Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][S:8](=[O:31])(=[O:30])[NH:9][CH2:10][CH2:11][O:12][NH:13][C:14]([C@@H:16]1[CH2:22][CH2:21][C@@H:20]2[CH2:23][N:17]1[C:18](=[O:29])[N:19]2[O:24][S:25]([OH:28])(=[O:27])=[O:26])=[O:15])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:29]=[C:18]1[N:17]2[CH2:23][C@@H:20]([CH2:21][CH2:22][C@H:16]2[C:14]([NH:13][O:12][CH2:11][CH2:10][NH:9][S:8](=[O:30])(=[O:31])[NH2:7])=[O:15])[N:19]1[O:24][S:25]([OH:28])(=[O:26])=[O:27]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl({2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}sulfamoyl)carbamate 81 (0.20 g, 0.40 mmol) in DCM (5.0 mL) was added trifluoroacetic acid (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 h and at room temperature for 2 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16]O)=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:20]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][Br:20])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)cc(C)c1CBr
Yield: 247.5 %

Procedure:
Cool a solution of (4-Benzyloxy-2,6-dimethyl-phenyl)-methanol (5.70 g, 24 mmol) in THF (100 mL) to 0° C. Treat the solution with Phosphorous tribromide (0.9 mL, 9.4 mmol) and stir the reaction for 2 hr at 0° C. Quench the reaction with water and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 7.1 g (99%) of product. 1H NMR (d6-CDCl3) δ 7.31-7.43 (m, 5H), 6.65 (s, 2H), 5.01 (s, 2H), 4.56 (s, 2H), 2.38 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([NH:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][C:20]([S:27]([NH:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([O:40]C6C=CC(C)=CC=6)(=[O:39])=[O:38])[CH:32]=5)(=[O:29])=[O:28])=[CH:21][C:22]=4[OH:26])[CH:17]=3)=[O:14])=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:48]([OH:51])(=[O:50])=[O:49])[CH:3]=1.[Na+].[Na+].S(C1C=C(NS(C2C=C3C(C=CC(NC(NC4C=C5C(C=CC(S([O-])(=O)=O)=C5)=CC=4)=O)=C3)=CC=2)(=O)=O)C=CC=1)(O)(=O)=O.S(C1C=C(NS(C2C=C3C(C=CC(NC(NC4C=C5C(C=CC(S([O-])(=O)=O)=C5)=CC=4)=O)=C3)=CC=2)(=O)=O)C=CC=1)(O)(=O)=O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([NH:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][C:20]([S:27]([NH:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([OH:40])(=[O:38])=[O:39])[CH:32]=5)(=[O:29])=[O:28])=[CH:21][C:22]=4[OH:26])[CH:17]=3)=[O:14])=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:48]([OH:51])(=[O:50])=[O:49])[CH:3]=1
Reactant: Cc1ccc(OS(=O)(=O)c2cccc(NS(=O)(=O)c3cc(O)c4ccc(NC(=O)Nc5ccc6c(O)cc(S(=O)(=O)O)cc6c5)cc4c3)c2)cc1
Agent: O=C(Nc1ccc2ccc(S(=O)(=O)[O-])cc2c1)Nc1ccc2ccc(S(=O)(=O)Nc3cccc(S(=O)(=O)O)c3)cc2c1
Agent: [Na+]
Product: O=C(Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1)Nc1ccc2c(O)cc(S(=O)(=O)Nc3cccc(S(=O)(=O)O)c3)cc2c1

Procedure:
This compound was prepared from compound 10 according to the procedure described for the synthesis of compound 12.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Yield: 93.2 %

Procedure:
In a similar manner as described in step 1 of Example 3, the title compound was prepared from 6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol (0.250 g, 0.564 mmol), prepared in step 2 of Example 8, methyl bromoacetate (0.103 g, 0.676 mmol) and cesium carbonate (0.920 g, 2.82 mmol). Purification on a Biotage FlashElute™ system with a KP-Sil Flash 40+M column (90 g Silica Gel, 60 Å) using 50% methylene chloride in hexane as the eluent gave methyl [(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetate as an off-white solid (0.271 g, 93%), mp 90–91° C. Elemental Analysis for C31H24F3NO3.0.09 C6H14 Calc'd: C, 72.39; H, 4.87; N, 2.68. Found: C, 72.26; H, 4.68; N, 2.28.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].[Mg]>C1COCC1>[C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:9][C:4]([C:1]([OH:3])([CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Reactant: C=CCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCC(C)(O)c1ccc(-c2ccccc2)cc1

Procedure:
4-Acetylbiphenyl (2 g) was dissolved in anhydrous THF (30 ml) and reacted with a grignard prepared from 5-bromopentene and magnesium in THF (15 ml) as described in example 23 to give the title compound as a yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O.CCOC(C)=O>CN(C=O)C>[N:18]([CH2:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1)=[N+:19]=[N-:20]
Reactant: C=C(C)c1cc(CCl)cc(N(C)S(C)(=O)=O)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1cc(CN=[N+]=[N-])cc(N(C)S(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of crude N-(3-(chloromethyl)-5-(prop-1-en-2-yl)phenyl)-N-methylmethanesulfonamide and 91.2 mg (1.40 mmol) of NaN3 in 4 mL of DMF was stirred at 70° C. for about 3 h. Water and EtOAc were added, and the organic layer was washed with water (2×) and then brine. The aqueous layer was extracted with EtOAc, and the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography provided 88.4 mg of N-(3-(azidomethyl)-5-(prop-1-en-2-yl)phenyl)-N-methylmethanesulfonamide as a mixture.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:22]=[C:18]([C:19]([OH:21])=[O:20])[C:17]([OH:23])=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C1(C)C=CC(S(O[CH2:34][CH2:35][CH2:36][CH2:37][O:38][N+:39]([O-:41])=[O:40])(=O)=O)=CC=1>O>[N+:39]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:14]([NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[CH:15]=[CH:16][C:17]=1[OH:23])([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(C(=O)O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCCO[N+](=O)[O-])cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(O)c(C(=O)OCCCCO[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a mixture comprising DMF (200 ml), 5-t-butoxycarbonylaminosalicylic acid (4.37 g, 17.3 mmol) and 4-nitrooxybutyl p-toluenesulfonate (5 g, 17.3 mmol), at room temperature and under stirring triethylamine was added (2,6 ml; 19 mmol). The reaction mixture was maintained 3 days under stirring at room temperature. It was then poured in water and extracted with ethyl ether. The combined organic phases were washed with a sodium carbonate solution and then with water. After drying on sodium sulfate, the evaporation of the solvent yields a raw product that purified by silica gel chromatography gives the title compounds with a yield of 65%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[CH2:13](I)[CH3:14]>CN(C=O)C>[CH2:13]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)[CH3:14]
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
Sodium hydride (60% in mineral oil, 1.65 g, 41 mmol) was added to a solution of 6-hydroxyindole (5.0 g, 38 mmol) in anhydrous DMF (25 mL) at −20° C. under N2. The resulting dark green solution was allowed to warm up to room temperature and stirred for 10 min. Ethyl iodide (3.3 mL, 6.4 g, 41 mmol) was added, and the resulting solution was stirred at room temperature for 1 h. The mixture was poured into ice-water (150 mL), and extracted with EtOAc (3×200 mL). The organic solution was dried (MgSO4) and concentrated at reduced pressure. The residue was purified by flash chromatography (SiO2, 5% then 15% EtOAc/hexanes) to give the title compound (4.5 g, 75%) as a white solid. 1H NMR (CDCl3) δ 7.98 (br. s, 1H), 7.50 (m, 1H), 7.10 (m, 1H), 6.90 (m, 1H), 6.80 (m, 1H), 6.45 (m, 1H), 4.10 (q, J=6.5 Hz, 2H), 1.45 (t, J=6.5 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[CH3:26][C:27]([CH3:32])([CH3:31])[C:28]([OH:30])=[O:29]>>[C:28]([O:30][C:4]1([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:29])[C:27]([CH3:32])([CH3:31])[CH3:26]
Reactant: CC(C)(C)C(=O)O
Reactant: ON=C1CCOCC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CC(C)(C)C(=O)OC1(N=O)CCOCC1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl pivalate was prepared from tetrahydro-pyran-4-one oxime, lead tetraacetate and trimethylacetic acid using conditions of General Method 3. 1H NMR (360 MHz, chloroform-d) δ 3.91-4.14 (2H, m), 3.57-3.77 (2H, m), 2.10-2.29 (2H, m), 1.75-1.93 (2H, m), 1.34 (9H, s).
Reaction SMILES: [C:1]1([S:11]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[N+:23]([O-])=O)[CH:18]=[O:19])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CO>C1COCC1.[Pd]>[NH2:23][C:22]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[CH2:14][S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12]
Reactant: O=Cc1ccc([N+](=O)[O-])c(CS(=O)(=O)c2cccc3ccccc23)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(C=O)cc1CS(=O)(=O)c1cccc2ccccc12
Yield: 94.9 %

Procedure:
A mixture of 3-(naphthalene-1-sulfonylmethyl)-4-nitro-benzaldehyde (2.5 g, 7.22 mmoles) and 10% Pd/C in THF (10 mL), and methanol (20 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 lb/in2 overnight. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum to afford the title compound as an off-white solid (2.4 g, 6.85 mmoles).
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:24][SiH:25]([CH3:27])[CH3:26])=[C:13]([CH:17]=[CH:18][C:19]=3[C:20]([CH3:23])([CH3:22])[CH3:21])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[SH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1.N1C=CC=CC=1>ClCCl>[C:1]12([C:11]3[C:12]([O:24][SiH:25]([CH3:27])[CH3:26])=[C:13]([CH:17]=[CH:18][C:19]=3[C:20]([CH3:21])([CH3:22])[CH3:23])[C:14]([S:28][C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)=[O:15])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)c1ccc(S)cc1
Reactant: C[SiH](C)Oc1c(C(=O)O)ccc(C(C)(C)C)c1C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[SiH](C)Oc1c(C(=O)Sc2ccc(C(=O)O)cc2)ccc(C(C)(C)C)c1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
The crude 3-(1-adamantyl)-4-tert.butyl-dimethylsilyloxybenzoic acid, prepared starting with 3.8 g (9.95 mmoles) of the corresponding acid, described in Example 3 of European Patent No. 0.232.199, is dissolved in 40 ml of dichloromethane. The solution is slowly added to a mixture of 1.54 g (9.95 mmoles) of 4-mercaptobenzoic acid and 15 ml of pyridine. The reaction mixture is stirred at ambient temperature for 12 hours, evaporated to dryness, taken up in water and acidified to pH 5 with 1N HCl. The solid is filtered, washed with water, ground with 50 ml of ethyl ether and dried at 60° C. under a vacuum. 5 g (96% yield) of a white powder whose melting point is 232°-233° C. are recovered.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH3:9])[N:3]=1.[NH2:15][C:16]1[S:17][C:18]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22]>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:18]2[S:17][C:16]([NH:15][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)[CH3:9])[N:3]=3)=[C:20]([C:21]([NH2:23])=[O:22])[CH:19]=2)=[CH:29][CH:28]=1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)sc1N
Reactant: CC(c1cccc(Br)n1)N1CCCC1
Product: CC(c1cccc(Nc2sc(-c3ccc(F)cc3)cc2C(N)=O)n1)N1CCCC1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-bromo-6-(1-pyrrolidin-1-ylethyl)pyridine (200 mg, 0.78 mmol) and 2-amino-5-(4-fluorophenyl)thiophene-3-carboxamide (204 mg, 0.86 mmol) as the starting materials.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:20][N:21]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:62])[CH2:36][CH2:37][C:38](=[O:61])[N:39]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:22](=[O:28])[CH2:23][CH2:24][C:25](O)=[O:26])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.Cl.[CH2:65]([O:72][NH:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][NH2:79])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>C(Cl)Cl>[C:49]([O:48][C:46]([NH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][N:39]([O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:38](=[O:61])[CH2:37][CH2:36][C:35](=[O:62])[NH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][N:21]([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:22](=[O:28])[CH2:23][CH2:24][C:25](=[O:26])[NH:79][CH2:78][CH2:77][CH2:76][CH2:75][CH2:74][NH:73][O:72][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)=[O:47])([CH3:51])([CH3:50])[CH3:52]
Reactant: NCCCCCNOCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
CDI (0.188 g, 1.16 mmol) was added to a solution of (10) (0.76 g, 1.09 mmol) in dry CH2Cl2 (45 mL). The solution was cooled to 0° C. after 1 hour and (6) (free amine, 0.240 g, 1.15 mmol) was added by cannula in CH2Cl2 (60 mL) over 5 minutes. The reaction was stirred at 0° C. to room temperature for 24 hours. Solvent was removed in vacuo and dilute brine (100 mL) was added to the residue. Extraction was carried out with EtOAc (5×75 mL), followed by washing with 50 mL of cold 0.5M citric acid, 5% NaHCO3, water and brine. Solvent removal gave 0.87 g (90% ) of (11) which was used directly in the next reaction: NMR δ 1.1-1.8 (m+s, 27 H) , 2.3-3.7 (m, 20 H), 4.5 (br s, 1 H), 4.67 (s, 2 H), 4.82 (s, 4 H), 6.2 (br s, 1 H), 7.2-7.4 (m, 15 H). An analytical sample of (11) was obtained from silica gel column chromatography, eluting with 5% MeOH/CHCl3. Anal. calcd. for C49H72N6O9 : C, 66.19; H, 8.16; N, 9.45. Found: C, 66.18; H, 8.17; N, 9.42.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][NH:6][C:7](=[O:11])[O:8][CH2:9][CH3:10].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:19]([N+:25]([O-:27])=[O:26])=[CH:18][C:17]=1[C:28]([F:31])([F:30])[F:29].[H-].[Na+].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]([C:16]1[C:17]([C:28]([F:30])([F:31])[F:29])=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[C:7](=[O:11])[O:8][CH2:9][CH3:10]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)NCc1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1cccc(Cl)c1)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1C(F)(F)F
Yield: 9.4 %

Procedure:
Ethyl 3-chlorobenzylcarbamate (720.3 mg) and 2-chloro-3,5-dinitrobenzotrifluoride (829.1 mg) were dissolved in tetrahydrofuran (20 ml), and to the solution was added sodium hydride (147.1 mg). The reaction mixture was heated at reflux for 1.5 hours. After allowing to cool, to the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (75 g, hexane:ethyl acetate=10:1) to give the title compound (129.5 mg, 9%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Br.N1CCCCC1>>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: OCCCCCCCCCCCBr
Agent: Br
Product: OCCCCCCCCCCCN1CCCCC1
Yield: 96.3 %

Procedure:
11-Bromoundecanol (11.00 g., 43.79 mmole) was dissolved in 100 ml. of piperidine and heated at reflux temperature for 18 hours. The reaction mixture was allowed to cool and most of the precipitated piperidine hydrobromide was removed by filtration. The excess piperidine is removed by simple distillation and the resultant solid residue is recrystallized from ethanol and water. After drying, 10.78 g. (96.3% yield) of 1-hydroxy-11-(N-piperidyl)undecane was obtained. m.p. 62°-65° C., 1H-NMR (200 MHz, CDCl3) δ=1.2-1.7 ppm, m, 24H; 2.10, broad s, 1H; 2.20-2.45, m, 6H; 3.63, t, 2H.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([O:20]C)=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:18]([C:14]2[N:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])[CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:25][CH2:24]1
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: NC1CC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)NC1CC1

Procedure:
Same procedure as described in preparation 133a was used from (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (900 mg, 80% purity, 2.28 mmols) and cyclopropanamine (0.48 ml, 6.86 mmols). After 3.5 h stirring at 80° C. the title compound was obtained (589 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)[C:5]([CH3:8])=[CH:6][CH:7]=1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:8][C:5]1[C:4]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc(F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(c2cc(F)ccc2CBr)OC1(C)C
Temperature: 25 °C
Yield: 84 %

Procedure:
3-Fluoro-6-methylphenylboronic acid pinacol ester (29a, 5.01 g, 21.2 mmol) and 140 ml CCl4 were placed in 500 ml round-bottom flask. NBS (3.97 g, 22.3 mmol, 1.05 eq) and AIBN (0.054 g, 0.33 mmol, 0.016 eq) were added and the reaction mixture was refluxed for 3.5 h in the presence of 75 W incandescent bulb. After 3.5 h the solution was cooled down to room temperature allowing the succinimide to precipitate out. The solid was filtered off. The solvent was removed and oily product was collected. Purification with column chromatography (95/5 Hexanes/Ethyl acetate) resulted in pure product (30a, 5.59 g, 84% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:23])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:24][CH2:25][C@H:26]([NH2:30])[C:27]([OH:29])=[O:28].C(N(CC)CC)C>C(O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([NH:30][C@@H:26]([CH2:25][CH3:24])[C:27]([OH:29])=[O:28])=[O:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](N)C(=O)O
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)O
Yield: 81.5 %

Procedure:
The title compound is prepared by the procedure of Example 255 using 29.46 g of product from Example 254, 9.5 g of L-2-aminobutyric acid, 25.5 ml of triethylamine and 1112 ml of 4:1 ethyl alcohol/water to give 21.2 g of the desired product after chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=2)[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:43][S:44]([NH2:47])(=[O:46])=[O:45].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29](=[O:31])[NH:47][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:32][CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Cl)cc2)Cc2ccc(C(=O)O)cc2)CC1
Reactant: CS(N)(=O)=O
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Cl)cc2)Cc2ccc(C(=O)NS(C)(=O)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
4-(((1-(tert-Butoxycarbonyl)piperidin-4-yl)(4-chlorophenethyl)amino)methyl)benzoic acid synthesized in Step 2 was dissolved in DCM (5 mL/mmol) and DIPEA (3 equiv) and methanesulfonamide (2 eqs) were added. The reaction mixture was cooled to 0° C. and TFFH (1.2 eq) was added in one portion. The reaction mixture was stirred at 0° C. for 6 hours and then for 15 hours at room temperature. Ethyl acetate (15 mL/mmol) was added and the solution was washed sequentially with 5% citric acid (2×), 5% NaHCO3 (2×) and brine (2×) and was dried over MgSO4. The drying agent was filtered off and the solvents were evaporated in vacuo. The crude product was purified by silica gel chromatography.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([NH2:10])=[O:9].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)Cl>[CH3:1][N:2]1[C:3]2[CH:7]=[CH:6][S:5][C:4]=2[C:8](=[O:9])[N:10]=[C:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNc1ccsc1C(N)=O
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccccc2)nc(=O)c2sccc21
Reaction time: 1.5 h

Procedure:
1.70 g (10.9 mmol) 3-Methylamino-thiophene-2-carboxylic acid amide were dissolved in 20 ml trichloromethane and 3.82 g (3.16 ml, 22.2 mmol) benzoyl chloride were added. The mixture was boiled for 90 min. After filtration the residue was dissolved in trichloromethane and washed with saturated sodium bicarbonate solution. The organic solution was dried over magnesium sulfate and evaporated under vacuum. The crude product was purified by column chromatography on silica, eluent dichloromethane/methanol 95/5.