Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)=[O:20])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)=[O:20])=[O:8]
Reactant: CC(C)NNC(=O)c1ccsc1
Reactant: O=C(O)COc1ccc(F)cc1Br
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccsc1)C(=O)COc1ccc(F)cc1Br
Yield: 66.4 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (226 mg, 0.91 mmol) and thiophene-3-carboxylic acid N′-isopropyl-hydrazide (200 mg, 1.09 mmol) in DMF (5 ml) was treated with diisopropylethyl amine (0.40 mL, 2.28 mmol) and PyBroP (636 mg, 1.37 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (251 mg, 66%).
Reaction SMILES: [Na+].[CH3:2][O:3][N:4]=[C:5]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([O-:26])=[O:25])=[C:13]([CH:16]=[CH:17][C:18]3[S:22][CH:21]=[N:20][C:19]=3[CH3:23])[CH2:14][S:15][C@H:10]12)=[O:7].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(OCC)(=O)C>CN(C)C=O>[C:35]([O:41][CH2:42][O:25][C:24]([C:12]1[N:11]2[C:27](=[O:28])[CH:9]([NH:8][C:6](=[O:7])[C:5](=[N:4][O:3][CH3:2])[C:29]3[N:30]=[C:31]([NH2:34])[S:32][CH:33]=3)[C@H:10]2[S:15][CH2:14][C:13]=1[CH:16]=[CH:17][C:18]1[S:22][CH:21]=[N:20][C:19]=1[CH3:23])=[O:26])(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=Cc3scnc3C)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(C=Cc3scnc3C)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C

Procedure:
7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid sodium salt (syn-isomer, trans-isomer) (0.03 g, 0.06 mmol) was dissolved in dimethylformamide (3 ml). To the resultant solution was added a solution in dimethylformamide (1 ml) of iodomethyl pivalate (as prepared by reacting chloromethyl pivalate (0.090 g, 0.60 mmol) with sodium iodide (0.090 g, 0.06 mmol) in acetone) under ice-cooling, followed by stirring the resultant mixture for 10 minutes. The reaction solution as obtained were admixed with ice-water (20 ml) and ethyl acetate (20 ml), stirred thoroughly and then allowed to stand until the mixture separated into aqueous phase and organic phase. The organic phase was separated from the aqueous phase and washed twice with water (10 ml) and then with aqueous saturated NaCl solution (10 ml). The organic phase as washed was subsequently dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified chromatographically on a column of silica-gel (Wako-gel C-300) (5 g) as developed with ethyl acetate. The titled compound was thus obtained (yield 0.025 g, 67%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]([CH2:15][O:16][C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=3)=[C:13]([CH3:17])[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C#N)cn1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 7.9 g, 181 mmol, 1.5 eq.) in THF (65 mL) was added within 30 minutes at room temperature a solution of [3-(4-Fluorophenyl)-5-methyl-isoxazol-4-yl]-methanol (25.0 g, 121 mmol) and 6-chloronicotinonitrile (16.7 g, 121 mmol) in THF (120 mL) and the resulting mixture was stirred for one hour. A solution of citric acid (18.5 g, 96.5 mmol) in water (185 mL) was added to the reaction mixture within 30 minutes. From the resulting THF/water mixture THF was distilled off under reduced pressure at a jacket temperature of 60° C. and replaced by ethanol. In total 284 g of ethanol were added. The resulting suspension was stirred for one hour at room temperature. The crystals were filtered off, washed with a mixture of ethanol (60 mL) and water (60 mL) and subsequently dried at 50° C./<25 mbar to afford 36.5 g (91% corrected yield) of the title nitrile as an off-white solid with an assay of 93% (w/w).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[CH2:32]([OH:35])[C:33]#[CH:34].C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:3][C:2]=2[C:34]#[C:33][CH2:32][OH:35])[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: C#CCO
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2C#CCO)CC1
Temperature: 120 °C
Yield: 44.2 %

Procedure:
2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (117 mg, 0.21 mmol, Example 69), propargyl alcohol (25 μL, 0.42 mmol, Sigma-Aldrich, St. Louis, Mo.), diethylamine (44 μL, 0.42 mmol, Sigma-Aldrich, St. Louis, Mo.), bis(triphenylphosphine) palladium(II) dichloride (15 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), triphenylphosphine (11 mg, 0.04 mmol, Sigma-Aldrich, St. Louis, Mo.), and copper iodide (4 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.) were combined in DMF (1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min. The reaction was diluted with CH2Cl2 (10 mL) and water (10 mL). The organic extracts were separated, washed with water (10 mL), dried (Na2SO4), filtered, and concentrated. Purification via column chromatography (12 g silica gel, 0 to 1% MeOH in CH2Cl2) afforded 3-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-propyn-1-ol (49 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.09 (br s, 1H), 7.45-7.75 (m, 3H), 7.33 (br s, 1H), 7.09 (d, J=7.63 Hz, 1H), 5.29 (br s, 1H), 4.27 (br s, 2H), 3.24-3.36 (m, 4H), 3.07-3.17 (m, 4H); m/z (ESI, +ve ion) 529.1 (M+H)+. GK-GKRP IC50 (Binding)=0.712 μM. GK-GKRP EC50 (LC MS/MS-2)=0.557 μM.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:31][CH2:32][CH2:33][CH3:34])=[C:15]([C:17]2[NH:18][C:19](=[O:30])[C:20]3[N:25]([CH3:26])[N:24]=[C:23]([CH2:27][CH2:28][CH3:29])[C:21]=3[N:22]=2)[CH:16]=1)=[O:10]>>[CH3:26][N:25]1[C:20]2[C:19](=[O:30])[NH:18][C:17]([C:15]3[CH:16]=[C:11]([C:9](=[O:10])[CH2:8][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:12]=[CH:13][C:14]=3[O:31][CH2:32][CH2:33][CH3:34])=[N:22][C:21]=2[C:23]([CH2:27][CH2:28][CH3:29])=[N:24]1
Reactant: C1COCCN1
Reactant: CCCOc1ccc(C(=O)CBr)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Product: CCCOc1ccc(C(=O)CN2CCOCC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 47 %

Procedure:
This compound was prepared from morpholine and 5-(5-bromoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Preparation 11), following the procedure of Example 1, and was obtained as white crystals (47%), m.p. 128°-129° C. Found: C,63.62; H,7.07; N,15.53. C24H31N5O4 requires C,63.56; H,6.89; N,15.44%.
Reaction SMILES: Br[C:2]1[C:3]([NH2:22])=[N:4][CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[CH:34]=[CH:35][CH:36]=2)O1>>[NH2:22][C:3]1[C:2]([C:35]2[CH:34]=[C:33]([NH:37][C:38](=[O:41])[CH2:39][CH3:40])[CH:32]=[CH:31][CH:36]=2)=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[N:6]=[CH:5][N:4]=1
Reactant: CCC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Nc1ncnc(Oc2ccc(Oc3ccccc3)cc2)c1Br
Product: CCC(=O)Nc1cccc(-c2c(N)ncnc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 82 %

Procedure:
N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)propionamide was prepared from 5-bromo-6-(4-phenoxyphenoxy)pyrimidin-4-amine and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionamide using Method C (82% yield). HPLC: 99%, RT=4.286 min. MS: m/z=427 [M+H]+, RT=4.25 min. 1H-NMR (DMSO-d6) δ 9.93 (s, 1H), 8.10 (s, 1H), 7.64-7.63 (m, 2H), 7.38 (t, 3H), 7.12 (t, 1H), 7.08-7.05 (m, 3H), 6.99 (d, 4H), 6.60 (broad s, 2H), 2.32 (q, 2H), 1.07 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2].[F:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1>>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:43]3[CH:42]=[CH:41][N:40]=[C:39]([F:38])[CH:44]=3)[CH:25]=[C:24]([C:43]3[CH:42]=[CH:41][N:40]=[C:39]([F:38])[CH:44]=3)[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2]
Reactant: OB(O)c1ccnc(F)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(Br)c2)c1CCC(=O)OCC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccnc(F)c3)cc(-c3ccnc(F)c3)c2)c1CCC(=O)OCC
Yield: 66.7 %

Procedure:
A similar procedure as described in Example 1, step 2 was used, starting from 4-{3-[6-(3,5-dibromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (321 mg, 0.5 mmol) and 2-fluoro-pyridin-4-ylboronic acid (422 mg, 3.0 mmol) to isolate 4-[3-{6-[3,5-bis-(2-fluoro-pyridin-4-yl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (225 mg, 67%) as a colorless oil: ES(+)-HRMS m/e calculated for C39H44F2N2O6 (M+H)+ 675.3240, found 675.3238.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[CH2:6][C:7](=O)[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH3:2].O.[NH2:17][NH2:18]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[NH:18][N:17]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1nccs1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2nccs2)[nH]n1
Yield: 33.2 %

Procedure:
A mixture of 2,4-diketo-4-(thiazol-2-yl)butyric acid ethyl ester (9.88 g), hydrazine hydrate (1.74 g), and ethanol (25 ml) was refluxed for one hour, concentrated and the residue chromatographed (silica gel, EtOAc/Hex 1/2) to afford 2.58 g of 5-(thiazol-2-yl)pyrazole-3-carboxylic acid ethyl ester. NMR: 1.42 (t, 3H), 4.44 (q, 2H), 7.37 (s, 1H, 4-pyrazolyl H), 7.40, 7.75 (2d, 2H, thiazolyl H's).
Reaction SMILES: [Br:1][C:2]1(O)[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[S:28]([C:31]2[CH:39]=[CH:38][C:37]3[N:36]4[CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][N:43]=[C:35]4[C:34]4(OCCC[O:46]4)[C:33]=3[CH:32]=2)(=[O:30])=[O:29])(=O)=O)=CC=1.CN(C=O)C>C1COCC1>[Br:1][C:2]1[C:7]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[S:28]([C:31]2[CH:39]=[CH:38][C:37]3[N:36]4[CH2:40][C:41]([CH3:44])([CH3:45])[CH2:42][N:43]=[C:35]4[C:34](=[O:46])[C:33]=3[CH:32]=2)(=[O:29])=[O:30])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C2(OCCCO2)C2=NCC(C)(C)CN23)cc1
Reactant: OC1(Br)C=CC=CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)CN=C2C(=O)c3cc(S(=O)(=O)N4CCC[C@H]4COc4cccnc4Br)ccc3N2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 2-bromo pyridinol (0.089 g, 0.510 mmol) in THF (3 mL) was added NaH (60% dispersion in mineral oil) (0.020 g, 0.085 mmol) and the reaction was stirred at rt for 1 hr. {(2S)-1-[(3′,3′-Dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)sulfonyl]pyrrolidin-2-yl}methyl 4-methylbenzenesulfonate (0.100 g, 0.170 mmol) in THF (2 mL)/DMF (2 mL) was added and the reaction was heated overnight at 100° C. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (30/70). The resulting product was dissolved in CH2Cl2 (3 mL) and methanesulfonic acid (2 mL) was added and the solution stirred at 35° C. overnight. The reaction mixture was poured onto ice, basified to pH 11 with ammonium hydroxide and extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, concentrated and purified on Biotage Si 12+M cartridge silica gel eluting with acetone/hexane (30/70) to give the title compound as a yellow foam (0.058 g, 56%). NMR (400 Mz, DMSO-d6): consistent. MS: (ESI+) m/z 533.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.C([N-]C(C)C)(C)C.[Li+].[CH:28](=[O:30])[CH3:29].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH:28]([OH:30])[CH3:29])[CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)C1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
In a round bottom flask, 2-chloro-9-cyclopentyl-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (0.840 g, 3.0 mmol) was dissolved in dry tetrahydrofuran (12 mL), cooled to −78° C., then added 2.0 M lithium diisopropyl amide in tetrahydrofuran (6.0 mmol) drop wise. After 30 minutes, acetaldehyde (1.056 g, 24.0 mmol) in 6.0 mL tetrahydrofuran was added slowly drop wise to it, continued stirring for 60 minutes. After disappearing the starting material, cooled the reaction flask to −78° C., then quenched with sat. ammonium chloride solution (3 mL). At room temperature, the resultant reaction mixture was taken into ethyl acetate (50 mL), washed with 0.1 N HCl, ammonium chloride solution and finally with water, dried over sodium sulphate and evaporated. Purified the product using column chromatography with hexane:ethyl acetate mixtures to give the product (0.842 g, 86%). [M+H] calculated for C15H21ClN4O2, 325. found 325.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12]Br)[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:34][OH:35])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH2:12][O:35][CH2:34][C:21]1([C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=2)[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.2 g, 3.78 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.96 g, 3.2 mmol) were combined in dimethylformamide (10 mL) and cooled to 0° C. The reaction was treated with sodium hydride (151 mg, 6.3 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.1 g (61%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.35 (s, 1H), 7.30-7.31 (m, 2H), 7.26 (s, 1H), 7.03-7.07 (m, 2H), 4.36 (s, 2H), 3.72-3.75 (m, 2H), 3.38 (s, 2H), 3.01-3.06 (m, 2H), 2.13-2.16 (m, 2H), 1.81-1.87 (m, 2H), 1.43 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 161.6 (d, J=245.7 Hz), 152.0, 141.9, 138.3, 133.3, 132.4 (q, J=32.6 Hz), 128.8, 127.5 123.2 (q, J=273.5 Hz), 122.8, 122.4, 115.5, 115.3, 79.7, 79.5, 71.7, 68.0, 41.4, 32.2, 28.5, 25.7. Mass spec.: 548.16 (MH)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1([CH2:37][OH:38])[CH2:36][O:35][CH2:34]1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3([CH2:37][OH:38])[CH2:36][O:35][CH2:34]3)=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC2(CO)COC2)c1OCC1CC1
Temperature: 70 °C
Yield: 19.1 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL), was added potassium carbonate (102 mg, 0.745 mmol) and (3-bromomethyl-oxetan-3-yl)-methanol (134 mg, 0.745 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 19.2%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.[F:19]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O.C([O-])(O)=O.[Na+]>O1CCCC1.O>[F:19][CH:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)[C:12]#[N:13]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: N#CCc1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(F)c1ccc2ncccc2c1
Yield: 44.4 %

Procedure:
A solution of quinolin-6-yl-acetonitrile (1.06 g, 6.3 mmol) in tetrahydrofuran (40 mL) was cooled to −78° C. to which tert-butyl lithium (0.8 M in pentane, 7.6 mmol, 7.9 mL) was added in a dropwise fashion over 10 minutes. After the addition was complete the mixture was stirred at −78° C. for 30 min before a solution of N-fluorodi(benzenesulfonyl)-amine (1.5 eq., 9.45 mmol, 3.0 g) in tetrahydrofuran (10 mL) was added. The reaction mixture was stirred for 2 hours at −78° C. before water was added followed by aqueous NaHCO3. The mixture was extracted with dichloromethane (3×80 mL), dried (Na2SO4) and concentrated in vacuo onto silica gel and purified via flash column chromatography (SiO2, hexane:ethyl acetate 100/0-50/50) to return the title compound as a red solid (520 mg, 2.8 mmol, 44%). 1H NMR 500 MHz (DMSO-d6) δ 6.05 (1H, d), 7.66 (1H, dd), 7.95 (1H, dd), 8.19 (1H, d), 8.32 (1H, t), 8.55 (1H, d), 9.03 (1H, dd); MS (m/z) 187 [M+H+]+.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][N:11]([CH3:15])[C:12](Cl)=[O:13]>>[CH3:10][N:11]([CH3:15])[C:12](=[O:13])[O:1][NH:2][C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)ONC(=O)OC(C)(C)C

Procedure:
[(tert-Butoxy)carbonyl]amino N,N-dimethylcarbamate is prepared from tert-butyl N-hydroxycarbamate and dimethyl carbamoyl chloride according to Scheme 1. (2.4 g, 78%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.82 (1H, br. s.), 3.02 (3H, s), 2.98 (3H, s), 1.49 (9H, s)
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+]>CO.O>[C:13]1([C:12]#[C:11][C:9]2[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=2)[C:4]([OH:19])=[O:3])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cncc(C#Cc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.3 %

Procedure:
To a solution of 5-phenylethynyl-nicotinic acid ethyl ester (1.17 g, 4.64 mmol) in methanol (10 mL) was added 5 N aqueous sodium hydroxide (2 mL, 10 mmol). The mixture was stirred at room temperature for approximately 20 h, before the reaction mixture was diluted with water (3 mL) and extracted with hexanes/EtOAc (95/5) (10 mL). The aqueous solution was acidified with 1 N HCl to pH 4. The white precipitate that formed was collected by filtration, washed with water (2 mL), and dried under vacuum to provide the title compound as a white solid (987 mg, yield 95%). 1H NMR (300 MHz, d6-DMSO) δ 9.02 (d, J=1.8 Hz, 1H), 8.94 (d, J=2.4 Hz, 1H), 8.34 (dd, J=1.8, 2.4 Hz, 1H), 7.63-7.60 (m, 2H), 7.48-7.44 (m, 3H); ESI-MS m/z 223.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]([O:13]C)=O)[CH2:7][C:6]=2[CH:15]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>C(Cl)Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:13])[CH2:7][C:6]=2[CH:15]=1
Reactant: COC(=O)C1COc2ccc(Cl)cc2C1
Reactant: C=CCN
Solvent: CCO
Solvent: ClCCl
Product: C=CCNC(=O)C1COc2ccc(Cl)cc2C1

Procedure:
A mixture of 500 mg of 6C, 5 ml of 2-propenamine and 25 ml of ethanol was refluxed for 18 hours. The sovlent was then stripped off and the residue was taken up in methylene chloride, triturated with hexane and cooled to give a solid. The solid was redissolved in ethanol, the solution was passed through a short silica gel column and the eluent was stripped of solvent. The residue was recrystallized from methylene chloride/hexane to give 6, as white needles, mp: 171°-171.5° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[O:27])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C1Cc2cccc(Sc3ccc(Cl)cc3)c2N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C1Cc2cccc(S(=O)c3ccc(Cl)cc3)c2N1
Yield: 52 %

Procedure:
A solution of 2-oxo-7-(4-chlorophenylthio)indoline (7.0 g) in chloroform (400 ml) and m-chloroperbenzoic acid (5.15 g) were treated in a similar manner to that of Preparation 28-(2) to give 2-oxo-7-(4-chlorophenylsulfinyl)indoline (3.85 g). mp 191°-194° C.