Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[O:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: NC1CCOCC1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Product: O=C(Nc1nc2cccc(NC3CCOCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and 4-aminotetrahydropyran (Apollo), 1.0 mL) as a white powder (15 mg, 14%). 1H NMR (DMSO-d6) δ 11.27 (s, 1H), 9.13 (d, J=1.9 Hz, 1H), 8.77 (d, J=4.9, 1.5 Hz, 1H), 8.33 (dd, J=8.0, 1.9 Hz, 1H), 7.58 (m, 1H), 7.51 (t, J=8.5 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 6.38 (d, J=7.9 Hz, 1H), 3.88 (m, 2H), 3.80 (m, 1H), 3.45 (m, 2H), 1.89 (m, 2H), 1.72 (m, 2H). HPLC, Rt: 1.51 min. (purity 99.0%). LC/MS, M+(ESI): 339.4, M−(ESI): 337.4.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]([CH:21]3[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]3)[C:12]([NH:14][C:15]3[S:16][C:17]([CH3:20])=[CH:18][N:19]=3)=[O:13])[CH2:7][CH2:6]2)[O:4]CC1>C(O)(=O)C>[CH3:27][CH:24]1[CH2:23][CH2:22][CH:21]([N:11]([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[C:12]([NH:14][C:15]2[S:16][C:17]([CH3:20])=[CH:18][N:19]=2)=[O:13])[CH2:26][CH2:25]1
Reactant: Cc1cnc(NC(=O)N(C2CCC(C)CC2)C2CCC3(CC2)OCCO3)s1
Solvent: CC(=O)O
Product: Cc1cnc(NC(=O)N(C2CCC(=O)CC2)C2CCC(C)CC2)s1

Procedure:
A solution of 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1-(4-methyl-cyclohexyl)-3-(5-methyl-thiazol-2-yl)-urea (100 mg, 0.25 mmol) in 80% aqueous acetic acid (1.15 mL) was heated at 60° C. for 3½ h. The reaction mixture was evaporated to dryness in vacuo to give a golden oil. The crude product was purified by HPLC to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1[Cl:13].CCO.[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].C(N(CC)CC)C>O>[C:17]([C:19](=[CH:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[Cl:13])[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Reactant: CCOC(=O)CC#N
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=Cc1c(Cl)n(C)c2ccccc12
Reaction time: 19 h

Procedure:
To 2 g of 1-methyl-2-chloroindole-3-carbaldehyde, dissolved in 50 ml of abs. EtOH, was added 2.3 g of ethyl 2-cyanoacetate and 4.2 g of triethylamine. After 19 hours with stirring, the solution was added to 200 ml of water, and the precipitate collected by filtration and dried to give (2a). Yield 2.68 g of (2a), m.p. 131°-132° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[BH4-].[Na+].O[N:15]1C(=O)C2=CC=CC=C2C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:59].O1CCOCC1>CO.C1COCC1.O>[ClH:59].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][NH2:15])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COc1cc(F)ccc1C=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(F)ccc1CON
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Fluoro-2-methoxybenzaldehyde (Fluorochem, 4.5 g) was dissolved in methanol (40 ml) and cooled to 0° C. Sodium borohydride (1.1 g) was added and the mixture was stirred for 1 hour. Water (200 ml) was added and the mixture was concentrated under reduced pressure (ca. 100 ml). The resulting precipitate was isolated by filtration, washed with water and dried under vacuum and gave 4-fluoro-2-methoxy-phenyl)-methanol (3.76 g). This alcohol (3.76 g) was dissolved in THF (100 ml) and N-Hydroxyphthalimide (3.93 g) and triphenylphosphine (6.32 g) was added followed by drop-wise addition of diisopropyl azodicarboxylate (4.87 g). The resulting turbid red reaction mixture was stirred at room temperature for 30 min. The mixture was filtrated through a pad of silica gel and the filtrate was evaporated under reduced pressure. Ethanol (70 ml) was added to the residue which dissolved on heating. On cooling a crystalline material formed that was isolated by filtration and dried under vacuum. This phthalimide intermediate (6.15 g) was suspended in ethanol (50 ml) and hydrazine monohydrate (1.0 ml) dissolved in ethanol (10 ml) was added. The reaction mixture was heated to reflux and stirred for ca. 3 hours. The mixture was cooled to room temperature and the solid material was removed by filtration. The filtrate was evaporated under reduced pressure and the residue was treated with EtOAc and filtrated. 4 M HCl in dioxane (1.0 eq.) was added to the filtrate and the resulting precipitated material was isolated by filtration and gave the title compound (3.26 g) as a white solid material. 13C-NMR (DMSO-d6) δ 163.7, 159.2, 132.6, 117.8, 106.6, 99.7, 70.2, 56.0.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([C:20]([O:22]C(C)C)=[O:21])[C@@H:12]([OH:19])[C:13]([O:15]C(C)C)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[C:20]([C@@H:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:12]([OH:19])[C:13]([OH:15])=[O:14])([OH:22])=[O:21]
Reactant: CC(C)OC(=O)[C@@H](CCOCc1ccccc1)[C@@H](O)C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](CCOCc1ccccc1)[C@@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
isopropyl 5-O-benzyl-3,4-dideoxy-3-(isopropoxycarbonyl)-L-threo-pentonate (7 g, 19.8 mmol) was taken in THF (50 mL), cooled to 0° C. and was treated with KOH (5.5 g, 99 mmol) in water (50 mL). The resulting mixture was stirred at RT for 3 h. THF was removed and the residue was taken in water. The aqueous layer was washed with ether (100 mL) and was acidified with an aqueous solution of HCl (1.5 N), then was then further extracted with EtOAc (2×100 mL), washed with water, dried over Na2SO4 and then concentrated to give the title product as colorless liquid (3.5 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][P:22]([O:34][CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])([CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:23])[C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:2]>CO.[Pd]>[CH2:1]([N:3]([CH2:21][P:22]([O:34][CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])([CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:23])[C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:2]
Reactant: CCN(CP(=O)(CCCCc1ccccc1)OCOC(=O)C(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCN(CP(=O)(CCCCc1ccccc1)OCOC(=O)C(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A solution of the diester product from part (a) in methanol is added to a 10% palladium on carbon catalyst and the resulting mixture is shaken in a Parr hydrogenation apparatus for several hours. The catalyst is filtered off and the methanol is stripped from the filtrate. The crude product is chromatographed on silica gel to yield 1-[[ethyl[[[(2,2-dimethyl-1-oxopropoxy) methoxy](4-phenylbutyl)phosphinyl]methyl]amino]carbonyl]-L-proline.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([O-:18])=[O:17]
Reactant: NCc1cccnc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=[N+]([O-])c1ccccc1NCc1cccnc1
Yield: 23 %

Procedure:
A mixture of 65 parts of 3-pyridinemethanamine, 94 parts of 1-chloro-2-nitrobenzene, 80 parts of sodium carbonate and 800 parts of 1-butanol is stirred and refluxed over week-end. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 33 parts (23%) of N-(2-nitrophenyl)-3-pyridinemethanamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH2:10][O:9][CH:8]([CH2:11]Br)[O:7][C:6]=2[CH:13]=1.[CH3:15][NH2:16]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:16][CH3:15])[O:7][C:6]=2[CH:13]=1
Reactant: CN
Reactant: Fc1cc(Br)cc2c1COC(CBr)O2
Solvent: CCO
Product: CNCC1OCc2c(F)cc(Br)cc2O1
Yield: 94 %

Procedure:
Preparation according to Example 12. 7-bromo-2-(bromomethyl)-5-fluoro-4H-1,3-benzodioxine (0.50 g, 1.53 mmol), methanamine (2.0 ml, 33% in EtOH) and EtOH (4.0 ml) were heated in a micro wave oven at 120° C. for 1 h 5 min. The volatiles were evaporated in vacuum and the crude product was chromathographed twice on a silica column using EtOAc/MeOH (4:1) as eluent. Collection of the fractions containing pure product and evaporation of the solvent afforded the title compound (0.40 g, 94%). 1H-NMR (400 MHz, MeOD): δ 6.93 (2H, m), δ 5.26 (1H, t, J 4.8 Hz), δ 4.93 (2H, dd, J1 18.4 Hz, J2 15.2 Hz), δ 3.02 (2H, m), δ 2.53 (3H, s) ppm.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([OH:18])[C:11]=3[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:24][C:25]1([CH3:29])[CH2:28][O:27][CH2:26]1.OP([O-])(O)=O.[K+]>CN(C=O)C>[CH3:24][C:25]1([CH2:29][O:18][CH:15]2[C:11]3[CH:12]=[N:13][CH:14]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=4)[C:10]=3[CH2:17][CH2:16]2)[CH2:28][O:27][CH2:26]1
Reactant: OC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Reactant: CC1(CI)COC1
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(COC2CCc3c(-c4ccc(C(F)(F)F)cc4)cncc32)COC1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A cooled (0° C.) solution of (rac)-4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (example 83) (75 mg, 0.27 mmol) in DMF (1.4 mL) was treated with NaH (55% in oil, 18.7 mg, 0.43 mmol) and after ½ h with 3-(iodomethyl)-3-methyloxetane (209 mg, 0.59 mmol, synthesized by refluxing 3-(chloromethyl)-3-methyloxetane with 5 eq. sodium iodide in acetone overnight) in DMF (1 mL). After warming up to room temperature over 5 h, the reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with Et2O (3×). The organic phases were washed once with aq. 10% NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (20 g SiO2, Telos-cartridge, 1 to 3% 2-propanol in CH2Cl2) to give the title compound (28 mg, 29%) as brown oil. MS: 364.5 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]#[C:22][CH3:23]>>[C:1]([O:5][C:6](=[O:18])[C:7]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])([CH2:16][C:11]#[C:12][CH3:13])[C:20]#[C:21][CH2:22][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC#CCBr
Reactant: CC(C)(C)OC(=O)CS(=O)(=O)c1ccc(F)cc1
Product: CC#CCC(C#CCC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(F)cc1
Yield: 77 %

Procedure:
2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynylhexynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. aSctarting from 2-(4fluoro-benzenesulfonyl)-acetic acid tert-butyl ester (4.87 g, 20 mmol) and 1-bromo-2-butyne (5.36 g, 40 mmol), 6.0 g of the product was isolated. Yield 77%; white solid; mp 85° C.; MS: 379.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].N1C=CC=CC=1.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>ClCCl>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([O:11][C:3]1[C:2]([CH3:1])=[CH:8][C:6]([OH:7])=[C:5]([CH3:9])[C:4]=1[CH3:10])=[O:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(O)c(C)c(C)c1OC(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask is equipped with a stirring bar and charged with 15.2 g (100 mmol) of trimethylhydroquinone and 23.7 g (3×100 mmol) of pyridine in 100 mL dichloromethane. The solution is stirred at ambient temperature and a solution of 20.8 g (100 mmol) of pivaloyl chloride in 100 mL of dichloromethane is added over 15 minutes. The final solution is stirred at ambient temperature for 48 hours, then washed with 1×100 mL of 3N hydrochloric acid solution, 1×50 mL of 3N hydrochloric acid solution, water, dried (magnesium sulfate) and evaporated leaving 26.6 g (>100%) of a pale yellow solid, mp 88°-112° C. (after drying 24.1 g). Recrystallization from hexane in the presence of charcoal affords the title compound as colorless cubes; mp 119°-121° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:12](Cl)[CH:13]=[CH2:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:14]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH:13]=[CH2:12]
Reactant: C=CCCl
Agent: Nc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCNc1cccc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
Toluene (1,830 g) and m-trifluoromethylaniline (1,127 g; 7 moles) were introduced in an inert atmosphere into a 6 liter round flask. The reaction medium was stirred and heated to a temperature of 110° C. At that temperature, allyl chloride (382.5 g; 5 moles) and triethylamine (506 g; 5 moles) were added in parallel, over approximately 3 hours, with a lead of the order of 10% for allyl chloride. When the addition was complete, the reaction medium was maintained at a temperature of 115° C. for 1 hour and was then cooled to a temperature 30° C. The reaction mass was washed with water (4 washes with a total of 1.3 liter of water), to extract triethylamine hydrochloride. The organic phase was then distilled at atmospheric pressure and then under reduced pressure (<3,000 Pa). This resulted in the separation of toluene and unconverted m-trifluoromethylaniline (460 g; 2.86 moles) from N-allyl-m-trifluoromethylaniline (588 g; 2.92 moles), which corresponds to a 57% yield based on allyl chloride and 70% based on converted m-trifluoromethylaniline.
Reaction SMILES: C(OC([N:8]1[CH2:23][CH2:22][CH2:21][C@H:9]1[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:30]>CCOCC>[ClH:30].[C:15]1([CH2:14][CH2:13][NH:12][C:10](=[O:11])[C@@H:9]2[CH2:21][CH2:22][CH2:23][NH:8]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccccc1)[C@@H]1CCCN1

Procedure:
A solution of 1-(tert-butyloxycarbonyl)-N-(2-phenylethyl)-L-prolinamide (2.46 g.) in ethyl acetate-hydrogen chloride (3.9 N, 30 ml.) was stirred for 20 minutes at room temperature, then diluted with ether (to about 200 ml.). The solvents were decanted from the resulting gum, which was triturated with ether, affording crystalline N-(2-phenylethyl)-L-prolinamide hydrochloride (1.91 g., m.r. 147°-150° ).
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[CH:10]([CH3:12])[CH3:11].[Br:26]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[Br:26][CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)N(CCCCOCCO)C1CCN(Cc2ccccc2)CC1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)N(CCCCOCCBr)C1CCN(Cc2ccccc2)CC1

Procedure:
4-[N-(7-Hydroxy-5-oxahept-1-yl)-N-(isopropyl)amino]-1-benzylpiperidine (2.0 g, 5.7 mmol) was treated with dibromotriphenylphosphorane (6.1 g, 14.4 mmol) in dichloromethane for 2 h. The reaction mixture was then was washed with 1 N sodium hydroxide, saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give the title intermediate, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:13](=[O:20])[C:12]3([CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21]3)[N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:34]>>[ClH:34].[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:13](=[O:20])[C:12]3([CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26]3)[NH:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)CN1C(=O)C2(COCCOC2)N(C(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1
Agent: Cl
Product: COC(=O)CN1C(=O)C2(COCCOC2)NC[C@H]1c1cc(F)cc(F)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
0.13 g (0.28 mmol) tert-butyl (R)-3-(3,5-difluoro-phenyl)-4-methoxycarbonylmethyl-5-oxo-8,11-dioxa-1,4-diaza-spiro[5.6]dodecane-1-carboxylate were combined with 20 ml of a 1M methanolic hydrochloric acid solution and stirred for 2 h at 50° C. The reaction mixture was concentrated by rotary evaporation and further reacted without any further purification.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:23][C:24]1[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:26][N:25]=1.Cl>N1C=CC=CC=1>[C:1]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:26][N:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)c1nnc(N)s1
Reactant: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(=O)OCC)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 65 %

Procedure:
To a solution of 4-decanamidobenzenesulfonyl chloride (220 mg, 0.64 mmol) in pyridine (4 mL) was added ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (100 mg, 0.58 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×30 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1 to give the product as a solid, mp 101-102° C., in 65% yield (183 mg, 0.38 mmol); 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, 3H, J=6.6 Hz), 1.22-1.32 (m, 15H), 1.56 (m, 2H), 2.31 (t, 2H, J=6.0 Hz), 4.33 (q, 2H, J=7.6 Hz), 7.71 (m, 4H), 10.19 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.6, 14.6, 22.8, 25.6, 29.3, 29.4, 29.5, 29.6, 31.3, 31.9, 37.1, 62.8, 119.1, 127.6, 136.8, 143.2, 147.7, 159.2, 170.3, 172.5; MS (LCQ, ESI+) Calcd for C21H31N4O5S2 483.2, found 483.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C21H31N4O5S2 483.1736, found 483.1728 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[CH2:8][CH2:7][N:6]([C@@H:9]3[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]3)[C:5]2=[O:22])[CH2:3][CH2:2]1.[ClH:23]>O1CCOCC1>[ClH:23].[CH:1]1([N:4]2[CH2:8][CH2:7][N:6]([C@@H:9]3[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]3)[C:5]2=[O:22])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCN(C3CC3)C2=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1N(C2CC2)CCN1[C@@H]1CCCNC1
Yield: 86 %

Procedure:
(R)-tert-Butyl 3-(3-cyclopropyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (391) (3.0 g, 9.7 mmol) was treated with commercial 4N HCl in dioxane at RT to afford (R)-1-cyclopropyl-3-(piperidin-3-yl)imidazolidin-2-one hydrochloride (392) (2.05 g, 86%) as a light brown solid after concentration in vacuo. Proton NMR (DMSO-d6): δ 9.37 (1H, s), 8.99 (1H, s), 3.89-3.82 (1H, m), 3.64-3.57 (1H, m), 3.28-3.18 (4H, m), 3.11-3.03 (1H, m), 2.97-2.87 (1H, m), 2.77-2.67 (1H, m), 2.44-2.29 (1H, m), 1.89-1.80 (1H, m), 1.75-1.64 (3H, m), 0.81-0.36 (4H, m) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[O:12]1[CH2:17][CH:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C1(C)C=CC=CC=1>[O:12]1[CH2:13][CH:14]=[C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:17]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: N#Cc1ccc(C2=CCOCC2)cc1
Yield: 63.5 %

Procedure:
2.2 g (15.1 mmol) of (4-cyanophenyl)boronic acid, 2.5 g (10.8 mmol) of 3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate, 373 mg (0.32 mmol) of tetrakis(triphenylphosphine)palladium(0) and 1.59 g (15.1 mmol) of sodium carbonate were heated under reflux in a mixed solvent comprising 4 mL of H2O, 57 mL of toluene, and 17 mL of methanol for 3 hours. After the completion of the reaction, the organic solvent was distilled off under reduced pressure, H2O was added to the residue, and ethyl acetate extraction was performed. Subsequently, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography, thereby giving 1.27 g of 4-(3,6-dihydro-2H-pyran-4-yl)benzonitrile (yield: 64%).