Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[N:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH:17]([N:19]5[C:20](=[O:29])[C:21]6[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=6)[C:27]5=[O:28])[CH3:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:33]=[N:32][CH:31]=1
Reactant: CC(c1ccc2c(c1)ncn2-c1cccc(Br)c1)N1C(=O)c2ccccc2C1=O
Reactant: OB(O)c1cncnc1
Product: CC(c1ccc2c(c1)ncn2-c1cccc(-c2cncnc2)c1)N1C(=O)c2ccccc2C1=O

Procedure:
This was prepared analogously from 2-{1-[1-(3-bromo-phenyl)-1H-benzoimidazol-5-yl]-ethyl}-isoindole-1,3-dione and 5-pyrimidineboronic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][NH2:13].CCO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:13][CH3:12])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CNc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-chloro-3-nitropyridine (Matrix, Columbia, USA, 9.8 g, 41.3 mmol) in 250 ml THF was added 8 M methylamine in EtOH (Aldrich, Buchs, Switzerland, 12.9 ml, 103 mmol). The reaction mixture was stirred 1 h at rt then was quenched with 300 ml water. The precipite was filtered and the filtrate concentrated before being filtered again. The yellow solids were combined and dried to give the title compound as a yellow solid (HPLC: tR 3.13 min (Method A)).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([CH3:24])[CH:18]=1>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12](=[O:13])[CH2:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[C:19]([CH3:24])[CH:18]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: COc1ccc(NC(=O)CC23CC4CC(CC(C4)C2)C3)c(C)c1
Yield: 46.5 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (2.0 g) and 4-methoxy-2-methylaniline (1.29 g) to give the title compound as a white solid (1.37 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:13][C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[C:28]1(B2OC(C)(C)C(C)(C)O2)[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[C:28]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:12]4[S:13][C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:15]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[N:16]=4)=[C:9]([CH3:11])[N:10]=3)[CH:7]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: CCOC(=O)c1sc(-c2c(C)nc3ccc(Br)cn23)nc1-c1ccccc1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1sc(-c2c(C)nc3ccc(C4=CCCCC4)cn23)nc1-c1ccccc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a mixture of ethyl 2-(6-bromo-2-methylimidazo[1,2-a]pyridin-3-yl)-4-phenyl-1,3-thiazole-5-carboxylate (267 mg, 0.6 mmol) obtained above in DME (18 mL) and water (3.6 mL), were added 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg, 1.2 mmol), cesium carbonate (586 mg, 1.8 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (49.1 mg, 0.06 mmol) under a nitrogen atmosphere, and the mixture was stirred at 95° C. for 3 h. The reaction mixture was allowed to cool to rt. The resulting precipitate was collected by filtration and washed with water and diethyl ether to give the title compound (223 mg, 84%) as a white solid.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[C:17]([OH:41])=[C:18]([C:23]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].O[CH2:43][C@H:44]1[CH2:48][CH2:47][CH2:46][N:45]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[C:17]([O:41][CH2:43][C@H:44]2[CH2:48][CH2:47][CH2:46][N:45]2[C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:23]([N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
Diisopropyl azodicarboxylate (1.21 g) was added to a solution of methyl 3-bromo-6-bis-(tert-butoxycarbonyl)amino-2-hydroxybenzoate (Intermediate 9, 2.23 g), tert-butyl (R)-2-hydroxymethylpyrrolidine-1-carboxylate (1.11 g) and triphenylphosphine (1.57 g) in anhydrous THF (25 mL) and the reaction mixture was stirred at room temperature for 30 minutes, then left to stand overnight. The mixture was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give tert-butyl (R)-2-[6-bromo-3-bis-(tert-butoxycarbonyl)amino-2-methoxycarbonyl-phenoxymethyl]pyrrolidine-1-carboxylate (3.17 g) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Si:19]([O:26][CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C1COCC1>[Si:19]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:34][NH:35][C:12](=[O:14])[C@H:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=2[CH3:18])[C@@H:15]([OH:17])[CH3:16])=[O:33])=[CH:36][CH:37]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (3 g, 11.16 mmol), 4-((tert-butyldimethylsilyloxy)methyl)benzohydrazide (3.44 g, 12.28 mmol) and anhydrous THF (250 mL) were placed in a 500 mL round bottomed flask and the mixture was cooled to −15° C. 1-Hydroxybenzotriazole hydrate (1.51 g, 11.16 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N′-ethylcarbodimide HCl (3.21 g, 16.74 mmol) at −15° C. followed by triethylamine (2.33 mL, 16.74 mmol), The reaction mixture was maintained at −15° C. and stirred for 1 h after which, stirring continued overnight while the mixture slowly warmed to room temperature. After 19 h, the mixture was filtered under vacuum and the residue washed with THF (70 mL). The THF solution was concentrated to ca. 20 mL, whereupon EtOAc (100 mL) was added followed by water (50 mL). The phases were partitioned and the organic phase washed with water (30 mL), brine (30 mL) dried (Na2SO4), filtered and concentrated to furnish a light brown solid (5.82 g). This crude product was not chromatographed. 1H NMR (400 MHz, acetone-d6, δ in ppm) 7.82 (d, J=9 Hz, 2H), 7.42 (d, J=8 Hz, 1H), 7.38 (d, J=8 Hz, 2H), 6.58 (d, J=8 Hz, 1H), 5.42 (d, J=8 Hz, 1 H), 4.75 (s, 3H), 4.31-4.22 (m, 1 H), 3.99-3.97 (m, 1H), 2.24 (s, 3 H), 0.82 (s, 9H) and 0.01 (s, 6H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:29])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][N:7]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)([CH3:13])[CH:9]([CH3:21])[CH2:8]1.Cl.COC(=O)C(CC1C=CC=CC=1)CN1CCCCC1.O.OC1C=C(C2(C)CCN(CC(CC3C=CC=CC=3)C(O)=O)CC2C)C=CC=1.[K+].[Br-]>>[ClH:1].[CH3:2][O:3][C:4](=[O:29])[C@@H:5]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][N:7]1[CH2:12][CH2:11][C@:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)([CH3:13])[C@@H:9]([CH3:21])[CH2:8]1
Reactant: COC(=O)C(Cc1ccccc1)CN1CCC(C)(c2cccc(O)c2)C(C)C1
Agent: CC1CN(CC(Cc2ccccc2)C(=O)O)CCC1(C)c1cccc(O)c1
Agent: COC(=O)C(Cc1ccccc1)CN1CCCCC1
Agent: Cl
Solvent: O
Product: COC(=O)[C@@H](Cc1ccccc1)CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1

Procedure:
Purity: 96.2% ((αS, 3R, 4R) -4-(3-hydroxyphenyl)-3,4-dimethyl-α- (phenylmethyl)-1-piperidinepropanoic acid methyl ester hydrochloride, 2.9% (αR, 3R, 4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-(α-(phenylmethyl)-1-piperidinepropanoic acid methyl ester hydrochloride and 0.7% (αS, 3R, 4R)-4-(3-hydroxyphenyl)-3,4 -dimethyl-α-(phenylmethyl)-1-piperidinepropanoic acid monohydrate (HPLC area %). mp 230°-232 ° C. (dec), IR (KBr): 3174, 1732, 1620, 1586, 1276, 785,749, 706 cm-1. 1H-NMR (DMSO-d6): d [0.78 (d, 0.85 ×3H, J=7.2 Hz) & 1.02 (d, 0.15×3H, J=7.2 Hz), diastereomeric salts], [1.28 (s, 0.15×3H), 1.34 (s, 0.85×3H), diastereomeric salts], 1.76 (br d, 1H), 2.10-2.48 (m, 2H), 2.75-3.65 (m, 12H), 6.60-6.90 (m, 3H), 7.11 (t, 1H, J=7.8 Hz), 7.15-7.35 (m, 5H), 9.43 (br s, 1H), 9.75 (br s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])[C@H:11]([CH3:18])[NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[Cl:8][C:6]1[N:5]=[CH:4][C:3]2[NH:9][C:10](=[O:19])[CH:11]([CH3:18])[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:2]=2[CH:7]=1
Reactant: CC(C)CCN[C@@H](C)C(=O)Nc1cnc(Cl)cc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCN1c2cc(Cl)ncc2NC(=O)C1C
Temperature: 125 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a stirred solution of N-(4,6-dichloropyridin-3-yl)-N2-(3-methylbutyl)alaninamide (350 mg, 1.15 mmol) in DMF (1.0 mL) was added tri-basic potassium phosphate (250 mg, 1.20 mmol). The reaction mixture was heated to 125° C. and stirred at the same temperature for 3 h. The reaction was then cooled to rt, diluted with water (5 mL) and the aqueous phase was extracted with ethyl acetate (25 mL×3). The combined organic phases were washed with water, dried over Na2SO4 and evaporated to give desired product (Yield: 33%), which was used for next step without any further purifications. 1HNMR (CDCl3, 300 MHz) δ 0.90-1.01 (m, 6H), 1.33 (d, 3H), 1.52-1.75 (m, 2H), 1.80 (s, 1H), 3.10-3.19 (m, 1H), 3.31-3.42 (m, 1H), 4.07 (q, 1H), 6.51 (s, 1H), 7.65 (s, 1H), 9.41 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][N:16]=2)[C:12]#[N:13])=[CH:5][CH:4]=1>CCO.[Pd]>[NH2:13][CH2:12][C:11]1[CH:14]=[CH:15][N:16]=[C:9]([NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: COc1ccc(CNc2cc(C#N)ccn2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CNc2cc(CN)ccn2)cc1

Procedure:
2-(4-Methoxy-benzylamino)-isonicotinonitrile (12 g, 50 mmole) was dissolved in a mixed solvent of EtOH (800 mL) Et3N (200 mL) and suspended with 2 g of Pd/C (10%). After removing air with vacuum, the flask was charged with H2 with a balloon. The H2 balloon was refilled every morning and evening. Pd/C was recharged twice (1.3 g each) on days 2 and 3. Reaction was completed on the 4th day and the reaction mixture was filtered through a pad of Celite®. The filter cake was rinsed with MeOH and the combined filtrate was concentrated in vacuo to give the desired compound as a light brown solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:29]=[C:28]([CH3:30])[C:17]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23](=[O:26])[CH2:24][OH:25])=[C:16]([CH3:31])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)=O.[CH3:32][NH:33][CH3:34]>>[CH3:32][N:33]([CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:29]=[C:28]([CH3:30])[C:17]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23](=[O:26])[CH2:24][OH:25])=[C:16]([CH3:31])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:34]
Reactant: Cc1cc(-c2noc(-c3ccc(C=O)cc3)n2)cc(C)c1OCC(O)CNC(=O)CO
Reactant: CNC
Product: Cc1cc(-c2noc(-c3ccc(CN(C)C)cc3)n2)cc(C)c1OCC(O)CNC(=O)CO

Procedure:
The title compound was prepared starting from rac-N-(3-{4-[5-(4-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide and dimethyl amine according to Method B. LC-MS*: tR=0.78 min; [M+1]+=455.38, 1H NMR (CDCl3): δ2.30 (s, 6H), 2.38 (s, 6H), 3.47-3.53 (m, 1H), 3.54 (s, 2H), 3.75-3.93 (m, 3H), 4.16-4.25 (m, 3H), 7.00 (br s, 1H), 7.53 (d, J=7.8 Hz, 2H), 7.86 (s, 2H), 8.19 (d, J=7.3 Hz, 2H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][O:8][P:9]([O-:12])[O:10][CH3:11].C[O-].[Na+]>CO>[CH3:7][O:8][P:9]([CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])(=[O:12])[O:10][CH3:11]
Reactant: COP([O-])OC
Reactant: C=CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCP(=O)(OC)OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
This procedure was reported by; Kreutzkamp, N.; Mengel, W. Chem. Ber., 1967, 100, 709-714. ##STR8## A mixture of methyl acrylate (30 mL, 28.7 g, 0.33 mol) and dimethylphosphite (36.7 g, 0.33 mol) was cooled to 0° C. and treated with a solution of sodium methoxide (1M) in methanol (5 mL). After a few min a vigorous exothermic reaction took place. When the reaction subsided, an additional portion of sodium methoxide was added. This procedure was repeated for a total of four times. The reaction was then allowed to stir at room temperature for 16 h and then the methanol removed by distillation. The residue was then vacuum distilled, bp 95° C. @ 0.15 mm, to provide 45.6 g, 70% of pure product. 1H NMR (CDCI3 /TMS/300 MHz) δ 3.71(d, J=11.1 Hz, 6H), 3.67(s, 3H), 2.57(td, J=8.4, 12.5 Hz), 2.06(td, J=8.4 12.5 HZ, 2H); 31P NMR (CDCI3) 33.3 (s); 13C NMR (CDCI3) 172.3, 52.3(d, J=6.5 Hz), 51.8, 27.0(d, J=4.1Hz), 20.8, 18.9.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:7][CH:6]([OH:8])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].O>O>[O:8]=[CH:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:7])[OH:11])[OH:10])[OH:9]
Reactant: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Frozen flocculated cells are immersed in water or a glucose syrup. The cell mass is allowed to thaw and is gently crushed by mechanical means or stirring to give particles of approximately uniform size. This slurry is then subjected to vacuum conditions for approximately 30 minutes to remove occluded gases from the cell particles. A jacketed column of 1 inch diameter is partially filled with water or glucose syrup and the degassed slurry is then poured into the column. The packed column is heated to 60° C. and a 2 M solution of glucose having a pH of 8.0 and containing 0.004 M MgCl2.6H2O is passed through the column at flow rates which are regulated to give the degree of glucose conversion desired. Conversions ranging up to 50 percent are attainable by this process.⟧
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]1[O:31][N:30]=[C:29]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[N:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:38](ON1C(=O)CCC1=O)([O:40][CH2:41][CH:42]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39]>C1COCC1>[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]1[O:31][N:30]=[C:29]([CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][CH:42]3[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=4[C:49]4[C:54]3=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:39])[CH2:34][CH2:33]2)[N:28]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nc(C3CCNCC3)no2)N1OCc1ccccc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC(c2noc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
DIPEA (1.6 mL, 10.0 mmol) was slowly added dropwise to a solution of (2S,5R)-6-(benzyloxy)-2-(3-(piperidin-4-yl)-1,2,4-oxadiazol-5-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (1.1 g, 2.0 mmol) in THF (50 mL) at 0° C. The mixture was stiffed under N2 atmosphere at 0° C. for 15 minutes, then, Fmoc-OSu (2.4 g, 7.2 mmol) was added and the mixture was stirred at rt. for 8 hrs. The mixture was concentrated and the residue was purified by silica gel column chromatography (gradient elution 1:6 to 1:2 EtOAc/hexanes) to give (9H-fluoren-9-yl)methyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (1.0 g, 86%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH:14]=[CH2:15]>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][CH:14]=[CH2:15])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C=CCC(C)(C)CN
Solvent: C1CCOC1
Product: C=CCC(C)(C)CNc1nc(Cl)cc(Cl)n1
Reaction time: 4 h

Procedure:
4.59 (25 mmoles) of 2,4,6-trichloropyrimidine are added to a solution of 6.23 g (55 mmoles) of 5-amino-4,4-dimethyl-1-pentene in 50 ml of tetrahydrofuran at room temperature, the reaction mixture is stirred at the same temperature for 4 hours, then evaporated. The evaporation residue is distributed between 60 ml of chloroform and 5 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 10 ml of water each, then dried and evaporated. The evaporation residue is subjected to chromatography on a silica gel column by using mixtures of hexane and ethyl acetate as eluents. Elution with a 19:1 hexane/ethyl acetate mixture gives 4,6-dichloro-2-[(2,2-dimethyl-4-penten-1-yl)amino]pyrimidine as an oily product in a yield of 2.62 g (40.3%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11])#[N:2].[H][H]>[Pd].N.CO>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CN(c1ccccc1C#N)S(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Product: CN(c1ccccc1CN)S(C)(=O)=O

Procedure:
N-(2-Aminomethyl-phenyl)-N-methyl-methanesulfonamide was prepared from N-(2-cyano-phenyl)-N-methyl-methanesulfonamide (0.75 g, 3.5 mmol) via hydrogenation using a Paar apparatus with 10% Palladium on Carbon (50% Wet)(5:45:50, palladium:carbon black:water, 0.75 g, 0.35 mmol) and hydrogen (50 psi) in 7M ammonia in methanol (50 mL). The mixture was shaken on a Paar apparatus until adsorption of hydrogen ceased. The mixture was degassed, backflushed with nitrogen, filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated under reduced pressure. Product isolated as a tan viscous oil (0.76 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.54 (d, J=7.7 Hz, 1H), 7.38 (ddd, J=7.6, 0.9, 0.9 Hz, 1H), 7.30 (ddd, J=7.9, 1.3, 1.3 Hz, 1H), 7.24 (dd, J=7.9, 0.8 HZ, 1H), 4.00 (br s, 2H), 3.26 (s, 3H), 2.99 (s, 3H). MS=215 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[O:27])[CH:20]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1cccc(Cl)c1

Procedure:
Example 13 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-chloro-3-isocyanatobenzene (16.6 μl) to give the title compound (0.0247 g). LC-MS (System A): Rt 2.46 mins, Mass Spectrum m/z 428 [MH+].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
Part A. A solution of 4-chloro-6-methyl-3-nitropyridone (5.0 g, 26.5 mmol) in acetonitrile (93 mL) was treated with benzylamine (2.89 mL, 26.5 mmol) and diisopropylethylamine (5.54 mL, 31.8 mmol). The mixture was heated to reflux for 4 hrs., then cooled to ambient temperature and allowed to stir for 12 hrs. The mixture was partitioned between dichloromethane and water (200 mL each), and the aqueous layer was extracted with dichloromethane (200 mL). The extracts were washed in sequence with water (200 mL) and combined, and the resulting precipitate was collected by filtration. The filtrate was dried over sodium sulfate, refiltered and evaporated to afford a second crop of crystalline product, 4-benzylamino-6-methyl-3-nitropyridone (6.74 g total, 26.0 mmol, 98%). m.p. 246-247° C. TLC RF 0.35 (10:90 isopropanol-ethyl acetate). 1H NMR (300 MHz, CDCl3): d 10.48 (1H, br s), 9.69 (1H, br s), 7.41-7.26 (5H, m), 5.66 (1H, s), 4.57 (2H, d, J=5.5 Hz), 2.26 (3H, s). MS (NH3 -CI): m/e 261 (10), 260 (70), 226 (100).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:23]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:24]C([O-])=O.Cl>O1CCCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH2:24][C:23]([O:29][CH2:30][CH3:31])=[O:28])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(Cl)s1
Reaction time: 6 h

Procedure:
To a solution of 5-chlorothiophene-2-carboxylic acid (10.12 g, 62.24 mmol) in tetrahydrofuran (80 ml) was added 1,1′-carbonyldiimidazole (11.1 g, 68.5 mmol) at room temperature and the mixture was stirred as it was for 6 hrs. Monoethyl malonate monomagnesium salt (9.81 g, 34.2 mmol) was added to this mixture at room temperature and the mixture was stirred at 60° C. for 3 hrs. The reaction solution was diluted with ethyl acetate and water, and acidified with conc. hydrochloric acid. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the objective substance.