Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O.O>CN(C)C=O>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][O:40][CH2:39]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCCC1CCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCCOC3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirring mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry N,N-dimethylformamide (2 ml) was heated with stirring at 60° C. for 1 h. 2-(Tetrahydro-2H-pyran-3-yl)ethyl methanesulfonate (142 mg) was added and the stirring mixture heated at 60° C. for 3 h. Water was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and stripped to give a brown oil. This was purified by C18 reverse phase chromatography using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to afford the title compound as a brown solid, yield 138 mg.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:24]=[CH:23][N:13]([C@@H:14]2[O:22][C@H:19]([CH2:20]O)[C@@H:17]([OH:18])[C@H:15]2[OH:16])[C:12](=[O:25])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:45]=[N+:46]=[N-:47].[Li+].C(Br)(Br)(Br)Br>CC(N(C)C)=O.C(OCC)(=O)C>[N:45]([CH2:20][C@H:19]1[O:22][C@@H:14]([N:13]2[CH:23]=[CH:24][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][C:12]2=[O:25])[C@H:15]([OH:16])[C@@H:17]1[OH:18])=[N+:46]=[N-:47]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1)c1ccccc1
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A suspension of cytidine (9.72 g, 40.0 mmol) in pyridine (200 ml) was added to trimethylchlorosilane (25.6 ml, 200 mmol). After 15 minutes of stirring, benzoyl chloride (23.2 ml, 200 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was then cooled on an ice bath, and water (40 ml) was added. Five minutes later, 28% aqueous ammonia (40 ml) was added, and the mixture was stirred at room temperature for 15 minutes. Then, the solvent was distilled off under reduced pressure, and acetone was added to precipitate a white solid. The precipitate was filtered off and recrystallized from water to give N4-benzoylcytidine (13.3 g, 96%). The N4-benzoylcytidine (13.0 g, 37.4 mmol), triphenylphosphine (28.0 g, 107 mmol) and lithium azide (13.0 g, 266 mmol) were suspended in dried DMA, and carbon tetrabromide (35.5 g, 107 mmol) was added to the suspension. After 3 hours of stirring at room temperature, ethyl acetate (1500 ml) was added, and the mixture was washed with water and a saturated aqueous solution of sodium chloride (1000 ml each). The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to give 5′-azido-5′-deoxy-N-benzoylcytidine (12.4 g, yield 89%). A solution of 5′-azido-5′-deoxy-N4-benzoylcytidine (10.0 g, 26.9 mmol) in methanol-DMF (1:1 v/v, 100 ml) was vigorously stirred with 10% palladium-on-carbon (about 1.0 g) in a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give 5′-amino-5′-deoxy-N4-benzoylcyridine (9.04 g, yield 97%).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][OH:14])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2].C(N(CC)CC)C.CCOC(C)=O>CS(C)=O>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-cyano-3-fluorobenzyl)-5-(hydroxymethyl) imidazole, as described above in Step F, (2.31 g, 10.0 mmol) in 20 mL of DMSO at 0° C. was added triethylamine (5.6 mL, 40 mmol), then SO3-pyridine complex (3.89 g, 25 mmol). After 30 minutes, the reaction was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the aldehyde as a pale yellow powder.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][CH:21]([CH2:25][CH3:26])[C:22](Cl)=[O:23]>C(Cl)Cl>[Cl:20][CH:21]([CH2:25][CH3:26])[C:22]([NH:1][C@H:2]([C:5]1[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:3][OH:4])=[O:23]
Reactant: CCC(Cl)C(=O)Cl
Reactant: N[C@@H](CO)c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Cl)C(=O)N[C@@H](CO)c1cc(F)cc(F)c1
Reaction time: 1 h

Procedure:
To a solution of (2R)-2-amino-2-(3,5-difluorophenyl)ethanol (2.60 g, 15.0 mmol, described in Intermediate 10) and triethylamine (4.19 mL, 30.0 mmol) in CH2Cl2 (150 mL) at 0° C. was slowly added 2-chlorobutyryl chloride (1.71 mL, 15.0 mmol). After 60 min, the reaction mixture was quenched with saturated aqueous NaHCO3 (40 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—70:30 to 0:100, to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10](=[O:31])[C@@H:11]2[C@@H:15]([CH2:16][CH3:17])[CH2:14][CH2:13][N:12]2[CH:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:35]>CN(C=O)C>[CH3:35][N:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C:10](=[O:31])[C@@H:11]1[C@@H:15]([CH2:16][CH3:17])[CH2:14][CH2:13][N:12]1[CH:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1
Reactant: CI
Reactant: CC[C@H]1CCN(C(C(=O)OC(C)(C)C)[C@@H]2CCCN2)[C@@H]1C(=O)NCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H]1CCN(C(C(=O)OC(C)(C)C)[C@@H]2CCCN2)[C@@H]1C(=O)N(C)Cc1cccc(Cl)c1
Temperature: 0 °C

Procedure:
N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-proline-N-(3-chlorophenylmethyl) amide (0.175 g, 0.39 mmol) was dissolved in dry DMF (4 mL) with stirring at 0° C. under Ar, treated with NaH (60% dispersion in mineral oil, 0.023 g, 0.58 mmol), and after 15 minutes treated with iodomethane (0.029 mL, 0.47 mmol). The reaction mixture was stirred at 25° C. for 2 h, then evaporated to dryness and partitioned between EtOAc and aqueous saturated NaHCO3 solution. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and concentrated to dryness to give the title compound.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:29])=[O:22])[CH:26]([CH3:28])[CH3:27])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@H](C(=O)O)C(C)C)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-valine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([C:8]1[CH:20]=[CH:19][C:11]2[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:10]=2[CH:9]=1)=[O:7])(O)=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].CC(C)=O>ClC1C=CC=CC=1Cl>[CH:15]1[C:14]2[C:10]3[CH:9]=[C:8]4[C:20]([C:1](=[O:2])[C:4]5[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=5[C:6]4=[O:7])=[CH:19][C:11]=3[S:12][C:13]=2[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc2sc3ccccc3c2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)c2cc3c(cc21)sc1ccccc13
Temperature: 140 °C
Yield: 16.1 %

Procedure:
To a mixture of 2-(o-carboxybenzoyl)dibenzothiophene (35.6 g, 107 mmol) and phosphorus pentachloride (33.5 g, 161 mmol) in anhydrous 1,2-dichlorobenzene (430 cm3) is added aluminum chloride (21.4 g, 161 mmol). The mixture is then heated at 140° C. for 17 hours. The reaction mixture cooled to 23° C. and the solvent removed under vacuum to give a black solid. Acetone (500 cm3) is added and the mixture filtered to give a green/yellow solid which is dried under vacuum. To the solid is added dichloromethane (1000 cm3) and the mixture heated. The hot mixture is passed through a very short plug of silica (dichloromethane) to give anthra[2,3-b]benzo[d]thiophene-7,12-dione as a yellow solid (5.43 g, 16%). MS m/z 314 (M+). 1H NMR (300 MHz, CDCl3) 9.04 (s, 1H), 8.73 (s, 1H), 8.31-8.41 (m, 3H), 7.86-7.93 (m, 1H), 7.78-7.85 (m, 2H), 7.50-7.61 (m, 2H); 13C NMR (75 MHz, CDCl3) 183.1, 182.8, 145.3, 141.3, 139.9, 134.7, 134.2, 134.1, 133.9, 133.8, 131.1, 129.9, 128.8, 127.4, 125.5, 123.2, 123.1, 122.4, 120.8.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:25])[C:23]#[CH:24]>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:25][CH2:22][C:23]#[CH:24])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCNC(=O)N1CC(Oc2ccc(Br)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
A stirred mixture of 5.8 g (0.02 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g (0.02 mole) of 2-propynylamine added dropwise from a needle and syringe. After stirring for 30 min, approximately 1 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 6.1 g. After drying, recrystallization from benzene-ligroin yielded 4.2 g (67.9%) of fine white crystals, m.p. 120°-122° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=O.Cl.NO.[N:17]1C=CC=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[C:5]#[N:17]
Reactant: c1ccncc1
Reactant: COc1cc(C=O)cc(I)c1OC
Agent: Cl
Agent: NO
Solvent: Cc1ccccc1
Product: COc1cc(C#N)cc(I)c1OC
Yield: 62.4 %

Procedure:
A mixture of 5.0 g of 3-iodo-4,5-dimethoxy-benzaldehyde, 1.18 g of hydroxylamine hydrochloride, 1.37 g of pyridine and 17 ml of toluene is held at reflux for 2 hrs. (see A. Saednya, Synthesis 1982, 190). The precipitate which separates after cooling is filtered off under suction. Chromatography on silica gel with methylene chloride/methanol 9:1 yields 3.09 g of 3-iodo-4,5-dimethoxy-benzonitrile as a colourless solid. Yield: 63%. Mass spectrum: peaks inter alia at m/e: 289 (100%), 274 (38%), 132 (30%), 119 (43%).
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:28])[CH:10]([CH2:14][C@H:15]1[CH2:19][C@@H:18]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]=[CH:16]1)[C:11](O)=O)[CH3:7].C=O.C(Cl)Cl>O>[CH2:6]([O:8][C:9](=[O:28])[C:10]([CH2:14][C@H:15]1[CH2:19][C@@H:18]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]=[CH:16]1)=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)O
Agent: C=O
Solvent: ClCCl
Solvent: CCNCC
Solvent: O
Product: C=C(C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Diethyl amine (0.31 mL; 3.0 mmol) was added to a mixture of 2-(cis-4-tert-butoxycarbonylamino-cyclopent-2-enylmethyl)-malonic acid monoethyl ester (0.66 g, 2.0 mmol) in 36% aqueous solution of formaldehyde (0.25 mL, 3.2 mmol), CH2Cl2 (1.6 mL) and water (1.6 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, poured onto ice-water (400 mL) and extracted with CH2Cl2. During the extraction, phase separation was improved by the addition of brine. The combined organic phases were washed with 5% NaHCO3, dried and concentrated under reduced pressure to yield 2-(cis-4-tert-butoxycarbonylamino-cyclopent-2-enylmethyl)-acrylic acid ethyl ester (0.56 g, 94%) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[N:10][CH:11]=1.[CH3:20][NH2:21]>CO>[CH3:20][NH:21][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: CN
Reactant: ClCCCOc1cncc(OCc2ccccc2)c1
Solvent: CO
Product: CNCCCOc1cncc(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 71.7 %

Procedure:
The 5-(3-chloropropoxy)-3-(phenylmethoxy)pyridine (1.52 g, 5.49 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and impurities were extracted with ether (3×15 mL). The aqueous layer was basified to pH 10 with 100% NaOH solution and extracted with chloroform (4×15 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.07 g (71.7%) of an oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([C:14]1([F:20])[CH2:18][CH2:17][CH2:16][CH:15]1[OH:19])=[O:13].Cl>N1C=CC=CC=1>[CH3:10][O:11][C:12]([C:14]1([F:20])[CH2:18][CH2:17][CH2:16][CH:15]1[O:19][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: COC(=O)C1(F)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)C1(F)CCCC1OC(=O)c1ccccc1
Reaction time: 5 h
Yield: 85.1 %

Procedure:
.045 g (3 mmol) of benzoyl chloride was added under ice cooling to a mixture of 0.5 g (3 mmol) of the 1-fluoro-2-hydroxy-1-cyclopentanecarboxylic acid methyl ester in cis form (compound number 2a) synthesized in Example 1 and 2 ml of pyridine, the temperature of the mixture was brought back to room temperature, and the mixture was stirred for 5 hours. The reaction solution was poured into a diluted aqueous hydrochloric acid solution and extracted with ethyl acetate and the extract was successively washed with saturated saline, a saturated aqueous sodium bicarbonate solution and saturated saline. The ethyl acetate layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to obtain 0.68 g (yield: 84%) of the objective 2-benzoyloxy-1-fluoro-cyclopentanecarboxylic acid methyl ester in cis form (compound number 4a).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.C([N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10]([C:40]3[CH:41]=[N:37][NH:38][CH:39]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1cn[nH]c1)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 30.1 %

Procedure:
To a solution of Example 57a (0.500 g, 1.00 mmoles) in DMF (7 ml), ethanol (4 ml) and water (4 ml), N-Boc-Pyrazole-4-boronic acid pinacol ester (0.445 g, 1.51 mmoles) and sodium carbonate (0.534 g, 5.04 mmoles) were added and the system is degassed for 30 min. Tetrakis triphenylphosphine Palladium (0.229 g, 0.198 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as yellow solid (0.131 g, 29% yield). MP: 235-237° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.20(s,1H), 8.20(s,1H), 8.10(s,1H), 8.05(dd, J=8.0, 1.7 Hz, 1H), 7.78(s,1H), 7.76(m,1H), 7.49(dt, J=8.0,0.8 Hz, 1H), 7.39-7.31(m, 6H), 5.45(s,2H). Mass: 436.20(M++1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:21])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[CH2:6][CH2:5]1.[O:22]=[C:23]1[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[O:24]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[Cl:20][C:15]1[CH:14]=[C:13](/[CH:12]=[CH:11]/[C:10]([N:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:28]([C:25]3[O:24][C:23](=[O:22])[NH:27][CH:26]=3)=[O:29])[CH2:9][CH2:8]2)=[O:21])[CH:18]=[C:17]([Cl:19])[CH:16]=1
Reactant: NCCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1c[nH]c(=O)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (E)-1-(4-(2-aminoethyl)piperidin-1-yl)-3-(3,5-dichlorophenyl)prop-2-en-1-one (Example 30, step 4) (110 mg, 0.336 mmol) and 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21, step 1) (167 mg, 0.504 mmol) in DMF (2 ml) was added DIPEA (0.470 mL, 2.69 mmol) and T3P® (50% in EtOAc, 1.571 ml, 2.69 mmol). The reaction mixture was stirred at RT overnight.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH3:9])=[CH:7][NH:6][C:5]2=[O:10])[CH2:3][CH2:2]1.[H-].[Na+].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH2:17]Br>CN(C=O)C.[Cl-].[Na+].O>[CH:1]1([N:4]2[C:8]([CH3:9])=[CH:7][N:6]([CH2:17][C:16]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[C:14]([F:24])([F:13])[F:25])[C:5]2=[O:10])[CH2:3][CH2:2]1
Reactant: Cc1c[nH]c(=O)n1C1CC1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(Cc2cc(F)ccc2C(F)(F)F)c(=O)n1C1CC1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Cyclopropyl-5-methyl-1,3-dihydro-imidazol-2-one (150 mg) was dissolved in DMF (5 mL) under argon and sodium hydride (55% in mineral oil, 71 mg) was added in one portion. The mixture was stirred until gas evolution stopped (approx. 20 minutes) and then a solution of 2-trifluoromethyl-5-fluorobenzyl bromide (307 mg) in DMF (2 mL) was added over 5 minutes. Stirring was continued for 1 hour and then the reaction mixture was poured into brine. The aqueous solution was extracted with ethyl acetate and the organic layer was separated and washed with brine. The combined organic extracts were dried over Na2SO4 and evaporated. Residual DMF was removed by co-evaporation with toluene. The crude material was purified by flash chromatography using a gradient of 20 to 50% ethyl acetate in heptane as an eluent. Fractions containing the desired product were combined and evaporated to give 3-cyclopropyl-1-(5-fluoro-2-trifluoromethyl-benzyl)-4-methyl-1,3-dihydro-imidazol-2-one as a colorless oil (201 mg). MS (ESI): 315.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:20])[CH2:16][CH2:15][C:14](B(O)O)=[CH:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+]>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>[Br:1][C:2]1[N:7]=[C:6]([C:14]2[CH2:15][CH2:16][C:11]([CH3:20])([CH3:10])[CH2:12][CH:13]=2)[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1I
Reactant: CC1(C)CC=C(B(O)O)CC1
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+]
Product: CC1(C)CC=C(c2nc(Br)ccc2N)CC1

Procedure:
The title compound was prepared from 6-bromo-2-iodo-pyridin-3-ylamine (as prepared in the previous step, 348 mg, 1.17 mmol), 4,4-dimethylcyclohexen-1-yl boronic acid (198 mg, 1.28 mmol), Pd(PPh3)4 (135 mg, 0.117 mol) and 2M Na2CO3 (15.2 mL, 30.5 mmol) according to the procedure in Example 44, step (b) (417 mg, 46%). 1H-NMR (CDCl3; 400 MHz): δ 7.06 (d, 1H, J=8.3 Hz), 6.85 (d, 1H, J=8.3 Hz), 5.95 (m, 1H), 3.86 (br s, 2H), 2.43-2.39 (m, 2H), 1.99-1.97 (m, 2H), 1.51 (t, 2H, J=6.4 Hz), 0.99 (s, 6H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([CH:14]([CH2:26][CH2:27][CH2:28][CH:29]1[O:31][CH2:30]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:13])[CH3:12]>O>[C:11]([CH:14]([CH2:26][CH2:27][CH2:28][CH:29]([OH:31])[CH2:30][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)=[O:22])(=[O:13])[CH3:12]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CCCCCCC(CCCC1CO1)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)C(CCCCCCC(=O)OCc1ccccc1)CCCC(O)COCc1ccccc1
Reaction time: 18 h

Procedure:
Sodium hydride (0.04 mole) is added in portions with stirring to benzyl alcohol (25 ml.). To the resulting solution, ethyl 8-acetyl-12,13-epoxytridecanoate (0.02 mole) is added and the mixture allowed to stand 18 hours at 55°-60°. The reaction mixture is then cooled and treated with water. The organic layer is separated and dried over magnesium sulfate. Excess benzyl alcohol is removed by distillation in vacuo by means of the rotary evaporator at oil pump pressure. The residue consists mainly of the title compound and is used in the next step without purification.