Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:6]=[C:5]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[C:4]=1[C:29]1[S:30][C:31]2[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.Cl>>[N:9]1([C:7]2[NH:8][C:3](=[O:2])[C:4]([C:29]3[S:30][C:31]4[C:37]([C:38]([F:40])([F:39])[F:41])=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[C:5]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)[N:6]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cccc(C(F)(F)F)c2s1
Agent: Cl
Product: O=c1[nH]c(N2CCOCC2)nc(N[C@@H]2CCCNC2)c1-c1nc2cccc(C(F)(F)F)c2s1

Procedure:
Following the same procedure as in step 4 of Example 337 using tert-butyl (3R)-3-[[6-methoxy-2-(morpholin-4-yl)-5-[7-(trifluoromethyl)-1,3-benzothiazol-2-yl]pyrimidin-4-yl]amino]piperidine-1-carboxylate (40.0 mg, 0.07 mmol, 1.00 equiv) and conce. hydrochloric acid (3.0 mL). The crude product was triturated in methanol and dissolved in 5.0 ml of water. The pH value of the solution was adjusted to 11 with sodium hydroxide (1 M). The solid was collected by filtration and dried in vacuo to afford the title compound. Yield: 16.1 mg (50%). 1H-NMR (400 MHz, DMSO-d6): ppm 1.54-1.57(m, 1H), 1.63-1.73(m, 2H), 1.94(m, 1H), 2.64-2.82(m, 3H), 3.08-3.11(m, 1H), 3.69-3.70(m, 8H), 4.17-4.18(m, 1H), 7.57-7.63(m, 2H), 8.00-8.02(d, J=7.6 Hz, 1H), 10.69-10.71(m, 1H); 19F-NMR (300 MHz, DMSO-d6): ppm −61.57; MS m/z [M+H]+ (ESI): 481. IRAK4 IC50=520 nM
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([NH:23][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH:13]=[CH:12][N:11]=[CH:10]3)=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1Cl
Product: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1NC1CCCCC1
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A mixture of 8 parts of 1-[(4-chloro-3-nitrophenyl)methyl]-1H-imidazole and 42 parts of cyclohexanamine was stirred for 2 hours at reflux temperature. The mixture was evaporated and the residue was stirred in 2,2'-oxybispropane. The precipitated product was filtered off, washed with water and 2,2'-oxybispropane and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in a mixture of 2,2'-oxybispropane and ethyl acetate. The product was filtered off, washed with ethyl acetate and 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 9.5 parts (93.8%) of N-cyclohexyl-4-(1H-imidazol-1-yl-methyl)-2-nitrobenzenamine; mp. 121.1° C. (int. 146).
Reaction SMILES: [N:1]([O-:3])=O.[K+].[CH3:5][O:6][C:7]1[CH:36]=[CH:35][C:10]([CH2:11][N:12]([CH:19]([OH:34])[C@H:20]2[O:26][C@:24]([CH2:27][CH2:28][CH2:29][CH3:30])([OH:25])[C@H:23]([OH:31])[C@@H:22]([OH:32])[C@@H:21]2[OH:33])[C:13](=[O:18])[NH:14][CH2:15][CH2:16][Cl:17])=[CH:9][CH:8]=1>O1CCCC1.Cl>[CH3:5][O:6][C:7]1[CH:36]=[CH:35][C:10]([CH2:11][N:12]([CH:19]([OH:34])[C@H:20]2[O:26][C@:24]([CH2:27][CH2:28][CH2:29][CH3:30])([OH:25])[C@H:23]([OH:31])[C@@H:22]([OH:32])[C@@H:21]2[OH:33])[C:13](=[O:18])[N:14]([CH2:15][CH2:16][Cl:17])[N:1]=[O:3])=[CH:9][CH:8]=1
Reactant: O=N[O-]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(Cc2ccc(OC)cc2)C(=O)NCCCl)[C@@H](O)[C@H](O)[C@H]1O
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC[C@]1(O)O[C@H](C(O)N(Cc2ccc(OC)cc2)C(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
Potassium nitrite (2 g) was added at 0° to 5° C. to a solution of the above synthesized 3-(p-methoxybenzyl)-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (3.85 g, 8.35 mmol) in a mixture of tetrahydrofuran (100 ml) and 10% hydrochloric acid (10 ml). After stirring at the same temperature for 10 minutes, the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, vacuum-concentrated at 25° C., and purified by column chromatography (packing: Kiesel gel 60; eluent: chloroform/methanol 10:1). Thus, 2.35 g of 3-(p-methoxybenzyl)-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea was obtained; yield 57.4%, m.p. 86°-88° C., [α]D20 +61.5° (C 1.0, methanol).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]([C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[OH:18])=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[C:9]([C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:10])[CH3:8]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(Br)cc1C(C)=O

Procedure:
Ethyl bromoacetate (0.62 mL) was added to a mixture of 5-bromo-2-hydroxyacetophenone (1.0 g) and potassium carbonate (0.96 g) in N,N-dimethylformamide (10 mL) at room temperature with stirring, and the mixture was stirred at that temperature overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford ethyl (2-acetyl-4-bromophenoxy)acetate as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:16][C:7]=2[C:6]([C:17]([O:19]C)=O)=[CH:5][CH:4]=1)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3.[Cl:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:29])[C:27]=1[CH3:28].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH4+].[Cl-]>O1CCCC1>[Cl:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:29])[C:27]=1[CH2:28][C:17]([C:6]1[C:7]2[O:16][C:10]3([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:19]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1ccc(OC)c2c1OC1(CCNCC1)O2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OC1(CCNCC1)O2
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A solution of methyl 7-methoxy-spiro[1,3-benzodioxole-2,4′-piperidine]-4-carboxylate (75 mg, 0.268 mol) and 3,5-dichloro-4-picoline (65 mg, 0.40 mmol) in tetrahydrofuran (2.5 mL) was cooled to 0° C. A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.80 mL, 0.80 mmol) was added and the reaction mixture was allowed to reach room temperature overnight. Saturated aqueous NH4Cl (10 mL) was added. The aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. Standard HPLC purification afforded compound 105 (58 mg, 53%). 1H NMR (DMSO) δ 8.66 (s, 2H), 7.38-7.36 (m, 1H), 6.83-6.80 (m, 1H), 4.62 (s, 2H), 3.91 (s, 3H), 3.02-2.91 (m, 4H), 2.12-1.93 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.[H-].[Na+].I[CH3:23]>C1COCC1>[CH3:23][N:6]1[CH2:5][CH2:4][N:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N2CCNC2=O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN([C@@H]2CCCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (50 g, 250 mmol) and Et3N (50.5 g, 500 mmol) in DCM (500 mL) was added 2-chloroethyl isocyanate (31.65 g, 300 mmol) dropwise. The resulting mixture was stirred at RT for 4 hours before being quenched with water (100 mL). The layers were separated and the organic layer was washed with brine, dried, concentrated, and subjected to silica flash column using 0 to 50% EA in to isolate (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364) (63.6 g, 81.5%) as a colorless oil. At 0° C., to a solution of (R)-tert-butyl 3-(3-(2-chloroethyl)ureido)piperidine-1-carboxylate (364, 31.0 g, 102 mmol) in anhydrous THF (350 mL) was added NaH (60% in mineral oil, 4.82 g, 122 mmol) in small portions slowly. The resulting mixture was stirred at RT for 6 hours before being quenched with water (50 mL). The layers were separated and the aqueous was extracted with DCM (20 mL×3). The combined organic layers were washed with brine, dried, concentrated and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (25.4 g, 93%) as a white solid. At 0° C., to a solution of (R)-tert-butyl 3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (365) (16.2 g, 60.2 mmol) in anhydrous THF (160 mL) was added NaH (60%, 3.6 g, 90.3 mmol) in small portions. The resulting mixture was stirred at RT for 30 min, cooled back to 0° C., and then iodomethane (12.9 g, 90.3 mmol) was added dropwise. After the addition, the mixture was stirred at RT for 3 hours. The reaction was quenched with water and extracted with DCM (50 mL×2). The combined organic layers were washed with brined, dried, concentrated, and purified by silica flash column using 0 to 3% MeOH in DCM to get (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (13.0 g, 74%) as a light yellow oil. (R)-tert-butyl 3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (366) (3.5 g, 12.37 mmol) was treated with 40 mL commercial 4N HCl in dioxane at RT for 2 hours. The solvent was removed in vacuo, and the residue was basified to pH 9 with ammonium hydroxide. The solvent was then removed in vacuo, and the residue was subjected to silica flash column using 0 to 10% MeOH in DCM to isolate (R)-1-methyl-3-(piperidin-3-yl)imidazolidin-2-one (367) (1.2 g, 53%) as an oil. LC-MS (ESI): m/z (M+1) 184.2. Proton NMR (CDCl3): δ 3.95-3.83 (2H, m), 3.75 (1H, s), 3.39-3.26 (5H, m), 3.08-2.97 (1H, m), 2.93-2.79 (1H, m), 2.78 (3H, s), 1.94-1.86 (2H, m), 1.82-1.56 (2H, m), 1.48-1.21 (1H, m) ppm.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Cl)=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[C:5]2=[N:4][CH:3]=1.[OH-:20].[K+]>C(O)C>[C:11]([C:10]1[CH:9]=[CH:8][C:7](=[O:20])[N:6]2[C:2]([Br:1])=[CH:3][NH:4][C:5]=12)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)n2c(Br)cnc12
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C(c1ccccc1)c1ccc(=O)n2c(Br)c[nH]c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 4.2 %

Procedure:
40 mg (0.12 mmol) of 3-bromo-5chloroimidazo[1,2-a]pyridin-8-yl)(phenyl)methanone (example L) are dissolved in 5 ml of potassium hydroxide—solution (10% in water) and 5 ml of ethanol. The mixture is stirred for 24 h at rt. The solvent is evaporated under vacuum and water is added to the crude. The solution is extracted for with ethyl acetate. The collected organic phases are reextracted with brine solution and dried over sodium sulfate. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP18-Column, eluent: acetonitrilewater-gradient) to yield 1.6 mg (4.2% of th.) 8-Benzoyl-3-bromoimidazo[1,2-a]pyridin-5(1H)-one.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:24](=[O:25])[C:19]2[N:20]=[C:21]([CH3:23])[S:22][C:18]=2[C:17](=[O:26])[CH:16]=1.[I-].[Na+].[CH3:29][O:30][C:31]1[CH:54]=[CH:53][C:34]([CH2:35][NH:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]2[C:50](=[O:51])[C:45]3[N:46]=[C:47]([CH3:49])[S:48][C:44]=3[C:43](=[O:52])[CH:42]=2)=[CH:33][CH:32]=1>C(#N)C>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][N:36]([CH2:37][CH2:38][CH2:39][NH:40][C:41]2[C:50](=[O:51])[C:45]3[N:46]=[C:47]([CH3:49])[S:48][C:44]=3[C:43](=[O:52])[CH:42]=2)[CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:24](=[O:25])[C:19]3[N:20]=[C:21]([CH3:23])[S:22][C:18]=3[C:17](=[O:26])[CH:16]=2)=[CH:53][CH:54]=1
Reactant: COc1ccc(CNCCCNC2=CC(=O)c3sc(C)nc3C2=O)cc1
Reactant: Cc1nc2c(s1)C(=O)C=C(NCCCBr)C2=O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(CCCNC2=CC(=O)c3sc(C)nc3C2=O)CCCNC2=CC(=O)c3sc(C)nc3C2=O)cc1
Temperature: 165 °C
Reaction time: 0.25 h

Procedure:
22 μl (128 μmol; 2 equivalents) of diisopropylethylamine, 21 mg (64 μmol; 1 equivalent) of 5-[(3-bromopropyl)amino]-2-methyl-1,3-benzothiazole-4,7-dione and a spatula tip's worth of sodium iodide are added to 23.6 mg (64 μmol) of 5-({3-[(4-methoxybenzyl)amino]propyl}amino)-2-methyl-1,3-benzothiazole-4,7-dione dissolved in 5 ml of acetonitrile. The reaction mixture is maintained under stirring under microwaves at 165° C. for 15 minutes, then the solvent is evaporated off under reduced pressure and the reaction residue is taken up in dichloromethane, followed by washing with 3 times 50 ml of water. The organic phases are combined, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. The expected product is purified by chromatography on a silica column (eluent: dichloromethane/methanol: 93/7) and obtained in the form of a red oil.
Reaction SMILES: [OH-].[K+].C(OC([C:8]1[O:9][C:10]2[C:17]([C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])=[CH:16][C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:14]([OH:29])[C:11]=2[C:12]=1[CH3:13])=O)C.Cl>O.CO>[CH3:13][C:12]1[C:11]2[C:14]([OH:29])=[C:15]([C:25]([CH3:27])([CH3:26])[CH3:28])[CH:16]=[C:17]([C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[C:10]=2[O:9][CH:8]=1
Reactant: CCOC(=O)c1oc2c(C(=O)c3cccs3)cc(C(C)(C)C)c(O)c2c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1coc2c(C(=O)c3cccs3)cc(C(C)(C)C)c(O)c12

Procedure:
To a solution of KOH (0.18 g, 3.21 mmol) in 8.0 mL water and 3.0 mL methanol was added ethyl-3-methyl-4-hydroxy-5-tert-butyl-7-(2-thienoyl)-benzofuran-2-carboxylate, compound 13 (0.412 g, 1.07 mmol). The reaction mixture was heated to reflux for 0.5 hours. The resulting solution was cooled in an ice bath and acidified by the dropwise addition of 2N HCl. The acid was collected by filtration, washed with water and pulled dry over night on the filter funnel to give desired product sufficiently pure for further use. mp 145° C. with decarboxylation; 1H NMR (DMSO-d6) d 1.44 (9H, s), 2.76 (3H, s), 7.17 (1H, dd, J=4 Hz), 7.73 (2H, d, J=4 Hz), 7.90 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[OH:8]>CO.[OH-].[OH-].[Pd+2]>[NH2:9][C:6]1[CH:5]=[C:4]([CH:12]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: CCOC(=O)C(CC(C)C)c1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C(CC(C)C)c1cc(N)c(O)c(Br)c1
Reaction time: 5 h
Yield: 72.7 %

Procedure:
To a stirred solution compound ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (6 g), in dry methanol (100 mL) was added Pd(OH)2 under an atmosphere of nitrogen. The reaction mixture was stirred for 5 h under an atmosphere of hydrogen. The reaction mixture was filtered through Celite™, washed with methanol and concentrated to dryness under reduced pressure. The crude material was purified by column chromatography to yield ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate (4 g, 72%). 1HNMR (CDCl3, 200 MHz): 6.80 (s, 1H); 6.62 (s, 1H); 5.35 (bs, 1H); 4.13 (q, 2H); 3.41 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97 (d, 6H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:48][C:49](Br)=[CH:50][CH:51]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:48][C:49]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:28])([F:29])[F:30])[N:12]=3)[CH:10]=2)=[CH:50][CH:51]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), commercially available 5-bromo-thiophene-2-sulfonic acid tert-butylamide (0.295 g, 0.99 mmol), tetrakis(triphenyl-phosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (290 mg, 57%). MS (ISP) 575.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C@@H:12]([NH2:14])[CH3:13])=[CH:6][CH:5]=1.[CH2:17]([O:24][C:25]([NH:27][C@@H:28]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:29](O)=[O:30])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:17]([O:24][C:25](=[O:26])[NH:27][C@H:28]([C:29](=[O:30])[NH:14][C@@H:12]([CH3:13])[CH2:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:9][CH:8]=1)[CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N[C@@H](CC1CCCCC1)C(=O)O)OCc1ccccc1
Reactant: C[C@H](N)CNc1ccc(OC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNc1ccc(OC(F)(F)F)cc1)NC(=O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
(S)—N-(4-trifluoromethoxy-phenyl)-propane-1,2-diamine (76.7 mg, 0.328 mmol), (S)-2-benzyloxycarbonylamino-3-cyclohexyl-propionic acid (100 mg, 0.328 mmol) and HATU (125 mg, 0.328 mmol) were added to a round bottom flask with 20 mL of dry DCM. DIPEA (127 mg, 0.982 mmol) was added dropwise over three minutes with vigorous stirring. The resulting slurry was stirred for 1.5 hours. The solution was then washed with sodium bicarbonate, the organic layer was separated and partially concentrated and the concentrate was purified by flash chromatography. Yield 138 mg, 81%.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=O)[CH2:4][CH:3]=1.C1(C)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)(=O)C([Cl:29])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([Cl:29])=[O:10])[CH2:4][CH:3]=1
Reactant: CC1=CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1=CC[C@H](C(=O)Cl)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-4-methylcyclohex-3-enecarboxylic acid 503 (371 mg, 2.65 mmol), azeotropically dried by evaporation from toluene, was treated with potassium phosphate tribasic (1.13 g, 7.94 mmol), suspended in dichloromethane (7.6 mL) and treated with dimethylformamide (4 drops). The reaction mixture was cooled to 0° C. and treated dropwise with oxalyl chloride (0.75 mL, 7.9 mmol). The reaction mixture was allowed to warm to ambient temperature while stirring for 2 hours. After filtering the solids, the solution was concentrated, treated with hexanes and concentrated again to afford (R)-4-methylcyclohex-3-enecarbonyl chloride 504 as a light yellow oil which was used immediately in the next step.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9]O)[OH:8])[OH:6])[OH:4].O.[NH2:12][NH2:13]>CO>[CH:9](=[N:12][NH2:13])[C@@H:7]([C@H:5]([C@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8]
Reactant: NN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Solvent: O
Solvent: CO
Product: NN=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reaction time: 8 h

Procedure:
A solution of 2.0 g of L-arabinose in 5 ml of methanol and 5 ml of hydrazine hydrate was stirred overnight and then evaporated in vacuo. A 5 ml portion of methanol was added to the residue. After standing overnight the oil solidified. The solid was collected and dried, giving 1.5 g of L-arabinose hydrazone.
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:14]CC)=[C:11]([CH3:13])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1[CH2:23][CH:22]=[CH:21][CH2:20][O:19][CH2:18]1>>[CH2:1]([C:8]1[C:22]2[CH2:23][O:17][CH2:18][O:19][CH2:20][C:21]=2[C:10]([OH:14])=[C:11]([CH3:13])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1oc(Cc2ccccc2)nc1C
Reactant: C1=CCOCOC1
Product: Cc1nc(Cc2ccccc2)c2c(c1O)COCOC2
Temperature: 180 °C

Procedure:
A mixture of 8.4 g (40 millimoles) of 2-benzyl-4-methyl-5-ethoxyoxazole and 20 g (200 millimoles) of 4,7-dihydro-1,3-dioxepine is heated for 4 hours at 180° C. in an autoclave. Unconverted 4,7-dihydro-1,3-dioxepine is distilled off under reduced pressure. The residue is taken up in methylene chloride and extracted with 10% strength sodium hydroxide solution. On neutralizing the alkaline solution, 5.2 g of 6-benzyl-8-methyl-1,5-dihydro-[1,3]dioxepino[5,6-c]pyridin-9-ol precipitate and these are extracted with methylene chloride.
Reaction SMILES: S(OCCC1OC=CC=1C(OC)=O)(C)(=O)=O.C1(CCCCCCN)C=CC=CC=1.[C:30]1([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]2[C:46](=[O:47])[C:45]3=C[CH:49]=[CH:50][CH:51]=[C:44]3[C:43]2=[O:52])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.NN.[OH-].[Na+].C(N(CC)C(C)C)(C)C>C(O)C.C(#N)C.O>[C:30]1([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:42]2[CH2:49][CH2:50][C:51]3[O:47][CH:46]=[CH:45][C:44]=3[C:43]2=[O:52])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCc1ccccc1
Agent: COC(=O)c1ccoc1CCOS(C)(=O)=O
Agent: NCCCCCCc1ccccc1
Agent: NN
Solvent: CCO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccoc2CCN1CCCCCCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of the above crude methyl 2-(2-mesyloxyethyl)furan-3-carboxylate, crude 6-phenylhexylamine [prepared by refluxing a solution of 1.79 g (5.81 mmol) of N-(6-phenylhexyl)phthalimide and 0.28 ml (5.8 mmol) of hydrazine monohydrate in 20 ml of ethanol for 1 hour, cooling the reaction mixture to room temperature, then pouring it into aqueous sodium hydroxide, extracting with ethyl acetate 3 times, drying the combined organic layer over anhydrous magnesium sulfate, and distilling off the solvent] and 2.02 ml (11.6 mmol) of N,N-diisopropylethylamine in 50 ml of acetonitrile was refluxed for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield the desired product.