Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][C:16]1[N:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([O:22][C:20]2[CH:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]([CH3:15])[N:21]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1nc(O)ccc1[N+](=O)[O-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 22 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
Add diisopropyl azodicarboxylate (3.0 mL, 15.5 mmol) dropwise to a cold mixture of 6-methyl-5-nitro-pyridin-2-ol (1.54 g, 10.0 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (2.05 g, 10.0 mmol), and triphenylphosphine (4.02 g, 15.3 mmol) in THF (25 mL) at 0° C. After addition is complete, remove cooling bath and stir the reaction mixture at 22° C. overnight. Concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to provide 4-(6-Methyl-5-nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil (2.69 g, 80% yield). MS(ES): m/z=338.2 [M+H].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:47])[C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][C:38]([N:37]([CH3:47])[CH3:36])=[O:46])[CH2:45][CH2:44]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 664.4 [(M+H)+]
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([CH3:24])[O:21][C:20]=2[CH3:25])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([CH3:24])[O:21][C:20]=2[CH3:25])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2cc(C)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(Oc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of cyclohexyl(2,5-dimethylfuran-3-yl)methanol (521 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (456 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (1.2 mL) and 1,1′-(azodicarbonyl)dipiperidine (1.2 g), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 12% ethyl acetate/hexane) to give methyl 4-[cyclohexyl(2,5-dimethylfuran-3-yl)methoxy]benzoate as an oil. The obtained methyl 4-[cyclohexyl(2,5-dimethylfuran-3-yl)methoxy]benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (1.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give the title compound (501 mg, 61%) as a white crystal.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C.O>[OH:3][CH2:4][C:5]1[O:6][C:7]([CH2:13][O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CC(C)(C)C(=O)OCc1cc(=O)c(O)c(CO)o1
Reactant: CCOC(=O)CCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCOc1c(CO)oc(COC(=O)C(C)(C)C)cc1=O
Yield: 27 %

Procedure:
To a solution of 1.84 g (0.028 mole) of potassium hydroxide in 38 ml of ethanol and 10 ml of water was added 6.76 g (0.026 mole) of 2-hydroxymethyl-3-hydroxy-6-(trimethylacetoxymethyl)-4-pyrone, and the resulting mixture heated to 50°. An 8.3 g (0.03 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atmosphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 2.9 g (27%) of oily product, 2-hydroxy-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone. NMR (CDCl3): δ1.22 (3H, t, J = 7 Hz), 1.23 (9H, s), 2.30 (2H, t, J = 5.5 Hz), 6.32 (1H, s).
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.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[CH2:26][C:27](O)=[O:28]>>[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][NH:13][C:27](=[O:28])[CH2:26][C:20]2[C:19]([F:18])=[CH:24][CH:23]=[CH:22][C:21]=2[F:25])[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1c(F)cccc1F
Product: O=C(Cc1c(F)cccc1F)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 66.4 %

Procedure:
Example 52 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and 2,6-difluorophenylacetic acid (0.035 g) to give thetitle compound (0.057 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH2:9][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[Cl:25]C1C=C2N(C3C=CC=CC=3[N+]([O-])=O)CC3(CCN(/C(/C([O-])=O)=C/C([O-])=O)CC3)C2=CC=1.C(O)C.Cl>[Fe].O>[ClH:1].[ClH:25].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21
Reactant: O=C([O-])/C=C(\C(=O)[O-])N1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1cc(Cl)ccc12
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21

Procedure:
A mixture of 2.1 g of 6-chloro-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], free base of Example 33, 95 ml of 95% ethyl alcohol, 7.5 ml of water and 4.4 g of iron powder is acidified with 0.2 ml of concentrated hydrochloric acid and then refluxed under nitrogen for 10 minutes. Thereafter, the mixture is permitted to cool before being filtered through celite. The filtrate is concentrated under vacuum leaving an oily residue which is basified. The alkaline mixture is extracted with ether and then dried. The product is converted to a solid dihydrochloric acid salt which is recrystallized from a methyl alcohol-ether mixture to provide off-white prisms, mp 270°-273° C. (after darkening) of 1-(2-aminophenyl)-6-chlorospiro[indoline-3,4'-piperidine]dihydrochloride.
Reaction SMILES: N1CCCCC1.C(O)(=O)C.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21]([O:27][CH3:28])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:29]([O:37][CH2:38][CH3:39])(=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:29]([O:37][CH2:38][CH3:39])=[O:36])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1OC)C(=O)OCC
Temperature: 125 °C
Reaction time: 5 h
Yield: 44.2 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with piperidine (0.108 g, 0.13 mL, 1.35 mmol) and acetic acid (0.081 g, 0.08 mL, 1.35 mmol). To this, toluene (20 mL) was added, followed by 4-(benzyloxy)-2-methoxybenzaldehyde (1.1 g, 4.5 mmol) and diethyl malonate (0.87 g, 5.5 mmol). The RM was heated at 125° C., by fitted with a dean-stark's apparatus for 5 h. After 5 h, the RM was concentrated; water (50 mL) was added and extracted with ethyl acetate (50 mL×2)). The organic layer was washed with saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as yellow solid. (0.775 g, yield: 44.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Reactant: Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Yield: 89.2 %

Procedure:
Following the procedure of example 1115 A, N-t-butoxycarbonyl-2-hydroxymethylpyrrolidine (0.80 g, 4.00 mmol) and phenol (1.13 g, 12.00 mmol) provided 0.99 g (89%) of the title compound. MS (DCI, NH3): 278 (MH+).
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]([F:25])([F:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[N:15][C:14]([N:17]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[H-].[Na+].[Cl:35][CH:36]([CH3:38])[CH3:37]>C1COCC1.CN(C)C=O>[ClH:35].[ClH:1].[CH:36]([N:20]1[CH2:21][CH2:22][CH2:23][N:17]([C:14]2[N:15]=[N:16][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([F:24])([F:3])[F:25])=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19]1)([CH3:38])[CH3:37]
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCCNCC3)nn2)cc1
Reactant: CC(C)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)N1CCCN(c2ccc(-c3ccc(C(F)(F)F)cc3)nn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.9 %

Procedure:
4-[6-(4-Trifluoromethylphenyl)pyridazin-3-yl]-[1,4]diazepane, dihydrochloride (0.028 g, 0.071 mmol) was suspended in THF (4 mL) and triethylamine (0.022 g, 0.21 mmol) was added. Sodium hydride (0.0085 g, 0.35 mmol) was added and the reaction mixture was stirred at rt for 20 min. Dry N,N-dimethylformamide (1 mL) and 2-chloropropane (0.056 g, 0.71 mmol) was added and the reaction mixture was heated 30 min at 160° C. and 30 min at 180° C. in a microwave oven. The reaction mixture was purified on a silicagel column (0.04-0.063 mesh) using dichloromethane/MeOH (9:1) as eluent. This afforded a crude oil containing several components that was purified further by preparative HPLC using Method B. This afforded 9 mg of an oil which was dissolved into MeOH. Addition of HCl in diethyl ether afforded 6.5 mg (21%) of the title compound as an oily dihydrochloride.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[N:4][C:3]=1[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH:30]1([C:2]2[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[N:4][C:3]=2[NH:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[CH2:32][CH2:31]1
Reactant: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Br)nc2C(N)=O)c1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(C3CC3)nc2C(N)=O)c1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 181) (50 mg), cyclopropylboronic acid (18 mg), tetrakistriphenylphosphine palladium (24 mg), potassium carbonate (71 mg), dioxane (2.5 mL) and water (0.5 mL) was stirred at 115° C. overnight. After cooling, the reaction liquid was partitioned using chloroform, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying, the organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=100:0:0 to 10:1:0.1). The resulting residue was solidified with ethyl acetate-hexane to give 6-cyclopropyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (10 mg) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][N:6]=1.Br[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[CH2:13]([N:5]1[N:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:6]1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1n[nH]nc1C
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1nn(CC(C)C)nc1C
Temperature: 60 °C
Yield: 43.3 %

Procedure:
To av solution of ethyl 5-methyl-2H-1,2,3-triazole-4-carboxylate (0.5 g, 3.2 mmol) in acetonitrile (40 mL) were added 1-bromo-2-methylpropane (1.25 mL, 11.5 mmol), potassium carbonate (2.66 g, 19.2 mmol) and a catalytic amount of potassium iodide. The reaction mixture was heated to 60° C. for 22 h. The reaction mixture was allowed to cool to ambient temperature and was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield 293 mg (43%) of the title compound; MS (APPI/APCI) m/z 212[M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH2:13])=[S:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14](OC(OCC)CBr)[CH3:15]>C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:14]=[CH:15][N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(=S)Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(CBr)OCC
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Nc2nccs2)cc1
Temperature: 100 °C
Yield: 48.9 %

Procedure:
To a suspension of 1-(4-nitrophenyl)-2-thiourea (5.00 g, 25.4 mmol) in acetic acid (40 mL) was added bromoacetaldehyde diethyl acetal (3.94 mL, 25.4 mmol) at RT. The resulting mixture was heated to 100° C. for 2 h. After cooling to RT, the solvent was removed in vacuo. The residue was diluted with 1M NaOH (100 mL) and EtOAc (100 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic extracts were dried over MgSO4 and concentrated. Purification by column chromatography (20-80% EtOAc in hexanes) afforded the product as a yellow solid (2.75 g, 49%). 1H-NMR (400 MHz, DMSO-d6) δ 11.02 (s, 8.231H), 8.23 (d, J=9.3 Hz, 2H), 7.85 (d, J=9.3 Hz, 2H), 7.41 (d, J=3.6 Hz, 1H), 7.15 (d, J=3.6 Hz, 1H). LC/MS (10-99%) M/Z: M+1 obs=222.1; tR=2.50 min.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[C:4]([O-:17])(=[O:16])[CH2:5][CH2:6]CCCCCCCCC.C([Sn+2]CCCC)CCC.[C:27]([O-])(=[O:39])[CH2:28]CCCCCCCCCC.COC1C=CC(O)=CC=1>C1(C)C=CC=CC=1>[C:4]([OH:17])(=[O:16])[CH:5]=[CH2:6].[NH2:1][C:2]([O:39][CH2:27][CH3:28])=[O:3]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: [N-]=C=O
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 70 °C

Procedure:
50 parts of toluene, 87 parts of isophorone diisocyanate subjected to isocyanurate modification (“BESTANATE T1890E”, trade name, produced by Degussa AG), nonvolatile content: 70%, isocyanate content: 12%], 59.8 parts of polycaprolactone-modified hydroxyethyl acrylate (“PLACCEL FA1”), 32.8 parts of polycaprolactone-modified hydroxyethyl acrylate (“PLACCEL FA20”, trade name, produced by Daicel Chemical Industries, Ltd.), 0.02 parts of dibutyltin laurate, and 0.02 parts of hydroquinone monomethyl ether were mixed and the mixture was maintained at 70° C. for 5 hours. Thereafter, 84.5 parts of toluene was added to obtain a urethane acrylate having a solid content of 50% by weight. The average number of repetitions per one molecule of the urethane acrylate relative to the number of repetitions of a caprolactone unit per one residue of an acrylate monomer is 2. Further, the maximum difference in the number of repetitions between two kinds of the urethane acrylates is 19.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][C:16]1[C:21]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:20](Cl)[N:19]2[N:28]=[CH:29][N:30]=[C:18]2[N:17]=1>ClCCl>[CH3:15][C:16]1[C:21]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:20]([N:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)[N:19]2[N:28]=[CH:29][N:30]=[C:18]2[N:17]=1
Reactant: CC1CCNCC1
Reactant: Cc1nc2ncnn2c(Cl)c1C1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ncnn2c(N2CCC(C)CC2)c1C1CCCC1

Procedure:
With stirring, a solution of 4-methylpiperidine (1.5 mmol) and triethylamine (1.5 mmol) in 10 ml of dichloromethane was added to a solution of 5-methyl-6-cyclopentyl-7-chloro[1,2,4]triazolo[1,5-a]pyrimidine (1.5 mmol, Ex. 3) in 20 ml of dichloromethane. The reaction mixture was stirred at 20-25° C. for about 16 hours and then washed with a 5% strength solution of HCl. The organic phase was separated off and dried. Following distillative removal of the solvent and chromatography on silica gel, this gave 0.26 g of the title compound of m.p. 145° C.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:15][NH:14][CH2:13]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH:12]3[CH2:13][N:14]([C:24](=[O:27])[CH2:25][CH3:26])[CH2:15]3)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2cc(-c3ccncc3)nn2C2CNC2)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CC(n2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(5-(4-fluorobenzyl)-1-(azetidin-3-yl)-1H-pyrazol-3-yl)pyridine (75 mg, 0.24 mmol) in CH2Cl2 (2 mL) was added propionyl chloride (22 μL, 0.24 mmol) and triethylamine (37 μL, 0.26 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The solution was then loaded directly onto a pre-wetted Biotage 25M column and purified by flash chromatography (0-5% MeOH/CH2Cl2) to give the title compound as a white solid, 68 mg, 78%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.57 (d, 2 H), 7.74 (d, 2 H), 7.26 (t, 2 H), 7.16 (t, 2 H), 6.72 (s, 1 H), 5.25-5.34 (m, 1 H), 4.32-4.45 (m, 2 H), 4.07-4.13 (m, 4 H), 2.09 (q, 2 H), 0.97 (t, 3 H); m/z (APCI+) for C21H21N4FO 365.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].C1(C2(CC(O)(C)C)OC(=O)N([C@H](C3C=CC(C4C=CN(C)C(=O)C=4)=CC=3)C)CC2)CC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(=O)c1ccc(Br)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Agent: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CCC(CC(C)(C)O)(C2CC2)OC1=O
Product: CC(=N[S@](=O)C(C)(C)C)c1ccc(Br)c(C)c1

Procedure:
The title compound was prepared from 1-(4-bromo-3-methyl-phenyl)-ethanone and (R)-2-methyl-2-propanesulfinamide following a procedure analogous to that described in Step 1 of Intermediate 1. Mass spectrum (ESI+): m/z=316/318 (Br) [M+H]+.
Reaction SMILES: C([C@H](NC(=O)C1C=CC(F)=[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][C:33]2=[O:37])C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH2:39]([C@H:46]([NH:61][C:62](=[O:72])[C:63]1[CH:68]=[C:67]([O:69][CH3:70])[CH:66]=[C:65](Br)[CH:64]=1)[C@@H:47]([OH:60])[CH2:48][C@H:49]([C:51](=[O:59])[NH:52][CH2:53][CH2:54][C:55]([CH3:58])(C)[CH3:56])[CH3:50])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[C:73]1(=O)NCCC[CH2:74]1>>[CH2:39]([C@H:46]([NH:61][C:62](=[O:72])[C:63]1[CH:64]=[C:65]([N:32]2[CH2:27][CH2:36][CH2:35][CH2:34][C:33]2=[O:37])[CH:66]=[C:67]([O:69][CH3:70])[CH:68]=1)[C@@H:47]([OH:60])[CH2:48][C@H:49]([C:51](=[O:59])[NH:52][CH:53]1[CH2:54][CH:55]2[CH2:56][CH:73]1[CH2:74][CH2:58]2)[CH3:50])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COc1cc(Br)cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NCCC(C)(C)C)c1
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(F)c(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Reactant: O=C1CCCCN1
Product: COc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCCC2=O)c1

Procedure:
Prepared in an analogous manner to E1, from N-[(1S,2S,4R)-1-benzyl-4-(3,3-dimethylbutylcarbamoyl)-2-hydroxypentyl]-3-bromo-5-methoxybenzamide (D17) and δ-valerolactam.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].I[CH2:30][CH2:31][CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]([CH3:42])[C:34]1=[O:43].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[CH3:42][N:35]1[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[N:33]([CH2:32][CH2:31][CH2:30][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[C:22]([O:24][CH3:25])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[C:34]1=[O:43]
Reactant: Cn1c(=O)n(CCCI)c2ccccc21
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)n(C)c5ccccc54)CC3)C2=O)c1
Temperature: 65 °C
Yield: 78.2 %

Procedure:
A mixture of methyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (400 mg, 0.962 mmol, 1 equiv), 1-(3-iodopropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (304.8 mg, 0.962 mmol, 1 equiv), and potassium carbonate (399 mg, 2.88 mmol, 3 equiv) was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and worked up using ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using preparatory thin layer chromatography in 5% methanol in dichloromethane to afford the title compound as an oil (427 mg, 78%); 1H NMR (400 MHz, DMSO-d6): δ 1.61 (d, 2H, J=13.2 Hz), 1.85 (t, 2H, J=7.2 and 6.8 Hz); 2.34 (d, 2H, J=6.4 Hz); 2.64-2.66 (m, 2H); 2.89 (s, 3H); 3.843 (s, 3H); 3.91 (t, 2H, J=6.4 and 6.8 Hz); 4.58 (s, 2H); 4.62 (s, 2H); 6.78 (t, 1H, J=7.2 Hz); 6.86 (d, 2H, J=8.8 Hz); 7.01-7.07 (m, 2H); 7.13-7.14 (m, 1H); 7.21-7.26 (m, 3H); 7.52-7.58 (m, 2H); 7.88 (s, 1H); 7.90 (s, 1H); MS for C33H37N5O4 m/z 568.13 (M+H)+.