Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[NH2:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[OH:22].[Cl:23][CH2:24][C:25](Cl)=[O:26]>O>[Cl:23][CH2:24][C:25]([NH:14][C:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[OH:22])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Nc1c(O)cccc1O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Product: O=C(CCl)Nc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
KH2PO4 (17.2 g, 126.3 mmol) and K2HPO4 (8.2 g, 35.7 mmol) in 188 ml of distilled water were deoxygenated by passing argon through the mixture for 0.5 hour. 2-Aminobenzene-1,3-diol (1 g, 8.0 mmol) was added to the buffer solution and chloroacetyl chloride (0.64 ml, 8.0 mmol) was added slowly to the reaction mixture. After addition was completed, the reaction mixture was stirred at room temperature for 1.5 hours. Water was removed by freeze-drying and the residue was dissolved in 20% MeOH in DCM. The insoluble salt was removed by filtration, the solvent was evaporated to give the subtitled compound which was used without purification in the next step.
Reaction SMILES: [I-:1].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:7]=[C:8]([C@H:11]([OH:24])[CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[C:9]=1[F:10]>CC(C)=O>[F:3][C:4]1[CH:5]=[C:6]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:7]=[C:8]([C@H:11]([OH:24])[CH2:12][I:1])[C:9]=1[F:10]
Reactant: [I-]
Reactant: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)CI)c1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
Sodium iodide (3.34 g, 22.3 mmol) was added to a solution of ethyl 3-[3,4-difluoro-5-((1S)-1-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)phenyl]propanoate (0.950 g, 2.22 mmol) in acetone (9.0 mL). The reaction mixture was heated at reflux for 18 h. The reaction was cooled to room temperature and concentrated. The residue was diluted with H2O and extracted two times with ethyl acetate. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. Column chromatography (0-40% ethyl acetate:hexane) afforded 0.552 g (65%) of product: 1H NMR (400 MHz, chloroform-d) δ ppm 7.13 (d, J=5.81 Hz, 1 H) 7.01 (dd, J=10.61, 7.58 Hz, 1 H) 5.09 (dd, J=8.34, 3.54 Hz, 1 H) 4.15 (q, J=7.07 Hz, 2 H) 3.58 (dd, J=10.23, 3.16 Hz, 1 H) 3.41 (dd, J=10.36, 8.34 Hz, 1 H) 2.94 (t, J=7.58 Hz, 2 H) 2.62 (t, J=7.71 Hz, 2 H) 2.26 (s, 1 H) 1.26 (t, J=7.20 Hz, 3 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:15][C:9]2=[CH:10][N:11]=[C:12]([Cl:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:14][C:12]1[CH:13]=[C:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[NH:15][C:9]2=[CH:10][N:11]=1
Reactant: CCOC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc(Cl)ncc2[nH]1

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (Preparation 7, 1.78 g, 7.9 mmol) in ethanol (70 mL) was added sodium hydroxide solution (5.2 mL, 2M, 10.3 mmol) and the mixture was heated under reflux for 2 h. The solvent was removed in vacuo and the solid dissolved in water (150 mL) and acidified to pH 4 with acetic acid to give the title compound as a solid that was isolated by filtration. δH (CD3OD): 7.13 (1H, s), 7.68 (1H, s), 8.58 (1H, s); m/z (ES+)=197 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:41](=[CH:42][CH:43]=2)[O:40][CH2:39][C:35]2([CH2:38][O:37][CH2:36]2)[C:15]23[CH2:19][O:18][C:17]([N:20](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:16]2)[CH:9]=[N:10][CH:11]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:41](=[CH:42][CH:43]=2)[O:40][CH2:39][C:35]2([CH2:38][O:37][CH2:36]2)[C:15]23[CH2:19][O:18][C:17]([NH2:20])=[N:16]2)[CH:9]=[N:10][CH:11]=1
Reactant: COCC#Cc1cncc(-c2ccc3c(c2)C2(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N2)C2(COC2)CO3)c1
Solvent: Cc1ccccc1
Product: COCC#Cc1cncc(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)CO3)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
A mixture of di-tert-butyl {6′-[5-(3-methoxyprop-1-yn-1-yl)pyridin-3-yl]dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl}imidodicarbonate (220 mg, 0.372 mmol), silica gel (neutral; 660 mg) and toluene (2.2 mL) was stirred for 3 hours at 100° C. The mixture was cooled down to ambient temperature, and concentrated at reduced pressure. Purification of the residue with column chromatography on silica gel (CHCl3-MeOH, a linear gradient of MeOH from 0 to 10%) afforded 6′-[5-(3-methoxyprop-1-yn-1-yl)pyridin-3-yl]dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (92.4 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10](=[O:22])[N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][C@H:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:30])[CH:7]=2)[N:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:10]1=[O:22])#[N:21]
Reactant: C[C@H](N)c1ccccc1
Reactant: N#Cc1ccccc1Cn1cc(-c2ccnc(Cl)c2)n(-c2ccc(F)cc2)c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cc(-c2cn(Cc3ccccc3C#N)c(=O)n2-c2ccc(F)cc2)ccn1)c1ccccc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
4-(2-Chloropyridin-4-yl)-3-(4-fluorophenyl)-1-(2-cyanobenzyl)-4-imidazolin-2-one (a compound of Reference Example 1 (6)), 79 μl of (S)-(−)-α-methylbenzylamine, 5.5 mg of palladium acetate, 15 mg of 2,2′-bis(diphenylphsophino)-1,1′-binaphthyl and 17 mg of sodium t-butoxide were suspended in 1 ml of toluene, and the mixture was stirred at 70° C. for 18 hours, under nitrogen flow. The reaction mixture was diluted by ethyl acetate, and insoluble matter was removed by filtration through Celite. To the filtrate was added 6N hydrochloric acid, and after separation, an aqueous layer was made alkaline with aqueous sodium bicarbonate solution. The mixture was extracted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane ethyl acetate=1:2), to give 38 mg of the title compound as colorless powder.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[N:22]1.O1CC(C2C3SC(NC(C4SC(C)=CC=4)=O)=NC=3C(OC)=CC=2)COCC1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:26]([C:24]4[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=4)=[O:27])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: Cn1cc(C(=O)O)cn1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Agent: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3cnn(C)c3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and 1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for 5-methyl-thiophene-2-carboxylic acid (7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-amide and obtained as white solid. MS: m/e=389(M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10]1[N:11]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=2)[C:12](=[O:23])[C:13]2[CH2:19][CH2:18][CH2:17][N:16]([C:20](=[O:22])[CH3:21])[C:14]=2[N:15]=1)[CH3:9])(C)(C)C.ClCCl>FC(F)(F)C(O)=O>[C:20]([N:16]1[C:14]2[N:15]=[C:10]([C@H:8]([NH2:7])[CH3:9])[N:11]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][CH:25]=3)[C:12](=[O:23])[C:13]=2[CH2:19][CH2:18][CH2:17]1)(=[O:22])[CH3:21]
Reactant: CCOc1ccc(-n2c([C@@H](C)NC(=O)OC(C)(C)C)nc3c(c2=O)CCCN3C(C)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(-n2c([C@@H](C)N)nc3c(c2=O)CCCN3C(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
D3 (268 mg, 0.59 mmol) was dissolved in 1:1 trifluoroacetic acid:dichloromethane (10 mL). The reaction stirred at room temperature for 30 min. The solvent was removed in vacuo, then 10% aqueous ammonium hydroxide was added until the aqueous pH=9. The aqueous layer was extracted three times with dichloromethane, then the combined organic layer was washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, and concentrated in vacuo, recovering 170 mg of D4. MS (MH+): 357.1. 1H NMR (400 MHz; CDCl3; T=298 K): δ 7.13 (ddd, 2H, J=18.9, 1.4, 1.1 Hz), 7.02 (ddd, 2H, J=9.0, 1.2, 0.8 Hz), 4.09 (dq, 2H, J=6.9, 1.2 Hz), 3.98-3.80 (ddq, 2H, J=62.6, 5.3, 1.0 Hz), 3.73 (dd, 1H, J=6.6, 1.2 Hz), 2.60 (s, 3H), 1.92 (m, 2H), 1.82 (broad s, 2H), 1.45 (ddd, 3H, J=8.3, 6.1, 1.3 Hz), 1.28-1.21 (m, 5H) ppm.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>[OH-].[Na+]>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([O:18][C:15]1[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=1)=[N:7]2
Reactant: Clc1ccc2nccn2n1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ccc3nccn3n2)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
A mixture of 6-chloroimidazo[1,2-b]pyridazine (768 mg, 5.0 mmol), 4-aminophenol (818 mg, 7.5 mmol), potassium carbonate (2073 mg, 15.0 mmol) and N-methylpyrrolidone (5.0 mL) was stirred at 120° C. for 18 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate=70/30→0/100) and precipitated from diisopropyl ether to give the title compound (759 mg, 67%) as a gray powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][CH:28]=[CH:29][C:30](=[O:32])[CH3:31]>>[C:30]([C:29]1[CH:15]([CH2:14][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:27]([CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[Cl:19])[CH:28]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)C=CNCc1ccccc1Cl
Reactant: COc1ccc2c(c1)CCN(C/C=C/C=O)C2=O
Product: COc1ccc2c(c1)CCN(CC1C=CN(Cc3ccccc3Cl)C=C1C(C)=O)C2=O

Procedure:
The title compound 41 is prepared according to the procedure reported in step D of Example 8 with aldehyde 44 (113 mg, 0.46 mmol) and enamine 45 (94 mg, 1 equiv) as reactants. (Yield 82.4 mg, 41%).
Reaction SMILES: CO.[OH:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:7][C:6](=[O:17])[C:5]=1[S:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][CH2:35][O:36][C:37](=[O:39])[CH3:38]>CN(C)C=O>[CH2:35]([O:36][C:37](=[O:39])[CH2:38][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:7][C:6](=[O:17])[C:5]([S:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:4]([OH:3])[CH:9]=2)=[CH:15][CH:14]=1)[CH3:34]
Reactant: CC(=O)OCCBr
Reactant: O=c1oc(-c2ccc(O)cc2)cc(O)c1SCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1
Reaction time: 3 h

Procedure:
To a methanol solution (3 ml) of the 4-hydroxy-6-(4-hydroxyphenyl)-3-[(2-phenylethyl)thio]-2H-pyran-2-one (0.500 g, 1.47 mmol) was added cesium carbonate (0.955 g, 2.94 mmol). The reaction was stirred for 3 hrs. and is then concentrated in vacuo. Next, dimethylformamide (15 mL) is added and the residue is reconcentrated in vacuo to dryness. The solid is then diluted with dimethylformamide (3 mL) and bromoethylacetate (0.491 mL, 2.94 mmol) is added. The slurry is then stirred for 3 hrs. The reaction is quenched by dilution with ethyl acetate (100 mL). The organic layer is washed in succession with; 1N HCl, water, saturated sodium chloride; dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by flash column chromatography (SiO2 --230 to 400 mesh) using a gradient of 15% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to 30% ethyl acetate/30% hexanes/40% methylene chloride.: m.p. 169°-171° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.20 (t, 3 H), 2.75 (t, 2 H), 2.96 (t, 2 H), 4.16 (q, 2 H), 4.87 (s, 2 H), 6.69 (s, 1 H), 7.06 (d, 2 H), 7.19 (m, 5 H), 7.73 (d, 2 H), 11.85 (bs, 1 H).
Reaction SMILES: [CH2:1]([CH:12]1[NH:16][C:15](=[O:17])[NH:14][C:13]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1COCC1.COCCO[AlH2-]OCCOC.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([CH:12]1[CH2:13][NH:14][C:15](=[O:17])[NH:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC1NC(=O)NC1=O
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC1CNC(=O)N1
Yield: 78.1 %

Procedure:
A dry 250 ml round bottom flask equipped with a nitrogen inlet, reflux condenser and stirring bar was charged with 2.44 g of 5-undecylhydantoin and 100 ml of THF. To this was added dropwise 10 ml of 3.5M Vitride in toluene. After the initial foaming had ceased the reaction mixture was refluxed for 30 hours. The reaction was quenched with saturated sodium sulfate solution and extracted with 3×50 ml of ether. The combined ether extracts were dried, filtered and concentrated. Recrystallization from ether gave 1.8 g (78%) of white crystals, m.p. 97°-99° C.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:16]([Si:20]([CH3:42])([CH3:41])[O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:40])[CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:27][CH:26]=1)([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([Si:20]([CH3:42])([CH3:41])[O:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:40][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:29][CH:30]=1)([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C(=O)CCc2ccccc2)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C2(CCc3ccccc3)CC(O)=CC(=O)O2)cc1

Procedure:
The title compound was prepared as described in General Methods 6 and 7 using 2.5 mL (23.2 mmol) of methyl acetoacetate, 0.96 g (24 mmol) of 60% sodium hydride, 15 mL (24 mmol) of 1.6M n-butyllithium, 4.5 g (11.7 mmol) of 1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxyl -phenyl}-3-phenyl-propan-1-one from Example O and 100 mL of THF. Purification by silica gel chromatography, eluting with EtOAc:hexane (25:75 to 50:50) gave the title compound. 1H NMR (CDCl3) δ 0.0 (s, 6 H), 0.81 (s, 9 H), 2.17 (m, 2 H), 2.42 (m, 1 H), 2.63 (m, 1 H), 2.85 (dd, 2 H), 3.22 (dd, 2 H), 3.86-3.96 (m, 4 H), 6.80-7.19 (m, 9 H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12]CC)=O.[C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH3:19].[Li]>>[C:22]([O:21][C:18](=[O:20])[CH2:19][C:10]([C:9]1[CH:15]=[CH:16][CH:17]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH:8]=1)=[O:12])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cccc(-c2nccn2C)c1
Agent: [Li]
Product: Cn1ccnc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
Prepared from ethyl 3-(1-methyl-1H-imidazol-2-yl)benzoate [CAS-No. 168422-44-4] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a light yellow liquid (1.26 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[O:17][CH2:18][CH2:19][Br:20].ClC1C=CC(OCCBr)=CC=1F.ClC1C=C(O)C=CC=1F.BrCCBr>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[O:17][CH2:18][CH2:19][S:12][C:10]1[N:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[O:17][CH2:18][CH2:19][Br:20]
Reactant: Cc1cc(C)n2nc(S)nc2n1
Agent: Fc1cc(OCCBr)ccc1Cl
Agent: Fc1ccc(OCCBr)cc1Cl
Agent: Oc1ccc(F)c(Cl)c1
Solvent: BrCCBr
Product: Cc1cc(C)n2nc(SCCOc3ccc(F)c(Cl)c3)nc2n1
Yield: 81 %

Procedure:
The title compound was prepared according to the experimentals described for Example 1 above from 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol and 3-chloro-4-fluorophenoxy-ethylbromide in 81% yield. The reagent 3-chloro-4-fluorophenoxy-ethylbromide was prepared by a similar procedure for the synthesis of 4-chloro-3-fluorophenoxy-ethylbromide in Example 4 above from 3-chloro-4-fluorophenol and 1,2-dibromoethane. EM (calc.): 352.1; MS (ESI) m/e: 353.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][C:25]1[N:26]=[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]2[C:34]=1[C:35](O)=[O:36]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:35]([C:34]2[N:28]3[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:27]3=[N:26][C:25]=2[CH3:24])=[O:36])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1nc2c(C)cccn2c1C(=O)O
Product: Cc1nc2c(C)cccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,8-Dimethyl-imidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([N+]([O-])=O)[C:12](/[CH:18]=[CH:19]/[N:20]2CCCC2)=[CH:11][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1>CO.[Pd]>[CH3:1][C:2]1[CH:14]=[C:13]2[C:12]([CH:18]=[CH:19][NH:20]2)=[CH:11][C:3]=1[O:4][C:5]1[CH:10]=[N:9][CH:8]=[N:7][CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])c(/C=C/N2CCCC2)cc1Oc1cncnc1
Agent: [Pd]
Solvent: CO
Product: Cc1cc2[nH]ccc2cc1Oc1cncnc1
Yield: 46.4 %

Procedure:
A red, heterogeneous solution of (E)-5-(2-methyl-4-nitro-5-(2-(pyrrolidin-1-yl)vinyl)phenoxy)pyrimidine (0.963 g, 2.95 mmol) and 10% Pd/C (0.314 g, 0.295 mmol) in methanol (49.2 mL) was hydrogenated overnight. The reaction was flushed with nitrogen, filtered through a pad of CELITE®, and rinsed with MeOH. The filtrate was concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 40 g column eluting with 0-5% MeOH/CH2Cl2. Appropriate fractions were collected and concentrated in vacuo to the desired product (0.3082 g, 1.37 mmol, 46.4%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[CH2:21](Br)[C:22]#C>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:21]#[CH:22])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: C#CCBr
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
5.85 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. dimethylformamide is treated under nitrogen with 1.14 g. sodium borohydride at not greater than 30° C. The mixture is stirred for 1 hour at 15°-20° C, then treated with 5 ml. of propargyl bromide at 20°-25° C. After a further three hours, water is added and the crude product extracted with chloroform. The dried chloroform solution is passed through a column of silica gel to remove a litte polar material. Pure 1-amino-2-nitro-4-(prop-2-yn-1-ylthio)benzene is obtained from the eluate.
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.[C:37]([NH2:43])(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].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.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:36][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:20](=[O:35])[N:21]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH3:27])=[O:18]
Reactant: CC(C)(C)C(N)=O
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(=O)C(C)(C)C)c2)cc1F
Temperature: 100 °C
Yield: 29.7 %

Procedure:
N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.15 g, 0.29 mmol, see: Example 1) was combined with pivalamide (0.12 g, 1.16 mmol), Xantphos (0.02 g, 0.033 mmol), and Cs2CO3 (0.14 g, 0.44 mmol) in dioxane (5 mL). The mixture was sparged with argon for several min, treated with Pd2(dba)3 (0.015 g, 0.016 mmol), and heated at 100° C. overnight. The mixture was cooled to RT and filtered, washing with dioxane. The filtrate was concentrated to dryness and the residue was purified by reverse-phase chromatography [10%-45% CH3CN/H2O with 0.1% TFA]. The pure fractions were combined and co-evaporated with MeOH. The aqueous layer was neutralized with NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (50 mg, 29.6% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1 H), 9.89 (s, 1 H), 8.34 (dd, J=12.6, 7.2 Hz, 1 H), 8.21 (d, J=5.7 Hz, 1 H), 7.92 (d, J=7.8 Hz, 1 H), 7.66 (d, J=2.4 Hz, 1 H) 7.51-7.48 (m, 3 H), 7.36 (t, J=8.7 Hz, 2 H), 6.76 (dd, J=5.7, 2.5 Hz, 1 H), 6.55 (d, J=7.9 Hz, 1 H), 4.28-4.27 (m, 2 H), 1.34 (t, J=6.98 Hz, 3 H), 1.05 (s, 9 H); MS (ESI) m/z: 581.2 (M+H+).