Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([Li])C=CC=CC=1.[CH:8]([S:11]([N:14]1[C:18]2[CH:19]=[C:20](I)[CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH2:24])(=[O:13])=[O:12])([CH3:10])[CH3:9].C([Li])(C)(C)C.CN(C)[CH:32]=[O:33]>O1CCCC1>[CH:8]([S:11]([N:14]1[C:18]2[CH:19]=[C:20]([CH:32]=[O:33])[CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH2:24])(=[O:13])=[O:12])([CH3:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(I)cc21
Agent: [Li]C(C)(C)C
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C=O)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
Add phenyllithium (750 mL, 1.8 M in cyclohexane/ether, 70/30) over 1 hour to a solution of 1-isopropylsulfonyl-2-amino-6-iodobenzimidazole (150 g, 0.41 mol) in tetra-hydrofuran (5.6 L) at −76° C. Stir for 15 minutes and then add tert-butyllithium (750 ml, 1.7 M in pentane). After 1 hour add dimethylformamide (250 mL) slowly over one hour and then warm to 0° C. Quench by pouring the reaction mixture into a mixture of cold saturated aqueous ammonium chloride (500 g, 5 L) and concentrated hydrochloric acid (300 mL). Separate the layers, wash the organic phase with water and then concentrate under reduced pressure. Slurry the residue in methanol (500 mL), filter the yellow precipitate, and dry to provide 85 g (76%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24](O)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:28][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]([CH3:26])([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH3:25])[N:9]=2)=[CH:4][CH2:3]1
Reactant: C1COCCN1
Reactant: CC1(C)CC=C(c2nc(C(C)(C)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC=C(c2nc(C(C)(C)N3CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-amide (as prepared in Example 56, step (e)), morpholine, and thionyl chloride in DCM solvent according to the procedure in Example 14, step (e).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22]N=CC=4NN=3)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-]>CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:11]=[N:10][N:9]4[CH:8]=[CH:6][CH:22]=[N:23][C:24]=34)=[O:15])=[CH:11][N:10]([CH2:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:35])[N:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1n[nH]c2cncnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1-c1nn(CC(=O)OC(C)(C)C)cc1NC(=O)c1cnn2cccnc12
Temperature: 30 °C
Reaction time: 8 h
Yield: 141.9 %

Procedure:
N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo pyrimidine-3-carboxamide (2.0 g, 5.4 mmol), t-butyl-bromoacetate (0.88 mL, 6.0 mmol), and cesium carbonate (2.1 g, 6.5 mmol) were combined and stirred at 30° C. overnight. The mixture was warmed to 65° C. at which time additional carbonate and t-butylbromoacetate was added and stirred 8 hrs. The mixture was cooled to ambient temperature and stirred overnight, then partitioned EtOAc/water. The organic phase was separated, washed with brine, dried (Na2SO4), filtered through silica gel, and concentrated to a solid. The solid was washed with 1:1 EtOAc/hexanes to yield 1.85 g (71%) of tert-butyl 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)acetate as yellow crystals. LCMS (ESI) m+H=483.0. 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 8.77 (m, 1H), 8.73 (s, 1H), 8.51 (m, 1H0, 8.38 (s, 1H), 8.02 (s, 1H), 7.58 (s, 1H), 7.31 (m, 1H), 6.97 (m, 2H), 4.85 (s, 2H), 3.83 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C:35]2[N:36]=[N:37][NH:38][N:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:37]4[N:38]=[N:39][C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[N:36]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: c1ccc(-c2nn[nH]n2)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4nnc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 5-phenyl-2H-tetrazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([S:22][CH3:23])=[N:10]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([S:22]([CH3:23])=[O:32])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(SC)nn2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(C)=O)nn2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)-3-(methylthio)-1H-1,2,4-triazole (150 mg, 0.458 mmol) and m-chloroperbenzoic acid (119 mg, 0.687 mmol) in dichloromethane (1.5 mL) was stirred for 3 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane-2% methanol in dichloromethane) to give 1,5-bis(4-methoxyphenyl)-3-(methylsulfinyl)-1H-1,2,4-triazole (152 mg, 96.6% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]([C:17]#[N:18])([CH3:16])[CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:28][OH:29]>C(O)C>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]([C:17](=[NH:18])[NH:28][OH:29])([CH3:16])[CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C#N)(CC1CC1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(CC1CC1)(NC(=O)OCc1ccccc1)C(=N)NO
Temperature: 60 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
To a solution of (1-Cyano-2-cyclopropyl-1-methyl-ethyl)-carbamic acid benzyl ester (Example 66b, 795 mg, 3.08 mmol) in ethanol (10 ml) were added triethylamine (343 mg, 472 μl, 3.39 mmol) and hydroxylamine hydrochloride (214 mg, 3.08 mmol). The reaction mixture was stirred at 60° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (640 mg, 71%) as a white solid. MS (ESI, m/z): 292.5 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH2:28]([NH2:31])[C:29]#[CH:30].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:28]([NH:31][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1)[C:29]#[CH:30]
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C#Cc3ccccn3)n[nH]c2c1
Reactant: C#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of 2-(3-Pyridin-2-ylethynyl-1H-indazol-6-ylamino)-benzoic acid (41 mg, 0.117 mmol), propargylamine (24 μL, 0.35 mmol), triethylamine (81 μl, 0.58 mmol), dissolved in DMF (0.5 mL), was treated with HATU (89 mg, 0.233 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 27 mg (59%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.78 (1H, s), 8.99 (1H, m), 8.61 (1H, d, J=2.1), 7.88 (1H, s), 7.72 (3H, m), 7.43 (4H, m), 7.29 (1H, s), 7.04 (1H, d, J=7.3), 6.91 (1H, t, J=5.2), 4.04 (2H, s), 3.04 (1H, s). ESIMS (M+H+): 392.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23]([O:25]C)=O.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:29]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Yield: 40 %

Procedure:
A solution of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (237.5 mg, 0.68 mM) in 10 mL THF and 40 mL concentrated aqueous ammonium hydroxide was sonicated for 20 h at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 89.7 mg (40%) of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.5-6.9 (m, 7H), 6.65 (m, 2H), and 5.75 (s, 2H). IR (KBr, cm1) 3395, 3192 (br), 1621, 1599, 1580, 1564, 1491, 1455, 1334, 1261, and 774. MS (ES) m/e 333, 335.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[S:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[C:3]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[S:24][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=c1c2ccccc2[nH]c(=S)n1Cc1ncc(C(F)(F)F)cc1Cl
Product: O=c1c2ccccc2nc(SCc2ccc(Cl)cc2)n1Cc1ncc(C(F)(F)F)cc1Cl

Procedure:
This compound was prepared from the product of Example 10 and 4-chlorobenzylbromide in analogous fashion to Example 8, m.p. 137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].C(O)C.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:37]([NH:36][C:34](=[O:35])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])=[S:38])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 90%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([S:22][C@H:23]1[N:26]([CH:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])Cl)[C:25](=[O:42])[C@@H:24]1[C@H:43]([O:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:47])[CH3:44])=[O:21])([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.[CH:59]1[CH:64]=[CH:63][C:62]([P:65]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:61][CH:60]=1>C1COCC1>[Si:1]([O:18][CH2:19][C:20]([S:22][C@H:23]1[N:26]([C:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])=[P:65]([C:66]2[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=2)([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:62]2[CH:61]=[CH:60][CH:59]=[CH:64][CH:63]=2)[C:25](=[O:42])[C@@H:24]1[C@H:43]([O:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:47])[CH3:44])=[O:21])([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
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
A solution in THF of 4(R)-t-butyldiphenylsilyoxyacetylthio-3(S)-[1(R)-p-nitrobenzyloxycarbonyloxyethyl]-1-(1-p-nitrobenzyloxycarbonyl-1-chloromethyl)-azetidin-2-one, obtained from the previous example, was treated with Ph3P (2.2 g, 8.5 mmole) and silica gel (20 g).
Reaction SMILES: Cl.[OH:2][NH:3][C:4]([C@H:6]1[C:11]([CH3:13])([CH3:12])[S:10][CH2:9][CH2:8][N:7]1[S:14]([C:17]1[CH:37]=[CH:36][C:20]([O:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5]>ClCCl.CO>[NH2:28][CH2:27][CH2:26][CH2:25][C:24]#[C:23][CH2:22][O:21][C:20]1[CH:36]=[CH:37][C:17]([S:14]([N:7]2[CH2:8][CH2:9][S:10][C:11]([CH3:12])([CH3:13])[C@@H:6]2[C:4]([NH:3][OH:2])=[O:5])(=[O:15])=[O:16])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)NO)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(OCC#CCCCN)cc2)[C@H]1C(=O)NO
Reaction time: 1 h
Yield: 108.5 %

Procedure:
Hydrogen chloride gas was bubbled into a solution of 0.104 g (0.192 mmol) of tert-butyl 6-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}sulfonyl)-phenoxy]-4-hexynylcarbamate in 6 mL of dichloromethane and 2 mL of methanol for 5 min, and the reaction was stoppered and let stand for 1 h and then concentrated in vacuo. The residue was triturated with ether to provide 0.092 g (100%) of (3S)-4-({4-[(6-amino-2-hexynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3-thiomorpholine carboxamide as a cream solid. Electrospray Mass Spec: 442.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]([C:21]2([C:24](=[O:33])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:23][CH2:22]2)=[O:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](C(N)=O)[CH:6]=1.O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.[N:56]1C=CC=CC=1>CN(C)C=O>[NH2:56][C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([NH:18][C:19]([C:21]3([C:24]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:33])[CH2:23][CH2:22]3)=[O:20])=[CH:17][C:2]=2[F:1])[CH:10]=[CH:9][N:8]=1
Reactant: c1ccncc1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reaction time: 8 h
Yield: 64 %

Procedure:
4-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide (4.81 g) was dissolved in N,N-dimethylformamide (50 ml) under a nitrogen atmosphere, and water (0.5 ml), [bis(trifluoroacetoxy)iodo]benzene (5.17 g) and pyridine (2.57 ml) were added in this order at room temperature, followed by stirring overnight. Water (0.5 ml), [bis(trifluoroacetoxy)iodo]benzene (5.17 g) and pyridine (2.57 ml) were added in this order at room temperature, followed by further stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate (200 ml) and water (100 ml). The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure and the residue was dried under reduced pressure to provide the titled compound as pale brown foam (2.878 g, 64%).
Reaction SMILES: [C:1]1([Si:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]1=[O:34]>N1C=CC=CC=1>[C:1]1([Si:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]2=[O:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1ccn(CCCCCO)c(=O)[nH]1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=c1ccn(CCCCCO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1

Procedure:
A solution of triphenylsilyl chloride (81 mg; 0.27 mmol) in pyridine (1 ml) was added to a solution of alcohol (25) (50 mg; 0.25 mmol) in dry Pyridine (1 ml) under atmosphere of nitrogen, at room temperature.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[CH2:29]([O:36][C:37]([N:39]([CH2:41][C:42]1[CH:43]=[C:44]([NH:48][C:49]([O:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57](Br)=[CH:56][C:55]=2[CH3:61])=[O:50])[CH:45]=[CH:46][CH:47]=1)[CH3:40])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]([N:39]([CH2:41][C:42]1[CH:43]=[C:44]([NH:48][C:49]([O:51][CH2:52][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([B:25]([OH:27])[OH:26])=[CH:56][C:55]=2[CH3:61])=[O:50])[CH:45]=[CH:46][CH:47]=1)[CH3:40])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc(Br)ccc1CCOC(=O)Nc1cccc(CN(C)C(=O)OCc2ccccc2)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: Cc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc(CN(C)C(=O)OCc2ccccc2)c1
Yield: 28 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 60C (2.9 g, 5.6 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 60D (720 mg, 28%) as a solid. MS (ESI) m/z 475.3 (M−H)−.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:7]=2N)=[N:2]1.N(OCCCC)=O.[CH3:21][S:22]C>[Cu](Cl)Cl>[CH3:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:7]([S:22][CH3:21])[C:6]=1[C:3]1[CH2:4][CH2:5][O:1][N:2]=1
Reactant: Cc1cccc(N)c1C1=NOCC1
Reactant: CSC
Agent: Cl[Cu]Cl
Agent: CCCCON=O
Product: CSc1cccc(C)c1C1=NOCC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
25 g (0.14 mol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline and 0.2 g of copper(II) chloride are initially charged in 200 ml of dimethyl sulfide, and 16.1 g of n-butyl nitrite (0.15 mol) are added dropwise at 55-62° C. The mixture is then stirred at 60° C. for 0.5 hours. For work-up, the mixture is then washed with dilute hydrochloric acid and water and then concentrated under reduced pressure. This gives 26.3 g (91%) of a dark oil which solidifies after a while (content according to HPLC 96%). The product can be purified further by trituration with methyl tert-butyl ether.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CCCCCC.[Li]CCCC.[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:27]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Brc1cccnc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccccc1)(c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A solution of 3-bromopyridine (10 g, 0.063 mol) in dry THF (200 mL)/hexane (50 mL) was cooled to −90° C. To this cooled solution was added n-BuLi (2.2 M, 32 mL, 0.063 mol) slowly and allowed to stir for 30 min under N2 atmosphere. A solution of benzophenone (11.5 g, 0.063 mol) in dry THF (50 mL) was added to this at the same temperature over a period of 30 min. The reaction mixture was warmed slowly to RT and allowed to stir another 3 h at RT. The reaction mixture was cooled, quenched with water (200 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was dried, concentrated under vacuum and the crude product was purified by column chromatography on silica gel (30% ethyl acetate in pet. ether) which gave the title compound (3.3 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][C:4](=[CH:8][CH3:9])[C:5]([OH:7])=O.CN1CCOCC1.C(Cl)(=O)C(Cl)=O.[CH3:24][NH:25][C:26](=[O:38])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[NH2:28]>ClCCl>[CH3:24][NH:25][C:26](=[O:38])[C@H:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[NH:28][C:5](=[O:7])[C:4]([CH2:3][CH:2]([CH3:1])[CH3:10])=[CH:8][CH3:9]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CC=C(CC(C)C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC=C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Temperature: 25 °C
Yield: 99.5 %

Procedure:
2-(2-methylpropyl)-but-2-enoic acid (37 g, 0.261M) prepared as described in Example 1 in dry dichloromethane (200 ml) and N-methyl morpholine (65 ml) was treated at -5° C. with oxalyl chloride (33.2 g, 0.261M) over 30 minutes. The mixture was heated under reflux for 10 minutes, then re-cooled to ca -60° C. and O-methyl-L-tyrosine N-methylamide (51 g, 0.245M) in dry dichloromethane (100 ml) added over 30 minutes. The mixture was left to warm up to room temperature over ca 1 hour, diluted with more dichloromethane then washed with aqueous sodium hydroxide (0.1N), aqueous saturated sodium hydrogen carbonate solution and saturated brine. The organic extract was dried, then evaporated in vacuo to afford N-[2-(2-methylpropyl)-but-2-enoyl]-O-methyl-L-tyrosine-N-methylamide as a yellow gum (81 g).