Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[H-].[Na+].Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)OCCN2CCN1CCCC1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
A solution of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (300 mg, 1.665 mmol) in DMF (10 mL) was treated with NaH (213 mg, 5.33 mmol, 60% wt in mineral oil) at 0° C., resulting in a bright orange suspension. The mixture was stirred for 10 minutes. 2-chloroethyl-pyrrolidine hydrochloride (566 mg, 3.33 mmol) was then added, and the reaction turned into a bright red suspension. The reaction was heated to 90° C. for 1 hour and then cooled to room temperature. The mixture was then diluted with water (20 mL), transferred to a separatory funnel, and extracted into EtOAc (2×15 mL). The combined organic layers were washed with brine (3×5 mL), dried (Na2SO4), filtered, and concentrated. The residue was subjected to flash chromatography on silica gel using CH2Cl2 followed by 5:95 (2M NH3 in MeOH):CH2Cl2 to give a solid (330 mg, 72%). 1H-NMR (DMSO-d6) δ 7.75 (dd, J=2.7, 9.3 Hz, 1H), 7.47 (d, J=2.7 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 4.18 (t, J=4.2 Hz, 2H), 3.58-3.55 (m, 4H), 2.63 (t, J=6.9 Hz, 2H), 2.58-2.48 (m, 4H), 1.70-1.63 (m, 4H); ESI-MS (m/z, %): 278 (MH+, 100), 98 (20).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([O:16][C:17](=[O:25])[C:18]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[CH2:9]2.[Cl-].[NH4+]>CCOCC.C1COCC1>[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([O:16][C:17](=[O:25])[C:18]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[OH:19])[CH2:9]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccco1
Reactant: Cl[Mg]C1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccco1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclopentylmagnesium chloride, 0.0472 mol (23.6 ml of a solution 2M in ether) was added to a solution of 9.4 g (0.0377 mol) of 2-fur-2-yl-2-oxoacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester dissolved in 125 ml of THF, at −70° C. under a N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 16 h, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, washed with water, and dried over MgSO4. After removal of the solvent, the oil obtained (7.5 g) was purified by chromatography on silica gel eluting with chloroform/methanol/ammonia 95:5:0.5. Appropriate fractions were combined and evaporated to obtain the two diastereomers: I-14a, I-14b
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([NH:26][C@H:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:33])=[O:25])[NH:16]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([NH:26][C@H:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:33])=[O:25])[NH2:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)[C@@H]2CCC[C@@H]2NC(=O)[C@H](CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(COC(=O)[C@@H]2CCC[C@@H]2NC(=O)[C@@H](N)CCCNC(=O)OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 76.9 %

Procedure:
To a mixture of 4-methoxybenzyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithyl}amino)cyclopentanecarboxylate (2.5 g) and methanol (25 ml) was added p-toluene sulfonic acid hydrate (1.2 g) at room temperature, followed by stirring at 40° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. Sodium hydrogen carbonate was added thereto under ice-cooling to adjust the pH to about 8, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml), and the organic layer was combined and extracted with a 10% aqueous citric acid solution. To the aqueous layer was added sodium hydrogen carbonate under ice-cooling to adjust the pH to about 8, followed by extraction with ethyl acetate and washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4-methoxybenzyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (1.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]=[N:10][NH:9]1.[CH3:14][C:15]1[S:16][CH:17]=[C:18]([CH3:27])[C:19]=1[N:20]([CH2:24][CH2:25][CH3:26])[C:21](Cl)=[O:22]>CN(C)C1C=CN=CC=1>[CH3:14][C:15]1[S:16][CH:17]=[C:18]([CH3:27])[C:19]=1[N:20]([CH2:24][CH2:25][CH3:26])[C:21]([N:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=[N:10]1)=[O:22]
Reactant: CCCN(C(=O)Cl)c1c(C)csc1C
Reactant: O=c1nn[nH]n1-c1ccccc1F
Agent: CN(C)c1ccncc1
Product: CCCN(C(=O)n1nnn(-c2ccccc2F)c1=O)c1c(C)csc1C

Procedure:
1.17 g (6.5 mmol) of 1,2-dihydro-1-(2-fluorophenyl)-5H-tetrazol-5-one, 1.5 g (6.5 mmol) of N-(2,4-dimethyl-thiophen-3-yl)-N-n-propylcarbamoyl chloride and 1.19 g (9.7 mmol) of 4-dimethylaminopyridine were reacted by the method of the process described in Example 1. Yield 1.9 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=1>>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)=[O:19])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: O=C(Nc1ccc2cnccc2c1)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 6-aminoisoquinoline (D97) (37 mg, 0.25 mmol) and 4-biphenylcarboxylic acid (75 mg, 0.38 mmol) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.20 (s, 1H), 8.52 (d, 1H), 8.46 (d, 1H), 8.09 (br.s, 1H), 8.00 (m, 3H), 7.77 (d, 2H), 7.65-7.70 (m, 4H), 7.50 (t, 2H), 7.43 (t, 1H).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([C:14]#[N:15])[C:12]=2[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].I[CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:5]1[N:6]([CH2:20][CH2:21][OH:22])[C:7]2[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([C:14]#[N:15])[C:12]=2[CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2[nH]1
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2n1CCO
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (200 mg, 0.82 mmol), 2-iodoethanol (77 μL, 0.98 mmol), cesium carbonate (534 mg, 1.64 mmol) and DMF (1.3 mL) was heated to 90° C. overnight. Then more 2-iodoethanol (77 μL, 0.98 mmol) was added and the reaction was stirred at 90° C. for 3 days. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate and then the combined ethyl acetate layers were washed with water (×3) and brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (50-100% CH2Cl2-Hexanes) to yield the product as a yellow solid (180 mg, -25% purity by NMR, product co-elutes with the indole starting material). ESI-MS m/z calc. 287.1, found 288.5 (M+1)+. Retention time 1.59 minutes. 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.14 (d, J=9.1 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H), 6.60 (s, 1H), 5.10 (t, J=5.5 Hz, 1H), 4.55 (t, J=6.3 Hz, 2H), 3.78-3.73 (m, 2H) and 1.49 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH2:22][CH3:23])=[C:15]([O:18][CH2:19][CH3:20])[CH:16]=3)[CH:11]=[C:10]([C:24](O)=[O:25])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH2:22][CH3:23])=[C:15]([O:18][CH2:19][CH3:20])[CH:16]=3)[CH:11]=[C:10]([CH2:24][OH:25])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOc1cc2cc(C(=O)O)cc(-c3ccnc(Cl)c3)c2cc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc2cc(CO)cc(-c3ccnc(Cl)c3)c2cc1OCC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-(2-chloro-4-pyridyl)-3-carboxy-6,7-diethoxynaphthalene in tetrahydrofuran (50 ml) is added dropwise a solution of 70% sodium aluminum bis(2-methoxyethoxy) hydride (70% toluene solution, 29.4 ml) in tetrahydrofuran (50 ml) at a temperature below 5° C. under nitrogen atmosphere, and the mixture is reacted at the same temperature for one hour. After the reaction is complete, to the mixture is added methanol (12 ml), and further thereto is added a 6.25 M aqueous sodium hydroxide solution (48 ml), and the mixture is stirred at 50° C. for one hour. The tetrahydrofuran layer is separated from the mixture, and the aqueous solution is extracted with methylene chloride, and the methylene chloride layer is separated, and combined with the tetrahydrofuran layer, then concentrated under reduced pressure. The resultant is extracted again with methylene chloride, washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=4:1), and crystallized from ether to give 1-(2-chloro-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (3.94 g).
Reaction SMILES: [OH-:1].[Na+].CS(C)=O.[CH:7]([N:10]1[C:14](S(C)(=O)=O)=[N:13][N:12]=[C:11]1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([O:28][CH2:29][O:30][CH3:31])=[CH:21][C:20]=1[O:32][CH2:33][O:34][CH3:35])([CH3:9])[CH3:8]>O>[CH:7]([N:10]1[C:11]([C:19]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([O:28][CH2:29][O:30][CH3:31])=[CH:21][C:20]=2[O:32][CH2:33][O:34][CH3:35])=[N:12][NH:13][C:14]1=[O:1])([CH3:9])[CH3:8]
Reactant: [OH-]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(S(C)(=O)=O)n1C(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1C(C)C
Temperature: 95 °C
Yield: 78 %

Procedure:
At room temperature, aqueous sodium hydroxide (1.0 M aqueous solution, 9 mL) was added to a dimethylsulfoxide (11 mL) solution of 4-isopropyl-3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-5-methyl sulfonyl-4H-[1,2,4]triazole (F63-05, 1.63 g, 3.82 mmol). The mixture was heated at 90-100° C. for 12 hours while stirring. After returning to room temperature, water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed twice with water and then with saturated sodium chloride solution. After drying the extract over anhydrous sodium, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain white solids. After suspension purification by diethyl ether, the solids obtained by filtration were dried under reduced pressure to obtain 4-isopropyl-5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-2,4-dihydro-[1,2,4]triazol-3-one (F63-06, white solids, 1.09 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:33](Cl)(=[O:35])[CH3:34].O>ClCCl>[C:33]([C:8]1[CH:7]=[CH:6][C:5]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:35])[CH3:34]
Reactant: COc1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a solution of N-(3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (1.0 g, 2.62 mmol) obtained in Example 72 in dichloromethane (20 mL) was added at −50° C. under an argon atmosphere aluminum chloride (769 mg, 5.77 mmol) and the resulting mixture was stirred for 10 minutes. To the reaction solution was added dropwise at the same temperature acetyl chloride (0.62 mL, 8.65 mmol and the resulting mixture was warmed to room temperature. The reaction solution was added to water and the product was extracted with ethyl acetate. The combined organic layers were washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 993 mg (yield: 89%) of the title compound. Melting point: 131-133° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[C:42]([O:48]COC)[C:3]=1[C:4]([C:6]1[CH:41]=[CH:40][C:9]([C:10]([O:12][C@@H:13]2[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C@H:14]2[NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32]([O:35]COC)=[CH:31][CH:30]=2)=[O:11])=[CH:8][CH:7]=1)=[O:5].C(O)(C)C.[ClH:56]>C(COC)OC>[ClH:56].[OH:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]([NH:27][C@H:14]2[C@H:13]([O:12][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([C:4](=[O:5])[C:3]4[C:42]([OH:48])=[CH:43][CH:44]=[C:45]([O:46][CH3:47])[C:2]=4[F:1])=[CH:41][CH:40]=3)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)=[O:39])=[CH:34][CH:33]=1
Reactant: COCOc1ccc(C(=O)N[C@@H]2CN(C(=O)OC(C)(C)C)CCC[C@H]2OC(=O)c2ccc(C(=O)c3c(OCOC)ccc(OC)c3F)cc2)cc1
Agent: Cl
Solvent: COCCOC
Solvent: CC(C)O
Product: COc1ccc(O)c(C(=O)c2ccc(C(=O)O[C@@H]3CCCNC[C@H]3NC(=O)c3ccc(O)cc3)cc2)c1F
Reaction time: 24 h

Procedure:
639.7 mg of tert-butyl (3R,4R)-4-[4-(2-fluoro-3-methoxy-6-methoxymethoxy-benzoyl)-benzoyloxy]-3-(4-methoxymethoxy-benzoylamino)-azepane-1-carboxylate were dissolved in 9 ml of dimethoxyethane and 9 ml of isopropanol and, after cooling to 0° C., saturated slowly with HCl gas and stored in a refrigerator for 24 hours. The solvent was removed completely under reduced pressure and the product was triturated with diethyl ether. The suspension obtained was stirred for several hours; the solvent was decanted off and, after the addition of a further amount of fresh solvent, the stirring was continued overnight. The product was filtered off, washed several times with diethyl ether and dried at 0.1 mbar and 50° C. There were obtained 479 mg of 4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoic acid (3R,4R)-3-(4-hydroxy-benzoylamino)-azepan-4-yl ester hydrochloride (1:1) as a yellow powder.
Reaction SMILES: O.NN.[N+:4]([C:7]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10])([O-])=O.[H][H]>CO.[Ni]>[NH2:4][C:7]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10]
Reactant: [H][H]
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1OC
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1OC
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Hydrazine hydrate (1.33 mL, 41.5 mmol) was added dropwise to a solution of 116 (2.83 g, 8.3 mmol) in methanol (142 mL) gently refluxing over Raney nickel (500 mg, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and the combined organic phase washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded the product (2.18 g, 6.5 mmol) as a brown oil: 1H NMR (270 MHz, CDCl3) δ1.6-2.0 (m, 3H), 2.1-2.2 (m, 1H), 3.4-3.7 (m, 4H), 3.8 (s, 3H), 3.8-3.9 (2×s, 6H), 4.4 (br s, 1H), 4.7-4.3 (br s, 1H), 6.6 (s, 1H); 13C NMR (67.8 MHz, CDCl3) δ144.7, 144.5, 141.6, 134.6, 107.1, 66.9, 61.0, 60.9, 60.5, 56.8, 50.9, 28.6, 24.9, 21.1, 14.2.
Reaction SMILES: BrC1C=NC([N:8]2[CH:12]3[CH2:13][CH2:14][CH2:15][CH:11]3[N:10](CCOC)[C:9]2=[O:20])=NC=1.[C:21]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30])#[CH:22]>>[F:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[C:21]1[C:12]([C:11]#[CH:15])=[N:8][C:9]([CH:14]2[CH2:15][CH:11]3[NH:10][C:9](=[O:20])[NH:8][CH:12]3[CH2:13]2)=[N:10][CH:22]=1
Reactant: C#Cc1cc(F)ccc1F
Reactant: COCCN1C(=O)N(c2ncc(Br)cn2)C2CCCC21
Product: C#Cc1nc(C2CC3NC(=O)NC3C2)ncc1-c1cc(F)ccc1F

Procedure:
The title compound was prepared in accordance with the general method of Example 1, step 5 starting from (rac)-1-(5-bromopyrimidin-2-yl)-3-(2-methoxy-ethyl)-hexahydro-cyclopenta[d]imidazol-2(1H)-one (Example 5, step 3) and 1-ethynyl-2,5-difluorobenzene to yield racemic material ((+/−)-(3aRS,6aSR)-1-(2-methoxy-ethyl)-3-(5-(2,5-difluoro-phenyl-ethynyl-pyrimidin-2-yl)-hexahydro-cyclopentaimidazol-2-one as a light brown solid; MS: m/e=399.2 (M+H+). Separation using chiral HPLC and similar separation conditions as described in example 1 yielded the enantiomerically pure enantiomers (−)-(3aR,6aS)-1-(2-methoxy-ethyl)-3-(5-(2,5-difluoro-phenylethynyl-pyrimidin-2-yl)-hexahydro-cyclopentaimidazol-2-one as an off-white solid; MS: m/e=399.2 (M+H+) and (+)-(3aS,6aR)-1-(2-methoxy-ethyl)-3-(5-(2,5-difluoro-phenylethynyl-pyrimidin-2-yl)-hexahydro-cyclopentaimidazol-2-one as a light yellow oil which solidified on standing; MS: m/e=399.2 (M+H+).
Reaction SMILES: N.[OH:2]O.[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]3[C:14]=2[CH2:15][CH2:16][C@H:17]3[O:23][C:24]2[CH:36]=[CH:35][C:27]3[C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)=[C:8]([CH3:37])[CH:7]=1)#[N:5]>C(O)C>[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]3[C:14]=2[CH2:15][CH2:16][C@H:17]3[O:23][C:24]2[CH:36]=[CH:35][C:27]3[C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)=[C:8]([CH3:37])[CH:7]=1)(=[O:2])[NH2:5]
Reactant: Cc1cc(C#N)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Reactant: OO
Agent: N
Solvent: CCO
Product: Cc1cc(C(N)=O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
30% Aqueous NH3 solution (250 μL) and 35% aqueous H2O2 solution (83 μl) are added at 0° C. to a solution of 2-((S)-6-((R)-4-(4-cyano-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (19 mg) in ethanol (2 mL). The mixture is stirred at room temperature for 12 hours, while warming to room temperature. The mixture is concentrated, diluted with water and neutralized with 4 M aqueous HCl solution. The resulting mixture is extracted with dichloromethane. The organic phase is dried (MgSO4). The solvent is evaporated to give the title compound. Yield: 19 mg; LC (method 20): tR=5.33 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:21]([OH:23])=O)=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=2.C[CH2:25][N:26]=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.CN.C(N(CC)CC)C.Cl>ClCCl>[CH3:1][O:2][C:3]1[C:4]([C:21]([NH:26][CH3:25])=[O:23])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=2
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cccc(-c2ccc3cc(OC)c(C(=O)O)cc3c2)c1
Agent: CN
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1cc2cc(-c3cccc(OC)c3)ccc2cc1OC
Temperature: 0 °C
Yield: 74 %

Procedure:
3-Methoxy-7-(3-methoxyphenyl)-2-naphthoic acid (323 mg, 1.05 mmol, 1 eq), EDCI (1 eq) and hydroxybenzotriazole (1 eq) are dissolved in 50 ml of dichloromethane. To this solution, cooled at 0° C., are added dropwise methylamine (1 eq) and triethylamine (1 eq) in 40 ml of dry dichloromethane. The reaction mixture is boiled under reflux for 1.5 h, and after cooling, the reaction is stopped by adding 20 ml of 0.1 M HCl. The organic phase is separated, washed with saturated sodium carbonate and chloride solutions, dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. Purification by column chromatography with hexane/ethyl acetate 8/2 as the eluent yielded the desired product in a yield of 74%, 250 mg.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([CH3:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[N:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:37][CH2:36][C:35]1[N:31]([C:27]2[CH:26]=[C:25]([C:24]3[CH2:23][C:22](=[O:45])[NH:21][C:9]4[CH:10]=[C:11]([CH3:20])[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:30]=[CH:29][CH:28]=2)[N:32]=[CH:33][N:34]=1
Reactant: Cc1cc(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)CC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3ncnc3CO)c1)CC(=O)N2
Yield: 73.5 %

Procedure:
Prepared from (RS)-[5-(isobutyl-methyl-amino)-4-methyl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M116) (0.96 g, 1.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale brown solid (480 mg, 73%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:20](=[O:22])[CH3:21]
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-trifluoromethoxyphenol (10.00 g) was dissolved in chloroform (30 mL), and triethylamine (6.11 mL) and acetic anhydride (6.37 mL) was added to the solution, and then the mixture was stirred at room temperature for 2 hours. To the reaction solution, 10% potassium carbonate was added, and then the mixture was extracted with chloroform. The organic layer was washed with an aqueous 5% citric acid solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (11.39 g) as a colorless oily substance.