Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12][CH3:13])[CH2:6][CH2:5]1.Br[C:38]1[CH:43]=[C:42]([CH3:44])[N+:41]([O-:45])=[C:40]([CH3:46])[CH:39]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[CH:43]=[C:42]([CH3:44])[N+:41]([O-:45])=[C:40]([CH3:46])[CH:39]=3)=[CH:18][CH:19]=2)[CH2:12][CH3:13])[CH2:6][CH2:5]1
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Product: CC[C@@H](c1ccc(-c2cc(C)[n+]([O-])c(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.185 min, m/z=489.2; 1H NMR (CDCl3) 0.96 (t, 3H), 1.03 (s, 3H), 1.12 (s, 3H), 1.81-2.00 (m, 4H), 2.11-2.22 (m, 5H), 2.30-2.42 (m, 1H), 2.57 (s, 6H), 2.87 (m, 1H), 5.43 (m, 1H), 7.09 (d, 2H), 7.18 (m, 1H), 7.22 (m, 4H), 7.26 (m, 2H), 7.31 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[N:12]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[Cl:1][C:2]1[N:7]=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[N:12]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccc(F)n2)OC1(C)C
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2nc(Cl)ncc2Cl)n1
Temperature: 80 °C
Yield: 72.3 %

Procedure:
A mixture of 2,4,5-trichloropyrimidine (49.3 mg, 0.269 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (50 mg, 0.224 mmol), PdCl2(dppf).CH2Cl2 adduct (18.31 mg, 0.022 mmol), DME (0.7 ml), and 2M sodium carbonate (0.247 ml, 0.493 mmol) reaction mixture was stirred at about 80° C. until the reaction mixture was complete, as indicated by LCMS. The reaction mixture was cooled, diluted with 5 ml of ethyl acetate and 1 ml of methanol, filtered and concentrated to yield a crude solid. The crude material was purified by silica gel chromatography using a 12 g column, eluting from 0%-40% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, to yield 39.5 mg of titled compound as a free base. LCMS (m/z): 244.0 (MH+), retention time=0.89 min.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:6]([NH:8][O:9]C1CCCCO1)=[O:7])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([NH:4][CH:5]([CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:18])=[O:19])[C:6]([NH:8][OH:9])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(=O)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a solution of the title compound of Example 15a (400 mg, 0.84 mmol) in methanol (40 mg), was added p-toluenesulfonic acid, monohydrate (40 mg, 0.21 mmol). After stirring at room temperature for 2 hours, the solution was concentrated. Purification by flash chromatography (4:96 MeOH/CHCl3) yielded the title compound as a white solid (140 mg, 42%): Anal. Calcd. for C17H18N2O5S2.0.8H2O: C, 49.94; H, 4.83; N, 6.85; S, 15.68. Found: C, 50.23; H, 4.62; N, 6.80; S, 15.29.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=3[CH3:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].C([O:43][P:44]([CH2:49]OS(C(F)(F)F)(=O)=O)([O:46]CC)=[O:45])C>CN(C)C(=O)C>[C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][CH2:49][P:44](=[O:43])([OH:46])[OH:45])=[CH:26][C:25]=3[CH3:31])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)(=[NH:9])[NH2:7]
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(N)cc2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2ccc(NCP(=O)(O)O)cc2C)c1
Temperature: 50 °C
Yield: 128.1 %

Procedure:
To a mixture of {[4-(4′-amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (30 mg, 58.0 μmol), as prepared according to the procedure of step b of Example 120, cesium carbonate (19 mg, 58 μmol), and N,N-dimethylacetamide (0.4 mL) was added a solution of trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 μmol) (Xu, Y. et al, J. Org. Chem. 61, 7697 (1996); Phimon, D. et al, Tetrahedron Lett. 27, 1477 (1986)), and heated at 50° C. for 48 h. Additional trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 μmol) was added. The mixture was heated at 50° C. for additional 24 h. Solvent was evaporated. The resulting mixture was partitioned between DCM and H2O. Aqueous layer was separated and extracted with DCM. All the DCM layers were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel column, eluting with EtOAc/DCM (20 and 30%) to give the title compound (38 mg, 98% yield) as an orange oil. 1H NMR (CDCl3): δ 8.23 (s, 1H), 7.92–7.88 (m, 2H), 7.53–7.46 (m, 2H), 6.98 (d, 1H, J=8.0 Hz), 6.56–6.53 (m, 2H), 4.23–4.15 (m, 4H), 3.56 (d, 2H, J=12.5 Hz), 2.43 (s, 3H), 2.16 (s, 3H), 1.52 (s, 9H), 1.35 (t, 6H, J=7.0 Hz). ESI-MS (m/z): Cald. For C29H39N3O7PS3: 668.2 (M+H); found: 667.8.
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][C:22]([OH:24])=[O:23])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].S(=O)(=O)(O)O>O>[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][C:22]([OH:24])=[O:23])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CC(C)C(N)C(=O)O
Agent: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)[C@H](N)C(=O)O
Temperature: 50 °C

Procedure:
A 11.7 g portion of DL-valine, 13.4 g of N-carbobenzoxy-L-aspartic acid and 2.5 g of sulfuric acid were added to 50 ml of water and the resulting solution was heated to 50° C. This solution was cooled to 20° C. at a rate of 2° C. per hour while stirring, and was stirred for another two hours. The resulting crystal was separated, washed with 20 ml of water and dried to give 9.7 g of an L-valine/N-carbobenzoxy-L-aspartic acid salt. Analysis showed that the optical purity of the L-valine was 98%.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]([C:16]([OH:18])=[O:17])[N:4]=1.Cl[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[C:5]([C:16]([O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[N:4]=1
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 0.08 h

Procedure:
0.4 g of a 55% suspension of sodium hydride in mineral oil are added to a suspension of 2.1 g of β-carbolin-3-carboxylic acid in 25 ml of dimethyl formamide, and after a period of 5 minutes, 1.2 ml of ethyl chloracetate are added. The mixture is refluxed for 4 hours and subsequently dimethyl formamide is evaporated in vacuo. After addition of 100 ml of water to the remainder, the mixture is extracted with chloroform to form 1 g of carbethoxymethyl β-carbolin-3-carboxylate having a melting point of 202°-203° C.
Reaction SMILES: [I-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]([CH3:5])[CH3:4].C([Li])CCC.[C:30]([O:34][CH2:35][C@H:36]([CH3:40])[CH2:37][CH:38]=O)([CH3:33])([CH3:32])[CH3:31].[NH4+].[Cl-].C([C@H](O[C@@H](C(C)(C)C)C(C)CC=CC(C)C)C(C)CC=CC(C)C)(C)(C)C>CCCCCC.C1C=CC=CC=1.O1CCCC1>[CH3:40][C@H:36]([CH2:37][CH:38]=[CH:2][CH:3]([CH3:5])[CH3:4])[CH2:35][O:34][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H](CC=O)COC(C)(C)C
Agent: CC(C)C=CCC(C)[C@@H](O[C@H](C(C)CC=CC(C)C)C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [I-]
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C=CC[C@@H](C)COC(C)(C)C
Reaction time: 0.17 h

Procedure:
A slurry of 2.67 g. (6 mmoles) of isobutyl triphenylphosphonium iodide in 50 ml. of dry tetrahydrofuran was stirred at 0° C. while a solution of 2.94 ml. (6 mmoles) of 2.04 M n-butyllithium in hexane was added dropwise. The resulting mixture was stirred for 10 minutes and then treated with a solution of 0.475 g. (3 mmoles) of (R)-4-tert. butoxy-3-methylbutanal in 25 ml. of dry tetrahydrofuran. After the addition was complete, the reaction mixture was stirred for one hour at room temperature then treated with saturated aqueous NH4Cl and worked up with hexane in the usual manner. The crude product (0.792 g.) was chromatographed on 25 g. of silica gel. Elution with 9:1 parts by volume hexane-ether followed by evaporative distillation gave 0.418 g. (70.4%) of (R)-(+)-tert. butyl-2,6-dimethyl-4-heptenyl ether as a colorless liquid, b.p. 75°-80° C. (bath temperature) (10 mm Hg.); [α]D25 +11.44° (c 0.61, C6H6).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[S:11](Cl)(=[O:14])(=[O:13])[NH2:12]>CC(N(C)C)=O>[C:4]([C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:12])(=[O:14])=[O:13])#[N:5]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1cc(F)ccc1N
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(F)ccc1NS(N)(=O)=O

Procedure:
A solution of 2-amino-5-fluorobenzonitrile (136 mg, 1 mmol) and sulfamoyl chloride (114 mg, 1 mmol) in DMA (2 mL) was stirred at room temperature for 2 hours. The reaction was purified by Varian HPLC (10% Acetonitrile/Water) to give N-(2-Cyano-4-fluorophenyl)sulfamide as a pale-white solid. 1H NMR (400 MHz, DMSO-d6) 7.18 (m, 2H), 7.56-7.60 (dd J=8.8 Hz, 2.8 Hz 2H), 9.44 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]2[C@@H:6]([C@:7]([C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]4[C:26]([CH2:27][O:28]C)=[CH:25][C:24]([Cl:30])=[CH:23][N:22]=4)[CH:15]=[CH:16][C:17]=3[F:18])([CH:9]([F:11])[F:10])[N:8]=1)[CH2:5]2.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[O:3][C@H:4]2[C@@H:6]([C@:7]([C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]4[C:26]([CH2:27][OH:28])=[CH:25][C:24]([Cl:30])=[CH:23][N:22]=4)[CH:15]=[CH:16][C:17]=3[F:18])([CH:9]([F:11])[F:10])[N:8]=1)[CH2:5]2
Reactant: COCc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@@]2(C(F)F)N=C(N)O[C@@H]3C[C@@H]32)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC1=N[C@@](c2cc(NC(=O)c3ncc(Cl)cc3CO)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A solution of N-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-3-(methoxymethyl) picolinamide (Example 42, 140 mg, 0.308 mmol) in DCM was cooled to 0° C. Boron tribromide (0.062 mL, 0.646 mmol) was added dropwise and the reaction mixture was allowed to warm to rt. After 3 hs, the reaction was quenched by the addition of water. The aq. phase was neutralized by the addition of aq. sat bicarbonate solution and extracted with EtOAc. The organic phase was over MgSO4. The filtrate material was absorbed onto a plug of silica gel and purified by chromatography eluting with a gradient of 15% to 100% EtOAc in hexane, to provide the title compound (62 mg, 0.141 mmol, 45.7% yield) as a whit solid. MS m/z=441 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: COc1ccnc(Cl)n1
Reactant: OB(O)c1ccc(Cl)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: Cc1ccccc1
Product: COc1ccnc(-c2ccc(Cl)cc2)n1
Temperature: 115 °C
Yield: 20.7 %

Procedure:
2-Chloro-4-methoxypyrimidine (509 mg, 3.52 mmol), 4-chlorophenylboronic acid (826 mg, 5.28 mmol), and sodium carbonate (3732 μl, 7.04 mmol) in toluene (17 ml) were sparged with argon for 2 minutes in a glass vial. Pd(PPh3)4 (203 mg, 0.176 mmol) was added and the reaction mixture was sparged an additional 1 minute. The vial was capped and the reaction heated to 115° C. for 19 hours. The reaction was cooled to ambient temperature and diluted with ethyl acetate. The organic layer was washed with water and brine, dried with sodium sulfate, filtered, concentrated and purified on silica gel. Elution with a 2-20% ethyl acetate/hexanes gradient provided the title compound (161 mg, 0.730 mmol, 20.7% yield) as a white foam.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:18])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[I-].[Na+].C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH2:37][CH2:38]Br)=[O:36])=[CH:31][CH:30]=1>CN(C)C=O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH2:37][CH2:38][N:2]([CH2:3][CH:4]([OH:18])[CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]3)[CH3:1])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(CCBr)c1ccc(F)cc1
Reactant: CNCC(O)COc1ccc2[nH]c(=O)ccc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCS(=O)c1ccc(F)cc1)CC(O)COc1ccc2[nH]c(=O)ccc2c1
Reaction time: 5 h
Yield: 13.8 %

Procedure:
A suspension (50 ml) of 6-(3-methylamino-2-hydroxypropoxy)carbostyril (3.0 g), sodium iodide (11.8 g), triethylamine (2.2 ml) and 2-(4-fluorophenylsulfinyl)ethyl bromide (3.9 g) in dimethylformamide is heated with stirring at 80°-90° C. for 5 hours. After concentration under reduced pressure, the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:methanol:ammonium hydroxide=200:10:1-150:10:1) and recrystallized from dichloromethane-diethylether to give 6-[3-{N-[2-(4-fluorophenylsulfinyl)ethyl]-N-methylamino}-2-hydroxypropoxy]carbostyril (0.7 g), as white powder, m.p. 126°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[C:19]([O:23][C:24](=[O:27])[CH2:25][O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=1[Cl:11])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2,6-dichloro-4-nitrophenol (2.5 g) and potassium carbonate (3.3 g) in dimethyl-formamide (50 mL) is added tert-butyl-bromoacetate (10 mL) and the mixture is stirred at room temperature for two days. The solution is then poured into 500 mL water, extracted three times with hexanes, and the pooled organic extracts are washed with saturated aqueous ammonium chloride and then dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure followed by trituration of the resulting oil with hexanes provides the desired product as a white solid.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:21][CH:22]=2)=[CH:13][CH:12]=1>>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(C)cc2)CC1
Reactant: ON=C1CCCCCC1
Product: Cc1ccc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C(#N)C>[CH3:32][C@H:27]1[CH2:28][C:29]([CH3:31])=[CH:30][C@@H:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:57])[CH2:6][C@H:7]([OH:56])[C@@H:8]([CH3:55])[C@@H:9](/[C:43](/[CH3:54])=[CH:44]/[C@H:45]2[CH2:46][C@@H:47]([O:52][CH3:53])[C@H:48]([OH:51])[CH2:49][CH2:50]2)[O:10][C:11](=[O:42])[C@H:12]2[N:17]([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:18](=[O:41])[C:19](=[O:40])[C@:20]2([OH:39])[O:35][C@@H:24]([C@@H:23]([O:36][CH3:37])[CH2:22][C@H:21]2[CH3:38])[C@@H:25]([O:33][CH3:34])[CH2:26]1
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reaction time: 1.5 h

Procedure:
17-Allyl-1,14-di-hydroxy-12-[2-(4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-vinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (FK506; 8.04 mg, 0.01 mmol) was dissolved in acetonitrile (CH3CN; 100 μl), a solution of phosgene (COCl2) in toluene (1.24 mmol/ml; 8 μl, 0.01 mmol) was added at room temperature, and this was followed by stirring for 1.5 hours. After the reaction solution was concentrated under reduced pressure, TOYO-Pearl resin (TSKgel AF-amino, 100 μl, free amino group (available amino group) 0.01 mmol; manufactured by Tosoh Corporation) and acetonitrile (CH3CN; 500 μl) were added, and this was followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the resin was washed with DMF two times and with water two times, a saturated aqueous solution of sodium hydrogen carbonate (1 ml) was added, and this was followed by stirring for 1 minute. After the resin was washed with water two times and with DMF two times, acetic anhydride (100 μl) and DMF (400 μl) were added, and this was followed by stirring at room temperature for 5 minutes. Subsequently, the resin was washed with DMF three times and with 20% aqueous ethanol two times, and the TOYO Pearl resin with FK506 obtained was used in the binding experiment described below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)[CH:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[N+:27]([O-])=O)=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].S(=O)(=O)(O)O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:10])[NH:11][C:12]3[C:13]([N:27]=2)=[CH:14][C:15]([CH:18]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(c1ccc(NC(=O)Cc2cccc(F)c2)c([N+](=O)[O-])c1)n1ccnc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(C)C(c1ccc2[nH]c(=O)c(-c3cccc(F)c3)nc2c1)n1ccnc1
Yield: 67.6 %

Procedure:
A solution of 14.5 parts of 3-fluoro-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrophenyl]benzeneacetamide in 49 parts of pyridine and 10 parts of a potassium hydroxide solution 20% was stirred for 1 hour at 85° C. The reaction mixture was poured into crushed ice and neutralized with a sulfuric acid solution 2N. After evaporation, the residue was purified by column chromatography over silica gel using a mixture of dichloromethane, methanol and ammonium hydroxide (95:5:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of dichloromethane and 2,2'-oxybispropane. The product was filtered off and dried, yielding 4.3 parts (67.6%) of 3-(3-fluorophenyl)-6-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2(1H)-quinoxalinone, N4 -oxide; mp. 212.9° C. (comp. 166).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[C:16]([O:35][CH3:36])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO[C:39]1C=CC(C)=C[C:40]=1S(Cl)(=O)=O>>[CH2:39]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[C:16]([O:35][CH3:36])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:40]
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCc2c(OC)cc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CC3)cc1F

Procedure:
2-Fluoro-4-{[4-methoxy-1-(2-methoxy-5-methyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 515.37 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 5 was performed using 2-methoxy-5-methyl-benzenesulfonyl chloride and yielded 2-fluoro-4-{[4-methoxy-1-(2-methoxy-5-methyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: COc1ccccc1Br
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1

Procedure:
This compound is prepared by method C using compound 12d and 2-bromoanisole.