Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:20][O:21][CH2:22][CH2:23][C:24]([OH:26])=O.CCN=C=NCCCN(C)C.[NH2:38][C@@H:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][C@H:40]1[NH:48][C:49]([C:51]1[NH:52][C:53]2[C:58]([CH:59]=1)=[CH:57][C:56]([Cl:60])=[CH:55][CH:54]=2)=[O:50]>C(Cl)Cl>[Cl:60][C:56]1[CH:57]=[C:58]2[C:53](=[CH:54][CH:55]=1)[NH:52][C:51]([C:49]([NH:48][C@@H:40]1[CH2:41][C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:39]1[NH:38][C:24](=[O:26])[CH2:23][CH2:22][O:21][CH3:20])=[O:50])=[CH:59]2
Reactant: COCCC(=O)O
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
DIPEA (180 μL, 1.05 mmol), HOBT (68 mg, 0.5 mmol), 3-methoxypropanoic acid (46 μL, 0.5 mmol) and EDAC (120 mg, 0.63 mmol) were added to a suspension of N-[(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl]-5-chloro-1H-indole-2-carboxamide (Method 5, 220 mg, 0.5 mmol) in anhydrous DCM (7 mL). The reaction was stirred at ambient temperature for approximately 16 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (10 mL), washed with water (2×10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue triturated (DCM), collected by filtration, washed with hexane (2×5 mL) and dried to give the title compound (84 mg, 41%) as a brown solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:15]C)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1.C1(=O)[O:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.O>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[O:15])[CH:9]=1
Reactant: COC(=O)c1cccnc1
Reactant: O=C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCCCO)c1cccnc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A solution of potassium tert-butoxide (83.55 g) in tetrahydrofuran (500 ml) at 22° C. is treated, dropwise, with a solution of methyl nicotinate (68.5 g) and delta-valerolactone (75.0 g) in tetrahydrofuran (125 ml) during a period of 1 hour. The solution is then stirred at 23° C. for 2 hours. The reaction mixture is diluted with water and washed with toluene (125 ml). The organic phase is discarded and the aqueous phase is treated dropwise with concentrated hydrochloric acid (400 ml;37% w/v). The solution Is stirred for a further 2 hours. The solution is then washed with dichloromethane (250 ml). The organic phase is discarded and the aqueous phase is treated with aqueous sodium hydroxide solution to bring it to between pH8 and pH9. The aqueous phase is then washed with toluene (125 ml) and the organic phase is back washed with water (3×100 ml). The two aqueous phases are combined and extracted with dichloromethane. The dichloromethane extract is dried over magnesium sulphate, and evaporated to dryness, to give 4-hydroxybutyl 3-pyridyl ketone (61.1 g) in the form of an oil which crystallises to form a pale brown solid, m.p. 36°-38° C. [NMR (CDCl3):- 1.7(m,2H),1.9(m,2H),3.1(t,2H),3.7(t,2H),7.4(m,1H), 8.2(dt,1H),8.8(m,1H),9.2(m,1H)].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1.[C:13](=O)(O)[O-:14].[Na+].BrBr.[Na+].[Cl-]>CO.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:14][CH3:13])=[O:9])[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1
Reactant: O=C([O-])O
Reactant: COc1c(Cl)nc(Cl)nc1C=O
Agent: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)nc(Cl)c1OC
Temperature: 0 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
The 2,6-dichloro-5-methoxy-pyrimidine-4-carbaldehyde crude material (32.5 mmol), prepared by Example 7, was cooled to 0° C. in an ice/water bath. It was assumed that approximately 60 mL of methanol was still present in the crude material. Additional methanol (60 mL) and water (13 mL) was added to the chilled crude material. Solid sodium bicarbonate (54.7 g) was added, and the solution stirred vigorously. A 2 M solution of bromine (81.4 mL, 163 mmol) in methanol and water (9:1) was dropwise added to the crude material solution over 30 minutes. The reacting mixture was stirred at 0° C. for 1 h. The mixture was then removed from the ice/water bath, and the reaction monitored using GCMS. About 6 h after initiating the reaction with bromine, a mixture of Na2S2O3.5H2O (4.5 g), saturated NaCl (150 mL), and ice (400 g) was prepared and, into this, the reaction mixture was poured. This was diluted with ethyl acetate (200 mL), and additional ethyl acetate (200 mL) was used to extract the product. The combined organic phases were dried over sodium sulfate, filtered, and toluene (50 mL) was then added. The product was then concentrated on a rotary evaporator with a bath temperature of less than or equal to 25° C. Obtained was a yellow oil comprising the title compound (3.1 g, 45% yield). The title compound was not isolated from the solution.
Reaction SMILES: BrC(Br)(Br)Br.CCN([CH:12]([CH3:14])C)C(C)C.[CH3:15][N:16]([CH3:39])[C:17]([C:19]1[N:23]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:22]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:21]([OH:37])[C:20]=1[OH:38])=[O:18].[P:40]([O-:47])([O:44][CH2:45][CH3:46])[O:41][CH2:42][CH3:43]>CN(C1C=CN=CC=1)C.CC#N>[CH2:42]([O:41][P:40]([O:37][C:21]1[C:20]([O:38][P:40]([O:47][CH2:12][CH3:14])([O:41][CH2:42][CH3:43])=[O:44])=[C:19]([C:17](=[O:18])[N:16]([CH3:15])[CH3:39])[N:23]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:22]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])([O:44][CH2:45][CH3:46])=[O:47])[CH3:43]
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOP([O-])OCC
Agent: BrC(Br)(Br)Br
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCOC(=O)c1c(OP(=O)(OCC)OCC)c(OP(=O)(OCC)OCC)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
Perbromomethane (207 mg, 0.62 mmol) and DIPEA (131 μL, 0.75 mmol) were added successively to a solution of DMAP (3.05 mg, 0.03 mmol) and ethyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-012) (87 mg, 0.25 mmol) in MeCN (3 mL) at −10° C. The reaction mixture was allowed to stir for 30 min and diethyl phosphite (166 μL, 0.75 mmol) added, the reaction was allowed to warm slowly to RT and stirred for 3 h. The reaction was quenched with 5% NaH2PO4 (aq.) (20 mL) and extracted with EtOAc (3×25 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40 g, 0-4% MeOH in DCM) to afford an orange oil. The compound was further purified by preparative HPLC (C-18 column, 21.2 mm i.d.×100 mm, 5 micron particle size, gradient 5-95% MeCN in 0.1% aq. formic acid over 16 min) to afford ethyl 3,4-bis((diethoxyphosphoryl)oxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-092) (35 mg, 22%) as a yellow oil: m/z 621 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.18-7.15 (m, 2H), 6.97-6.94 (m, 2H), 4.22-4.02 (m, 10H), 3.79 (s, 3H), 2.75 (s, 3H), 2.71 (s, 3H), 1.31-1.24 (m, 12H),1.07 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]1[CH2:24][O:23][CH:19]([CH2:20][CH2:21]Cl)[CH:18]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[O:17]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:16]1[CH2:24][O:23][CH:19]([CH2:20][CH2:21][N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:15][CH2:14]2)[CH:18]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[O:17]1
Reactant: COc1ccc(C2OCCOC2CCCl)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C2OCCOC2CCN2CCC(CNC(=O)OC(C)(C)C)CC2)cc1
Yield: 37.7 %

Procedure:
4-(tert-Butoxycarbonylaminomethyl)piperidine (10.0 g) as a starting compound, 4-ethylenedioxy-4-(4-methoxyphenyl)butyl chloride (12.0 g) and potassium carbonate (19.3 g) were reacted and treated in the same manner as in Preparation Example 181 to give 7.65 g of 1-(4-ethylenedioxy-4-(4-methoxyphenyl)butyl)-4-(tert-butoxycarbonylaminomethyl)piperidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:12]2[C:13]3[C:8]([C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[CH2:3]1.[Br:21]Br.O>C(O)(=O)C>[Br:21][C:6]1[CH:7]=[C:8]2[C:13]3=[C:4]([CH2:3][C:2]([CH3:1])([CH3:20])[N:12]3[CH:11]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]2=[O:19])[CH:5]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cn2c3c(cccc3c1=O)CC2(C)C
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cn2c3c(cc(Br)cc3c1=O)CC2(C)C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Ethyl 2,2-dimethyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate (Preparation 12, 1.03 g) is dissolved in acetic acid (10 mL) and bromine (213 μL) is added dropwise. The reaction is stirred an additional 30 min and then poured into water (50 mL). The resulting precipitate is filtered and then washed with ether to give 506 mg (38%) of the title compound as white crystals. Physical characteristics: M.p. 227-228° C.; 1H NMR (DMSO-d6) δ8.76, 7.90, 7.79, 4.23, 3.41, 1.63, 1.29; IR (diffuse reflectance) 1727, 1636, 1612, 1592, 1547, 1505, 1393, 1373, 1327, 1303, 1217, 1171, 1167, 1128, 804 cm−1; HRMS (FAB) 350.0386 (C16H16BrNO3+H).
Reaction SMILES: [SiH3]O[SiH3].O.O.O.[F-:7].C([N+]([CH2:21][CH2:22][CH2:23][CH3:24])(CCCC)CCCC)CCC.[O:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:7][C:22]([CH2:23][CH:24]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:21][CH:22]=[CH:23][CH2:24][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:21][CH2:29][CH2:28][CH2:27][CH2:26][OH:25]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Reactant: [F-]
Agent: [SiH3]O[SiH3]
Solvent: O
Product: CCCCCC=CCCCCC=CCC(F)=CCCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of the silylether (58 mg, 0.1 mmole) in tetrahydrofuran (2 ml) was added tetra-n-butylammonium fluoride trihydrate (50 mg, 0.15 mmole). The mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride, washed with water and dried over sodium sulfate. Filtration and concentration under reduced pressure afforded an oil. Flash chromatography on silicagel and elution with a 2:8 mixture of ethyl acetate and hexane afforded the expected alcohol as an oil (21 mg, 68%).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[CH:24]=[C:23]([C:25](O)=[O:26])[S:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.[CH3:38][NH:39][CH3:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:38][N:39]([CH3:40])[C:25]([C:23]1[S:22][C:21]2[CH:28]=[C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:31])[CH3:1])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:18]=[CH:19][C:20]=2[CH:24]=1)=[O:26]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)sc2c1
Reactant: CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)N(C)C)sc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
6-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid (290 mg, 0.642 mmol) in CH2Cl2 (5.0 mL) is treated with DMAP (235 mg, 1.93 mmol) and EDC (184 mg, 0.962 mmol). The mixture is stirred for 15 min at RT, and dimethylamine hydrochloride (78 mg, 0.962 mmol) is added. The reaction is stirred for 18 h and quenched with aqueous NH4Cl (5.0 mL). The organic layer is loaded onto a silica gel column and purified with 50% EtOAc/Hex to afford the title compound (280 mg, 91%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:24][CH:23](OS(C)(=O)=O)[CH2:22]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>CN(C)C=O>[C:30]([S:32][CH:23]1[CH2:22][N:21]([C:18]2[S:19][CH:20]=[C:16]([C:14](=[O:15])[NH:13][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH2:11][CH3:12])[N:17]=2)[CH2:24]1)(=[O:33])[CH3:31]
Reactant: CC([O-])=S
Reactant: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(SC(C)=O)C2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.02 g, 2.20 mmol) (obtained as described in Reference Example 34(5)) in dimethylformamide (50 ml) was added potassium thioacetate (1.51 mg, 13.2 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→2:1) as the eluant to afford 3-acetylthio-1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}azetidine (618 mg, yield 63%) as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2[S:33][C:14]3=[N:15][C:16]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[CH:17][C:18](=[O:19])[N:13]3[N:12]=2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[NH4+:34].[Cl-].[CH3:36][CH2:37][O:38]C(C)=O>CCO.O.[Fe]>[NH2:34][CH2:36][C:37]([NH:8][C:6]1[CH:5]=[C:4]([C:11]2[S:33][C:14]3=[N:15][C:16]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:17][C:18](=[O:19])[N:13]3[N:12]=2)[CH:3]=[C:2]([Br:1])[CH:7]=1)=[O:38]
Reactant: [NH4+]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cc(Br)cc([N+](=O)[O-])c4)sc3n2)CC1
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: NCC(=O)Nc1cc(Br)cc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)c1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To a suspension of tert-butyl 4-(2-(3-bromo-5-nitrophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (460 mg, 0.86 mmol) in EtOH (5 ml) and water (1 ml) are added iron powder (239 mg, 4.38 mmol) and NH4Cl (137 mg, 2.57 mmol) and the mixture is heated at 70° C. for 5 h. After cooling to room temperature, EtOAc (30 ml) is added and the mixture is further stirred for 10 min then filtered through a pad of Celite. The combined filtrate is washed with brine and the organic layer is dried over Na2SO4. After the removal of EtOAc in vacuo, the crude residue is purified by Biotage column chromatography (MeOH/DCM: 1/100 to 1/20 gradient) to give the desired product (380 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20](=[O:27])[N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.18 (1H, br m), 8.55 (1H, s), 7.15 (2H, dd, J=9, 5 Hz), 7.02 (2H, t, J=9 Hz), 6.96 (1H, s), 4.94 (2H, s), 4.11 (2H, s), 3.63 (2H, q, J=5 Hz), 3.56 (2H, t, J=5 Hz), 3.50 (2H, t, J=5 Hz), 3.44 (2H, t, J=5 Hz), 3.39 (3H, s), 1.68 (2H, m), 1.60-1.50 (4H, m); HRMS calcd for C26H29FN4O5+H+: 497.2200. Found: 497.2183.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([OH:13])[CH2:11][Cl:12])=[CH:4][C:3]=2[O:2]1.[CH2:14]([NH2:16])[CH3:15]>C(O)C>[ClH:12].[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([OH:13])[CH2:11][NH:16][CH2:14][CH3:15])=[CH:4][C:3]=2[O:2]1
Reactant: CCN
Reactant: OC(CCl)c1ccc2c(c1)OCO2
Solvent: CCO
Product: CCNCC(O)c1ccc2c(c1)OCO2
Product: Cl

Procedure:
19.5 g. of 1-(3,4-methylenedioxyphenyl)-2-chloroethanol are added to a solution of 170 g. of ethylamine in 200 ml. of cooled ethanol and the mixture is heated at 80° C. for 8 hours in an autoclave. After cooling, the ethanol and excess ethylamine are distilled off under reduced pressure. The residue is extracted with 100 ml. of 1N HCl and the extract is washed twice with 100 ml. of ether. The hydrochloric acid extract solution is made basic with 1N caustic soda and the liberated oil is extracted with ether. The ether extract is dried and an etherial hydrochloric acid solution is added thereto. The crystals which settle out on standing are filtered off and washed with ether. Upon recrystallization from isopropyl alcohol 7.8 g. of 1-(3,4-methylenedioxyphenyl)-2-ethylaminoethanol hydrochloride are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Cl:11])[CH:3]=1.B1([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1.C([O-])(=O)C.[K+].CS(C)=O>C(OCC)(=O)C>[CH3:17][C:15]([OH:16])([C:14]([CH3:20])([OH:13])[CH3:19])[CH3:18].[Cl:11][C:4]1[CH:3]=[C:2]([B:21]2[O:22][C:23]([CH3:28])([CH3:29])[C:24]([CH3:26])([CH3:27])[O:25]2)[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(O)C(C)(C)O
Product: CC1(C)OB(c2cc(Cl)cc([N+](=O)[O-])c2)OC1(C)C
Temperature: 120 °C
Yield: 84.6 %

Procedure:
A 20 mL microwave vial was charged with a stir bar, 1-bromo-3-chloro-5-nitrobenzene (1.182 g, 5.0 mmol), bis(pinacolato)diboron (1.397 mg, 5.5 mmol), PdCl2 (dppf)-dichloromethane adduct (204 mg, 0.25 mmol), potassium acetate (1.472 g, 15.0 mmol) and DMSO (10.00 mL). The vial was sealed and heated in a microwave at 120° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed twice with water, brine, and then dried over Na2SO4 to give 2,3-dimethylbutane-2,3-diol-2-(3-chloro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1:1) (1.7 g, 85%) after filtration and solvent evaporation. The crude product mixture was used as is in the next reaction.
Reaction SMILES: C(O[C:6](=[O:35])[NH:7][C@H:8]([C:13](=[O:34])[NH:14][CH:15]1[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][N:18]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:26])=[O:25])[CH2:17][CH:16]1[OH:33])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.Cl.O1CCOCC1.Cl.[O:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[CH:46]=[C:45]1C(O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[OH:33][CH:16]1[CH:15]([NH:14][C:13]([C@@H:8]([NH:7][C:6]([C:45]2[O:44][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[CH:46]=2)=[O:35])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:34])[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][N:18]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:25])=[O:26])[CH2:17]1
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CC(C)(C)CN(S(=O)(=O)c2ccccn2)CC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To {(S)-1-[3-Hydroxy-6,6-dimethyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester of Example 92h (0.22 g, 0.43 mmol) was added HCl/dioxane (4M, 20 ml, 80 mmol). The mixture was stirred at r.t. for 2 h before solvents and excess amount of HCl was removed on rotavapor. The resulting white solid was dissolved in 5 ml DMF. To the solution was added 2-benzofurancarboxylic acid (84 mg, 0.52 mmol), HBTU (0.2 g, 0.52 mmol) and NMM (0.2 g, 2 mmol). The mixture was stirred at r.t. overnight. DMF was then removed and the residue was redissolved in EtOAc (50 ml), washed with 10% NaHCO3 (50 ml×2) and brine (50 ml). Evaporation of the solvent gave crude product 0.26 g. Purification by column chromatograghy gave the title compound 0.15 g in 63% total yield; MS (M+H+): 556.8; 1H-NMR (400 MHz, CDCl3): •8.66-8.63(m, 1H), 7.94-7.11(m, 10H), 4.72(m, 1H), 4.01-2.98(m, 7H), 1.78-1.39(m, 5H), 1.02-0.85(m, 12H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl.ClCCl.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:10]([OH:14])[C:11]([NH:31][O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NOCc1ccccc1

Procedure:
A solution of Example 1C (0.20 g, 0.66 mmol), O-benzyl hydroxylamine hydrochloride (0.22 g, 1.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.17 g, 0.89 mmol), 1-hydroxybenzotriazole (0.14 g, 1.0 mmol), and N-methylmorpholine (0.40 mL, 3.6 mmol) in 5:1 dichloromethane/DMF (6 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with aqueous NaHCO3, brine, 10% KHSO4, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 98:2/dichloromethane:methanol to provide the desired product.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[OH-].[Na+].I[CH2:33][CH:34]([OH:37])[CH2:35][OH:36].CCOCC>O>[F:1][C:2]([F:28])([F:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([O:25][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[O:24])=[CH:21][CH:20]=1
Reactant: OCC(O)CI
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 7.34 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphoshoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield the product as a white solid.