with 500 mL of water to give 5-bromo-4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine. LRMS (ESI) calc'd for C12H8BrN4O2[M+H]+: 319, found 319.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]([CH2:10][C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.O>CN(C)C=O.C(OCC)C>[CH2:25]([O:24][C:22]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:3][C:4]2[C:5]([CH2:10][C:11]3[NH:15][CH:14]=[CH:13][N:12]=3)=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:28][CH:27]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: Oc1cccnc1Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(COc2cccnc2Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
Sodium hydride (1.81 g of 50% dispersion in mineral oil) was added in portions to a stirred solution of 3-hydroxy-2-(1-imidazolylmethyl)pyridine (6.00 g) in dry N,N-dimethylformamide (100 ml) at 0° C. The mixture was stirred for 15 minutes and a solution of ethyl 4-bromomethyl-benzoate (8.34 g) in dry N,N-dimethylformamide (20 ml) was then added over a period of 10 minutes. The mixture was allowed to warm to room temperature, stirred for 4 hours and water (5 ml) was then added. The solution was evaporated and the residue chromatographed on silica gel, eluting with chloroform. The product-containing fractions were combined and evaporated to give an oil which solidified on trituration with diethyl ether. Recrystallization from diethyl ether gave 3-(4-ethoxycarbonylbenzyloxy)-2-(1-imidazolylmethyl)pyridine (4.85 g), m.p. 100°-101° C.
Reaction SMILES: [C:1]1([N:7]([C:23]2[CH:28]=CC=CC=2)[C:8]([NH:10][S:11]([C:14]([CH3:22])=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:13])=[O:12])=[O:9])C=CC=[CH:3][CH:2]=1.N1CCCCC1.CN(C)C=O>CCOCC>[N:7]1([C:8]([NH:10][S:11]([C:14]([CH3:22])=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:13])=[O:12])=[O:9])[CH2:1][CH2:2][CH2:3][CH2:28][CH2:23]1
Reactant: CC(=Cc1ccccc1)S(=O)(=O)NC(=O)N(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCNCC1
Product: CC(=Cc1ccccc1)S(=O)(=O)NC(=O)N1CCCCC1
Temperature: 25 °C

Procedure:
A solution of 1.9g. of N-(N,N-diphenylcarbamoyl)-1-phenylpropene-2-sulfonamide and 1.7g of piperidine in 10ml. of N,N-dimethylformamide is maintained at ca. 95°C. for 6 hours. It is then cooled to ambient temperature, and 100 ml. of ether is added. The mixture is extracted with 50 ml. of water, and then the water extract is acidified using concentrated hydrochloric acid. This causes the crude product to precipitate. It is filtered off, and then it is recrystallized from a mixture of acetone and water giving 670 mg. of N-(piperidinocarbonyl)-1-phenylpropene-2-sulfonamide, m.p. 159°-161° C.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C(O)CCCCCCCCCCc1ccc(Br)cc1

Procedure:
By the similar procedure of synthesis of B10, compound B2 (330 mg, 0.643 mmol) and 4-bromobenzaldehyde (91.5 mg, 0.495 mmole) were used as starting materials to afford B18 (98.0 mg, 0.287 mmol, 58%) as off-white solids. mp: 91° C. 1H-NMR (CDCl3, 400 MHz) δ 7.37 (d, J=8.3 Hz, 1H), 7.02 (d, J=8.3 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H), 2.34 (t, J=7.5 Hz, 2H), 1.52-1.63 (m, 4H), 1.20-1.37 (m, 12H). 13C-NMR (CDCl3, 100 MHz) δ 179.94, 141.79, 141.79, 131.22, 130.14, 119.22, 35.31, 34.11, 31.27, 29.44, 29.38, 29.36, 29.19, 29.12, 29.03, 24.68. HRMS (ESI) calculated C17H26BrO2 [M+H]+: 341.1116, found: 341.1111.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([N+:17]([O-])=O)[C:11]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH4+].[Cl-]>CCOC(C)=O.[Fe]>[CH2:1]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([NH2:17])[C:11]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(N)cc(Br)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A 1000 mL RBF equipped with an overhead stirrer was charged with 5-bromo-2-methyl-3-nitro benzoic acid benzyl ester (75.0 g, 0.214 mol) and water (200 mL). While stirring vigorously, Fe powder (−325 mesh, 47.81 g, 0.857 mol) and NH4Cl (13.88 g, 0.257 mol) were added. The mixture was heated to reflux for 4.5 hours. The reaction mixture was then allowed to cool to room temperature, diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed with water (2×), saturated NaCl (1×), dried (MgSO4), and concentrated. Upon trituration with hexanes, 63.2 g (92.1%) of an off-white powder was obtained. 1H NMR (CDCl3) δ 7.38 (m, 6H), 6.90 (s, 1H), 5.31 (s, 2H), 3.76 (br s, 2H), 2.25 (s, 3H).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:39][CH:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)[CH2:41]1>C(N(CC)CC)C.C(Cl)(Cl)Cl>[C:1]([NH:9][CH2:10][C:11]([NH:39][CH:40]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)[CH2:41]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: NC1CCN(Cc2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CNC(=O)c1ccccc1)NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
N-Benzoylglycine (9.3 mg, 0.055 mmol), 3-ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (1.05 mg) and 1-hydroxybenzotriazole hydrate (HOBt) (7.4 mg) were added to a chloroform (2.5 mL) solution of 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride (14.2 mg, 0.050 mmol) and triethylamine (15.2 mg). The resulting reaction mixture was stirred at 25° C. for 16 hours and then washed with a 2 M aqueous solution of NaOH (2 mL×2) and brine. After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to provide 3-(N-benzoylglycyl)amino-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 1) as an off-white oil (17.7 mg, 95%). The purity was determined by RPLC/MS (95%). ESI/MS m/e 372.0 (M++H, C20H22ClN3O2).