Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([OH:30])([CH3:29])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.[OH:39][C:40]1[CH:44]=[C:43]([C:45](O)=[O:46])[O:42][N:41]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.O.[OH-].[Li+]>C(Cl)Cl.CN(C=O)C.C1COCC1.O>[F:28][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:6]([CH2:5][C:4]([OH:30])([CH3:29])[C:3]([OH:2])=[O:31])[NH:7][C:45]([C:43]3[O:42][N:41]=[C:40]([OH:39])[CH:44]=3)=[O:46])=[CH:17][CH:18]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1cc(O)no1
Reactant: COC(=O)C(C)(O)CN(Cc1ccc(-c2cccc(F)c2)cc1)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(O)(CN(Cc1ccc(-c2cccc(F)c2)cc1)NC(=O)c1cc(O)no1)C(=O)O
Temperature: 25 °C
Yield: 0 %

Procedure:
3-[N′-t-Butoxycarbonyl-N-(3′-fluorobiphenyl-4-ylmethyl)-hydrazino]-2-hydroxy-2-methyl-propionic acid methyl ester (100 mg, 231 mmol, 1.0 eq.) was dissolved in DCM (2.0 mL). TFA (2.0 mL) was added and the mixture was stirred at room temperature until the reaction was complete (˜45 minutes). The mixture was then concentrated. 3-Hydroxyisoxazole-5-carboxylic acid (38.8 mg, 300 mmol, 1.3 eq.) and 1 HOAt (40.9 mg, 300 μmol, 1.3 eq.) were dissolved in DMF (2 mL) of DMF, then EDCI (53.2 μL) was added followed by DIPEA (121 μL) and the mixture was stirred for 30 minutes. To this was added the concentrated mixture from above in DMF (2 mL) and the resulting mixture was stirred at room temperature until the reaction was complete (˜2.5 hours). The mixture was then dissolved in THF (2.0 mL), followed by the addition of lithium hydroxide monohydrate (97.0 mg, 2.3 mmol) in water (2.0 mL. The resulting mixture was stirred at room temperature until the reaction was complete (˜1 hour). The reaction was quenched by addition of AcOH, then the solution was concentrated. The crude product was purified by preparative HPLC (10-70% MeCN/water) to yield the title compound (43 mg; purity 99%). MS m/z [M+H]+ calc'd for C21H20FN3O6, 430.13; found 430.4.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:12])[CH2:10][NH2:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].[BH4-].[Na+].Cl>CO>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:11][CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH3:12])=[CH:29][CH:30]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CC(CN)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(CNCc1ccc(C(C)(C)C)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
618 mg of [rac]-2-(4-chloro-phenyl)-propylamine hydrochloride (3 mmol) were dissolved in 8 ml methanol at rt and treated with 415 mg of potassium carbonate (3 mmol) and after 5 min stirring treated with 0.755 ml of 4-tert-butylbenzaldehyde (4.5 mmol). After 30 min stirring at rt, the reaction mixture was refluxed for 3 h, and After cooling down to rt, treated with 170 mg (4.5 mmol) sodium borohydride in portions. After 10 min at rt, the reaction mixture was refluxed for 20 h. After cooling down to rt, the reaction mixture was treated with 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 753 mg light brown oil (79%). MS(ISP) 316.3 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1.[CH3:29][N:30]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[N:31]1.[NH4+].[Cl-]>C1COCC1>[Br:21][C:22]1[N:23]=[C:24]([CH2:28][CH:35]([C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)[OH:36])[CH:25]=[CH:26][CH:27]=1
Reactant: Cn1cc(C=O)cn1
Reactant: Cc1cccc(Br)n1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1cc(C(O)Cc2cccc(Br)n2)cn1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Diisopropylamine (0.73 mL, 5.09 mmol) was taken up in THF (10 mL) and cooled to −78° C. n-BuLi (2.04 mL, 5.09 mmol) was added dropwise and the resulting mixture stirred at −78° C. for 90 minutes. The resulting LDA solution was transferred by cannula to a solution of 2-bromo-6-methylpyridine (500 mg, 2.91 mmol) in THF (20 mL) at −78° C. After stirring for 1 hour at −78° C., a solution of 1-methyl-1H-pyrazole-4-carbaldehyde (640 mg, 5.81 mmol) in THF (3 mL) was added and stirring continued for 30 minutes. Saturated NH4Cl was added and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (12-100% EtOAc-hexanes followed by 0-10% MeOH-EtOAc) gave the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(OC([NH:37][C:38]([N:40]([CH3:42])[CH3:41])=S)=O)(C)(C)C.C(OCC)(=O)C>CN(C=O)C.FC(F)(F)C(O)=O.Cl[Hg]Cl>[CH3:41][N:40]([CH3:42])[C:38](=[NH:37])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1
Reactant: CN(C)C(=S)NC(=O)OC(C)(C)C
Reactant: Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Agent: Cl[Hg]Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=N)Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 5-amino-3-(4-quinolylmethylen) -2-oxindole (431 mg, 1.5 mmol) in DMF (100 ml) containing triethylamine (202 mg, 2 mmol) was added 1-t-butoxycarbonyl-3,3-dimethylthiourea (409 mg, 2 mmol) and HgCl2 (543 mg, 2 mmol). The mixture was stirred at room temperature for 1 h and then filtered on a pad of celite. The residue was washed with ethyl acetate, the organic layer washed several times with water, dried and evaporated to dryness. The residue was chromatographed on silica gel using as eluant ethyl acetate/cyclohexane 2:1. The above obtained BOC-derivative was taken up in trifluoroacetic acid (10 ml) and then stirred for 1 h at room temperature. Ethyl acetate was added, the organic layer washed with 1N sodium hydroxide and brine, dried and evaporated. The residue was chromatographed on a LoBar RP18 column with water as eluant to give pure title compound after freeze-drying. Yield 50% (268 mg).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:17](=[O:38])[CH:18]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:17]([OH:38])[CH:18]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:36])([F:37])[CH:33]([F:34])[F:35])[CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (9.14 g, 67.0 mmol) in diethyl ether (100 ml) was added sodium borohydride (5.07 g, 134 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, and to the filtrate was added a solution of ethyl 3-[3-(benzyloxy)phenyl]-3-oxo-2-[3-(1,1,2,2-tetrafluoroethoxy)-benzyl]propanoate (19.0 g, 33.5 mmol) in diethyl ether (200 ml) at 0° C. The mixture was stirred for 30 min. and 1N hydrochloric acid was added to stop the reaction. Then, water (500 ml) was added and the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1-ethyl acetate) to give the objective substance (10.7 g, crude).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1F)[C:13]([O:15]C)=[O:14])#[N:9].FC1C=CC(C=O)=CC=1C#N.[Li+].[OH-]>CN(C=O)C.C1COCC1.O>[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])[C:13]([OH:15])=[O:14])#[N:9]
Reactant: CC1CCCCN1
Reactant: COC(=O)c1ccc(F)c(C#N)c1
Agent: N#Cc1cc(C=O)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCCN1c1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Methylpiperidine (2.38 mL; 20.29 mmol; 5 eq.) was added to a solution of methyl 3-cyano-4-fluorobenzoate, prepared as described in J. Med. Chem. 2004, 47, 1339-1350 from 2-fluoro-5-formylbenzonitrile (Aldrich; 49, 408-9), (727 mg; 4.06 mmol; 1 eq.) in DMF (4 mL). The resulting mixture was stirred at RT for 2 days. The solution was partitioned between EtOAc and water and the phases separated. The organic layer was washed with 0.1M HCl then with NaCl sat. solution, dried over magnesium sulfate. Evaporation under reduced pressure afforded a greenish oil. The latter was taken up in THF (10 mL), LiOH (340.57 mg; 8.12 mmol; 2 eq.) then water (10 mL) were added and the reaction mixture was stirred at RT for 16 hours. The resulting solution was diluted with water and washed with Et2O. The aqueous layer was made acidic (pH 2) by addition of 1M HCl and extracted with EtOAc. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a slightly yellow oil. The oil was triturated in a mixture of EtOAc and n-pentane and the resulting precipitate was filtered and dried to afford the title compound as an off-white solid. 1H NMR (DMSO-d6, 300 MHz) δ 13 (hr s, 1H), 8.08 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.8, 2.1 Hz, 1H), 7.18 (d, J=8.9 Hz, 1H), 4.12-4.08 (m, 1H), 3.35-3.25 (m, 2H), 1.84-1.53 (m, 6H), 1.09 (d, J=6.6 Hz, 3H). LC/MS (Method B): 243.2 (M−H)−; 245.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH:12]1[CH2:14][CH2:13]1)[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20].[CH2:21]([NH:23][C:24](=[O:44])[NH:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[C:28]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[CH:27]=1)[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH:12]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:29]4[CH:30]=[N:31][C:26]([NH:25][C:24](=[O:44])[NH:23][CH2:21][CH3:22])=[CH:27][C:28]=4[C:35]4[S:36][CH:37]=[C:38]([C:40]([F:43])([F:41])[F:42])[N:39]=4)=[CH:11][N:10]=3)[C:5](=[O:20])[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7]2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cn(C2CC2)c2ncc(Br)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)OCC)cn3C2CC2)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
In a round bottomed flask, ethyl 6-bromo-1-cyclopropyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 16, 200 mg, 0.59 mmol), 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 9, 367 mg, 0.83 mmol) and sodium carbonate (125 mg, 1.18 mmol) were combined and suspended in dimethylformamide (10 mL). Argon gas was purged through the above suspension for 15 min. At the end of this period, tetrakis (triphenylphosphine) palladium (68 mg, 0.05 mM) was added under argon atmosphere and the reaction mixture was heated to 40° C. for 6 h. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was poured into water and stirred for 30 min to obtain a solid which was filtered and washed with water and dried to afford 70 mg (20%) of ethyl 1-cyclopropyl-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([NH2:17])=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[N:14]=[N:13]1.B(Br)(Br)Br.CO.[OH-].[Na+]>ClCCl.O>[NH2:17][C:16]1[N:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[F:1])[N:13]=[N:14][C:15]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COc1ccc(-c2nnn(-c3ccc(C(F)(F)F)cc3F)c2N)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Nc1c(-c2ccc(O)cc2)nnn1-c1ccc(C(F)(F)F)cc1F
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a stirred solution of 3-(2-fluoro-4-trifluoromethyl-phenyl)-5-(4-methoxy-phenyl)-3H-[1,2,3]triazol-4-ylamine (14) (0.400 g, 1.1354 mmol) in anhydrous dichloromethane (25 ml), cooled to −78° C. and under a nitrogen flow, a solution of boron tribromide (1.991 g, ˜0.75 ml, 7.9478 mmol) in 5 ml of anhydrous dichloromethane is added drop-wise. The mixture is allowed to reach room temperature spontaneously overnight and it is then cooled again in an ice-salt bath and the excess of the reagent is decomposed upon drop-wise addition of 10 ml of methanol and 10 ml of water. After 5 min stirring, 10% sodium hydroxide solution (10 ml) is added and the aqueous layer, once separated, is acidified with 10% hydrochloric acid solution and extracted with chloroform (3×70 ml). The combined organic layers are dried over MgSO4, filtered and evaporated to afford a solid residue (0.350 g). This is purified by column chromatography over silica gel (60-120 mesh) eluting with 16% ethyl acetate in hexane (0.150 g, 40% yield). M.p. 163.5-165.2° C. LC-ESI-HRMS of [M+H]+ shows 339.0853 Da. Calc. 339.086898 Da, dev. −4.7 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14]S[CH2:12][CH2:11]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[S:27](S([O-])=O)([O-:30])(=O)=[O:28].[Na+].[Na+]>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:11][CH2:12][S:27](=[O:30])(=[O:28])[CH2:14][CH2:15]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: COc1cc(Br)cc(N2CCSCC2)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Br)cc(N2CCS(=O)(=O)CC2)c1
Reaction time: 3 h

Procedure:
To a mixture of 4-(3-bromo-5-methoxy-phenyl)-thiomorpholine (239 mg, 0.83 mmol) in methylene chloride (10 ml) and methanol (5 drops) was added m-CPBA (409 mg, 1.83 mmol). After 1 hour methanol (10 drops) was added to enhance solubility. The mixture was stirred another 3 hours. Methylene chloride (25 ml) and a 10% solution of aqueous sodium metabisulfite (35 ml) were added and the material was shaken in a reparatory funnel. The organic phase was collected and washed consecutively with equal volumes of 5% aqueous sodium bicarbonate and then brine solution. The aqueous phases were back-extracted with methylene chloride (2×25 ml), the organic phases combined, dried (MgSO4), filtered and stripped to a crude residue. The material was loaded onto 2 preparative TLC plates, eluting with 40% ethyl acetate in hexanes. The product band was collected to afford 76 mg of 4-(3-bromo-5-methoxy-phenyl)-thiomorpholine 1,1-dioxide as a off-white solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([O:23][CH2:24][CH3:25])[CH:14]=3)[CH:10]=[C:9]([C:26]([F:29])([F:28])[F:27])[N:8]=2)[CH:6]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[CH2:24]([O:23][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([C:26]([F:29])([F:28])[F:27])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:34]4[CH:35]=[CH:36][C:31]([NH2:30])=[N:32][CH:33]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[C:19]([F:22])([F:21])[F:20])[CH3:25]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(N)nc4)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.9) (0.24 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a yellow solid (0.038 g, 15%). MS (ISP) 495.3 [(M+H)+]; mp 266.5° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]#[C:11][Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)#[CH:11]
Reactant: C[Si](C)(C)C#Cc1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cc2ccccc2o1

Procedure:
A solution of Example 652 (0.74 g, 3.47 mmol) and potassium carbonate (1.45 g, 10.41 mmol) in methanol (3 mL) was stirred at room temperature for about 2 hours. The solution was poured into water and was extracted with diethyl ether. The combined organic extracts were dried (MgSO4), filtered and concentrated under vacuum to provide Example 653. 1H NMR (300 MHz, CDCl3) δ 3.49 (s, 1H), 7.01 (s, 1H), 7.25 (m, 1H), 7.35 (m, 1H), 7.46 (m, 1H), 7.56 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3C=CC=[CH:19][CH:18]=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].CC1N=C(N2CCN(CCC)C2=O)SC=1C(OCC)=O>>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH3:19])[C:13]2=[O:23])[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Agent: CCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Product: CCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Yield: 94 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-propylimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 94% yield: 1H NMR (300 MHZ, DMSO-d6) δ 3.98-3.89 (m, 2H), 3.57-3.44 (m, 2H), 3.14 (t, J=7.2 Hz, 2H), 2.45 (s, 3H), 1.54-1.42 (m, 2H), 0.79 (t, J=7.2 Hz, 3H); MS (ES+) m/z 270.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:16])[C:6](I)=[CH:7][O:8]2.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:7]2[O:8][C:9]3[C:4]([C:5](=[O:16])[CH:6]=2)=[C:3]([O:2][CH3:1])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=3)=[N:18]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: COc1cc(OC)c2c(=O)c(I)coc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3n[nH]c4ccccc34)oc2c1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
A mixture of 5,7-dimethoxy-3-iodochromone (166 mg) prepared in Example 16, indazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted from chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and recrystallized from benzene/hexane to give the titled compound (117 mg; yield=73.0%) as light yellow needle crystals. Melting point: 253°-255° C. Mass spectrum (M+): 332. 1 H-NMR(CDCl3, δ ppm): 6.62 (s, 1H, H6), 8.26 (s, 1H, H8), 6.71 (s, 1H, H3), 6.43 (s, 1H, H3'), 7.80 (d, 1H, H4'), 7.58 (d, 1H, H5'), 7.34 (t, 1H, H6'), 8.11 (d, 1H, H7'), 3.96 (s, 3H, 5MeO), 3.97 (s, 3H, 7MeO).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7](O)=[O:8].C(OC(=O)C)(=O)C>CC(O)=O>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:13][C:12]2=[O:14]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(C(F)(F)F)ccc21

Procedure:
25.0 g of 4-trifluoromethyl-phthalic acid were dissolved in 50 ml of HOAc and 15.1 ml of acetic anhydride added. The mixture was refluxed for 6 h. The solvent was then removed in vacuo. The residue was treated three times with 50 ml of toluene each followed by the removal of the solvent in vacuo. Yield 23.1 g of a colorless oil (Rf(CH2Cl2)=0.60).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:15]2[C:16]([O:22]C)=[N:17][CH:18]=[CH:19][C:20]=2I)[N:6](O)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(N(CC)CC)C.Cl.[NH2:32][CH2:33][C@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[OH:35]>C(O)(=O)C.Cl.CN(C)C=O>[Cl:42][C:38]1[CH:37]=[C:36]([CH:34]([OH:35])[CH2:33][NH:32][C:20]2[CH:19]=[CH:18][NH:17][C:16](=[O:22])[C:15]=2[C:5]2[NH:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:3]([CH2:1][CH3:2])[N:4]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: CCc1nc(-c2c(I)ccnc2OC)n(O)c1-c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCc1nc(-c2c(NCC(O)c3cccc(Cl)c3)cc[nH]c2=O)[nH]c1-c1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
4-Ethyl-2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol (0.379 g, 0.90 mmol) was dissolved in acetic acid/hydrochloric acid (2 ml/2 mL) and the resulting mixture was stirred at 95° C. for 1 hour. The solvent was evaporated and the crude residue (HPLC 95% (220 nm), LCMS (+ESI, M+H+) m/z 408) was dissolved in methanol (6 mL) and treated with titanium (III) chloride (9.25 wt % in 27.4 wt % hydrochloric acid, ˜1 mL). The reaction was heated at 65° C. for ˜2.5 hours, then water was added and the solvent was evaporated to give a residue (HPLC 83% (220 nm), LCMS (+ESI, M+H+) m/z 392) which was dissolved in N,N-dimethylformamide (6 mL). The resulting solution was treated with triethylamine (0.38 mL, 2.7 mmol) and the hydrochloric acid salt of (S)-2-amino-1-[3-chlorophenyl]ethanol (0.281 g, 1.35 mmol) and this was heated at 65° C. for 4 hours. The solvent was evaporated and the residue was purified by Prep HPLC (ammonium acetate/acetonitrile/water) to give the title compound (0.132 g, 34%) as a beige solid. HPLC 97.5% (220 nm), LCMS (+ESI, M+H+) m/z 435; IR ν (cm−1): 3261, 2965, 1642; 1H NMR (400 MHz, methanol-d4) δ (ppm): 1.36 (3H, t, J=7.5 Hz), 2.97 (2H, qa, J=7.5 Hz), 3.64 (1H, dd, J=13.5 and 6.9 Hz), 3.70 (1H, dd, J=13.7 and 5.0 Hz), 4.97 (1H, br t), 6.25 (1H, d, J=7.5 Hz), 7.21-7.33 (4H, m), 7.35-7.47 (4H, m), 7.52 (1H, s), 7.69 (1H, d).