Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([F:28])[C:21]=1[OH:29].[Cl-].[NH4+]>CN(C)C=O>[F:19][C:20]1[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([F:28])[C:21]=1[O:29][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2c(F)c(F)cc(F)c2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 29.2 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.22 g of 2,3,5,6-tetrafluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined and washed with diluted hydrochloric acid and then with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.10 g of 4-(2,3,5,6-tetrafluorophenoxy)-6-(2-butynyloxy)pyrimidine (the present compound (90)).
Reaction SMILES: [C:1]1(=[O:14])[N:5]([CH2:6][CH2:7][OH:8])[C:4](=[O:9])[C:3]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:2]12.[H-].[Na+].[CH2:17](Br)[C:18]#[CH:19].CO>CN(C)C=O>[C:4]1(=[O:9])[N:5]([CH2:6][CH2:7][O:8][CH2:19][C:18]#[CH:17])[C:1](=[O:14])[C:2]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:3]12
Reactant: C#CCBr
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C#CCOCCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
To a stirred solution of compound 3 (1.14 g, 5.96 mmol) in N,N-dimethylformamide (20 mL) was added NaH (0.36 g, 80%) dropwise. After complete NaH addition, stirring was continued for 0.5 h at room temperature, and then the reaction was cooled to 0° C. Propargyl bromide 4 (1.5 mL, 13.47 mmol) was added, and the stirring was continued for an additional 0.5 h at 0° C., then, at room temperature for 2 h. After careful addition of methanol to decompose excess NaH, the solvent was evaporated and the crude product was purified by flash column chromatography (3:2 to 1:1 to 2:3 hexane-ethyl acetate) to give compound 5 as a solid (495 mg, 36.2%) having an RF of 0.22 (3:2 hexane-ethyl acetate). See FIG. 5.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:24]([Cl:25])[C:18]=2[N:17]=1.C(N(CC)C(C)C)(C)C>>[Cl:25][C:24]1[C:18]2[N:17]=[C:16]([N:12]3[CH2:11][CH2:10][N:9]([C:4]4[C:3]([Cl:2])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:14][CH2:13]3)[NH:20][C:19]=2[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc(Cl)c2nc(Cl)[nH]c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(Cl)c2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2c1

Procedure:
The reaction of 1-(3-chloropyridin-2-yl)piperazine hydrochloride (99 mg, 0.5 mmol, Example 3b) and 2,4-dichloro-6-trifluoromethyl-1H-benzoimidazole (76 mg, 0.3 mmol, Example 5b) and N,N-diisopropylethylamine (0.17 mL, 1 mmol, Aldrich) under the conditions of Example 3c afforded the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 416 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])=[CH:4][C:3]=1[C:24]1[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=1[C:30]#[N:31].[C:36]([O:42][CH2:43]Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C.[Na+].[I-]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[O:11][CH2:12][CH2:13][C:14]([O:16][CH2:43][O:42][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:15])=[O:7])=[CH:4][C:3]=1[C:24]1[CH:25]=[N:26][C:27]([C:32]([F:35])([F:33])[F:34])=[CH:28][C:29]=1[C:30]#[N:31]
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)OCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-4 (500 mg, 0.95 mmol), chloromethyl pivalate (276.4 μL, 1.9 mmol), triethylamine (399 μL, 2.85 mmol), NaI (142.5 mg, 0.95 mmol) in DMF (5 mL) was stirred at rt for 2 days. Ethyl acetate was added and the mixture was washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to afford 2,2-dimethyl-propionic acid 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyloxymethyl ester 36-1 as a white foam. MS [M+H]+: 618.2; tR=32.7 min (method 5).
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[C:11]([OH:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([CH2:36][CH2:37]O)=[CH:34][CH:33]=2)=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[C:11]([O:19][CH2:37][CH2:36][C:35]1[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)=[CH:40][CH:39]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1
Reactant: OCCc1ccc(OCCCCc2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1cccnc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(OCCc1ccc(OCCCCc2ccc(Cl)cc2)cc1)c1cccnc1
Yield: 53.7 %

Procedure:
Benzenesulfonyl chloride (7.66 ml, 0.06 mole) is added with stirrin to a 9.2 g (0.075 mole) of nicotinic acid in 30 ml of pyridine, and then 15.2 g (0.05 mole) of 4-(4-chlorophenylbutoxy)phenethyl alcohol is added to the solution. The mixture is stirred as discribed in Example 1. The reaction mixture is poured into water, and extracted with chloroform, the chloroform layer is washed with potassium carbonate solution and water. The chloroform is removed to give a red-syrup. The red-syrup is purified by chromatography on silica gel using a mixture of benzene and chloroform (1:1) as eluent, to give 11 g (53.6%) of a title compound.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([C:37]([F:40])([F:38])[F:39])[CH:31]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3c2ccn3Cc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene in a manner similar to that described in Example 25 as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.67-7.58 (m, 2 H), 7.48-7.38 (m, 2 H), 7.34 (d, J=7.8 Hz, 2 H), 7.16 (t, J=9.3 Hz, 1 H), 7.05 (d, J=3.5 Hz, 1 H), 6.26 (d, J=3.5 Hz, 1H), 5.60-5.45 (m, 3 H), 2.75 (s, 3 H), 2.47 (s, 3 H), 0.95 (s, 9 H); LCMS (m/z) ES+=529 (M+1).
Reaction SMILES: NC1SC(C2C=CC=CC=2)=CC=1C(OC)=O.C(CC(OC)=O)#N.C(Cl)(=O)C1C=CC=CC=1.[C:33]([CH2:36][C:37]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[S:39][C:38]=1[NH:48][C:49]([CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)=[O:50])([OH:35])=[O:34]>CN(C)P(N(C)C)(N(C)C)=O.O>[C:33]([CH2:36][C:37]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[S:39][C:38]=1[NH:48][C:49](=[O:50])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)([OH:35])=[O:34]
Reactant: O=C(O)Cc1cc(-c2ccccc2)sc1NC(=O)C1CCCCC1
Agent: COC(=O)CC#N
Agent: COC(=O)c1cc(-c2ccccc2)sc1N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Product: O=C(O)Cc1cc(-c2ccccc2)sc1NC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
Methyl 2-amino-5-phenyl-thiophene-3-carboxylate (1.3 g, 0.0055 mole) in hexamethyl phosphoramide (prepared by the method of Chemische Berichte, 99, 94 (1966) but using methyl cyanoacetate in place of ethyl cyanoacetate) (20 ml.) was stirred and treated with benzoyl chloride (1.56 g, 1.28 ml, 0.011 mole). The solution was stirred for 2 hours, poured into water (750 ml), stored overnight and the title compound filtered off (1.31 g) m.p. 190° C. Similarly prepared was: N-(3-Carboxymethyl-5-phenyl-2-thienyl) cyclohexane carboxamide, m.p. 121°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH3:29])[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:7])[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:27][CH2:28][CH3:29])[CH:21]=2)=[CH:30][CH:31]=1
Reactant: CCCOc1cccc(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1cccc(-c2cc(=O)n(C)c3ccc(C(O)c4ccc(Cl)cc4)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
A solution of interm. (7-i) (3.55 g) in methanol (20 ml) and THF (20 ml) was cooled. Sodium borohydride (0.37 g) was added portionwise. The mixture was stirred at room temperature for 30 minutes, hydrolized and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 3.5 g (100%) of (±)-6-[(4-chlorophenyl)hydroxymethyl]-1-methyl-4-(3-propoxyphenyl)-2(1H)-quinolinone (interm. 7-j).
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][CH2:9][C@H:10]2[O:15][C@@H:14]([O:16][C:17]3[C:26](=[O:27])[C:25]4[C:24]([OH:28])=[CH:23][C:22]([OH:29])=[CH:21][C:20]=4[O:19][C:18]=3[C:30]3[CH:31]=[CH:32][C:33]([OH:37])=[C:34]([OH:36])[CH:35]=3)[C@H:13]([OH:38])[C@@H:12]([OH:39])[C@@H:11]2[OH:40])[C@H](O)[C@H](O)[C@H]1O.S(=O)(=O)(O)O.C(#N)C.P(=O)(O)(O)O>O.[OH-].[Na+]>[CH:31]1[C:30]([C:18]2[O:19][C:20]3[C:25](=[C:24]([OH:28])[CH:23]=[C:22]([OH:29])[CH:21]=3)[C:26](=[O:27])[C:17]=2[O:16][C@@H:14]2[O:15][C@H:10]([CH2:9][OH:8])[C@@H:11]([OH:40])[C@H:12]([OH:39])[C@H:13]2[OH:38])=[CH:35][C:34]([OH:36])=[C:33]([OH:37])[CH:32]=1
Reactant: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H](Oc3c(-c4ccc(O)c(O)c4)oc4cc(O)cc(O)c4c3=O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=c1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12
Temperature: 72 °C

Procedure:
Rutin (5 g) was dispersed in about 90 ml of water. One of the various edible components (food additives) listed in Table 1 was added thereto in a proportion of 0.05 wt. % or 0.5 wt. %, and dissolved or dispersed. The mixture was heated to 72° C. The pH thereof was adjusted to 4.7 by pH adjustors (sulfuric acid, sodium hydroxide). Water was added to the mixture to a total volume of 100 ml. The reaction was initiated by introducing 1 ml of an aqueous solution of naringinase (manufactured by Amano Enzyme, Inc., trade name: naringinase “Amano”) prepared by mixing 0.02 g of naringinase (specific activity: 3000 U/g) with 10 ml of water. Five hours later, 4 μl of the reaction solution was sampled and dissolved in 50 μl N sodium hydroxide. A mixed solution of 15 volume % acetonitrile and 0.085 w/v % phosphoric acid was added (2 ml in total) thereto to stop the reaction. The reaction solution thus obtained was subjected to HPLC under the conditions described below. The amount of isoquercitrin produced was calculated based on the ratio of the peak area for isoquercitrin relative to the sum of the peak areas for rutin and isoquercitrin. The yield (%) of isoquercitrin was calculated from the amount of isoquercitrin. As a control experiment, a similar reaction was conducted in a system in which none of the edible components was present, and the isoquercitrin yield (%) was obtained in the same manner.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)(C)C>[N+:8]([C:7]1[C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccnc1N1CCNCC1
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-3-nitropyridine (10.05 g, 63.39 mmol) in isopropyl alcohol (350 mL) at room temperature was added piperazine (27.48 g, 319.0 mmol) in one portion. After 2 hours, the solvent was removed under reduced pressure and the residue partitioned between water and dichloromethane. The organic phase was dried (sodium sulfate), filtered and concentrated to a bright yellow solid. This material was used without further purification. 1H NMR (300 MHz, CDCl3) δ 1.74 (s, 1H), 2.98 (m, 4H), 3.43 (m, 4H), 6.73 (dd, 1H, J=8.1, 4.8 Hz), 8.11 (dd, 1H, J=8.1, 1.7 Hz), 8.32 (dd, 1H, J=4.4, 1.7 Hz); MS (DCI/NH3) m/e 209 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:13](=[CH2:16])[C:14]#[N:15]>O>[NH2:15][C:14]1[CH:13]=[CH:16][N:4]([CH2:3][CH2:2][OH:1])[N:5]=1
Reactant: C=C(Cl)C#N
Reactant: NNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccn(CCO)n1
Reaction time: 17 h

Procedure:
2-Hydroxyethylhydrazine (7.6 g.) was added slowly to a solution of potassium carbonate (13.8 g.) in water (40 ml.). The mixture was cooled to 0°, then 2-chloroacrylonitrile (8.75 g.) was added slowly with vigorous stirring. Stirring was continued for a further 17 hours and the mixture was then continuously extracted with EtOAc for 20 hours. On evaporation of the solvent, 3-amino-1-(2-hydroxyethyl)pyrazole was obtained, (7.7 g.; 60%), b.p. 170°/0.5 mm.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([C:10]3[C:14]4[CH2:15][NH:16][CH2:17][CH2:18][C:13]=4[NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1.[CH2:23]([N:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27])[CH3:24]>>[CH2:23]([N:25]([CH2:29][CH3:30])[C:26]([N:16]1[CH2:17][CH2:18][C:13]2[NH:12][N:11]=[C:10]([C:8]3[NH:7][C:6]4[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][C:5]=4[N:9]=3)[C:14]=2[CH2:15]1)=[O:27])[CH3:24]
Reactant: FC(F)(F)c1ccc2[nH]c(-c3n[nH]c4c3CNCC4)nc2c1
Reactant: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)N1CCc2[nH]nc(-c3nc4cc(C(F)(F)F)ccc4[nH]3)c2C1

Procedure:
By proceeding in a manner similar to Example 258(a) above but using 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine [Example 251(d)] and diethylcarbamyl chloride there was prepared 3-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1,4,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid diethylamide (103 mg) as a white solid. MS: 407.17 (M+H)+. HPLC (METHOD E1): RT=10.81 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:22]1([NH:32][C:33](=[O:36])[CH2:34]Cl)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:34][C:33](=[O:36])[NH:32][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=C(CCl)Nc1cccc2ccccc12
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.7 %

Procedure:
A mixture of 290 mg of 1-[bis(4-fluorophenyl)methyl]piperazine and 400 mg of N-(1-naphthyl)chloroacetamide was dissolved in 10 ml of a 1:1 by volume mixture of tetrahydrofuran and N,N-dimethylformamide. 1.2 g of anhydrous potassium carbonate were then added to the solution, after which the reaction mixture was stirred for 15 hours at 25° C. and then diluted with ethyl acetate. The organic layer was washed three times with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure. The residue was subjected to silica gel thin layer chromatography using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to afford 430 mg of 1-[bis(4-fluorophenyl)methyl]4-(1-naphthylcarbamoylmethyl)piperazine, melting at 173° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.C([NH+](CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[C:15]3[CH2:23][NH:22][CH2:21][CH2:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CN(Cc2ccccc2)CC3)C1
Agent: [Pd+2]
Agent: CC[NH+](CC)CC
Agent: O=C[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
Pd(OH)2/C (1.54 g, 2.2 mmol) was flushed with nitrogen, (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (8.5 g, 20.67 mmol) dissolved in methanol (50 mL) was added followed by the addition of triethylammonium formate (7.9 g, 53.7 mmol). The reaction mixture was refluxed for 1 h, cooled down to room temperature, filtered through a celite pad and the filtrate was partitioned between 2-Me-THF (50 mL) and water (20 mL). The upper organic phase was collected and the bottom aqueous phase was re-extracted with 2-Me-THF (10 mL). All the organic layers were combined and concentrated under vacuum to provide (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (6.2 g, 94% yield) as a yellow gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(N)(=S)C1C=CC=CC=1.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[S:24][CH:25]=2)=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: NC(=S)c1ccccc1
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccccc3)n2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 4-chloromethyl-2-phenyl-thiazole (prepared from thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-[2-methyl-4-(2-phenyl-thiazol-4-ylmethoxy)-phenyl]-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH:37]1([C:40]([NH2:42])=[O:41])[CH2:39][CH2:38]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[CH:37]1([C:40]([NH:42][C:2]2[CH:7]=[C:6]([O:8][C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]4[C:20](=[O:35])[N:21]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[CH:22]=[CH:23][C:24]=4[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[O:41])[CH2:39][CH2:38]1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Reactant: NC(=O)C1CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(=O)C3CC3)c2)cc1F
Temperature: 100 °C
Yield: 30.1 %

Procedure:
A mixture of N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.100 g, 0.194 mmol, see: Example 1), cyclopropanecarboxamide (0.033 g, 0.388 mmol), Cs2CO3 (0.095 g, 0.291 mmol) and Xantphos (5.05 mg, 8.72 μmmol) in dioxane (2 mL) was sparged with argon, treated with Pd2(dba)3 (2.66 mg, 2.91 μmmol), sparged again with argon, then fitted with a reflux condensor capped with an argon-filled balloon and heated to 100° C. overnight. The mixture was cooled to RT and partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (33 mg, 30% yield) as a solid. MS (ESI) m/z: 565.2 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=4[F:22])[C:13]([CH3:23])=[C:12]([O:24][CH3:25])[C:11]3=[O:26])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([O-])(=O)C.[NH4+]>CO>[NH:1]1[C:5]2[CH:6]=[C:7]([N:10]3[C@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=4[F:22])[C:13]([CH3:23])=[C:12]([O:24][CH3:25])[C:11]3=[O:26])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC1=C(C)C(c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: COC1=C(C)[C@@H](c2cccc(F)c2F)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
20 mg/5 ml of 1-(1H-benzo[d]imidazol-6-yl)-5-(2,3-difluorophenyl)-3-methoxy-4-methyl-1H-pyrrol-2(5H)-one (which may be prepared in accordance with Example 8) were subjected to semi-prep chiral chromatography on a 250/21 Chirobiotic Tag (Supplier: Supelco), 5μ, detection: UV @ 214 nm, Mobile phase: 40% Ammonium acetate buffer (pH 4.0, 40 mM)/60% MeOH, isocratic, 10 ml/min, r.t., yield 8 mg as first eluting enantiomer, optical rotation c=0.5 g/100 ml (MeOH) αD20=215°