Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:27]1[CH:32]=[CH:31][C:30](C(O)=O)=[CH:29][CH:28]=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[C:41]([OH:45])[CH:42]=[CH:43][CH:44]=1>>[CH3:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[C:21]=1[C:27]1[CH:28]=[CH:29][C:30]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([OH:45])[CH:40]=2)=[O:18])=[O:7])=[CH:31][CH:32]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)cc1
Reactant: NCCc1cccc(O)c1
Product: CON=C1C[C@@H](C(=O)NCCc2cccc(O)c2)N(C(=O)c2ccc(-c3c(C)cccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,6′-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 3-(2-aminoethyl)phenol, the title compound was obtained in 81% purity by HPLC. MS(ESI+): m/z=486.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[C@@H:23]([CH2:24][OH:25])[CH2:22][O:21][CH2:20][C@@H:19]1[CH2:26][CH:27]=[CH2:28])=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[C@H:23]([CH:24]=[O:25])[CH2:22][O:21][CH2:20][C@@H:19]1[CH2:26][CH:27]=[CH2:28])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C=CC[C@H]1COC[C@H](CO)N1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=CC[C@H]1COC[C@@H](C=O)N1C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 111.8 %

Procedure:
Dimethyl sulfoxide (498 mg, 6.38 mmol) was added at −70° C. to a solution of oxalyl chloride (405 mg, 3.19 mmol) in DCM (5 mL), then after 15 min a solution of (3S,5S)-3-allyl-5-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (547 mg, 2.13 mmol) in DCM (3 mL) was added. The reaction mixture was stirred at −70° C. for 30 min, then treated with Et3N (1.29 g, 12.8 mmol), then after 20 min the ice bath was removed. After 30 min the reaction mixture was washed with sat. aq. sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to afford the title compound (608 mg) as a light yellow gum, which was directly used in the next step.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:10])[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=[O:24])=CC=1.[C-:28]#[N:29].[K+]>C1COCC1.O>[OH:24][CH:8]([C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:10])[C:28]#[N:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: [C-]#N
Reactant: CC(C#N)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccccc1)(c1ccccc1)C(O)C#N
Temperature: 40 °C
Yield: 86.4 %

Procedure:
42.3 g (0.201 mol of 2,2-diphenylpropionitrile [sic] were dissolved in 230 ml of THF, and 41.4 g (0.217 mol) of p-toluenesulfonic acid were added. Then 14.09 g (0.217 mol) of KCN in 60 ml of water were added dropwise. The mixture was then heated at 40° C. for 3 hours. The reaction mixture was concentrated to about 30% under reduced pressure, taken up in water and extracted three times with ethyl acetate. The combined organic phases were washed twice with sodium disulfite solution, dried with MgSO4 and concentrated under reduced pressure. The crude product was chromatographed on silica gel with n-heptane/ethyl acetate (20:1). 41.2 g (86%) of 2-hydroxy-3,3-diphenylbutyronitrile were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=O)[CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC.CCCCCC>[CH2:12]([NH:19][C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: NCc1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(NCc1ccccc1)c1cc(Cl)ccn1

Procedure:
A mixture of 5 g of methyl 4-chloropicolinate and 3.44 g of benzylamine is heated at 100° for 16 hours. Cooling and trituration with ether/hexane affords N-benzyl-4-chloro-pyridine-2-carboxamide. This material is heated with 5 g of sodium azide in 50 ml of dimethylformamide at 100° for 10 hours. After dilution with water the product is extracted with ether. Drying and removing the solvent affords 4-azido-N-benzyl-pyridine-2-carboxamide as an oil. This material is stirred under 1 atom of hydrogen in 50 ml of ethanol with 1.0 g of 10% palladium on carbon catalyst for 4 hours. Filtration and removal of solvent affords 4-aminopyridine-2-(N-benzyl)-carboxamide as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[C:26]([C:28](O)=[O:29])[CH:25]=[CH:24][N:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:26]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:21])[CH:27]=3)=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1cc(C(=O)O)ccn1
Product: Cc1cc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)ccn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2-methyl-4-pyridinecarboxylic acid, as starting materials, MS (LC/MS): 422.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1Cl)([O-:3])=[O:2].[OH-].[NH4+:19]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[NH2:19])([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: [OH-]
Solvent: c1ccccc1
Product: Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 40.5 g. of 2,6-dinitro-4-trifluoromethyl-1-chlorobenzene in 300 ml. of benzene was mixed with 250 ml. of 14 N ammonium hydroxide. The reaction mixture was stirred at room temperature for about 1.5 hours, at which point in time another 100 ml. of 14 N ammonium hydroxide were added and the stirring was continued for an additional 2 hours. The organic layer was separated, was washed with water and was dried. Removal of the solvents in vacuo yielded 2,6-dinitro-4-trifluoromethylaniline, which melted at about 142°-144° C. after recrystallization from a hexane-benzene solvent mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)[CH3:52]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:56]6[CH2:57][CH2:58][N:53]([CH2:51][CH3:52])[CH2:54][CH2:55]6)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:49][CH:50]=1
Reactant: CCN1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Product: CCN1CCN(C(=O)c2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c(F)c2)CC1

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (65.6 mg, 0.0968 mmol) obtained in Step A in Example 1-D-21 and N-ethylpiperazine (24.6 μl, 0.194 mmol) instead of 1-pyridin-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, and a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone was obtained as a yellow solid (64.2 mg). Then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-138) as a yellow powder (39.2 mg, 76%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Br[CH2:14][CH2:15][CH2:16][Cl:17]>CN(C)C=O.O>[NH:8]1[C:9]2[C:5](=[C:4]([O:3][CH2:14][CH2:15][CH2:16][Cl:17])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: ClCCCBr
Reactant: Oc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1cccc2[nH]ccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
A suspension of 1.6 gm (39.7 mMol) sodium hydride (60% dispersion in mineral oil) in 80 mL dimethylformamide was cooled to 0° C. under a nitrogen atmosphere. To this suspension were added 5.0 gm (37.6 mMol) 4-hydroxyindole in portions over 30 minutes. The reaction mixture was stirred at room temperature for 1.5 hours after this addition was complete. To the resulting mixture was then added dropwise a solution of 5.91 gm (37.6 mMol) 1-bromo-3-chloropropane in dimethylformamide and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture was diluted with water and then extracted well with ethyl acetate. The ethyl acetate phases were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 10% ethyl acetate in hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 4.62 gm (59%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]([NH2:7])=O>O.CC#N.Cl[Pd]Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]#[N:7]
Reactant: NC(=O)c1cc(Br)cc(C=O)c1
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(Br)cc(C=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
To a solution of 3-bromo-5-formylbenzamide (1.5 g, 6.58 mmol) in H2O (50.0 mL) and MeCN (50.0 mL) was added PdCl2 (117 mg, 0.658 mmol). The mixture was stirred for 72 h at room temperature and another portion of H2O (100 mL) and MeCN (100 mL) was added followed with addition of PdCl2 (100 mg, 0.56 mol). The mixture was stirred for another 12 hr and concentrated. The residue was dissolved in EtOAc (200 mL), washed with brine (3×50.0 mL), dried over Na2SO4 and concentrated, and then was purified by chromatography (10% EtOAc in hexanes) to give 550 mg of 3-bromo-5-formylbenzonitrile (40%).
Reaction SMILES: [F:1][C:2]([F:19])([C:7]1[CH:11]=[C:10]([NH2:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1)[C:3]([F:6])([F:5])[F:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>C1COCC1>[F:19][C:2]([F:1])([C:7]1[CH:11]=[C:10]([NH:12][C:27](=[O:28])[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.9 %

Procedure:
To a stirred mixture of 3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-amine (300 mg, 1.08 mmol) and potassium carbonate (223 mg, 1.62 mmol) in THF (3 mL) at rt, was added a solution of phenyl chloroformate (169 mg, 1.08 mmol) in THF (2 mL) dropwise. After stirring for a further 15 h at rt, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give an oil. Purification via silica gel flash column chromatography (eluting with a gradient of 100% petroleum ether to 5% ethyl acetate in petroleum ether) afforded phenyl 3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (360 mg, 84%) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.55-7.62 (m, 5H), 7.39-7.43 (m, 2H), 7.29 (m, 1H), 7.14 (m, 2H), 6.91 (m, 1H); LC-MS (ESI) m/z 398 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3].[C:10]1(=[O:15])[CH2:13][C:12](=[O:14])[CH2:11]1>C(OCC)(=O)C>[CH:4]1([NH+:2]([CH3:3])[CH3:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:15][C:10]1[CH2:13][C:12](=[O:14])[CH:11]=1
Reactant: CN(C)C1CCCCC1
Reactant: O=C1CC(=O)C1
Solvent: CCOC(C)=O
Product: C[NH+](C)C1CCCCC1
Product: O=C1C=C(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of 3.21 g of N,N-dimethylcyclohexylamine (99 percent; 25.0 mmol) in 10 g of ethyl acetate was instilled in a suspension of 2.1 g of 1,3-cyclobutanedione (91.9 percent; 23.0 mmol) in 40 g of ethyl acetate at 20° C. in 15 minutes. After 1 hour of stirring at room temperature, the suspension was filtered and dried under vacuum. 4.27 g of the title product with a purity of 94.8 percent (according to HPLC), corresponding to a yield of 83.3 percent, relative to the cyclobutanedione, was obtained. Data for the title compound was:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=1.N1C=CC=CC=1C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I.O>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Clc1cccc(I)c1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccn1
Solvent: O
Product: Nc1ncccc1-c1ccc(Oc2cccc(Cl)c2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
To a mixture of 4-(2-aminopyridin-3-yl)phenol (400 mg), 1-chloro-3-iodobenzene (615 mg), picoline acid (52.9 mg) and tripotassium phosphate (1368 mg) in DMSO (6 mL) was added copper (I) iodide (82.0 mg). The reaction mixture was stirred under a nitrogen atmosphere at 120° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and concentrated under reduced pressure to give the title compound (307 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=O)[C:11]=1[C:19]([OH:21])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]2[C:11]=1[C:19](=[O:21])[N:23]([CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26])[C:13]2=[O:15]
Reactant: COc1ccccc1Nc1cccc(C(=O)O)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccccc1Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 92 %

Procedure:
A mixture of 3-(2-methoxyphenylamino)phthalic acid (0.55 g, 1.9 mmol) and rac-α-aminoglutarimide hydrochloride (0.31 g, 1.9 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 95:5 methylene chloride-methanol, eluting 0.66 g of the product, in 92% yield: mp 223-225° C.; 1H NMR (CDCl3) δ 2.13-2.20 (m, 1H), 2.73-2.95 (m, 3H), 3.88 (s, 3H), 4.97 (dd, J=11.9 Hz, J=5.0 Hz, 1H), 6.94-7.00 (m, 2H), 7.09-7.15 (m, 1H), 7.21-7.26 (m, 1H), 7.38-7.52 (m, 3H), 8.08 (s, 1H), 8.15 (s, 1H); 13C NMR (CDCl3) δ 22.8, 31.4, 49.0, 55.7, 111.4, 112.1, 113.6, 118.8, 120.6, 121.1, 124.8, 128.2, 132.5, 135.7, 143.6, 151.4, 167.4, 168.1, 169.1, 170.8; Anal. calcd for C20H17N3O5.0.1H2O: C, 63.02; H, 4.55; N, 11.02. Found: C, 62.91; H, 4.42; N, 10.71.
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:9][C@H:10]([OH:32])[C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:47]([O:54][P:55]([O:65][CH2:66][C:67]([CH3:73])([CH3:72])[CH2:68][C:69](O)=[O:70])([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:58]([O:57][P:55]([O:65][CH2:66][C:67]([CH3:73])([CH3:72])[CH2:68][C:69]([O:32][C@H:10]([C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:24]([CH3:30])=[CH:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:9][C@@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:70])([O:54][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:56])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: CC(C)(COP(=O)(OCc1ccccc1)OCc1ccccc1)CC(=O)O
Reactant: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O)OC(=O)CC(C)(C)COP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
To a solution containing the compound of Example 3 (0.075 g, 0.12 mmol), the product from Example 9C (0.056 g), and DMAP (0.017 g) in DMF (1.2 mL) was added EDAC (0.027 g) and the mixture was stirred at room temperature for 16 hours. Additional product from Example 9C (0.056 g) and EDAC (0.027 g) were added and the reaction was stirred at room temperature for 3 hours. The solvent was evaporated and the reaction mixture was partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with a gradient starting with 33% ethyl acetate in chloroform and ending with 5% methanol in chloroform, to give the title compound (0.101 g, 84%).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:7][CH2:8][CH3:9])=[CH:3]\[C:4]([OH:6])=O.ClC(OCC)=O.C(N(CC)CC)C.[CH:23]([NH:26][CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24].Cl>>[CH:23]([N:26]([CH:27]([CH3:29])[CH3:28])[C:4](=[O:6])/[CH:3]=[C:2](\[CH3:1])/[CH2:7][CH2:8][CH3:9])([CH3:25])[CH3:24]
Reactant: CC(C)NC(C)C
Reactant: CCC/C(C)=C/C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCC/C(C)=C/C(=O)N(C(C)C)C(C)C
Yield: 34 %

Procedure:
3-Methyl-2E-hexenoic acid 1 eq, ethyl chloroformate 1.5 eq, triethylamine 1.6 eq, diisopropylamine 3.0 eq, quench with 10% hydrogen chloride solution, yield=34%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH:9]1[CH2:14][CH2:13][S:12][CH2:11][CH2:10]1)[OH:8].B1([O-])OO1.[OH2:19].[OH2:20].O.O.[Na+]>C(O)(=O)C>[O:19]=[S:12]1(=[O:20])[CH2:11][CH2:10][CH:9]([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[OH:8])[CH2:14][CH2:13]1
Reactant: OC(c1ccccn1)C1CCSCC1
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: O=S1(=O)CCC(C(O)c2ccccn2)CC1
Reaction time: 18 h
Yield: 68.6 %

Procedure:
Placed pyridin-2-yl(tetrahydro-2H-thiopyran-4-yl)methanol (1.560 g, 7.453 mmol) in glacial acetic acid (2 mL). Sodium perborate tetrahydrate (2.293 g, 14.91 mmol) was added and stirred for 18 hours. The reaction was partitioned between saturated sodium bisulfite and CH2Cl2. The solids were filtered off, washed with water and dried to afford the title compound (1.233 g, 68.56% yield)
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H:36]2[C@@H:27]([CH2:28][N:29]3[C@H:34]([CH2:35]2)C2NC4C=C(OC)C=CC=4C=2CC3)[CH2:26][C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O.C(#[N:68])C>>[CH2:1]([N:8]1[CH:12]=[C:11]([C:28]2[N:29]=[CH:34][CH:35]=[CH:36][C:27]=2[C:26]#[N:68])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Reactant: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Product: N#Cc1cccnc1-c1cnn(Cc2ccccc2)c1

Procedure:
The title compound was prepared from 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using General Procedure 3. 1H NMR (DMSO-d6, 400 MHz) δ 5.46 (s, 2H), 7.30-7.38 (m, 5H), 7.41 (dd, J=4.9 Hz, J=7.9 Hz, 1H), 8.21 (s, 1H), 8.30 (dd, J=1.8 Hz, J=7.9 Hz, 1H), 8.62 (s, 1H), 8.80 (dd, J=1.7 Hz, J=4.8 Hz, 1H); RP-HPLC (Hypersil® HS C18, 5 μm, 100 Å, 25 cm; 50%-100% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min), then 100% acetonitrile isocratic 2 minutes, Rt 5.95 min. (99.0%), MS: M+H+ 261.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[C:4]([O:8][C:9]([O:11]C(OC(C)(C)C)=O)=O)([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9]([N:2]([CH3:1])[NH2:3])=[O:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CNN
Solvent: CCO
Product: CN(N)C(=O)OC(C)(C)C

Procedure:
10 mL of methyl hydrazine was dissolved in 90 mL of ethanol, and under stirring at ice-cooling, a solution of 41 g of di-tert-butyldicarbonate in 90 mL of ethanol was added dropwise over 45 minutes. After stirring at room temperature for 7 hours, the solvent was evaporated, to afford 24.7 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].Cl[CH2:29]/[CH:30]=[CH:31]\[CH2:32]Cl.C[N:35](C)C=O>>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([N:12]2[CH:30]([CH:31]=[CH2:32])[CH2:29][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1](=[NH:35])[NH2:2])[CH:4]=3)[C:10]2=[O:11])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2cccc(C#N)c2)CC1
Reactant: CN(C)C=O
Reactant: ClC/C=C\CCl
Agent: [H-]
Agent: [Na+]
Product: C=CC1CN(c2cccc(C(=N)N)c2)C(=O)N1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-(3-cyanophenyl)-N′-(1-(t-butoxycarbonyl)-piperidin-4-yl)urea (0.50 g, 1.45 mmol) and sodium hydride (0.20 g of a 60% suspension in mineral oil, 8.3 mmol) in dimethylformamide was stirred at ambient temperature for 30 min. then cis-1,4-dichloro-2-butene (0.18 g, 1.44 mmol) was added. This mixture was heated at 70° C. for 4 h, after which an addition 0.2 g of 60% sodium hydride and 0.04 g of cis-1,4-dichloro-2-butene was added. The mixture was heated at 70° C. for an addition 2 h during which the remaining starting material was consumed. The reaction was diluted with brine (50 ml) and extracted with ethyl acetate (3×). The ethyl acetate extracts were washed with brine, then dried (Na2SO4) and evaporated. The residue was purified by flash chromatography on silica gel, eluting with 2:1 hexane:ethyl acetate to give 0.20 g of 1-(1-t-butoxycarbonylpiperidin-4-yl)-3-(3-amidinophenyl)-5-ethenyl-2-imidazolidinone; LRMS (M+H)+ m/z 397.