Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[CH2:6]([C:8]1[S:20][C:11]2[N:12]([CH3:19])[C:13](=[O:18])[N:14]([CH3:17])[C:15](=[O:16])[C:10]=2[C:9]=1[CH2:21][C:22]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([F:40])[CH:31]=2)[N:29]=1)=[O:23])[CH3:7].[P:41]([O:53][CH2:54]I)([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].[H-].[Na+]>CN(C=O)C>[P:41]([O:53][CH2:54][N:29]1[C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([F:40])[CH:31]=2)=[CH:27][S:26][C:25]1=[N:24][C:22](=[O:23])[CH2:21][C:9]1[C:10]2[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[S:20][C:8]=1[CH2:6][CH3:7])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:42]
Reactant: CCc1sc2c(c1CC(=O)Nc1nc(-c3ccc(C(F)(F)F)c(F)c3)cs1)c(=O)n(C)c(=O)n2C
Reactant: CC(C)(C)OP(=O)(OCI)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1sc2c(c1CC(=O)N=c1scc(-c3ccc(C(F)(F)F)c(F)c3)n1COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared according to the general procedure as described in method A for the preparation of phosphate derivatives by coupling reaction of 2-(6-Ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)-N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide (1.00 g, 1.901 mmol) with freshly prepared intermediate 2 (1.33 g, 3.802 mmol) in presence of sodium hydride (60% dispersion in mineral oil, 115 mg, 2.0851 mmol) in dry DMF (10 ml) to yield 1.15 g of pure product a pale yellow solid. 1H NMR (300 MHz, CDCl3): δ 1.20-1.38 (m, 3H), 1.50 (s, 18H), 2.81 (q, J=7.8 Hz, 2H), 3.32 (s, 3H), 3.53 (s, 3H), 4.40 (s, 2H), 6.47 (d, J=7.2 Hz, 2H), 7.21-7.33 (m, 1H), 7.59-7.81 (m, 3H); ESI (m/z): 748.71 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].CN(C)C=O.C(=O)(O)[O-].[Na+].I[CH2:25][CH3:26]>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH2:25][CH3:26])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
A mixture of 3-methyl-4-nitrobenzoic acid (1) (362.3 g, 2.0 mol), N,N-dimethylformamide (2000 mL), sodium bicarbonate (200 g, 2.38 mol) and iodoethane (623.9 g, 4.0 mol) was stirred at 70° C. for 18 h. The mixture was allowed to cool to room temperature and poured into water (2000 mL. The resulting solid was collected by filtration, washed with water and dried. The solid was washed further with hexane and dried to provide the title product (382.1 g, 91%) as an off-white solid: mp 51°-52.5° C.; 1H NMR (CDCl3) δ 8.04-7.98 (m, 3H), 4.42 (q, 2H), 2.63 (s, 3H), 1.42 (t, 3H); Mass spectrum (NH3 --CI) m/z 210 (100%, M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[C:4]([F:19])[C:3]=1OB(O)O.FC1C=C(C=C(F)C=1)C=O.[I-].C(OC1C=CC(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1)C.C=CC1C=CC=CC=1.Br[C:73]1[CH:78]=[CH:77][C:76]([CH2:79][CH2:80][CH3:81])=[CH:75][CH:74]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:73]3[CH:78]=[CH:77][C:76]([CH2:79][CH2:80][CH3:81])=[CH:75][CH:74]=3)=[C:4]([F:19])[CH:5]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: CCCc1ccc(Br)cc1
Reactant: CCOc1ccc(CCc2cc(F)c(OB(O)O)c(F)c2)cc1
Agent: CCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=Cc1cc(F)cc(F)c1
Solvent: C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2c(F)cc(CCc3ccc(OCC)cc3)cc2F)cc1

Procedure:
A mixture of 9.2 g of 2,6-difluoro-4-[2-(p-ethoxyphenyl)ethyl]phenylboric acid (prepared by reacting 3,5-difluorobenzaldehyde with p-ethoxybenzyltriphenylphosphonium iodide by the Wittig method and subsequently hydrogenating the resulting styrene derivative on Pd/C), 6.0 g of 1-bromo-4-n-propylbenzene, 38 ml of 2 ml [sic] aqueous Na2CO3 solution, 0.6 g of tetrakis(triphenyl-phosphine)palladium(0) an d 75 ml of toluene is refluxed for two hours. The aqueous phase is extracted twice with toluene and combined with the organic phase. Conventional aqueous work-up and chromatographic purification of the residue give 4-[2-(p-ethoxyphenyl)ethyl]-2,6-difluoro-4′-n-propylbiphenyl.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25](O)=[O:26])[N:21]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:22]3[N:21]=[C:20]([CH3:19])[O:24][N:23]=3)=[O:26])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)no1
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Yield: 15.3 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (573 mg, 2.20 mmol) was coupled with 5-methyl-1,2,4-oxadiazole-3-carboxylic acid (338 mg, 2.64 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: silica, eluent: 0-100% EtOAc in heptane) to yield 125 mg (15%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.61 (d, 3H), 2.66 (s, 3H), 4.28-4.39 (m, 2H), 4.41-4.53 (m, 1H), 6.95 (d, 1H), 6.83 (d, 1H), 7.94 (dd, 1H), 7.99 (dd, 1H), 8.09 (m, 1H), 9.02 (d, 1H).
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.Cl.CCOC(C)=O.CCCCCC>C1COCC1>[F:18][C:17]([F:19])([F:20])[C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH:3]=[O:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: COC=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=CCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a 0° C. solution of 4′-(2-methoxy-vinyl)-4-trifluoromethyl-biphenyl (464 mg, 1.67 mmol) in THF (17 mL) is added dropwise concentrated hydrochloric acid (2.98 mL) and the reaction is warmed to room temperature. After 1 h TLC (30% EtOAc/hexane) indicates complete consumption of starting material. The reaction mixture is diluted with water and the pH is adjusted to 8 with solid NaHCO3. The reaction mixture is concentrated and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (40 g SiO2, 5% EtOAc/Hexanes) to yield the title compound (424 mg, 96%). 1NMR (400 MHz, CDCl3) δ ppm: 9.81 (t, 1H, J=2.2 Hz), 7.69 (s, 4H), 7.61 (d, 2H, J=8.4 Hz), 7.33 (d, 2H, J=8.4 Hz), 3.78 (d, 2H, J=1.8 Hz).
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](Cl)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[S:30]1[CH2:34][CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32][CH2:31]1.C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25]([N:32]2[CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:34][S:30][CH2:31]2)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCOC(=O)C1CSCN1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)N2CSCC2C(=O)OCC)cc1

Procedure:
One-tenth mole of 4-(hexadecylamino)cinnamoyl chloride hydrochloride in methylene chloride is added to a solution of 0.1 mole of ethyl thiazolidine-4-carboxylate in chloroform containing two equivalents of triethylamine. After 5 hours at 20° C. the solution is filtered and evaporated to a white solid which is recrystallized from acetonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.C(Cl)Cl.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C([O-])(=O)C.C([O-])(=O)C.[Cu+2]>[O:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2([C:12]([N:9]3[CH2:10][CH2:11][CH:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:8]3)=[O:13])[CH2:16][CH2:15]2)=[CH:22][CH:21]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(N1CCC(c2cccnc2)C1)C1(c2ccc(O)cc2)CC1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCC(c2cccnc2)C1)C1(c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenol (40.0 mg, 0.000130 mol) in methylene chloride (1 mL, 0.02 mol) were added phenylboronic acid (15.8 mg, 0.000130 mol), copper(II) diacetate (0.0236 g, 0.000130 mol) and molecular sieves at rt. Triethylamine (0.0904 mL, 0.000648 mol) was then added and the reaction mixture was stirred at rt overnight. The reaction mixture was filtered and the filtrate was concentrated. The desired product from the residue was isolated and purified by prep-HPLC. LCMS: m/z 385.1 (M+H)+
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:17]=[C:18]4[C:24]([C:25]([F:28])([F:27])[F:26])=[N:23][NH:22][C:19]4=[N:20][CH:21]=3)=[CH:13][CH:14]=2)[C:9]([C:29]2[N:34]=[C:33]([N:35]3[CH2:40][CH2:39][CH:38]([NH:41]C(=O)OC(C)(C)C)[CH2:37][CH2:36]3)[CH:32]=[N:31][CH:30]=2)=[N:8]1.Cl>O1CCOCC1>[F:28][C:25]([F:26])([F:27])[C:24]1[C:18]2[C:19](=[N:20][CH:21]=[C:16]([C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[NH:7][N:8]=[C:9]4[C:29]3[N:34]=[C:33]([N:35]4[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]4)[CH:32]=[N:31][CH:30]=3)[CH:17]=2)[NH:22][N:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cnc6[nH]nc(C(F)(F)F)c6c5)cc34)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2cncc(-c3n[nH]c4ccc(-c5cnc6[nH]nc(C(F)(F)F)c6c5)cc34)n2)CC1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A suspension of tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (compound 1e) (150 mg, 0.269 mmol), crude 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine 6a (177 mg, 0.57 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol, Strem) and aqueous Na2CO3, 2.0 M (0.27 mL, 0.54 mmol) in dioxane (3 mL) was capped, degassed and backfilled with argon. The reaction was heated at 120° C. in a microwave for 45 min. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated NaHCO3 solution (50 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 0.5-3.5% MeOH/DCM), affording tert-butyl 1-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (94 mg, 52% yield). MS (ESI, pos. ion) m/z: 664.3 (M+1). A solution of tert-butyl 1-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (87 mg, 0.13 mmol) in dioxane (3 mL) was treated with HCl, 36.5-38.0% (0.11 mL, 1.31 mmol). The reaction mixture was heated at 90° C. After 3 h, the reaction mixture was cooled to 23° C. and concentrated. The residue (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was diluted in MeOH and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 1-(6-(5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine. MS (ESI, pos. ion) m/z: 480.2 (M+1).
Reaction SMILES: [S:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O)[C:2]#[N:3].S(=O)(=O)(O)[OH:18]>C(O)(=O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:3][C:2](=[O:18])[S:1][CH:4]=2)=[CH:8][CH:9]=1
Reactant: N#CSCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 22.52 g (91.8 mmole) of 2-thiocyanato-1-(4-trifluoromethyl-phenyl)-ethanone 9 mL of 50% aqueous sulfuric acid and 45 mL of acetic acid was heated at reflux for 1.5 hours. The mixture was cooled, poured into 500 mL of ice water and stirred for 30 minutes. The solid was collected by filtration, washing with water, to give 21.33 g of 4-(4-trifluoromethyl-phenyl)-3H-thiazol-2-one as a tan solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[C:15]1([O:21][CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[N+](C1C=CC=CC=1)([O-])=O>[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:18]2[CH:19]=[CH:20][C:15]([O:21][CH3:22])=[CH:16][CH:17]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(I)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Nitrobenzene (45 ml) was cooled in an ice-bath and treated portionwise with aluminum chloride (13.5 g, 101 mmol, 1.15 eq.) and followed by 4-iodobenzoic acid chloride (25 g, 94 mmol, 1.07 eq.) in nitrobenzene (25 ml) at a maximum of 10° C. The mixture was stirred at 0° C. for 10 minutes, where upon anisole (9.5 g, 88 mmol, 1 eq.) was added dropwise in such a manner that the temperature didn't excess 10° C. The solution then was left to warm to room temperature overnight. The yellow suspension was poured into ice-water (750 ml). The precipitate was collected by filtration and washed with water and then dissolved in dichloromethane (2 L), which was washed NaHCO3 (aq.) (150 ml×2), dried over MgSO4. Evaporation of solvent under reduced pressure to provide the title product in (26.7 g, 90%), 1H NMR (400 MHz, CDCl3) δ 3.89 (s, 3H), 6.96 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H);
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[NH:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:13]2[C:17]([N:18]=1)=[N:16][CH:15]=[N:14]2>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[NH:11][C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:13]3[C:17]([N:18]=2)=[N:16][CH:15]=[N:14]3)[CH2:4][CH2:3]1
Reactant: Fc1ccc(CNc2[nH]c(Cl)nc3ncnc2-3)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: N[C@H]1CC[C@H](Nc2nc3ncnc-3c(NCc3ccc(F)cc3)[nH]2)CC1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
570 mg of trans-1,4-diaminocyclohexane are heated to its melting point 70° C., 290 mg of the product obtained in stage 1 above are added and the medium is then heated at approximately 140° C. for about 4 hours and then left overnight at room temperature. After purification by chromatography on silica with, as eluent, a mixture of CH2Cl2:MeOH:NH4OH (75:22:3) 93 mg of the expected product are obtained in the form of a beige crumbly foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.N12CCN(CC1)CC2.[F:27][C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=1[S:36](Cl)(=[O:38])=[O:37]>C(#N)C>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:36]([C:29]1[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:28]=1[F:27])(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a solution of the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (0.76 g, 3.10 mmol) prepared in Example 14a and 1,4-diazabicyclo[2.2.2]octane (0.70 g, 6.20 mmol) in acetonitrile (20 mL), 2,4,5-trifluorobenzenesulfonyl chloride (1.43 g, 6.20 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was vacuum concentrated, and the residue was purified with silica gel chromatography (hexane/ethyl acetate=67:33) to yield the title compound (0.72 g, 53%) as a colorless solid.
Reaction SMILES: FC1C=N[C:5]([N:8]2[CH2:12][CH:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=NC=1.[F:22][C:23](F)([F:27])C(O)=O.C1(C)C=CC=CC=1>ClCCl>[F:22][CH:23]([F:27])[CH2:5][N:8]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[N:10]([CH3:20])[C:9]1=[O:21]
Reactant: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1C(=O)N(CC(F)F)CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2,2-difluoroethyl trifluoromethanesulfonate (428 mg, 1.998 mmol) in N,N-dimethylformamide (4 ml) at −35° C. under argon was added sodium hydride (80 mg, 1.998 mmol). The reaction mixture was warmed to 0° C. over 2 hours, quenched with water (10 ml) and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (15 ml), water (10 ml×2) and brine (15 ml). The organic layer was dried (magnesium sulfate), filtered and evaporated. The residue was purified by silica gel chromatography eluting with 10-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg). LC/MS [M+H]+=265. (ii) 1,1-dimethylethyl 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.757 mmol) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (1 ml) added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co-evaporated with toluene (×2) to give 1-(2,2-difluoroethyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (0.757 mmol) which was used in the next step. LC/MS [M+H]+=209.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:13][C:14]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=1)([CH3:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:14]([NH:13][C:4](=[O:5])[CH2:3][C:1]#[N:2])([CH3:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:26][CH:25]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCOc1ccc(C(C)(N)CC(=O)OC)cc1
Reactant: N#CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(C)(CC(=O)OC)NC(=O)CC#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a stirred solution of 2-cyanoacetic acid (128 mg, 1.507 mmol) in CH2Cl2 (5 mL) was added oxalyl chloride (0.754 mL, 1.507 mmol) and 1 drop of DMF. The reaction was stirred at rt for 1 h and then concentrated. The resulting acid chloride was dissolved in CH2Cl2 (1 mL) and was then added to Intermediate 107C (200 mg, 0.754 mmol) and pyridine (0.183 mL, 2.261 mmol) in CH2Cl2 (5 mL). The reaction was stirred at rt for 5 h. The reaction mixture was concentrated and the residue was diluted with EtOAc. The organic layer was washed with saturated NH4Cl, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (24 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (218 mg, 87%) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.22 (d, J=8.80 Hz, 2H), 6.85 (d, J=8.80 Hz, 2H), 3.94 (t, J=6.46 Hz, 2H), 3.65 (s, 3H), 3.30 (s, 2H), 3.03 (d, J=15.13 Hz, 1H), 2.85 (d, J=15.13 Hz, 1H), 1.80 (s, 3H), 1.71-1.78 (m, 2H), 1.44-1.53 (m, 2H), 0.97 (t, J=7.29 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:24]=3)=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+:31]>O1CCCC1>[CH3:1][C:2]([CH3:29])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[NH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][N:24]=3)=[CH:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([O-:5])=[O:4].[Na+:31]
Reactant: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cn2)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cn2)cc1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In tetrahydrofuran (2.5 mL) was dissolved 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoic acid (250 mg), 10M aqueous sodium hydroxide solution (65 μL) was added to the solution dividing into several times, and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with tetrahydrofuran (1 mL), and dried at 40° C. under reduced pressure to obtain sodium 2,2-dimethyl-3-(4-{5-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-2-yl}phenoxy)propanoate (216 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH:12]=O.CN.CO.CC(O)=O.[C:22]([BH3-])#[N:23].[Na+]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[CH2:12][NH:23][CH3:22]
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1c(C)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To 1,3-dimethyl-1H-indole-2-carboxaldehyde (13.0 g, 75 mmole) was added a solution of 2.0 M methylamine in methanol (150 mL, 300 mmole) and HOAc (4.3 mL, 75 mmole). The solution was stirred at RT for 4 hr, then was cooled to 0° C., and sodium cyanoborohydride (5.0 g, 80 mmole) was added portionwise over 5 min. The reaction was then allowed to warm to RT. After 16 hr, the reaction was concentrated under vacuum and the residue was taken up in Et2O. The solution was washed with 1.0 N NaOH then with brine, dried (Na2SO4), and concentrated to dryness. Flash chromatography on silica gel (95:5 CHCl3/methanol containing 5% NH4OH) gave the title compound (7.34 g, 52%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=7.8 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.20 (t, 1H), 7.09 (t, 1H), 3.88 (s, 2H), 3.76 (s, 3H), 2.46 (s, 3H), 2.32 (s, 3H), 1.36 (br s, 1H).