Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].[OH-].[Na+]>O1CCCC1.O>[CH3:15][O:14][N:13]([CH3:12])[C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CNOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
Based on a procedure found in the literature (Guanti, G.; Banfi, L.; Riva, R. Tetrahedron 50(41), 1994, 11945-11966), a solution of phenylacetic acid (10 g, 73 mmol) in tetrahydrofuran (150 mL) is combined with a solution of N,O dimethylhydroxylamine hydrochloride (13 g, 130 mmol) in water (150 mL). The pH is adjusted to 4.5 by the addition of 1 N aqueous sodium hydroxide solution. To the mixture is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine hydrochloride (36 g, 190 mmol) as a solution in water (510 mL) dropwise over 30 minutes. Over the course of the addition, pH is maintained at 4.5 by the addition of 1 N aqueous sodium hydroxide solution. The reaction mixture is allowed to stir for 3 hours at room temperature and is then saturated with sodium chloride and extracted thrice with ethyl acetate. The combined extracts are washed with saturated aqueous sodium hydrogen carbonate (×2), water, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a golden liquid (13 g, 100%). MS (ES+): (M+H)=180.1
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2([F:24])[CH2:16][CH2:15][N:14](C(OCCCC)=O)[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[ClH:25]>O1CCOCC1>[Cl-:25].[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2([F:24])[CH2:16][CH2:15][NH2+:14][CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCCCOC(=O)N1CCC(F)(c2nc(C(=O)OCC)cs2)CC1
Reactant: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(C2(F)CC[NH2+]CC2)n1
Product: [Cl-]
Temperature: 0 °C

Procedure:
To tent-butyl 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]-4-fluoropiperidine-1-carboxylate (8.80 g) was added, under an argon atmosphere at 0° C., a solution of hydrogen chloride in dioxane (4 M, 92 ml). The mixture was stirred at 0° C. and then slowly warmed to room temperature. After stirring for 24 hours, the excess acid and the solvent were removed under reduced pressure. This gave 4-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]-4-fluoropiperidinium chloride (7.70 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: CN1CCC(N)CC1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of 1-methylpiperidin-4-amine (4.6 mg) in N,N-dimethylformamide (200 μL) were added a solution of N,N-diisopropyl ethylamine (8.7 μL) in N,N-dimethylformamide (50 μL) and a solution of 1-[4-chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (9.2 mg) in N,N-dimethylformamide (300 μL), followed by stirring at 80° C. overnight. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform at room temperature, followed by liquid-liquid phase separation, and the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 4-[2-(difluoromethyl)-1H-benzimidazolyl]-N-(1-methylpiperidin-4-yl)-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (11.1 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])CCC.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:32]=1.O>CCOCC>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)([OH:31])[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[CH:32]=1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: COc1ccc2c(c1)CCCCC2=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)CCCCC2(O)c1cc(OC)c(OC)c(OC)c1
Temperature: -30 °C
Yield: 49.6 %

Procedure:
200 mL of anhydrous ether was, added to 3,4,5-trimethoxybromobenzene (1.23 g, 4.97 mmol) in a 500 mL round bottom flask under nitrogen. The temperature of the reaction mixture was brought to −78° C. n-Butyllithium (4.5 mL, 11.25 mmol) was added dropwise. The reaction mixture was then stirred until the temperature was raised gradually to −30° C. 30 (0.86 g, 4.5 mmol) dissolved in 25 mL of dry ether was added dropwise and the reaction mixture was allowed to stir until the temperature warmed up to room temperature. 25 mL of water was added and the product was extracted with ether (3×50), combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Purification by column chromatography (silica gel, 20:80 EtOAc:Hexanes) yielded 800 mg (49%) of 32 as pale yellow oil Rf: 0.16 (30:70, EtOAc:Hexanes).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1C=CC(C=O)=CC=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([N:40]=[CH:1][C:2]5[CH:7]=[CH:6][C:5]([CH3:10])=[CH:4][CH:3]=5)[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=Cc1ccccc1
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Product: Cc1ccc(C=NC2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3)C2)cc1

Procedure:
In the described fashion of Example 1 replacing benzaldehyde and p-fluorobenzaldehyde and using the acid (1) (R=cyclopropyl) described in Example 19 one obtains 1 cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-(p-fluorobenzylidene)amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid (3) (R=cyclopropyl, Z=p-fluorophenyl). mp 228°-229° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][O:11][S:22]([CH3:21])(=[O:24])=[O:23])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Boc-glycinol (25.0 g, 155 mmol) and N,N-diisopropylethylamine (32.4 mL, 186 mmol) in anhydrous dichloromethane (70 mL) was added methanesulfonyl chloride (19.5 mL, 171 mmol) dropwise under ice-water cooling. The mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the product was extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was removed in vacuo to give methanesulfonic acid 2-(tert-butoxycarbonylamino)ethyl ester as a crude oil (37 g, 99.7% yield) which was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[N:5]([C:16]3[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].CN(C)C=[O:38]>>[OH:38][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:4]1[CH:3]=[CH:2][CH:14]=[CH:13][C:12]=1[C:11]1[C:6]2[NH:5][C:16]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Oc1ccc(-n2c3cc(Br)ccc3c3ccc(Br)cc32)cc1
Reactant: OCCCCCCCCBr
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: OCCCCCCCCOc1ccccc1-c1cccc2c1[nH]c1ccccc12
Reaction time: 1 h

Procedure:
2,7-Dibromo-N-(4-hydroxyphenyl)carbazole (1.24 g) and 60% sodium hydride (0.11 g) were added at 0° C. to N,N-dimethylformamide (DMF) (40 mL), followed by stirring for 1 hour. Then, 8-bromooctanol (0.65 g) was added thereto, and the mixture was stirred at room temperature for 3 hours and at 50° C. for 2 hours. The resultant mixture was extracted with ethyl acetate, washed with water and dried. The crude product was treated through silica gel column chromatography (eluent: 25% ethyl acetate/toluene solution), to thereby obtain 1.30 g of 2,7-dibromo-N-4-[(8-hydroxyoctyloxyphenyl]carbazole as colorless viscous liquid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1.[C:21](=[O:23])=[O:22]>O1CCCC1.CCCCCC.Cl>[C:21]([C:17]1[C:16]([Cl:20])=[N:15][C:14]([Cl:13])=[CH:19][N:18]=1)([OH:23])=[O:22]
Reactant: Clc1cncc(Cl)n1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1ncc(Cl)nc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.78 g) in tetrahydrofuran (40 ml) is added dropwise a 1.6M solution of n-butyl lithium in hexane (4.82 ml) in a dry ice-acetone bath over a period of 3 minutes. The mixture is stirred in the same bath for 30 minutes. To the mixture is added dropwise a solution of 2,6-dichloropyrazine (0.50 g) in tetrahydrofuran (5 ml) at the same temperature over a period of 15 minutes, and the mixture is stirred for one hour. The reaction mixture is poured into dry ice, and the mixture is stirred at room temperature for one hour. The reaction mixture is diluted with a 10% aqueous hydrochloric acid solution in order to adjust the pH value thereof to about 2, and then extracted with ethyl acetate. The combined organic layers are extracted with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous extract is washed with ethyl acetate, acidified with a 10% aqueous hydrochloric acid, and extracted with ethyl acetate. The combined organic layer is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is triturated with a mixture of chloroform and hexane (1:1) to give 2-carboxy-3,5-dichloropyrazine (234 mg) as a slightly brown crystalline powder, m.p. 139-141° C., MS (m/z): 191 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([OH:17])(=[O:16])[C:10]([CH2:12][C:13](O)=[O:14])=[CH2:11]>O>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([N:1]2[C:13](=[O:14])[CH2:12][CH:10]([C:9]([OH:17])=[O:16])[CH2:11]2)=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: O
Product: Cc1ccc(N2CC(C(=O)O)CC2=O)cc1
Temperature: 130 °C
Yield: 97 %

Procedure:
p-Toluidine (23.05 g) and itaconic acid (28.0 g) are mixed and heated at 130° C. for 1 hour to melt and then allowed to cool. Water (200 ml) is added thereto and the reaction mixture is crushed. The resulting precipitate is collected by filtration, washed with water and recrystallized from a mixed solvent (about 300 ml) of ethyl acetate and hexane [1:3 (v/v)] to give the desired product (45.73 g), m.p. 185°-187° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.[CH2:23]([Mg]Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1.CN1C(=O)CCC1.CCOCC>[CH2:23]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: CCCCCC[Mg]Br
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCc1ccc2c(C(=O)OC)cccc2c1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
In accordance with the procedure of Furstner (Angew. Chem. Int. Ed., 2002, 41, 609-612), a solution of methyl 6-(((trifluoromethyl)sulfonyl)oxy)-1-naphthoate (334 mg, 1.0 mmol) and Fe(acac)3 in THF (6 mL) and NMP (0.56 mL) was treated with n-hexylmagnesium bromide (1.2 mL of a 2.0 M solution in Et2O, 2.4 mmol) at room temperature. After 30 min, the mixture was diluted with Et2O (20 mL) and quenched with 1 N aqueous HCl (5 mL). The phases were separated and the organic phase was washed with water (2×15 mL) and brine (15 mL), then dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified on 40 g silica gel (100% hexanes→20% EtOAc/hexanes, gradient) to afford 206 mg (76%) of methyl 6-hexyl-1-naphthoate.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(OCC)C>[CH2:17]([O:16][C:14]([C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[O:11][CH2:10][CH2:9][CH2:8][C:6]([OH:7])=[O:5])=[O:15])[CH3:18]
Reactant: CCOC(=O)c1ccccc1OCCCC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccccc1OCCCC(=O)O
Yield: 95.2 %

Procedure:
Ethyl 2-(3-tert-butoxycarbonylpropoxy)benzoate (3.60 g, 11.7 mmol) was treated with an excess of trifluoroacetic acid at room temperature over one hour. The solution was concentrated in vacuo and the oily residue purified by silica gel flash chromatography using (10:1) hexane:ethyl acetate to pure ethyl ether to provide 4-(2-ethoxycarbonylphenoxy)butyric acid as a colorless crystalline solid (2.81 g, 95% yield); 1H NMR (300 MHz, CDCl3): 7.80 (d, 1H), 7.50 (tr, 1H), 7.00 (m, 2H), 4.40 (q, 2H), 4.15 (tr, 2H), 2.65 (tr, 2H), 2.20 (m, 2H), 1.40 (tr, 3H).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][NH2:9].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2O[C:26]([C:29]34[CH2:36][CH2:35][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([CH2:33][CH2:34]3)[CH2:31][CH2:30]4)=[N:27][N:28]=2)=[C:20]([C:43]([F:46])([F:45])[F:44])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:9]([CH3:8])[C:26]([C:29]34[CH2:36][CH2:35][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([CH2:31][CH2:30]3)[CH2:33][CH2:34]4)=[N:27][N:28]=2)=[C:20]([C:43]([F:44])([F:45])[F:46])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: FC(F)(F)c1cc(OCc2ccccc2)ccc1-c1nnc(C23CCC(c4ccccc4)(CC2)CC3)o1
Reactant: CN
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: Cn1c(-c2ccc(OCc3ccccc3)cc2C(F)(F)F)nnc1C12CCC(c3ccccc3)(CC1)CC2
Temperature: 150 °C

Procedure:
The trifluoroacetate salt of methylamine (380 mg, 2.61 mmol) and 2-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole (8-D) were suspended in a 2 M solution of methylamine in methanol (1.3 mL, 2.61 mmol) and heated at 150° C. overnight. After being-cooled to room temperature, the reaction mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer extracted with twice with ethyl acetate (25 mL). The combined organic layers were washed with brine, dried (MgSO4), and solvent removed in vacuo. The residue was then dissolved in methanol (8 mL) and purified by reverse phase chromatography using gradient elution with 10% acetonitrile (0.1% TFA)/water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 10 min (20 mL/min). The fractions containing product were partitioned between saturated aqueous sodium bicarbonate (25 mL) and methylene chloride (15 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (15 mL) three times, dried (MgSO4), and the solvent removed in vacuo to afford 3-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)4H-1,2,4-triazole (8-E). MS: m/z 518 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]#[N:47])[CH:41]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]#[N:47])[CH:41]=2)[CH:35]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Product: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(2-methoxy-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J32) (263 mg, 0.75 mmol) and 3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K24) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (278 mg, 61%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3](=[O:20])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:9]([O:18]C)[CH:8]=1)=[O:6].C[S-].[Na+].O>CN(C=O)C>[F:22][C:2]([F:1])([F:21])[C:3](=[O:20])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:9]([OH:18])[CH:8]=1)=[O:6]
Reactant: COc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1cscn1
Agent: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cscn2)c(O)c1
Temperature: 120 °C
Yield: 99.9 %

Procedure:
To a stirred solution of 4,4,4-trifluoro-1-[3-methoxy-4-(1,3-thiazol-4-yl)phenyl]-1,3-butanedione (395 mg, 1.2 mmol) in DMF (6 ml) was added sodium thiomethoxide (420 mg, 6.0 mmol) and the mixture was heated at 120° C. for 3 hours. The mixture was cooled down to room temperature, and poured into water. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give title compound (378 mg, 99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:34][CH:35]=[CH2:36])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Li+].CO.Cl>O>[CH3:1][O:2][C:3]1[C:4]([CH2:34][CH:35]=[CH2:36])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(=O)NC)c1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCc1c(OCCCOc2cccc(OCC(=O)O)c2CCC)ccc(C(=O)NC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound of Example 52 (95 mg, 0.19 mmol) and 380 μl (0.38 mmol) of 1 M lithium hydroxide were added to 2.0 ml of methanol, and the reaction mixture was stirred for four hours at room temperature. The solvent was removed under vacuum to give a white solid which was suspended in 5.0 ml of water. The mixture was acidified with 10% hydrochloric acid, stirred and filtered to remove the resultant solid which was then dried at 40° C. overnight in a vacuum oven to give the product.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[C:21]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1)#[N:22]
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C#N)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(C#N)c2)=CC1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution containing (S)-2-[4-(3-cyano-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (2.20 g, 0.007 mol) in tetrahydrofuran (35 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 28 mL, 0.014 mol). The mixture was stirred at 20° C. for 2 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(3-cyano-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1.80 g, 85%) as an off-white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:9](O)(=O)C.[CH2:13]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:29][CH3:30])=[C:22]([C:24]2[NH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)(=[O:17])=[O:16])[CH3:14]>C(O)C>[CH2:13]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:29][CH3:30])=[C:22]([C:24]2[NH:25][C:26]([CH2:9][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:27][CH:28]=2)[CH:23]=1)(=[O:16])=[O:17])[CH3:14]
Reactant: CCS(=O)(=O)c1ccc(OC)c(-c2ccc[nH]2)c1
Reactant: CC(=O)O
Reactant: C1CCNCC1
Agent: C=O
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(OC)c(-c2ccc(CN3CCCCC3)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of piperidine (0.027 g, 0.32 mmol) in dry ethanol (2 ml) at room temperature was treated with aqueous formaldehyde (40%; 0.030g, 0.34 mmol) and glacial acetic acid (0.027 g, 0.45 mmol). The mixture was stirred at room temperature for 30 mins then was added dropwise to a solution of 2-(5-ethylsulphonyl-2-methoxyphenyl)-1H-pyrrole (0.086 g, 0.32 mmol) in dry ethanol (1 ml). The reaction mixture was stirred at room temperature for 18 hours then evaporated in vacuo. Chromatography on alumina (Brockmann grade 1) with ethyl acetate as eluant gave the title compound (E2)as a waxy solid after trituration with pentane (0.082 g, 70%).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C([O-])(=O)C.[NH4+:21].[C:22]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:23]C([O-])=O.C(OCC)(=O)C>CCO>[NH2:21][C:2]1([CH2:23][C:22]([O:28][CH2:29][CH3:30])=[O:27])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(N)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of benzyl 3-oxopyrrolidine-1-carboxylate (2.03 g, 10 mmol) and ammonium acetate (977 mg, 12.7 mmol) in EtOH (10 mL) was treated with ethyl malonate (1.07 mL, 9.09 mmol). The resulting solution was heated to reflux for 4 h and cooled to room temperature. Ethyl acetate (200 mL) was added and the solution was washed with saturated NaHCO3 (25 mL), brine (25 mL), dried over MgSO4 and concentrated to dryness. The mixture was filtered through a silica gel plug with ethyl acetate followed by methanol to elute the title compound as a yellow oil (600 mg, 19%). 1H NMR (400 MHz, CD3OD) δ 7.40-7.32 (m, 5H), 4.23 (q, 2H, J=7.4 Hz), 3.81-3.76 (m, 1H), 3.66-3.56 (m, 3H), 2.94 (s, 2H), 2.29-2.24 (m, 2H), 1.29 (t, 3H, J=7.4 Hz). MS ESI 307.1 [M+H]+, calcd for [C16H22N2O4+H]+ 307.16.