Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@@H:19]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[O:18][C@@H:13]2OC(=O)C)[CH3:10])[C:4](=[O:35])[CH2:3]1.[BrH:37]>C(O)(=O)C.C(Cl)Cl>[CH3:1][C:2]1([CH3:36])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[C@@H:19]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[O:18][C@@H:13]2[Br:37])[CH3:10])[C:4](=[O:35])[CH2:3]1
Reactant: Br
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-1,3,4,6-tetra-O-acetyl-α-D-glucopyranose (100 mg, 0.19 mmol) and HBr in acetic acid (45%) (1.0 ml) was stirred at room temperature for 30 min. The reaction mixture was diluted with cold CH2Cl2 (10 ml), washed twice with cold H2O (30 ml), saturated NaHCO3 solution (20 ml) and with H2O again (20 ml). The organic phase was dried over MgSO4 and evaporated, giving 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranosyl bromide (3) (95 mg, 91%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:34]12[S:42][CH:38]([CH2:39][CH2:40][CH2:41]1)[CH2:37][C:36](=O)[CH2:35]2>C1COCC1>[CH3:12][O:13][CH:14]=[C:36]1[CH2:37][CH:38]2[S:42][CH:34]([CH2:41][CH2:40][CH2:39]2)[CH2:35]1
Reactant: O=C1CC2CCCC(C1)S2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=C1CC2CCCC(C1)S2
Reaction time: 16 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide 1M in THF (37.9 ml, 37.9 mmol) was added dropwise to a suspension of (methoxymethyl)triphenylphosphonium chloride (13.40 g, 37.9 mmol) in THF (60 ml) at −10° C., followed by the addition of 9-thia-bicyclo[3.3.1]nonan-3-one (3.95 g, 25.3 mmol) at −10° C. The suspension was allowed to warm to Rt and stirring was continued for 16 hrs.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3].[C:17]([O-])([O-])=O.[K+].[K+].CI>CO>[CH3:17][N:5]([CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(CNS(C)(=O)=O)cc1
Agent: [K+]
Solvent: CI
Solvent: CO
Product: COC(=O)c1ccc(CN(C)S(C)(=O)=O)cc1
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-[(methanesulfonamido)methyl]benzoate (5 g, 20.6 mmol) in MeOH (100 mL) at rt was added K2CO3 (2.9 g, 21 mmol). Methyl iodide (7 ml, 16 g, 112 mmol) was added and the mixture stirred overnight. The reaction was filtered and the solid washed with CHCl3/MeOH. The combined filtrates were evaporated and the residue was purified by flash chromatographyon eluting with 0-5% MeOH/CHCl3. The title compound was isolated as a white solid (4.9 g, 94%): 1H (CDCl3): d 8 .08 (d, 2H); 7.48 (d,2H); 4.41 (s, 1H); 3.97 (s, 3H); 3.91 (s, 3H); 2.83 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:14]([Cl:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:7]=1[C:8]([OH:10])=O.O.[CH3:20]COC(C)=O>CN(C=O)C>[Cl:5][C:6]1[C:14]([Cl:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:7]=1[C:8](=[O:10])[CH3:20]
Reactant: CCOC(C)=O
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
To thionyl chloride, obtained from Aldrich, (125 mL) at 0° C. was slowly added 2,3-Dichloro-5-nitrobenzoic acid (246) (21.7 g, 91.9 mmol). The ice bath was taken away and the resulting solution was heated to reflux for 17 hours (note: acid completely dissolves upon heating). After cooling to ambient temperature, the excess thionyl chloride was removed under vacuum and the resulting acid chloride was allowed to stand under high vacuum for 15 h and used in the next step without further purification. To a 1M solution of NaH, 60% oil dispersion obtained from Aldrich, (11.39 g, 285 mmol) in DMF at 0° C. was slowly added diethylmalonate, obtained form Aldrich, (14.65 mL, t—s 96.5 mmol) dropwise and the resulting solution was allowed to stir for 30 minutes. The acid chloride was dissolved in DMF (184 mL) and slowly added via cannula to the reaction mixture. The resulting solution was then allowed to stir for 16 h as ambient temperature was reached followed by recooling to 0° C. and slowly quenching with excess 2M aqueous HCl (200 mL). To the crude reaction was added H2O (500 mL) and EtOAc (500 mL). The aqueous layer was extracted three times with EtOAc (500 mL), the organic layers were combined, washed four times with saturated aqueous brine (500 mL), dried over Na2SO4, and concentrated under vacuum to yield an oil which was used in the next step without further purification. The resulting product was dissolved in 111 mL of a 7.7/5/1 AcOH/H2O/conc. H2SO4, solution and heated to reflux for 22 hours. The AcOH was removed under vacuum followed by EtOAc addition (200 mL). The solution was neutralized using 2M aqueous NaOH, extracted 3 times with EtOAc (200 mL). The combined organic layers were washed twice with saturated aqueous brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography (30% CH2Cl2 in hexane) to yield 17.6 g (82%) of ketone 248 as a light brown solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C:5]1=O)[CH:2]=[CH2:3].C1(P(=[CH:40][C:41]([O:43][CH3:44])=[O:42])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C:5]1=[CH:40][C:41]([O:43][CH3:44])=[O:42])[CH:2]=[CH2:3]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCC1CCN(C(=O)OCc2ccccc2)CC1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CCC1CCN(C(=O)OCc2ccccc2)CC1=CC(=O)OC
Temperature: 20 °C

Procedure:
A solution containing 16.3 g of (4RS)-4-allyl-1-benzyloxycarbonylpiperidin-3-one in 200 cm3 of toluene was stirred under reflux with methyl (triphenylphosphoranylidene)acetate, under an inert atmosphere, for 16 hours. After cooling to about 20° C., the reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C., the residue obtained, solubilized in 50 cm3 of dichloromethane in the hot state, was purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 μ; diameter 10 cm; height 45 cm), eluting with a cyclohexane-ethyl acetate (80/20 by volume) mixture. 250-cm3 fractions were collected. Fractions 13 to 15 were combined and then concentrated as above. 5.8 g of methyl (4RS)-4-allyl-1-benzyloxycarbonylpiperidin-3-ylidenacetate (Z isomer) were obtained in the form of a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC(S(O)(=O)=[O:21])=CC=1.[OH2:24].C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:24])[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Reactant: O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: OC1CN(Cc2ccccc2)CC1O
Yield: 86.9 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 46.2 g (0.24 mol) of p-chlorobenzenesulfonic acid (produced by Tokyo Chemical Industry Co., Ltd.), 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at 40° C. without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.8 g of 1-benzyl-3,4-dihydroxypyrrolidine (yield 86.9%) was obtained.
Reaction SMILES: C([Li])CCC.CCCCCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1.[I:21]I.[Li]>O.CCOCC>[I:21][C:13]1[S:12][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=1
Reactant: II
Reactant: c1ccc2sccc2c1
Agent: [Li]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: Ic1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Butyllithium 1.6 M in hexane (112.5 ml, 180 mmol) and abs. ether (70 ml) was initially introduced into a 500 ml three-necked flask under an argon atmosphere and the mixture was cooled to 0° C. in an ice bath. Benzothiophene (20.1 g, 150 mmol) then dissolved in abs. ether (40 ml) and the solution added dropwise in the course of 30 minutes, while cooling with ice, and the mixture subsequently stirred in an ice bath for 2.5 h. The reaction mixture stood in a refrigerator overnight. Iodine (75.0 g) and abs. ether (50 ml) were initially introduced into a 500 ml three-necked flask under an argon atmosphere and the solution of the lithium compound was added dropwise, while cooling with ice. The mixture was warmed slowly to room temperature, hydrolysed with water and washed with sodium thiosulfate solution and the organic phase was dried over sodium sulfate. The reaction solution was then concentrated i. vac. and the residue was purified by means of flash chromatography with cyclohexane. Yield: 24.1 g (62%) semi-solid, pale brown crystals
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[NH:11])[CH:6]=[CH:7][CH:8]=1.C(N([CH:20]([C:26]([O:28]CC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])CC)C.[C:31](=O)([O-])[O-].[K+].[K+].Cl>O.C(O)C>[O:28]=[C:26]1[NH:12][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)=[N:11][CH:31]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: N=C(N)Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(C(=O)OCC)N(CC)CC
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2cccc(C(F)(F)F)c2)[nH]c1=O
Reaction time: 7 h
Yield: 83.2 %

Procedure:
A mixture of N-(3-trifluoromethylphenyl)guanidine (10 g), diethyl N,N-diethylaminomalonate (11.8 g) and potassium carbonate (13.4 g) in water (100 ml) and ethanol (100 ml) is refluxed with stirring for 7 hours. After cooling, the mixture is acidified to pH 3 with 10% aqueous HCl. The precipitate is collected by filtration, washed with water and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylate (13.4 g). M.p. 229°-231° C.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:13]([O:12][CH2:11][C@H:10]([CH2:9][OH:8])[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCCCOC[C@H](COCc1ccccc1)OCCCCCCCCCCCCCCCCCCCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCCCOC[C@H](CO)OCCCCCCCCCCCCCCCCCCCC
Yield: 72.2 %

Procedure:
3-O-benzyl-1,2-di-O-eicosyl-Sn-glycerol (1.47 g, 1.98 mmol) and 10% palladium-charcoal (200 mg) were stirred in ethyl acetate (30 ml) under the hydrogen atmosphere at room temperature for 18 h. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to obtain the title compound (934 mg, 72%) as white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]([OH:19])[C:8](=[O:18])[NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11].C(N(CC)CC)C.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCOCC1>[OH:19][CH:7]([C@@H:6]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:41]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:42])[C:8](=[O:18])[NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11]
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCN)NC(=O)OC(C)(C)C)c1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 78.9 %

Procedure:
To a slurry of 1.04 g (2.7 mmol) of tert-butyl (1S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate and 0.38 mL (2.7 mmol) of trietylamine in 45 mL of dioxane was added 0.24 mL (2.7 mmol) of 4-morpholinecarbonyl chloride. The flask was heated with a heat gun until the mixture became homogeneous and was stirred at room temperature for 5 d. The reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 6:4 acetone:hexanes to afford 1.05 g (78%) of tert-butyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (m, 1H), 7.27 (m, 4H), 7.16 (m, 1H), 6.41 (m, 1H), 6.01 (d, J=9 Hz, 1H), 5.47 (d, J=6 Hz, 1H), 4.87 (qnt, J=7 Hz, 1H), 3.80 (dd, J=3 Hz, J=6 Hz, 1H), 3.65 (m, 1H), 3.46 (t, J=5 Hz, 4H), 3.16 (t, J=5 Hz, 4H), 2.93 (q, J=6 Hz, 2H), 1.13-1.44 (m, 18H). ES-LCMS m/z 493 (M+H).
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][C:22]=2[N:23]=1.[CH2:34](O)[CH:35]([CH3:37])[CH3:36].CCOC(C)=O.O>CN(C=O)C>[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:16])=[O:17])[CH:12]=[CH:11][C:10]=1[C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:3]([O:5][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:4])[CH2:30][CH2:29]3)=[CH:24][C:22]=2[N:23]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)CO
Reactant: CS(=O)(=O)c1ccc(-c2nc3cc(C4CCNCC4)ccc3o2)c(F)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COC(=O)N1CCC(c2ccc3oc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Temperature: 60 °C

Procedure:
2-[2-fluoro-4-(methylsulfonyl)phenyl]-5-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (Example 61) (140 mg, 0.29 mmol), isobutanol (42 mg, 0.58 mmol), N,N-Carbonyl diimidazole (82 mg, 0.50 mmol) and TEA (0.2 ml, 1.26 mmol) were dissolved in DMF (2.4 ml). Reaction mixture heated to 60° C. for 18 h. Work up (EtOAc/H2O) followed by purification of the crude by column chromatography on 60-120 mesh silica gel using EtOAc and Petether as eluent to afford the titled compound as a white solid. M.P.: 169-173° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.49-8.43 (m, 1H), 7.83-7.90 (m, 2H), 7.69 (d, J 1.4, 1H), 7.58 (d, J 8.5, 1H), 7.30 (dd, J 1.7, 8.5, 1H) 4.42-4.26 (m, 2H), 3.90 (d, J 6.7, 2H), 3.13 (s, 3H), 3.00-2.78 (m, 3H), 2.00-1.88 (m, 3H), 1.80-1.65 (m, 2H), 0.96 (d, J 6.7, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#N)=[N:6][CH:7]=1.CC[O:12]CC.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O.C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[N:4][CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOCC
Reactant: N#Cc1ncc(Br)cn1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
5-Bromo-pyrimidine-2-carbonitrile (2.5 g, 13.59 mmol) is dissolved ether (30 mL), and PhMgBr (3 ether solution, 13.59 mmol, 4.53 mL) is added dropwise at rt. The mixture is heated to reflux for 3 h under N2, and then cooled to rt. THF (30 mL) is added followed by the addition of 2 N aqueous HCl (10 mL). The resulting solution is stirred at rt for 30 min, and water (30 mL) is added. The aqueous layer is extracted with EtOAc (3×20 mL). The combined organic layer is washed with saturated aqueous NaHCO3 (15 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting 70% EtOAc in heptane to afford (5-bromo-pyrimidine-2-yl)-phenyl-methanone (3.01 g, 84%) as a solid. MS: 264 (M+H).
Reaction SMILES: [CH2:1]([C:4]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)([CH2:8][OH:9])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[C:19]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:19][O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([C:4]([CH2:5][CH:6]=[CH2:7])([CH2:8][OH:9])[CH2:1][CH:2]=[CH2:3])=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCC(CO)(CC=C)c1ccc(C(=O)O)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCC(CO)(CC=C)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 4-(1-allyl-1-hydroxymethyl-but-3-enyl)-benzoic acid (0.793 g, 3.22 mmol) in DMF (11.0 mL) is treated with K2CO3 (0.685 g, 4.96 mmol), and iodomethane (0.25 mL, 4.02 mmol), and stirred at room temperature overnight. The mixture is poured into water (25 mL) and extracted with EtOAc (3×25 mL). The combined extracts are washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% to 75% EtOAc to give 0.774 g, (92%) of the title compound as a clear syrup. 1H NMR (CDCl3): δ 8.03-8.00 (m, 2H), 7.44-7.41 (m, 2H), 5.65-5.54 (m, 2H), 5.11-5.06 (m, 4H), 5.05-5.02 (m, 4H), 3.91 (s, 3H), 3.84 (d, 2H, J=6.2 Hz), 2.59-2.46 (m, 4H), 1.33 (t, 1H, J=6.2 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]=1.[H][H]>C(O)C.Cl.[Pd]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2]1
Reactant: O=C(NCc1cccnc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(NCC1CCCNC1)c1ccccc1
Yield: 82.6 %

Procedure:
Ba) A solution of 42.5 g of N-(3-pyridinylmethyl)-benzamide in 220 ml of ethanol and 220 ml of 1N hydrochloric acid is treated with 4.2 g of palladium on charcoal and hydrogenated at room temperature for 24 hours over 100 bar of hydrogen. Then, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in methylene chloride and shaken with 1N sodium hydroxide solution. The organic phase is washed with water, dried and evaporated. There are obtained 36.1 g of (RS)-N-piperidin-3-ylmethyl-benzamide, MS (FAB): 218 M+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[CH:4]=[C:3]2[CH2:8][CH2:9][CH2:10][C:2]=12.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C(#N)C>[N:1]1[CH:6]=[C:5]([NH:7][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=[C:3]2[CH2:8][CH2:9][CH2:10][C:2]=12
Reactant: Nc1cnc2c(c1)CCC2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1cnc2c(c1)CCC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6,7-Dihydro-5H-cyclopenta[b]pyridin-3-amine (D) (250 mg, 1.86 mmol) was dissolved in acetonitrile. The reaction mixture was added pyridine (0.18 mL, 2.23 mmol) and phenyl chloroformate (0.26 mL, 2.05 mmol) and stirred at room temperature for 3 h under N2. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic part was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl 6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylcarbamate (E). (372 mg, 78%)
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]3[CH:25]=2)=[CH:12][CH:11]=1)(=O)=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].CO.ClCCl>C(#N)C>[N:26]1([CH2:6][CH2:7][C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]4[CH:25]=3)=[CH:12][CH:11]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1ccn2cc(-c3ccc(C#CCCOS(C)(=O)=O)cc3)nc2c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccn2cc(-c3ccc(C#CCCN4CCCCC4)cc3)nc2c1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
The product of Step C (1.00 g) in acetonitrile (15 mL) was treated with piperidine (0.269 g) and potassium carbonate (1.17 g) and heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature, washed with water (20 mL), dried over magnesium sulfate, filtered and evaporated to give crude product. Silica gel chromatography (methanol/dichloromethane) afforded the title compound (1.0 g). MS (ESI) m/z 344.1 (M+H+). 1H NMR (DMSO) δ 8.23 (d, J=6.95 Hz, 1H), 8.15 (s, 1H), 7.73 (d, J=8.37 Hz, 2 H), 7.25 (d, J=8.34 Hz, 2 H), 7.17 (s, 1H), 6.58 (dd, J=6.9, 1.45 Hz, 1H), 2.33 (m, 6 H), 2.23 (b, 2 H), 2.18 (s, 3 H). 1.33 (pent, 4 H), 1.21 (pent, 2 H). HRMS: MH+ calcd for C23H26N3, 344.2127. found, 344.2134. Analysis: Calc'd for C23H25N3; C, 80.43; H, 7.34; N, 12.23. Found: C, 80.27; H, 7.15; N, 11.81.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](S(C)(=O)=O)=[N:11][C:10]=1[C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC#[N:27]>>[CH3:24][O:23][C:21]([C:10]1[N:11]=[C:12]([NH2:27])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: COC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: CC#N
Product: COC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1

Procedure:
In a round-bottomed flask, methyl 5-(benzyloxy)-1-methyl-2-(methylsulfonyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (3.65 g, 10.4 mmol) was combined with CH3CN (50 ml) to give a colorless solution. Gaseous ammonia was bubbled at 25° C. for 20 min. The crude material was purified by flash chromatography (silica gel, 30% to 50% EtOAc in hexanes) and then through a second column (5% MeOH/DCM) to give the title product as a white solid. LCMS: m/z=290 (MH+).