Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:13]([OH:15])=O)=[C:10]([CH3:12])[N:11]=[C:5]2[CH:4]=1.C[CH2:17][N:18]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CN>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:13]([NH:18][CH3:17])=[O:15])=[C:10]([CH3:12])[N:11]=[C:5]2[CH:4]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccn2c(C(=O)O)c(C)nc2c1
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)nc2cc(OC)ccn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 7-methoxy-2-methylimidazo[1,2-α]pyridine-3-carboxylic acid (1.2 g, 5.82 mmol) in DMF (25 ml) was added EDCl (1.23 g, 6.41 mmol), HOBt (0.87 g, 6.41 mmol), N-methyl morpholine (767 ul, 11.64 mmol), methylamine (2M in THF, 6 ml, 11.64 mmol) and DMAP (70 mg, 0.58 mmol) sequentially, and the resulting mixture stirred at ambient temperature for 16 hours. The resulting solution was concentrated in-vacuo and pre-absorbed onto SiO2 and then purified by flash chromatography (eluting with 5-8% MeOH/DCM) to yield 7-Methoxy-N,2-dimethylimidazo[1,2-α]pyridine-3-carboxamide, 1.11 g, 87%, as a white solid.
Reaction SMILES: Cl.[CH:2]1([NH:8][NH2:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10]([O:12][C:13](=[O:21])[CH:14]([C:18](=O)[CH3:19])[C:15](=O)[CH3:16])[CH3:11].N1C=CC=CC=1>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15]([CH3:16])=[N:9][N:8]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[C:18]=1[CH3:19])=[O:21])[CH3:11]
Reactant: NNC1CCCCC1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(C2CCCCC2)c1C

Procedure:
Similar to Example 1, equimolar amounts of cyclohexyl hydrazine hydrochloride and 2-acetyl-3-oxobutyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis confirmed synthesis of the named product (m.p. 66° C.–67° C.).
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15].C(=O)(O)[O-].[Na+].ClCCl>C(OCC)(=O)C.O>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:5]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: Nc1cccc(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CC(F)=C(F)F)Nc1cccc(C(=O)O)c1
Temperature: 0 °C
Yield: 69.4 %

Procedure:
2.2 g (0.0139 mole) 3,4,4-trifluoro-3-butenoyl chloride is added to a mixture of 3-aminobenzoic acid (1.37 g, 0.01 mole), sodium bicarbonate (0.84 g, 0.01 mole), water (20 mL) and dichloromethane (20 mL) with stirring at 0° C. After stirring for 15 min at room temperature, the mixture is diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer is washed with 2N HCl and brine, and dried. The residue obtained after evaporation of the solvent is triturated with dry ether and filtered to give 1.8 g of the title compound as a light pink solid, a 69% yield. m.p. 252°-255° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1.Cl.[NH2:24][C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@H:10]([C:18]([NH:24][C@H:25]([C:34]([O:36][CH3:37])=[O:35])[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 73.5 %

Procedure:
In 500 ml of a mixture of chloroform-tetrahydrofuran (2:1), were dissolved 29.9 g of N-(4-methoxybenzoyl)-phenylalanine, 23.2 g of methyl tyrosinate hydrochloride, 10.1 g of trethylamine and 11.6 g of H-hydroxysuccinimide and the mixture was cooled with ice. To the cold solution was added 20.6 g of N,N'-dicyclohexylcarbodiimide. The mixture was stirred for 2 hours and then allowed to sit at room temperature overnight. The precipitates were removed by filtration and the filtrte was concentrated. The residue was extracted with ethyl acetate. The extract was washed with 2% hydrochloric acid, 4% sodium bicarbonate and water, then dried and concentrated to dryness. The residue was crystallized from ethyl acetate to give 35 g of methyl N-(4-methoxybenzoyl)phenylalanyltyrosinate with a mp. 195°-197° C in a yield of 74%. Analysis, calculated for C27H28O6N2C 68.05, H 5.92, N 5.88, found C 67.84, H 5.92, N 5.57.
Reaction SMILES: [OH-].[K+].Cl[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8].[CH3:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>OS(O)(=O)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1C=CC(C(C2C=CC(C)=CC=2)C(=O)C(C)C)=CC=1.CC(O)(C)C>[CH3:13][N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CNc1ccccc1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Pd]
Agent: Cc1ccc(C(C(=O)C(C)C)c2ccc(C)cc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: CN(c1ccccc1)c1cccc(C(=O)O)c1
Temperature: 100 °C
Yield: 102.5 %

Procedure:
An oven-dried resealable Schlenk flask was evacuated and backfilled with argon. The flask was charged with Pd2 dba3 (9.2 mg, 0.01 mmol, 2 mol % Pd), Ligand 1 (19 mg, 0.04 mmol, 4 mol %), pulverized KOH (168 mg, 3.0 mmol), and 3-chlorobenzoic acid (156 mg, 1.0 mmol). The flask was evacuated and backfilled with argon (3×) and then capped with a rubber septum. To the flask was added t-BuOH (2.0 mL), N-methyl-aniline (0.163 mL, 1.5 mmol) and t-BuOH (0.5 mL). The septum was replaced with a Teflon screwcap, the flask was sealed, and the mixture was heated to 100° C. with stirring until the starting aryl chloride was consumed by GC analysis (3 h, GC monitoring was conducted by diluting a small aliquot from the reaction with MeOH (1-2 mL), adding 2-3 drops H2SO4 and heating until 0.5 mL liquid was left, filtering through a small pipette silica plug and observing the disappearance of the corresponding methyl ester). The reaction was cooled to room temperature, diluted with 5% aq. NaOH and extracted with Et2O. The aqueous layer was cooled to 0° C. and acidified with HCl (12.0 M) until pH ˜4. The aqueous layer was extracted with Et2O, dried over anh. MgSO4, filtered, and concentrated under reduced pressure to give crude product (233 mg). The product was purified by recrystallizing in hot hexanes/chloroform (5:1) to give a light yellow solid (191 mg, 84%, ≧95% pure).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:13][Si](C)(C)C)[CH:11]=O.[F:18][C:19]([F:26])([F:25])[C:20]1([CH2:23][NH2:24])[CH2:22][CH2:21]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N.C1COCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([OH:13])[CH2:11][NH:24][CH2:23][C:20]1([C:19]([F:26])([F:25])[F:18])[CH2:22][CH2:21]1
Reactant: NCC1(C(F)(F)F)CC1
Reactant: C[Si](C)(C)OC(C=O)c1c(Cl)ccc(F)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: C1CCOC1
Product: OC(CNCC1(C(F)(F)F)CC1)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a solution of crude 2-(2,6-dichloro-3-fluorophenyl)-2-((trimethylsilyl)oxy)acetaldehyde (0.258 g, 0.874 mmol) in MeCN (9 ml) was added (1-(trifluoromethyl)cyclopropyl)methanamine (0.122 g, 0.874 mmol) followed by AcOH (0.050 ml, 0.874 mmol). The reaction mixture was stirred at room temperature for 1 h. Then NaBH(OAc)3 (0.370 g, 1.748 mmol) was added. The reaction mixture was stirred at room temperature for 23 h. Then it was quenched by adding saturated aqueous NaHCO3 solution and stirred for 30 min. It was extracted with DCM (2×5 mL). The combined organic layer washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to provide a yellow oil. The yellow oil was dissolved in 2 mL of THF. Then TBAF, 1.0 M solution in THF (0.874 ml, 0.874 mmol) was added. The reaction mixture was stirred at room temperature for 15 min. It was quenched with saturated aqueous NaHCO3 and extracted with DCM. The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, eluent: 0% to 50% EtOAc/heptane) to provide 1-(2,6-dichloro-3-fluorophenyl)-2-(((1-(trifluoromethyl)cyclopropyl)methyl)amino)ethanol (116 mg, 0.335 mmol, 38.3% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.25-7.31 (m, 1H), 7.06 (dd, J=8.9, 8.0 Hz, 1H), 5.45 (dd, J=9.7, 4.5 Hz, 1H), 3.45 (br. s., 1H), 3.28 (dd, J=12.6, 9.8 Hz, 1H), 2.89-2.92 (m, 3H), 0.99-1.04 (m, 2H), 0.69-0.76 (m, 2H); LCMS: 346.0 [M+H]+.
Reaction SMILES: FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](OCC=C)CN2)OC(=O)N1.N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1COCCN1C(C1C=CC=CC=1)C1C=CC=CC=1)O.[F:57][C:58]1[CH:59]=[C:60]([CH:87]=[C:88]([F:90])[CH:89]=1)[CH2:61][C@H:62]1[C@@H:66]([C@H:67]2[CH2:72][O:71][CH2:70][CH2:69][N:68]2[CH:73]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[O:65][C:64](=[O:86])[NH:63]1.[Li+].[OH-]>CCO.O>[F:57][C:58]1[CH:59]=[C:60]([CH:87]=[C:88]([F:90])[CH:89]=1)[CH2:61][C@H:62]1[C@@H:66]([C@H:67]2[CH2:72][C@H:70]([OH:71])[CH2:69][N:68]2[CH:73]([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[O:65][C:64](=[O:86])[NH:63]1
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2COCCN2C(c2ccccc2)c2ccccc2)O1
Agent: C=CCO[C@H]1CN[C@@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)C1
Agent: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1COCCN1C(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Step D (8): (1S,2S)-2-Amino-1-((R)-4-benzhydrylmorpholin-3-yl)-3-(3,5-difluorophenyl)propan-1-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-4-benzhydrylmorpholin-3-yl)oxazolidin-2-one (step D (7), 85 mg, 0.18 mmol) in EtOH (2 mL) was added a solution of LiOH (66 mg, 2.75 mmol) in H2O (1 mL). This reaction mixture was brought to 98° C. and stirred for overnight. Solvent was removed and 1N HCl solution (50 mL) was added to the mixture and washed with diethyl ether. The aqueous phase was basified with 50% aqueous NaOH solution. This mixture was extracted with ethyl acetate. The combined organic layer was dried (Na2SO4), and concentrated in vacuo to give 80 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ 1.94-2.06 (3H, m), 2.30 (1H, dd, J=10, 15 Hz), 2.51-2.59 (1H, m), 2.73-2.81 (1H, m), 2.90 (1H, m), 2.95 (1H, m), 3.08 (1H, m), 3.70 (1H, m), 3.80 (1H, dt, J=5, 10 Hz), 3.91 (1H, m), 4.09 (1H, m), 4.14 (1H, m), 5.05 (1H, s), 6.60-6.68 (3H, m), 7.15-7.31 (6H, m), 7.37 (2H, d, J=10 Hz), 7.42 (2H, d, J=5 Hz). MS (ESI) (M+H)+ 439.20.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([S:33][C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([S:33][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:35][CH:36]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(SC2CCCCC2)cc1
Solvent: C1COCCO1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(SC4CCCCC4)cc3)c2CC1)C(F)(F)F
Yield: 79.6 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (167 mg, 0.392 mmol) with 4-cyclohexylthio-benzylamine (95.4 mg, 0.431 mmol) in anhydrous 1,4-dioxane (5 mL). Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 13:7 gradient) to obtain 7-chloro-6-(4-cyclohexylthio-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (155 mg, 79%). MS (ES+) m/z: 519 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>CN(C)C=O>[O:13]1[C:12]2[CH:16]=[CH:17][C:9]([C:3]3[C:4]([O:8][CH2:25][CH:26]4[CH2:28][CH2:27]4)=[N:5][N:6]([CH3:7])[C:2]=3[NH2:1])=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: Cn1nc(O)c(-c2ccc3c(c2)OCO3)c1N
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(OCC2CC2)c(-c2ccc3c(c2)OCO3)c1N
Reaction time: 8 h

Procedure:
To 5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-ol (500 mg) (Preparation 46) in anhydrous dimethylformamide (21 ml) under an atmosphere of nitrogen at room temperature was added solid potassium carbonate (980 mg) and bromomethylcyclopropane (230 μl). The mixture was stirred overnight then quenched by the addition of water (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The solution was extracted with ethyl acetate (3×40 ml). The organic fraction was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 30 g) eluted with hexane:ethyl acetate (1:2) to yield the title compound as a colourless oil (365 mg).
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].[CH3:7][O:8][C:9](=[O:52])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH:24]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=3[O:40][CH3:41])[CH2:23][CH:22]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]Cl)[CH2:21]2)=[C:14]([O:50][CH3:51])[CH:13]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:51][O:50][C:14]1[CH:13]=[C:12](/[CH:11]=[CH:10]/[C:9]([O:8][CH3:7])=[O:52])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][CH:20]1[CH2:25][CH:24]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38][CH3:39])=[O:37])=[CH:30][C:29]=2[O:40][CH3:41])[CH2:23][CH:22]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:4][C:3](=[O:5])[C:2]([CH3:1])=[CH2:6])[CH2:21]1
Reactant: C=C(C)C(=O)O
Reactant: COC(=O)/C=C/c1ccc(OCC2CC(COc3ccc(/C=C/C(=O)OC)cc3OC)CC(OCCCCCCCl)C2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCCCCOC1CC(COc2ccc(/C=C/C(=O)OC)cc2OC)CC(COc2ccc(/C=C/C(=O)OC)cc2OC)C1
Temperature: 80 °C
Reaction time: 20 h
Yield: 94.1 %

Procedure:
786 mg (5.16 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) in 5 ml N,N-dimethylformamide were added dropwise to a solution of 413 mg (4.8 mmol) 2-methylacrylic acid in 5 ml N,N-dimethylformamide over a period of 30 minutes. After addition of 4 mg phenothiazine, 146 mg tetrabutylammonium iodide and 2.6 g (3.9 mmol) (E)-3-[4-[[3-[(6-chlorohexyl)oxy]-5-[[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]cyclohexyl]methoxy]-3-methoxyphenyl]acrylic acid methyl ester dissolved in 10 ml N,N-dimethylformamide the resulting mixture was stirred at 80° C. for 20 hours. The reaction mixture was poured into 50 ml of an ice cold 1 M HCl solution. The aqueous phase was extracted three times with 50 ml ethyl acetate. The organic phase was washed with 50 ml of a saturated sodium bicarbonate solution and repeatedly with water, dried over magnesium sulfate, filtered and concentrated by vacuum evaporation. Purification of the residue by column chromatography on 270 g silica gel using toluene/ethanol (9:1) as eluent yielded 2.6 g (92%) of 2-methylacrylic acid 6-[3,5-bis[[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]cyclohexyloxy]hexyl ester as yellowish oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.[C:14]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:19]1[S:20][C:16]([C:14]#[N:15])=[CH:17][CH:18]=1)[CH:11]=[CH:10]2
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: N#Cc1ccc(B(O)O)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccc3cc(O)ccc3n2)s1

Procedure:
Followed the two step synthesis shown in Scheme 1 starting with 2-chloro-6-methoxyquinoline and 5-cyanothiophen-2-ylboronic acid, with minor variations: the base used in step 1 was sodium carbonate and the solvent was DME (dimethoxyethane)/water. In step 2, after quenching w/ice water, a standard ethyl acetate extraction was preformed followed by purification by prep-TLC (PE:EA=1:1).
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]([NH:19][CH2:20][C:21]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:22]=1[O:23][CH2:24][C:25]([OH:27])=O)=[O:18])=[O:11])=O)(C)(C)C.Cl.C(OC(=O)[CH2:46][NH2:47])(C)(C)C.C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Cl:32][C:30]1[CH:29]=[CH:28][C:22]2[O:23][CH2:24][C:25](=[O:27])[NH:47][CH2:46][C:6](=[O:5])[NH:8][C@H:9]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:10](=[O:11])[N:12]3[CH2:16][CH2:15][CH2:14][C@H:13]3[C:17](=[O:18])[NH:19][CH2:20][C:21]=2[CH:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1OCC(=O)O)C1CCCCC1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C1COc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)[C@@H](C2CCCCC2)NC(=O)CN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.049 g (0.09 mmol) [2-({[((2S)-1-{(2R)-2-[(tert-butoxycarbonyl) amino]-2-cyclohexylethanoyl} pyrrolidin-2-yl)carbonyl]amino} methyl)-4-chlorophenoxy]acetic acid (J. Med. Chem 1998, 41, 3210) in 3 mL DMF was added 0.018 g (0.1 mmol) glycine tertbutyl ester hydrochloride, 0.015 mL (0.1 mmol) triethylamine, 0.014 g (0.1 mmol) HOAt and 0.029 g (0.15 mmol) EDC. After 3 hours the reaction mixture was diluted with 100 mL EtOAc, washed with 50 mL each of 10% aqueous KHSO4, dilute brine, and brine, then dried over Na2SO4, filtered, and concentrated. The residue was dissolved in 3 mL CH2Cl2 and cooled to 0° C. whereupon 1.5 mL trifluoroacetic acid was added and the mixture stirred 30 minutes at 0° C. then warmed to room temperature for 2 hours. To this was added 50 mL toluene and the mixture concentrated, redissolved in CH2Cl2 and toluene and concentrated. The residue was dissolved in 50 mL DMF and to this was added 0.03 mL (0.2 mmol) triethylamine, 0.015 g (0.1 mmol) HOAt and 0.030 g (0.15 mmol) EDC. After 64 hours the reaction mixture was concentrated and the residue diluted with 50 mL EtOAc, washed with 20 mL each of 10% aqueous KHSO4, dilute brine, and brine, then dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography (1.5×12 cm silica gel, linear gradient 1–9% MeOH/CH2Cl2 afforded (6R,20aS)-16-chloro-6-cyclohexyl-2,3,6,7,9,10,18,19-octahydro-1H-pyrrolo[1,2-j][1,4,7,10,13] benzoxatetraazacyclohexadecine-5,8,11,20 (12H,20aH)-tetrone as a white flaky solid. 1H NMR (CD3OD, 400 MHz): δ 7.32 (d, J=2.65 Hz, 1H), 7.24 (dd, J=2.65 and 8.8 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 4.75 (d, J=14.0 Hz, 1H), 4.69 (d, J=14.3 Hz, 1H), 4.60 (d, J=14.3 Hz, 1H); 4.45 (dd, J=3.2 and 8.5 Hz, 1H), 4.3 (d, J=9.97 Hz, 1H), 4.15 (d, J=15.6 Hz, 1H), 4.13 (d, J=14.0 Hz, 1H), 3.97 (m, 1H), 3.73 (d, J=15.6 Hz, 1H), 3.61 (m, 1H), 2.16 (m, 1H), 2.08 (m, 1H), 2.0–1.88 (m, 3H), 1.8–1.6 (m, 5H), 1.58 (m, 1H), 1.28 (m, 2H), 1.04 (m, 1H); exact mass calculated for C24H31C1N4O5: 491.2056 found 491.2067. Analytical HPLC (Zorbax SB-C18 4.6×75 mm, 5% to 95% CH3CN in 0.1% aqueous H3PO4):>99% at 215 nm.
Reaction SMILES: C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:25]=[C:26]1[NH:30][CH2:29][C@@H:28]([C:31]([OH:33])=O)[O:27]1.[N+]([O-])(O)=O.[N+:38]([O:41][CH2:42][CH2:43][NH2:44])([O-:40])=[O:39]>O1CCCC1>[N+:38]([O:41][CH2:42][CH2:43][NH:44][C:31]([C@H:28]1[O:27][C:26](=[O:25])[NH:30][CH2:29]1)=[O:33])([O-:40])=[O:39]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC[C@@H](C(=O)O)O1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Solvent: C1CCOC1
Product: O=C1NC[C@@H](C(=O)NCCO[N+](=O)[O-])O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.4 %

Procedure:
0.35 ml of triethylamine and 0.22 ml of diphenylphosphoryl azide were added, whilst ice-cooling and stirring, to a suspension of 110 mg of (5S)-2-oxooxazolidine-5-carboxylic acid (prepared by a procedure similar to that described in Preparation 3) and 170 mg of N-(2-nitrooxyethyl)amine nitrate in 10 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 6 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent. The pale yellow oil thus obtained was triturated with ethyl acetate, and the resulting precipitate was collected by filtration and washed, to give 79.8 mg of the title compound as a colorless powder, melting at 101°-103° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:28]>C(O)C>[C:1]1([CH2:7][C:8]2[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=2[C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:28]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1

Procedure:
A mixture of 4.90 g of methyl 4-[[2-(phenylmethyl)benzoyl]amino]benzoate in 100 ml of absolute ethanol and 3.50 ml of 10 N sodium hydroxide is heated on a steam bath for 3 hours. The aqueous phase is filtered and the resulting solid collected and dried to give 4.25 g of the desired product m.p. 340°-346° C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:15]2[C:11](=[N:12][S:13][N:14]=2)[C:10]([C:16]#[C:17][Si](C)(C)C)=[CH:9][CH:8]=1)(C)C.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CO>[C:16]([C:10]1[C:11]2[C:15](=[N:14][S:13][N:12]=2)[C:7]([C:6]#[CH:5])=[CH:8][CH:9]=1)#[CH:17]
Reactant: C[Si](C)(C)C#Cc1ccc(C#C[Si](C)(C)C)c2nsnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(C#C)c2nsnc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4,7-Bis(trimethylsilylethynyl)benzo[c][1,2,5]thiadiazole (0.126 g, 3.83×10−4 mol), K2CO3 (0.214 g, 1.55×10−3 mol), CH2Cl2 (5.0 ml) and MeOH (5.0 ml) were added to a 100-ml round-bottom flask. The reaction mixture was stirred at room temperature for 2.5 h under Ar. The reaction mixture was fdtered and the solvent was evaporated. The residue was chromatographed on short silica gel column with CH2Cl2 as the eluent. Yield=0.0663 g (94% based on 0.126 g of 4,7-bis(trimethylsilylethynyl)benzo[c][1,2,5]thiadiazole). 1H NMR (300 MHz, CDCl3): δ 7.78 (s, 2H, Ph-H), 3.70 (s, 2H, ethynyl-H). CI MS m/z: 184.010 (M+) (calcd 184.010).