Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18](OCC)=[O:19])=[CH:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[CH2:18][OH:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cc2cc(Br)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1-benzyl-1H-indole-2-carboxylate and lithium aluminum hydride in substantially the same manner, as described in step 3 of Example 1. The product was obtained as a semi-solid. Mass spectrum (ESI, [M−H]−) m/z 314. 1H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.58–7.15 (m, 4H), 7.12 (d, 1H, J=8.69 and 1.97 Hz), 6.98 (d, 2H, J=8.34 Hz), 6.41 (s, 1H), 5.43 (s, 2H), 5.33 (t, 1H, J=5.57 Hz), and 4.54 ppm (d, 2H, J=5.43 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[O:20][C:21]([F:24])([F:23])[O:22][C:14]3=[CH:13][C:12]=2[NH:11][CH:10]=1)=[O:8].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[O:20][C:21]([F:23])([F:24])[O:22][C:14]3=[CH:13][C:12]=2[N:11]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[F:29])[CH:10]=1)=[O:8]
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OC(F)(F)O4)cc1C
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccccc3F)c3cc4c(cc3c2=O)OC(F)(F)O4)cc1C
Yield: 31.2 %

Procedure:
Compound 4v was prepared following the procedure outlined in Step 3 of Example 1 using 10.4 mg (0.26 mmol) of sodium hydride (60%), 71 mg (0.20 mmol) of 7-(3,4-dimethyl-benzoyl)-2,2-difluoro-5H-[1,3]dioxolo[4,5-g]quinolin-8-one, 3 mL of anhydrous dimethylformamide, and 49.1 mg (0.26 mmol) of 2-fluorobenzylbromide. The crude product was purified by flash chromatography to yield 29 mg of 4v as a colorless solid: Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.922 min; LC-MSD, m/z for C24H18F3NO4, [M+H]+=466.4, [M+2H]+=467.4; 1H NMR (400 MHz, CDCl3/HCl): δ 2.2-2.4 (d, 6H), 5.40 (s, 2H), 7.02-7.10 (m, 2H), 7.12-7.22 (m, 3H), 7.34-7.42 (m, 1H), 7.52-7.57 (d, 1H), 7.62 (s, 1H), 8.10 (s, 1H), 8.24 (s, 1H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][O:30][CH3:31])=[CH:25][CH:24]=3)=[N:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:31][O:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[C:17]([N:14]3[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][NH:7][CH3:6])[CH2:16][CH2:15]3)=[N:18][CH:19]=[CH:20][N:21]=2)=[CH:28][CH:27]=1
Reactant: COCc1ccc(-c2nccnc2N2CCN(CCN(C)C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCN1CCN(c2nccnc2-c2ccc(COC)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
Dissolve {2-[3′-(4-methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (1.01 g, 2.3 mmol, 1 eq.) in dichloromethane (20 mL). Add trifluoroacetic acid (10.5 g, 7.1 mL, 92 mmol, 40 eq.). Stir at room temperature for 1.5 hr. Partition the reaction mixture between aqueous 5N NaOH (pH aqueous layer=14) and dichlormethane. Separate the layers. Extract the aqueous layer with dichloromethane (2×50 mL). Combine the organic layers, dry over anhydrous Na2SO4, filter and concentrate to afford the title preparation (0.76 g, 97% yield). MS (loop): m/z=342.3 [M+H].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)CCC>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
2-chloro-3-nitropyridine (25 g, 158 mmol), aniline (17.62 g, 189 mmol), and triethylamine (19.15 g, 189 mmol) were mixed in 1-butanol (500 mL). The reaction was heated to reflux overnight. After it cooled to room temperature, the solvent was distilled. The residue was purified by column chromatography using hexanes/ethyl acetate to give 3-nitro-N-phenylpyridin-2-amine (29 g, 85% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:13](OCC)=[O:14])[CH2:12][CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2].[BH4-].[Li+].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1(n2cc([N+](=O)[O-])cn2)CCC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cnn(C2(CO)CCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 1-(4-nitro-1H-pyrazol-1-yl)cyclobutanecarboxylate (500 mg) obtained in Step A of Example 127 in tetrahydrofuran (30 mL) was added lithium tetrahydroborate (68 mg), and the mixture was stirred at room temperature for 3 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (410 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:12][C@H:13]1[NH:14][CH2:15][CH2:16][N:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:18]1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: C[C@@H]1CNCCN1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Temperature: 140 °C
Yield: 68.5 %

Procedure:
A suspension of 2-bromo-5-trifluoromethyl-pyridine (2.37 g; 10.0 mmol; 1.0 eq.), (R)-2-methylpiperazine (2.00 g; 20.0 mmol; 2.0 eq.) and DIEA (1.94 g; 15.0 mmol; 1.5 eq.) in 4 mL of DMA was heated at 140° C. for 14 h. The mixture was cooled to room temperature. After evaporation of the solvent under vacuum, the residue was dissolved in a 1/1 mixture of DCM/Et2O. A 4N solution of HCl was added (10 mL) then the resulting precipitate was collected and washed with Et2O. The solid was then poured to an aq. solution of NaOH (5N, 20 mL) and the resulting mixture was extracted with Et2O (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give the title compound as an orange solid (1680 mg, 69%) used without further purification for the next steps. M+(ESI): 246.3. HPLC (Condition A), Rt: 1.0 min (HPLC purity: 99.9%).
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:29])([F:28])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>CS(C)=O>[Cl:1][C:2]1[C:8]([O:27][C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(C(F)(F)F)cc2)c(Cl)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (5 g, 24.15 mmol) in DMSO (15 ml) was added potassium carbonate (6.62 g, 47.90 mmol) and 4-(trifluoromethyl)phenol (6.6 g, 40.71 mmol) in several batches. The resulting solution was stirred for 8 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was then quenched by the addition of water (200 ml), extracted with ethyl acetate (5×100 ml) and the organic layers combined. The resulting mixture was washed with sodium chloride (3×100 m), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to produce 4-chloro-2-nitro-5-[4-(trifluoromethyl)phenoxy]aniline as a yellow solid (1.43 g, 18%). Next, to a solution of 4-chloro-2-nitro-5-[4-(trifluoromethyl)phenoxy]aniline (499 mg, 1.50 mmol) in ethanol (30 ml) was added hydrogen chloride (conc) (0.4 mL) and Zn powder (586 mg) in several bacthes. The resulting solution was stirred for 1.5 h at 85° C. in an oil bath and then concentrated under vacuum. The residue was dissolved in ethyl acetate (150 ml), washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to afford 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine as a red solid (359 mg, 79%). Finally, a solution of 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (100 mg, 0.33 mmol) in trifluoroacetic acid (5 ml) and HCl ((conc), 1 ml) was stirred for 4.5 h at 80° C. in an oil bath. The solution was poured into water (100 ml), adjusted pH value of the solution to 8 with sodium bicarbonate (sat) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Pre-TLC with 11% ethyl acetate in petroleum ether to produce 5-chloro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy]-1H-1,3-benzodiazole as a white solid (78.2 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCc2ccc(F)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(F)cc2C1=O
Yield: 71 %

Procedure:
A solution of 19.7 g of 6-fluoro-1-indanone, 27.0 ml of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 200 ml of 2,2-dimethoxypropane was boiled under reflux for 67 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 18.9 g (71%) of (RS)-2-(2-buten-1-yl)-6-fluoro-1-indanone were obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>O1CCCC1>[C:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][N+:12]([O-:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc(S(=O)(=O)C[N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 7.5 %

Procedure:
(4-Aminophenylsulphonyl)nitromethane (1.62 g, 7.5 mmol) was dissolved in dry tetrahydrofuran (35 ml) under an atmosphere of argon. Triethylamine (1.14 g, 11.25 mmol) was added, followed by butyryl chloride (0.88 g, 8.25 mmol). The mixture was stirred for 2 hours. The precipitated triethylamine hydrochloride was removed by filtration and the filtrate concentrated in vacuo. The brown oil obtained was purified by MPLC, eluting with dichloromethane/methanol (99:1 v/v) to give (4-butyramidophenylsulphonyl)nitromethane (0.16 g, 7.5% yield) as a solid, m.p. 155 156° C.; microanalysis, found: C, 45.8; H, 4.8; N, 9.6%; C11H14N2O5S requires: C, 46.1; H, 4.9; N, 9.8%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[OH:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:30](=[O:31])[C:29]([OH:28])([CH3:34])[CH3:33])[CH2:2][CH2:3]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C(=O)C(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
To a stirred solution of [(S)-1-(1-piperidin-4-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine 113 (97 mg, 0.268 mmol) in DMF (5 mL) were added 2-hydroxy-2-methylpropionic acid (31 mg, 0.294 mmol), DIPEA (230 μL, 1.34 mmol) and HATU (153 mg, 0.401 mmol). Stirring at RT was continued for 18 h then the crude reaction mixture was partitioned between EtOAc and a saturated solution of NaHCO3. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 121 as a pale beige solid (33 mg, 31%). LCMS: RT 2.28 min [M+H]+ 449.1. 1H NMR (CDCl3, 400 MHz): δ 8.51 (1H, s), 7.98 (1H, s), 7.79 (1H, d, J=7.80 Hz), 7.36-6.99 (4H, m), 5.32 (1H, bs), 5.02-4.88 (2H, m), 4.78 (1H, bs), 4.59-4.49 (1H, br), 2.64-2.44 (2H, m), 2.37-2.22 (1H, m), 2.05 (1H, d, J=12.70 Hz), 2.95-1.49 (11H, m)
Reaction SMILES: C(O[N:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:16]=[C:17]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:22])[CH:18]=[CH:19][CH:20]=1)C.[NH2:31][NH:32][C:33](=O)[CH2:34][N:35]([CH3:37])[CH3:36].C[O-].[Na+].Cl>CO.C(OCC)(=O)C>[CH3:36][N:35]([CH2:34][C:33]1[N:4]=[C:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[NH:31][N:32]=1)[CH3:37]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(C(=O)Nc4ccc(F)cc4)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)Cc1n[nH]c(-c2ccc3[nH]nc(-c4cccc(C(=O)Nc5ccc(F)cc5)c4)c3c2)n1
Yield: 50 %

Procedure:
Prepared according to the procedure of Example 367 C using (3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl)-N-(4-fluorophenyl)carboxamide.2HCl (1.50 g, 3.15 mmol), N-amino-2-(dimethylamino) acetamide (1.2 g, 10.33 mmol) and sodium methoxide (1.8 mL of a 25% w/w in methanol) in anhydrous methanol (20.0 mL) with a reaction time of 1.5 days. Purification by flash chromatography on silica gel using 50% methanol in ethyl acetate afforded a solid which was dissolved in anhydrous methanol and treated with anhydrous hydrogen chloride gas for 10 min at 0° C. After stirring at ambient temperature for 5 min anhydrous ethyl acetate was added to precipitate the desired product which was collected on a sintered glass funnel, washed with methanol and ethyl acetate and dried under vacuum to give the title compound (267 mg, 50% yield) as a light yellow solid 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 10.5 (s, 1H), 8.5 (s, 1H), 8.2 (br d, 1H), 8.1 (d, 1H), 8.0 (d, 1H), 7.84 (dd, 2H), 7.75-7.6 (m, 2H), 7.2 (t, 2H), 3.6 (bs, 2H), 2.2 (s, 6H), ES-MS (m/z) 456 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[S:13][C:12]([C:14](OCC)=[O:15])=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:8][C:9]1[S:13][C:12]([C:14](=[O:15])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: Cc1ccncc1
Reactant: CCOC(=O)c1ccc(Cl)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccc(Cl)s1
Temperature: 5 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of 4-methylpyridine (32.3 mmol) and ethyl 5-chlorothiophene-2-carboxylate (35.5 mmol) in anhydrous THF (58 mL) at 0° C., under N2 was added dropwise a solution of lithium bis(trimethylsilyl)amide (1 molar solution in hexanes, 64.5 mmol). The mixture was stirred 3 h at 5° C. The resulting precipitate was filtered and acidified with 6 molar HCl. The precipitate was then filtered and dried to afford 2.9 g (35% yield) of 1-(5-chloro-2-thienyl)-2-(pyridin-4-yl)ethanone.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[O:12][CH:13]=[C:14]([C:16]3[N:17]=[N:18][NH:19][N:20]=3)[N:15]=2)[CH2:7][CH2:6]1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[Br:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[O:12][CH:13]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:20]=3)[N:15]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: Fc1ccc(Br)c(OC2CCN(c3nc(-c4nn[nH]n4)co3)CC2)c1
Product: CCOC(=O)Cn1nnc(-c2coc(N3CCC(Oc4cc(F)ccc4Br)CC3)n2)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 6, step 7, from 4-(2-bromo-5-fluorophenoxy)-1-[4-(2H-tetrazol-5-yl)-1,3-oxazol-2-yl]piperidine and ethy bromoacetate. The mixture of regioisomers was purified by Combiflash chromatography (SiO2-12 g, gradient elution of 15-50% EtOAc/hexanes over 25 min) to afford the title product as the more polar isomer.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[N:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:19]=[O:20]>C1COCC1>[F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:5](=[O:8])[N:6]([C:19]([NH:18][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: Oc1ncc(F)c(NCc2ccccc2F)n1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)n1cc(F)c(NCc2ccccc2F)nc1=O
Reaction time: 4.5 h
Yield: 67.5 %

Procedure:
A 25 mL screw-top vial was charged with 5-fluoro-4-(2-fluorobenzylamino)pyrimidin-2-ol (74.3 mg, 0.313 mmol), THF (2 mL), and isocyanatobenzene (0.33 mL, 0.313 mmol). The resulting mixture was then agitated on an orbital shaker for 4.5 h at which time it was concentrated to dryness in vacuo. The dried material was then purified by normal phase chromatography (gradient, EtOAc/Hexane) to provide 5-fluoro-4-(2-fluorobenzylamino)-2-oxo-N-phenylpyrimidine-1(2H)-carboxamide (75.3 mg, 68%) as a white solid: mp 154-157° C.; 1H NMR (400 MHz, CDCl3) δ 12.65 (s, 1H), 8.51 (d, J=7.1 Hz, 1H), 7.63-7.55 (m, 2H), 7.46 (td, J=7.5, 1.7 Hz, 1H), 7.41-7.28 (m, 3H), 7.19-7.05 (m, 3H), 6.03 (s, 1H), 4.86 (d, J=5.9 Hz, 2H); ESIMS m/z 355 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:2]=1[Br:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)c(Br)c1
Yield: 164 %

Procedure:
A solution of Example 35a (2.011 mL, 16.90 mmol), and potassium carbonate (5.84 g, 42.3 mmol) in ethanol (100 mL) was refluxed for 2 hours, cooled, concentrated and the residue was partitioned with ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by chromatography (silica gel, 0-20% ethyl acetate in hexane) afforded the title compound (4.84 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:37]([O:39]CC)=[CH2:38])CCC.CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:37]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1)(=[O:39])[CH3:38]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in Example 11, step (f), 100 mg, 0.199 mmol), tributyl(1-ethoxyvinyl)tin (86.3 mg, 0.239 mmol) and Pd(PPh3)2Cl2 (10.5 mg, 0.0149 mmol) in 2 mL of 1,4-dioxane was stirred at 90° C. for 2 h under Ar. After cooling to RT, the reaction was treated with EtOAc (40 mL) and washed with 15% citric acid aqueous solution (2×10 mL), H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10-20% EtOAc/hexane) to give 80.1 mg (86%) of the title compound as a light brown oil. Mass spectrum (ESI, m/z): Calcd. for C25H32N4O3Si, 465.2 (M+H), found 465.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:38]=[CH:37][C:24]([O:25][C@H:26]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[OH-].[Na+:40].C(O)C>C(O)C>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]2[CH:22]=[CH:23][C:24]([O:25][C@H:26]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([O-:29])=[O:28])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1.[Na+:40]
Reactant: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)[O-])cc2)cc1
Yield: 70 %

Procedure:
To a solution of (2R)-2-{4-[5-methyl-1-(4-pentylphenylpropyl)-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoic acid (1.00 g, 2.08 mmol) in ethanol (20 ml) was added 1N sodium hydroxide-ethanol solution (2.04 ml, 2.04 mmol) and the mixture was concentrated. To the residue was added hexane to give the object compound as a solid. 730 mg, (yield 70%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:21])([C@H:15](S(C)(=O)=O)[CH3:16])[CH2:10]S(C)(=O)=O.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]1([CH2:10][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[C@H:15]([CH3:16])[O:21]1
Reactant: c1nc[nH]n1
Reactant: C[C@H]([C@](O)(CS(C)(=O)=O)c1cc(F)ccc1F)S(C)(=O)=O
Product: C[C@@H]1O[C@@]1(Cn1cncn1)c1cc(F)ccc1F
Yield: 56 %

Procedure:
In the same manner as that described in Example 7(iv) above 7.00 g (18.7 mmol) of (2R,3 R)-2-(2,5-difluorophenyl)-1,3-bis(methanesulfonyl)-2-butanol [prepared as described in Step 8(iii) above] were reacted with 1H-1,2,4-triazole and the reaction product was purified by chromatography on a silica gel (100 g) column using a 1:1 to 3:2 mixture of ethyl acetate and hexane as the eluant to afford 2.65 g (yield 56%) of the title compound as an oil.