Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:20][S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:6][C:7](=[O:19])[C:8]([NH:11][C:12]([O:14]C(C)(C)C)=O)([CH3:10])[CH3:9])[CH3:2].[OH-].[Na+].Cl>CCO>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:20][S:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH:6][C:7](=[O:19])[C:8]([NH:11][C:12](=[O:14])[C@@H:22]([SH:21])[CH:23]([CH3:28])[CH3:24])([CH3:9])[CH3:10])[CH3:2]
Reactant: CCOC(=O)[C@H](CSCc1ccccc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@H](CSCc1ccccc1)NC(=O)C(C)(C)NC(=O)[C@@H](S)C(C)C

Procedure:
Under an argon atmosphere, the thioacetyl compound of Example 2 (0.48 g, 1.0 mmol) is dissolved in absolute EtOH (5 mL) and treated with 1 N NaOH of (1.0 mL, 1.0 mmol). The mixture is stirred for 4 hours at room temperature before treatment with 1 N HCl until pH 3. The mixture is evaporated to remove most of the EtOH and the aqueous residue is extracted with EtOAc (2×10 mL). The combined extracts are washed with H2O (5 mL) and then with brine solution (5 mL). The solution is dried over Na2SO4, filtered and concentrated in vacuo. The product solidifies from tert-butyl methyl ether/hexane to give product; m.p. 87–91° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=[O:4].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:35])[C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][OH:33])[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1.O[C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[N:42]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=C(Cl)C=C(C(OO)=O)C=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH3:35])[C:19](=[O:34])[C:20]3[CH:30]=[C:29]([CH2:31][CH2:32][O:33][C:37]4[CH:46]=[CH:45][CH:44]=[C:43]5[C:38]=4[CH:39]=[CH:40][CH:41]=[N+:42]5[O-:4])[CH:28]=[N:27][C:21]=3[N:22]([CH2:25][CH3:26])[C:23]=2[N:24]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Oc1cccc2ncccc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3cccc4c3ccc[n+]4[O-])cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
Diethyl azodicarboxylate (DEAD) (160 μL, 1.01 mmol) was added drop-wise to a solution of 2-chloro-5,11-dihydro-11-ethyl-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (225 mg, 0.68 mmol), 5-hydroxyquinoline (147 mg, 1.01 mmol) and Ph3P (266 mg, 1.01 mmol) in THF (3.4 mL) at room temperature. The mixture was stirred at room temperature for 3 h then was concentrated under reduced pressure. The residue was partially purified by flash chromatography (EtOAc:MeOH; 95:5). The fractions containing the 5-quinolinyloxy derivative were concentrated, dissolved in CH2Cl2 (2 mL) and THF (5 mL) and treated with mCPBA (80%, 248 mg, 1.15 mmol) at room temperature. The solution was stirred at room temperature for 2.5 h, then was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), washed successively with aqueous 10% Na2S2O3 (3×10 mL), aqueous saturated NaHCO3 (3×10 mL) and brine (10 mL), then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:MeOH, 95:5 to CH2Cl2:MeOH, 9:1) to give the title compound (113 mg, 35% yield for 2 steps) as a white solid: MS (ESI) m/z 476/478 (MH)+.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][O:27]C4CCCCO4)=[O:25])=[CH:18][CH:17]=3)[CH2:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:36]>CO>[ClH:36].[ClH:36].[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][OH:27])=[O:25])=[CH:18][CH:17]=3)[CH2:11]2)=[CH:34][CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN2CC[C@@H](Nc3ccc(/C=C/C(=O)NOC4CCCCO4)cn3)C2)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1ccc(CN2CC[C@@H](Nc3ccc(/C=C/C(=O)NO)cn3)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of (2E)-3-(6-{[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (270 mg) was suspended in methanol (1 mL) and to this suspension was added hydrogen chloride in methanol solution (10%, 3 mL). The mixture was stirred at ambient temperature for 15 minutes and concentrated in vacuo. The residual solid was triturated with acetonitrile to give (2E)-3-(6-{[(3R)-1-(4-tert-butylbenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide dihydrochloride (228 mg) as a pale tan solid.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]1([C:9]2[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH:34]=4)=[CH:26][CH:25]=3)[N:8]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Reactant: ClCc1cncc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cncc(-c4ccccc4)c3)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 81.4 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (840 mg), 3-chloromethyl-5-phenylpyridine (550 mg), potassium carbonate (500 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-phenyl-1-[4-(5-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1010 mg, yield: 81%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:31]([N:38]1[CH:46]=[C:45]2[C:40]([CH:41]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:43]=[CH:44]2)=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]2=[C:8]([C:42]3[CH:43]=[CH:44][C:45]4[C:40]([CH:41]=3)=[N:39][N:38]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:46]=4)[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(Br)c4c(N)ncnn34)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cc2)CC1
Temperature: 80 °C
Yield: 50.3 %

Procedure:
To a stirred solution of tert-butyl 4-[4-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)phenyl]piperazine-1-carboxylate (4 mg, 1.25 mmol), 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (1.04 g, 1.87 mmol), and tetrakis(triphenylphosphine)palladium(0) (144 mg, 0.13 mmol) in degassed DME (5.5 mL) was added aqueous Na2CO3 solution (2 M, 1.87 mL). The reaction was heated at 80° C. for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and H2O (25 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude material was purified by ISCO® chromatography using a gradient of 25 to 75% ethyl acetate in hexanes to afford 378 mg (58%) of the desired product, which contained trace impurities. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1 H), 7.88 (s, 1 H), 7.78 (d, 1 H), 7.57 (s, 1 H), 7.36-7.31 (m, 5 H), 7.13 (d, 1 H), 6.61 (s, 1 H), 5.64 (s, 2 H), 4.13-3.98 (m, 2 H), 3.35-3.25 (m, 1 H), 2.05-1.96 (m, 2 H), 1.63-1.50 (m, 2 H), 1.41 (s, 9 H); ES-MS m/z 524.2 [M+H]+, HPLC RT (min) 3.08.
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[C:11]([OH:13])=O.Cl.[CH3:22]OCN.C(Cl)CCl.C1C=C[C:33]2[N:38]([OH:39])N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[C:11]([N:38]([O:39][CH3:22])[CH3:33])=[O:13]
Reactant: COCN
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C(=O)O
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H]1Cc2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
Boc-D-Tic-OH (14.9 g, 53.7 mmol), methoxymethylamine hydrochloride (5.24 g, 53.7 mmol), EDC (11.3 g, 59.1 mmol), HOBT (7.98 g, 59.1 mmol), DIEA (9.83 ml, 59.1 mmol) and THF (500 ml) were combined, and the resulting mixture was stirred for about 18 hours at r.t. under nitrogen. The reaction mixture was concentrated and the residue was taken up in ethyl acetate. The resulting mixture was washed with 1M HCl, saturated NaHCO3 and brine, which was then dried via filtration through phase separator paper. Removal of solvent gives a residue, which was chromatographed on silica gel using (1:1 ethylacetate/hexane) to give about 12.3 g of Boc-D-Tic-NMeOMe (Weinreb amide).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Sc1ccccc1
Reactant: CC1(C)OC(=O)Nc2c(OCCCCCl)cccc21
Product: CC1(C)OC(=O)Nc2c(OCCCCSc3ccccc3)cccc21

Procedure:
Prepared analogously to Example 1 from 8-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and thiophenol.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Mg]Cl)C.C(O[CH:15]1[NH:18][C:17](=[O:19])[CH2:16]1)(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH:15]1[NH:18][C:17](=[O:19])[CH2:16]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)OC1CC(=O)N1
Agent: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#CC1CC(=O)N1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of trimethylsilylacetylene (1715 ml) in tetrahydrofuran (18.0 l) was added ethyl magnesium chloride (2.0M solution in tetrahydrofuran; 6.19 l) was added dropwise below −30° C. under nitrogen atmosphere. The reaction mixture was allowed to 0° C. and stirred for 1 hour. After cooling to −30° C., 4-acetoxy-2-azetidinone (320 g) was added and warmed to room temperature, and stirred for 2 hours. After cooling to −20° C., saturated ammonium chloride (4.0 l) was added. Ethyl acetate (20 l) was added and washed with water (10 l×2) and brine. The organic layer was dried over magnesium sulfate, filtered off and evaporated in vacuo to give 4-(2-trimethylsilylethynyl)-2-azetidinone (425 g), which was essentially pure, so it was used to the next step without further purification.
Reaction SMILES: Br[C:2]1[C:15]2[C@:14]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].[C:33]([Zn]C#N)#[N:34].CN(C=O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:20][C:17]1[O:18][CH2:19][C@@:14]2([N:16]=1)[C:15]1[C:2]([C:33]#[N:34])=[C:3]([O:27][CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH:4]=[CH:5][C:6]=1[O:7][C:8]1[C:13]2=[CH:12][C:11]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:10][CH:9]=1
Reactant: N#C[Zn]C#N
Reactant: CC(C)(C)COc1ccc2c(c1Br)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COc1ccc2c(c1C#N)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2

Procedure:
A vial was charged with (S)-1′-bromo-2′-(neopentyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (68.1 mg, 0.138 mmol), dicyanozinc (81 mg, 0.689 mmol), tetrakis(triphenylphosphine)palladium(0) (31.8 mg, 0.028 mmol), and DMF (689 μL). The vial was sealed and placed in a 120° C. oil bath for 12 hours. The mixture was diluted with water and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 25-g SNAP column, eluting with a 90:10:1 mix of DCM/MeOH/NH4OH in DCM. This gave ca. 40 mg of a white powder that was impure by HPLC. The solid was combined with 104487-6-2 in DMSO/MeOH and purified by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined in saturated aq. sodium bicarbonate solution with the aid of methanol and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-2-amino-2′-(neopentyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-1′-carbonitrile as an off-white powder after evaporation from DCM/hexane.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[S:47](Cl)(=[O:49])=[O:48]>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:47]([C:41]3[CH:42]=[CH:43][C:44]([Cl:46])=[CH:45][C:40]=3[Cl:39])(=[O:49])=[O:48])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 2,4-Dichlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 133 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (120 mg, 65%) as a sticky off-white solid. MS cald. for C24H23Cl2FNO4S [(M+H)+]: 510, obsd. 510.2.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[C:22]([Cl:24])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[C:9]([O:25][C:20]2[CH:19]=[C:18]([Cl:17])[CH:23]=[C:22]([Cl:24])[CH:21]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2]
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1cccc(Oc2cc(Cl)cc(Cl)c2)c1[N+](=O)[O-]

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.), 3,5-dichlorophenol (7.4 g.), anhydrous potassium carbonate (8.5 g.) and cupric oxide (1 g.) was treated in a similar manner to the above to give oil of the captioned compound (7.6 g.).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][CH2:36][CH2:37][CH2:38][OH:39]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCCCO
Product: CON=C1C[C@@H](C(=O)NCCCO)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and 3-amino-1-propanol, the title compound was obtained in 64% purity by HPLC. MS(ESI+): m/z=432.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.S1C=CC=C1C1C=C(C2N=C(CCC(OC)=O)OC=2)C=C(C(F)(F)F)C=1>>[S:23]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]([C:12]3[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)=[CH:24]1
Reactant: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Reactant: OB(O)c1ccsc1
Agent: COC(=O)CCc1nc(-c2cc(-c3cccs3)cc(C(F)(F)F)c2)co1
Product: COC(=O)CCc1nc(-c2cc(-c3ccsc3)cc(C(F)(F)F)c2)co1
Yield: 81 %

Procedure:
The title compound was prepared from methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 44) and thiophene-3-boronic acid by a procedure similar to the one described for methyl 3-(4-(3-(thiophen-2-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 47) to provide methyl 3-(4-(3-(thiophen-3-yl)-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (0.371 g, 81%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][CH2:38][NH2:39]>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:5]1[CH:6]=[N:7][C:2]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:40])[CH3:33])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1ccnc(N2CCOCC2)c1
Reactant: CN(C)CCCCN
Product: CN(C)CCCCNc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2Cl)cn1
Yield: 61 %

Procedure:
Using an analogous procedure to that described in Example 21, 6-chloro-N-[2-chloro-5-(2morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-3-carboxamide was reacted with 4-dimethylaminobutylamine to give the title compound in 61% yield; NMR Spectrum: (DMSOd6) 1.49 (m, 4H), 2.09 (s, 6H), 2.19 (t, 2H), 3.51 (m, 4H), 3.71 (m, 4H), 6.49 (d, 1H), 7.1 (d, 1H), 7.23 (m, 2H), 7.5 (d, 1H), 7.68 (d, 1H), 7.89 (d, 1H), 8.06 (s, 1H), 8.64 (s, 1H), 9.64 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M+H+ 552 and 554.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][C:21](=[CH:23][C:24]#[N:25])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1.N12CCCN=C1CCCCC2>C(#N)C>[Si:1]([O:18][CH:19]1[CH2:22][C:21]([CH2:23][C:24]#[N:25])([N:26]2[CH:30]=[C:29]([C:31]3[C:32]4[CH:39]=[CH:38][N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:33]=4[N:34]=[CH:35][N:36]=3)[CH:28]=[N:27]2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)[Si](OC1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a solution of (3-{[tert-butyl(diphenyl)silyl]oxy}cyclobutylidene)acetonitrile (1.859 g, 4.065 mmol) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.28 g, 4.06 mmol) in acetonitrile (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.61 mL, 4.1 mmol). The reaction was stirred overnight. The solvent was remove in vacuo. The crude was purified with silica gel column to give of the product (2.7 g, 79%) as an oil. LCMS (M+H)+: 663.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([S:18](CCC(OC)=O)(=[O:20])=[O:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CO.C[O-].[Na+:31]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([S:18]([O-:20])=[O:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[Na+:31]
Reactant: COC(=O)CCS(=O)(=O)c1cnc2cc(-c3ccc(F)cc3)ccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=S([O-])c1cnc2cc(-c3ccc(F)cc3)ccc2c1
Reaction time: 1 h
Yield: 60.1 %

Procedure:
Methyl 3-{[7-(4-fluorophenyl)quinolin-3-yl]sulfonyl}propanoate (4.23 g, 11.3 mmol) was dissolved/suspended in hot tetrahydrofuran (240 mL). Methanol (60 mL) was added and the mixture allowed to cool to about 30° C., at which point sodium methoxide (0.91 g, 17 mmol) was added and the resulting mixture stirred for 1 hour. The solid present was collected under suction, washed with tetrahydrofuran and dried in vacuo to afford a first crop of sodium 7-(4-fluorophenyl)quinoline-3-sulfinate (2.1 g). The filtrate was concentrated and the residue triturated with tetrahydrofuran. The solid was collected under suction, washed successively with small volumes of tetrahydrofuran, ice-cold water then tetrahydrofuran, and dried in vacuo to give a second crop of product (0.87 g). The combined yield of the title product was 2.97 g (85%). 1H NMR (500 MHz, CD3OD) δ 9.13 (1H, d, J 1.9 Hz), 8.52 (1H, d, J 1.6 Hz), 8.24 (1H, s), 8.11 (1H, d, J 8.5 Hz), 7.94 (1H, dd, J 1.7, 8.5 Hz), 7.84-7.82 (2H, m), 7.26 (2H, t, J 8.7 Hz).