Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1.Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Reactant: O[C@H]1CNC[C@@H]1O
Agent: Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 500 mg, 1.322 mmol), (3S,4S)-pyrrolidine-3,4-diol (205 mg, 1.984 mmol) and TEA (553 μL, 3.97 mmol) in DMSO (994 μL) was stirred at 90° C. for 24 h. Additional (3S,4S)-pyrrolidine-3,4-diol, (68.2 mg, 0.661 mmol) and TEA (183 μL, 1.322 mmol) were added and mixture was stirred at 100° C. for 16 h. The cooled treated with 0.5 M HCl (20 mL) and extracted with TBME/EtOAc (1:1). The combined extracts were washed with 0.5 M HCl (20 mL) and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue which was crystallised from cyclohexane/EtOAc to afford the title compound as an off-white solid. UPLC-MS (condition 1) tR=2.41 min, m/z=460.9/462.9 [M+H]+, m/z=459.0/461.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.24 (d, J=10.76 Hz, 2H) 3.88 (dd, J=10.51, 3.67 Hz, 2H) 4.02 (br. s, 2H) 5.15 (d, J=3.18 Hz, 2H) 6.89 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.84 (dd, J=8.68, 2.08 Hz, 1H) 7.85-7.89 (m, 2H) 8.13 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=O)[CH2:18]Br)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]2[C:9]3=[C:10]4[C:5]([C:6](=[O:11])[CH2:7][CH2:8]3)=[CH:4][CH:3]=[CH:2][N:1]4[CH:18]=2)=[CH:15][CH:14]=1
Reactant: O=C1CCCc2ncccc21
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: O=C1CCc2c(-c3ccc(Br)cc3)cn3cccc1c23
Temperature: 25 °C

Procedure:
5,6,7,8-Tetrahydroquinolin-5-one (20 g) was dissolved in 500 ml of toluene. To this solution was added 4-bromophenacyl bromide (37.8 g) gradually and refluxed for 18 hours. The reaction mixture was cooled to room temperature, and depositing solids were collected by filtration (33 g). These crystals were dissolved in 300 ml of N,N-dimethylformamide. To this solution was added, molecular sieves 3A (15 g) and triethylamine (13 ml), and the reaction mixture was heated at 100 ° C. for 1 hour. The reaction mixture became dark brown. The dark brown solution that obtained after removing insoluble matter by filtration was concentrated under reduced pressure. To the residue was added 300 ml of water and extracted with 200 ml of methylene chloride three times. The methylene chloride solution was washed with 100 ml of brine and dried over anhydrous sodium sulfate. The dark brown solution that obtained after removing drying agent by filtration was concentrated under reduced pressure, the resultant dark brown residue was purified by alumina column chromatography. The title compound was obtained as dark brown crystals (12 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:9]2=[O:20])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu+]>[N:14]1([C:10]2[C:9](=[O:20])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:3][CH:4]=3)[CH2:13][CH2:12][CH:11]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: O=C1C(N2CCOCC2)=CCCN1c1ccc(I)cc1
Reactant: O=C1CCCCN1
Agent: [Cu+]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=C1CCCCN1c1ccc(N2CCC=C(N3CCOCC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Part B. Soluble copper(I)-catalyzed Ullmann coupling reaction. A suspension of 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (10, 2.2 g, 5.73 mmol), piperidin-2-one (42, 851 mg, 8.59 mmol, 1.5 equiv), and Cs2CO3 (3.73 g, 11.46 mmol, 2.0 equiv) in toluene (15 mL) was treated with Cu(PPh3)3Br (1.065 g, 1.146 mmol, 20% equiv) at room temperature under N2, and the resulting reaction mixture was degassed three times under a steady stream of nitrogen. The reaction mixture was warmed up to reflux for 6 h. When HPLC showed the Ullmann coupling reaction was complete, the reaction mixture was cooled down to 5–10° C. before being quenched with 14% of ammonium hydroxide aqueous solution (20 mL) and EtOAc (30 mL) at 5–10° C. The mixture was stirred for an additional 4 h at 25° C. The two layers were then separated, and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15–40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-1-[4-(2-oxo-piperidin-1-yl)-phenyl]-5,6-dihydro-1H-pyridin-2-one (63, 1.568 g, 2.036 g theoretical, 77%) as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. For 63, CIMS m/z 356 (M++H, C20H25N3O3).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH:14]([Cl:20])[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7].[CH2:21]([OH:23])[CH3:22]>>[ClH:20].[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH:14]([O:23][CH2:21][CH3:22])[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CC(C)NCC(Cl)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: CCO
Agent: Cl
Product: CCOC(CNC(C)C)c1ccc(O)c(NS(C)(=O)=O)c1

Procedure:
A 1 g sample of 2'-hydroxy-5'-[1-chloro-2-(isopropylamino)ethyl]methanesulfonanilide hydrochloride is added to 10 ml of absolute ethanol and heated at reflux for 30 minutes. The mixture is evaporated to dryness and the residue is washed with ethyl ether thus yielding the product compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36].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>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:35](=[O:36])[C:34]([F:33])([CH3:39])[CH3:38])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1([C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20]1)=[O:18]
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: CC(C)(F)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(F)C(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (250 mg, 0.565 mmol) and 2-fluoro-2-methylpropanoic acid (108 mg, 1.02 mmol) in anhydrous CH2Cl2 (30 mL) was added HATU (323 mg, 0.85 mmol) and DIPEA (2.5 mL) under N2. This reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was poured into water (100 mL), extracted with ethyl acetate (3×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. This crude product was purified by silica gel chromatography to give N-(2,5-difluoro-4-((2-(2-fluoro-2-methylpropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (128 mg, 43% yield). 1H-NMR (400 MHz, Methanol-d4): δ 8.21-8.17 (m, 2H), 7.73 (d, J=2.4 Hz, 1H), 7.54-7.51 (m, 2H), 7.23 (dd, J=10.8, 7.2 Hz, 1H), 7.08-7.04 (m, 2H), 6.75 (dd, J=5.6, 2.4 Hz, 1H), 1.76-1.69 (m, 4H), 1.62 (s, 3H), 1.56 (s, 3H); MS (ESI): m/z 531.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O[C:13]1C=CC([N+]([O-])=O)=CN=1.[Na].C(C(CC)(C([O-])=O)C([O-])=O)C>>[Br:1][C:2]1[C:3]([CH3:13])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: CCC(CC)(C(=O)[O-])C(=O)[O-]
Agent: [Na]
Product: Cc1ncc([N+](=O)[O-])cc1Br
Yield: 75 %

Procedure:
3-Bromo-2-chloro-5-nitropyridine (25 g, 105 mmol; prepared from 2-hydroxy-5-nitropyridine according to the procedure of V. Koch and S. Schnatterer, Synthesis 1990, 499-501) was treated with the sodium salt of diethylmalonate (17.6 mL, 116 mmol) according to the procedure of Odashima et al Bull Chem Soc Jpn 1993, 66, 797-803) to provide 17.1 g (78.8 mmol, 75%) of dark red oil: TLC Rf 0.5 (4:1 hexanes/EtOAc); 1H NMR (CDCl3, 300 MHz) δ: 2.81 (s, 3H), 8.61 (d, 1H, J=2.0 Hz), 9.26 (d, 1H, J=2.0 Hz).
Reaction SMILES: [C:1]12([C:11]3[N:12]([CH2:22][C:23]([NH:25][C:26]([NH2:28])=[NH:27])=[O:24])[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>C(Cl)Cl>[C:1]12([C:11]3[N:12]([CH2:22][C:23](/[N:25]=[C:26](/[NH2:28])\[NH:27][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:24])[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCS(=O)(=O)Cl
Reactant: N=C(N)NC(=O)Cn1c(-c2ccccc2)ccc1C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N/C(N)=N\C(=O)Cn1c(-c2ccccc2)ccc1C12CC3CC(CC(C3)C1)C2
Reaction time: 0.21 h

Procedure:
A solution of 1 equivalent of N-[2-(2-adamantan-1-yl-5-phenyl-pyrrol-1-yl)-acetyl]-guanidine in 2.0 mL CH2Cl2 was cooled to 7° C. To the solution 1.0 equivalent of triethylamine was added. The reaction was stirred for 10-15 minutes, after which time ethylsulfonyl chloride was added. The reaction was concentrated and the residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL total) and purified by Gilson preparative HPLC system. HPLC conditions: YMC Pro C18 column, 20 mm×50 mm ID, 5 uM; 2 mL injection; Solvent A: Water (0.05% NH4OH buffer); Solvent B: acetonitrile (0.05% NH4OH buffer); Gradient: Time 0: 5% B; 2 min: 5% B; 12 min: 95% b, Hold 95% B 3 min; Flow rate 22.5 mL/min; Detection: 254 nm DAD. [M+H] 469, retention time 2.7 min.
Reaction SMILES: Cl.Cl[C:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=1.[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][C:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=1
Reactant: ClC(C1=NCCCCN1)(c1ccccc1)c1ccccc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(C1=NCCCCN1)(c1ccccc1)c1ccccc1

Procedure:
2-(Chlorodiphenylmethyl)-4,5,6,7-tetrahydro-1H-1,3-diazepine hydrochloride (0.003 mole) is stirred at room temperature for two days in dry methanol (25 ml) containing sodium methoxide (0.006 mole). After removal of the solvent the residue is dissolved in chloroform washed with water and dried over magnesium sulphate. Removal of the solvent gives the title compound.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[C:43](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:43][N:3]1[NH:2][N:1]=[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)[NH:4]1
Reactant: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(-c3nnn[nH]3)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(C3=NNN(C)N3)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide (44 mg, 0.172 mmol) in acetone (5 mL), sodium bicarbonate (84 mg, 1 mmol) and dimethyl sulfate (30 uL, 0.22 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (26 mg) and the other regioisomer (12 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH3:30])=[O:18].Br[C:32]1[S:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:32]2[S:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[CH:5]=[CH:4][C:3]=1[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH3:30])=[O:18]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: CS(=O)(=O)c1ccc(Br)s1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(S(C)(=O)=O)s2)cc1F
Yield: 78 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone (458 mg, 1.1 mmol) and 2-Bromo-5-methanesulfonyl-thiophene (CAS 2160-61-4) (255 mg, 1.0 mmol) to give 350 mg (78% yield). MS (ES+) 451.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([NH:22][NH2:23])[CH:14]=[C:15]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[CH:29]1[CH:34]=[C:33]2[C:35]([CH:38]=O)=[CH:36][NH:37][C:32]2=[CH:31][CH:30]=1>C(O)C>[NH:37]1[C:32]2[C:33](=[CH:34][CH:29]=[CH:30][CH:31]=2)[C:35]([CH:38]=[N:23][NH:22][C:13]2[CH:14]=[C:15]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:10]3[N:9]=[C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[CH:24]=[C:11]3[N:12]=2)=[CH:36]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Cc1ccc(-c2cc3nc(NN)cc(N4CCOCC4)n3n2)cn1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(-c2cc3nc(NN=Cc4c[nH]c5ccccc45)cc(N4CCOCC4)n3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
There was suspended, in ethanol (3.0 mL), [2-(6-methyl-pyridin-3-yl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl]-hydrazine (70 mg, 0.22 mM), then acetic acid (6.3 μL, 0.11 mM) and indole-3-carboxy-aldehyde (35 mg, 0.24 mM) were added to the suspension and the mixture was stirred at room temperature for 16 hours. The precipitated solid was recovered through filtration and then washed with diethyl ether to thus give the title compound (46 mg, yield: 47%).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[Li]CCCC.[I:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([OH:23])=[O:22].ICC>C1COCC1>[I:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:1][CH3:2])[C:21]([OH:23])=[O:22]
Reactant: O=C(O)Cc1ccccc1I
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C(=O)O)c1ccccc1I
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
To a solution of diisopropylamine (5.6 mL, 40 mmol) in dry THF (60 mL) at -10° C. was added 1.6M BuLi (25 mL, 40 mmol). After 30 min, a solution of 2-iodophenylacetic acid (5.24 g, 20 mmol) in THF (20 mL) was slowly added. The solution was stirred for 1 h, at which point iodoethane (1.6 mL, 117 mmol) was added. After 2 h at r.t. the reaction was quenched with 0.5M NH4OAc solution and 6M HCl (10 mL) and the product was extracted with EtOAc. The organic layer was dried (MgSO4) and evaporated to give an oily residue which was purified by flash chromatography (15:85 EtOAc:hexane containing 5% AcOH) to give 4.37 g of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[O:4][C:5]([C:8]([OH:10])=O)=[CH:6][N:7]=1.Cl.[NH2:12][C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Cl:33][C:29]1[CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C@@H:13]([NH:12][C:8]([C:5]3[O:4][C:3]([O:2][CH3:1])=[N:7][CH:6]=3)=[O:10])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][CH:23]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: COc1ncc(C(=O)O)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(OC)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxyoxazole-5-carboxylic acid, intermediate 16, (98 mg, 0.69 mmol) and (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (210 mg, 0.57 mmol) in DMF (10 mL) and CH2Cl2 (4 mL) is added HATU (272 mg, 0.72 mmol) and TEA (0.50 mL, 3.58 mmol). The crude is stirred at room temperature for 2 hrs. The crude is quenched with water and diluted in EtOAc. The organic layer is washed with water 3×, brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-methoxyoxazole-5-carboxamido)butanoate (122 mg). HPLC retention time=1.89 minutes (condition A); MS (m+1)=443.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.1 Hz, 3 H), 2.52-2.66 (m, 2 H), 2.94 (dd, 1 H), 3.08 (dd, J=13.6, 6.3 Hz, 1 H), 4.12 (s, 3 H), 4.14-4.23 (m, 2 H), 4.60-4.71 (m, 1 H), 6.81 (d, J=8.8 Hz, 1 H), 7.25-7.32 (m, 3 H), 7.35 (t, J=7.7 Hz, 1 H), 7.42 (s, 1 H), 7.43-7.47 (m, 1 H), 7.48-7.54 (m, 2 H), 7.55 (t, J=1.6 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[C:8]([CH:41]=1)[C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:40])[C:19]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=2[C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[CH2:13][CH2:12]1)=[O:10])([O-])=O>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:42]2[CH:43]=[C:44]([O:52][CH3:53])[C:45]([O:50][CH3:51])=[C:46]([O:48][CH3:49])[CH:47]=2)=[C:8]([CH:41]=1)[C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:40])[C:19]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=2[C:28]2[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: COc1cc(-c2ccc([N+](=O)[O-])cc2C(=O)N2CCCN(C(=O)c3cc([N+](=O)[O-])ccc3-c3cc(OC)c(OC)c(OC)c3)CC2)cc(OC)c1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc(N)cc2C(=O)N2CCCN(C(=O)c3cc(N)ccc3-c3cc(OC)c(OC)c(OC)c3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
Added to a solution of 39 mg (0.050 mmol) of 1,4-bis[5-nitro-2-(3,4,5-trimethoxy-phenyl)benzoyl]hexahydro-1,4-diazepine synthesized by the process described in Example 71 in acetic acid-ethyl acetate (3:2, 2.5 ml) were 39 mg of 10% palladium on carbon, and the mixture was stirred for 2 hours at room temperature under hydrogen. The catalyst was removed from the reaction mixture by suction filtration through Celite, and the filtrate was concentrated under reduced pressure. A chloroform solution of the residue was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel to obtain 32 mg (yield: 90%) of the title compound as a pale yellow amorphous powder.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].C(=O)(O)[O-].[Na+].I[CH2:18][CH3:19]>CN(C)C=O.O>[CH:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[C:1]([O:3][CH2:18][CH3:19])=[O:2])=[O:7]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
2-Carboxybenzaldehyde (2.018g, 13.4 mmol, 1.0 eq.) was combined with sodium bicarbonate (2.258 g, 26.9 mmol, 2.0 eq.) and iodoethane (2.15 ml, 26.9 mmol, 2.0 eq.) in dimethylformamide (13.4 ml, 1M) and stirred at room temperature for 16 hours. The reaction was diluted with water (25 ml) and extracted with ether: hexane (1:1, 3X20 ml). The combined organic extracts were washed with aqueous 10% sodium bisulfite (1X25 ml), water (1X25 ml) and aqueous saturated sodium chloride (1X25 ml), dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on Merck silica gel (20 g) eluting with hexane: ether (14:1) to provide the title A compound (1.485 g).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][C:9]([CH3:12])([CH3:11])[C:8]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:7]=2[NH:6][C:5]1=[O:20])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.O>>[NH2:1][CH:4]1[CH2:10][C:9]([CH3:12])([CH3:11])[C:8]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:7]=2[NH:6][C:5]1=[O:20]
Reactant: CC1(C)CC(N=[N+]=[N-])C(=O)Nc2cc([N+](=O)[O-])ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(N)C(=O)Nc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Azido-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (3.10 g, 10.3 mmol), Triphenylphosphine Resin (12 g, 11.55 mmol), THF (120 mL, 1400 mmol) and Water (0.9 mL, 50 mmol) were combined and stirred at rt for 16 h. The reaction mixture was filtered. Product isolated as a beige solid. (HPLC purity >98%)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[C:3]=1[CH:12]=[O:13].[CH3:14][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:14][O:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[C:3]=1[CH:12]=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1nc2ccc(O)c(C=O)c2s1
Solvent: CO
Solvent: c1ccccc1
Product: COc1ccc2nc(C)sc2c1C=O

Procedure:
6-Hydroxy-2-methyl-benzothiazole-7-carboxaldehyde (75 mg, 0.362 mmol) was taken up in 30% methanol in benzene (7 mL) and treated with (trimethylsilyl)diazomethane (2.0M solution in hexanes) (0.5 mL, 1.0 mmol) for 2 hours at room temperature. The mixture was evaporated, and the title compound was purified by flash chromatography eluting with 25-30% ethyl acetate in hexane.